PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Protocol Amendment 9, 29 October 2020090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)A PHASE 1/2/3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLIND,
DOSE-FINDING STUDY TO EVALUATE THE SAFETY, TOLERABILITY,IMMUNOGENICITY, AND EFFICACY OF SARS-COV-2 RNA VACCINECANDIDATES AGAINST COVID-19 IN HEALTHY INDIVIDUALS

Study Sponsor:

BioNTechStudy Conducted By:

PfizerStudy Intervention Number:

PF-07302048

Study Intervention Name:

RNA-Based COVID-19 Vaccines

US IND Number:

19736

EudraCT Number:2020-002641-42

Protocol Number:

C4591001

Phase:
1/2/3
Short Title: A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, andEfficacy of RNA Vaccine Candidates Against COVID-19 in Healthy IndividualsThis document and accompanying materials contain confidential information belonging to Pfizer. Except asotherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold thisinformation in confidence and not copy or disclose it to others (except where required by applicable law) or
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer
must be promptly notified.

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Protocol Amendment Summary of Changes Table
Document History
Document
Protocol amendment 9

Version Date

Summary and Rationale for Changes
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29 October 2020

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Protocol amendment 8

15 October 2020

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To better align with the natural history of
SARS-CoV-2 infection, added Phase 2/3
secondary efficacy objectives, estimands, andendpoints to include COVID-19 cases that occur
from 14 days after the second dose; also
modified the existing secondary efficacy
objectives, estimands, and endpoints to include
COVID-19 cases that occur from 14 days, aswell as 7 days, after the second dose; Made corresponding changes to the study
design, study assessments and procedures,and statistical analysis sections.
For operational reasons, removed the interim
analysis planned after accrual of 32 cases.
Clarified that interim analyses will be conducted
after accrual of at least 62, 92, and 120 cases.
Included any participants 16 through 17 years ofage enrolled under this amendment in thereactogenicity subset.
Added an unblinded clinical scientist to support
DMC activities.
Clarified that serology data after a postbaseline
positive SARS-CoV-2 test result will not be
included in the analysis based on the evaluable
immunogenicity populations.
Removed “N-binding antibody” and“SARS-CoV-2 detection by NAAT” asendpoints from the third exploratory objective,
as these results are used for the determination of
the population, and are not endpoints.
Clarified that the “Process 1” participants
included in the descriptive analysis of“Process 1”- and “Process 2”-manufactured
study interventions will be selected randomly.
Clarified that surveillance of potential
COVID-19 symptoms should continue even if aparticipant has a positive SARS-CoV-2 testearlier in the study.
Further modified the circumstances in which a
local NAAT result may be used in the
COVID-19 case definition.
Clarified that for participants who are not in thereactogenicity subset, local reactions andsystemic events following vaccination should be
detected and reported as AEs.
Clarified that premenarchal females are not
WOCBP.

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Protocol amendment 7

Version Date

Summary and Rationale for Changes

06 October 2020

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Made various editorial changes.
Reduced the lower age range to include
adolescents 12 to 15 years of age and added
corresponding objectives.
Removed reference to COVID-19 antibody
testing in Section 2.3.2.
Clarified with efficacy estimands and endpoints
that last dose refers to second dose.
Added an additional exploratory objective todescribe safety and immunogenicity inparticipants 16 to 55 years of age vaccinatedwith study intervention produced bymanufacturing “Process 1” or “Process 2.”
Clarified exclusion criterion 5.
Added Section 6.1.1 to describe manufacturing“Process 1” and “Process 2.”
Clarified the degree of unblinding on the
unblinded submissions team in Section 6.3.3.
Made provision for a second dose of BNT162b2
in participants who were affected by a
medication error at Visit 2 in Section 6.6.
Provided further clarification regarding
discontinuation of study intervention in
Section 7.1.
Modified the circumstances in which a local
NAAT result may be used in the COVID-19
case definition.
Added that 2 periods of potential COVID-19
symptoms within 4 days will be considered as asingle illness.
Provided guidance in Section 8.13 regarding
circumstances in which a SARS-CoV-2 test
might be required even if symptoms within 7days following each vaccination are consideredmore likely due to vaccine reactogenicity.
Made allowance in Section 8.13 for a second
SARS-CoV-2 test to be performed within thesame potential COVID-19 illness if it is inaccordance with routine practice.
Added Section 8.15 to describe the reporting of
SARS-CoV-2 test results and their implications
for participants receiving a second vaccine dose.
Added statistical hypothesis and power analysis
for evaluation of noninferiority of the immune
response to BNT162b2 in participants 12 to 15
years of age to the response in participants 16 to
25 years of age.
Amended scope of analyses of safety data in
Section 9.5.1.

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Version Date

Summary and Rationale for Changes

Protocol amendment 6(Germany-specific)

23 September 2020

Protocol amendment 6

08 September 2020

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Made various editorial changes.
According to regulatory request, inclusion
criterion 1 now specifies that participants lessthan 18 years of age will not be enrolled in theEU.
Reordered some procedures in the Phase 2/3
schedule of activities for consistency with themain body of the protocol.
Corrected the window for the 6-month follow-up
visit to be approximately 6 months after
Vaccination 2.
Reduced the volume of blood draws to ~20 mL.
Removed the need to have safety data reported
for participants to be included in the safety
objective assessment.
Added an exploratory objective to describe
safety, immunogenicity, and efficacy inparticipants with stable HIV disease.
Increased the sample size for Phase 2/3 to~43,998.
Clarified that inclusion criterion 4 (ie,participants at higher risk for acquiring COVID19) is applicable for Phase 2/3 only, andprovided some examples.
Removed exclusion criterion 2 (ie, known
infection with HIV, HCV, or HBV) for Phase 3
and added criteria for HIV-positive participants.
Decreased the lower age limit and removed theupper age limit for inclusion in Phase 2/3 inorder to evaluate BNT162b2 30 µg in older
adolescents and those over 85 years of age;
updated the title and other references to adults toalign with this change.
Renamed the immunological assays to alignwith other program-level documents.
Removed reference to the SARS-CoV-2 fulllength, P2 mutant, prefusion spike glycoprotein(P2 S) being “heads up.”Clarified that a positive SARS-CoV-2 NAAT
result without symptoms should not result in
discontinuation of study intervention.
Added clarification that potential COVID-19
illnesses that are consistent with the clinicalendpoint definition should not be recorded as
AEs.
Updated the analysis population descriptions toalign with the study SAP.

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Protocol Amendment 9, 29 October 2020

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Protocol amendment 5

Version Date
24 July 2020

Summary and Rationale for Changes
Following regulatory feedback: Renamed Stage 1 to Phase 1, removed Stage 2,
and renamed Stage 3 to Phase 2/3.
 Clarified that a single vaccine candidate,administered as 2 doses 21 days apart, will be
studied in Phase 2/3.
 Stated that the vaccine candidate selected forPhase 2/3 evaluation is BNT162b2 at a dose of
30 µg.
 Removed the potential to study BNT162b3.
 Immunogenicity data will be summarized for the
first 360 participants through 1 month after Dose2, rather than through 21 days after Dose 1.
 Provided further details of sponsor staff that will
be unblinded in Phase 2/3.
 Clarified which stopping rules apply to which
phase of the study.
In addition:
 Clarified the AE reporting requirements forpotential COVID-19 illnesses.
 Updated that Visit 1 may be conducted across 2
consecutive days in Phase 2/3.
 Moved the immunogenicity objectives inPhase 2/3 to become exploratory.
 Added an additional inclusion criterion to enroll
participants who, in the judgment of theinvestigator, are at risk for acquiring COVID-19.
 Modified exclusion criterion 5, so thatparticipants with a previous clinical or
microbiological diagnosis of COVID-19 are
excluded from all phases of the study.
 Clarified that there will be 2 all-available
efficacy populations.
 Clarified that immunogenicity samples will bedrawn for all participants; analyses will be based
upon results from subsets of samples, according
to the purpose.
 Updated that the 3-tier approach to summarizing
AEs will only be performed in Phase 2/3.
 Updated that at each interim analysis for
efficacy, only the first primary objective will be
evaluated.
 Changed to use the same posterior probability(99.5%) for all interim analyses, resulting incase split changes in Tables 5, 6, and 7.
 Updated the stopping and alert rule parameters
for enhanced COVID-19.

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Protocol amendment 4

Version Date
30 June 2020

Summary and Rationale for Changes
Given the rapidly evolving pandemic situation, andthe need to demonstrate VE as soon as possible, theprotocol has been amended to be powered to meet
new efficacy objectives. These new efficacy
objectives and corresponding endpoints have been
added to Section 3.
Further nonclinical data are available to support the
study of the BNT162b3 candidate in humans, and thecandidate has been added to the protocol.
The 6-month safety follow-up telephone contact has
been changed to an in-person visit for Stage 3
participants, to allow collection of an
immunogenicity blood sample.

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)The COVID-19 illness visit has now added
flexibility to permit a remote or in-person visit.
The COVID-19 illness symptoms have been updated
to align with the FDA-accepted definitions; thischange is also reflected in the criteria for temporary
delay of enrollment.
AEs that occur between consent and dosing will now
be reported on the AE (rather than Medical History)
CRF, to align with the latest Pfizer protocol
template.
Changes have been made to the headings to alignwith the latest Pfizer protocol template.
Clarified that only an unblinded site staff member
may obtain the participant’s randomization number
and study intervention allocation.
Additional interim analyses have been added toevaluate VE and futility during the study.

Protocol amendment 3

As a result of regulatory feedback, an appendix has
been added to outline the stopping and alert rules tomonitor for potential enhanced COVID-19.
As data have become available from this study andthe BNT162-01 study in Germany, the following
decisions were made: Not to study the BNT162a1 and BNT162c2
vaccine candidates at this time. Therefore, thesecandidates have been removed from theprotocol.

10 June 2020

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Version Date

Summary and Rationale for ChangesTo study further lower dose levels of the
modRNA candidates. Therefore, a 20-µg doselevel is formally included for BNT162b1 and
BNT162b2.
To permit individual and group dosing
alterations for the second dose of study
intervention.

Following regulatory feedback, the BNT162b3
vaccine candidate has been removed from theprotocol until further nonclinical data are available tosupport study in humans.

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Given the rapidly evolving pandemic situation,
additional blood draws for exploratory COVID-19
research, intended to establish an immunologicalsurrogate of protection, will be taken from selectedparticipants who consent.
In order to increase flexibility enrolling participants,
an extended screening window (increased from 14 to
28 days) for sentinel participants in Stage 1 has been
added. This is considered acceptable since eligible
participants are expected to be either healthy or havestable medical conditions.
To increase the number of doses that can be obtained
from available vaccine vials, not all dose levels will
result in a dosing volume of 0.5 mL. Precise dosing
instructions will be provided in the IP manual.

Protocol amendment 2

To facilitate the reporting of COVID-19 illness
diagnoses and potential symptoms to theinvestigator, participants may utilize a COVID-19
illness e-diary.
Given the urgent nature of the pandemic situation,
the following changes allow determination of theappropriate human dose level for both younger andolder adults to move speedily into the next phase ofclinical evaluation:
 Added a new vaccine candidate, BNT162b3,
modRNA encoding a membrane-anchored RBD
 Added a 50-µg dose level for vaccine candidates
based on the modRNA platform (ie, BNT162b1,
BNT162b2, and BNT162b3)
 Modified the criteria required for the IRC todetermine dose escalation in the 18- to 55-year
age cohort and advancement to groups ofparticipants 65 to 85 years of age

27 May 2020

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Protocol amendment 1

Version Date

Summary and Rationale for Changes
In addition:
 Removed hemoglobin change-from-baseline
abnormalities from the laboratory abnormality
grading scale as abnormalities should be gradedbased upon absolute values
 Following regulatory feedback: Modified exclusion criteria and prohibitedinhaled/nebulized corticosteroids for sentinel
participants in Stage 1
 Clarified that the rapid test for prior COVID-19
infection for sentinel participants in Stage 1 will
be used only for screening purposes Removed time frames for stopping rules
 Stated that data supporting the selection of
vaccine candidate(s)/dose level(s) andschedule(s) for Stages 2 and 3 will be submitted
to the FDA for review

13 May 2020

Following preliminary experience in the
BioNTech study conducted in Germany(BNT162-01):
Decreased the dose levels for BNT162a1 and
BNT162c2

Additionally: Clarified the roles of BioNTech and Pfizer
 Amended text so that the IRC decision toprogress group(s) into Stages 2 and 3 can bebased upon safety and immunogenicity data
after Dose 1 or 2
 Clarified safety data requirements to permit dose
escalation
 Amended text so that the progression toparticipants 65 to 85 years of age can be based
upon data from the same RNA platform Incorporated a protocol administrative change tocorrect the variant designation and the encoded
antigen to BNT162c2
 Clarified that the SARS-CoV-2 neutralizing
assay does not employ wild-type virus
 Clarified that the SARS-CoV-2 spike protein–binding antibody assay is specific for the S1subunit Clarified that efficacy against COVID-19 isbased upon illness (not infection) rate ratio Incorporated a protocol administrative change tostate that the study placebo may be supplied in a
glass or plastic vial

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Original protocol

15 April 2020

Corrected a typographical error in Section 6.5.1
regarding the time frame for prior receipt ofblood/plasma products or immunoglobulins
Corrected a typographical error in Table 2
regarding the lower limit of diameter (cm) for
mild redness and swelling
Updated the °C fever scale in Table 4 to ensurethat all potential °F values are correctly assigned
Incorporated a protocol administrative change toclarify that a rapid test for prior COVID-19
infection will be performed for sentinel
participants in Stage 1, and a serum sample will
be drawn for potential future assessment
Clarified that, after screening, physicalexaminations in sentinel participants in Stage 1
will be directed
Clarified the descriptions of the populations foranalysis to align with the statistical analysis plan
Added a complete safety and immunogenicity
analysis approximately 6 months after Dose 2
for all participants in Stage 3
Amended text so that the stopping rules apply to
an RNA platform rather than a specific vaccine
candidate

N/A

This amendment incorporates all revisions to date, including amendments made at therequest of country health authorities and IRBs/ECs.

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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................15
1. PROTOCOL SUMMARY...................................................................................................17
1.1. Synopsis ..................................................................................................................17
1.2. Schema ....................................................................................................................25
1.3. Schedule of Activities .............................................................................................26
1.3.1. Phase 1 ........................................................................................................26
1.3.2. Phase 2/3.....................................................................................................31
2. INTRODUCTION ...............................................................................................................34
2.1. Study Rationale .......................................................................................................34
2.2. Background .............................................................................................................34
2.2.1. Clinical Overview.......................................................................................35

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2.3. Benefit/Risk Assessment.........................................................................................35
2.3.1. Risk Assessment .........................................................................................37
2.3.2. Benefit Assessment.....................................................................................39
2.3.3. Overall Benefit/Risk Conclusion................................................................39
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................39
3.1. For Phase 1 ..............................................................................................................39
3.2. For Phase 2/3 ...........................................................................................................41
4. STUDY DESIGN.................................................................................................................44
4.1. Overall Design.........................................................................................................44
4.1.1. Phase 1 ........................................................................................................44
4.1.2. Phase 2/3.....................................................................................................45
4.2. Scientific Rationale for Study Design .....................................................................47
4.3. Justification for Dose ..............................................................................................47
4.4. End of Study Definition ..........................................................................................48
5. STUDY POPULATION ......................................................................................................48
5.1. Inclusion Criteria.....................................................................................................48
5.2. Exclusion Criteria....................................................................................................49
5.3. Lifestyle Considerations..........................................................................................52
5.3.1. Contraception..............................................................................................52

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5.4. Screen Failures ........................................................................................................52
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study
Intervention Administration ......................................................................................52
6. STUDY INTERVENTION..................................................................................................53
6.1. Study Intervention(s) Administered ........................................................................54
6.1.1. Manufacturing Process ...............................................................................54
6.1.2. Administration ............................................................................................54
6.2. Preparation/Handling/Storage/Accountability ........................................................55
6.2.1. Preparation and Dispensing ........................................................................56
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................56
6.3.1. Allocation to Study Intervention ................................................................56
6.3.2. Blinding of Site Personnel ..........................................................................56
6.3.3. Blinding of the Sponsor ..............................................................................57
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6.3.4. Breaking the Blind......................................................................................58
6.4. Study Intervention Compliance...............................................................................58
6.5. Concomitant Therapy..............................................................................................58
6.5.1. Prohibited During the Study .......................................................................58
6.5.2. Permitted During the Study ........................................................................59
6.6. Dose Modification...................................................................................................59
6.7. Intervention After the End of the Study ..................................................................60
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANTDISCONTINUATION/WITHDRAWAL...........................................................................60
7.1. Discontinuation of Study Intervention ....................................................................60
7.2. Participant Discontinuation/Withdrawal From the Study .......................................61
7.2.1. Withdrawal of Consent ...............................................................................62
7.3. Lost to Follow-up ....................................................................................................62
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................62
8.1. Efficacy and/or Immunogenicity Assessments .......................................................63
8.1.1. Biological Samples .....................................................................................66
8.2. Safety Assessments .................................................................................................66
8.2.1. Clinical Safety Laboratory Assessments (Phase 1 Participants Only) .......67
8.2.2. Electronic Diary..........................................................................................67
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8.2.2.1. Grading Scales...........................................................................68
8.2.2.2. Local Reactions .........................................................................68
8.2.2.3. Systemic Events ........................................................................69
8.2.2.4. Fever..........................................................................................70
8.2.2.5. Antipyretic Medication .............................................................71
8.2.3. Phase 1 Stopping Rules ..............................................................................71
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19
and Phase 2/3 Stopping Rule ...........................................................................72
8.2.5. Randomization and Vaccination After a Stopping Rule Is Met .................73
8.2.6. Pregnancy Testing ......................................................................................73
8.3. Adverse Events and Serious Adverse Events..........................................................73
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......73
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................74
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8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................74
8.3.2. Method of Detecting AEs and SAEs ..........................................................75
8.3.3. Follow-up of AEs and SAEs.......................................................................75
8.3.4. Regulatory Reporting Requirements for SAEs...........................................75
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational
Exposure ..........................................................................................................75
8.3.5.1. Exposure During Pregnancy......................................................76
8.3.5.2. Exposure During Breastfeeding ................................................77
8.3.5.3. Occupational Exposure .............................................................78
8.3.6. Cardiovascular and Death Events...............................................................78
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not
Qualifying as AEs or SAEs..............................................................................78
8.3.8. Adverse Events of Special Interest .............................................................79
8.3.8.1. Lack of Efficacy ........................................................................79
8.3.9. Medical Device Deficiencies......................................................................79
8.3.10. Medication Errors .....................................................................................79
8.4. Treatment of Overdose............................................................................................80
8.5. Pharmacokinetics ....................................................................................................80
8.6. Pharmacodynamics..................................................................................................80
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8.7. Genetics ...................................................................................................................80
8.8. Biomarkers ..............................................................................................................81
8.9. Immunogenicity Assessments .................................................................................81
8.10. Health Economics .................................................................................................81
8.11. Study Procedures...................................................................................................81
8.11.1. Phase 1 ......................................................................................................81
8.11.1.1. Screening: (0 to 28 Days Before Visit 1) ................................81
8.11.1.2. Visit 1 – Vaccination 1: (Day 1) .............................................82
8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1to 3 Days After Visit 1) .....................................................................84
8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to
8 Days After Visit 1) .........................................................................86

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8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1) ...........87
8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to
8 Days After Visit 4) .........................................................................89
8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to
16 Days After Visit 4) .......................................................................90
8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After
Visit 4) ...............................................................................................91
8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (175 to 189 Days
After Visit 4)......................................................................................92
8.11.1.10. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 4)......................................................................................92
8.11.1.11. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 4)......................................................................................93
8.11.2. Phase 2/3...................................................................................................93
8.11.2.1. Visit 1 – Vaccination 1: (Day 1) .............................................93
8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days After Visit 1) ...........96
8.11.2.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2):(28 to 35 Days After Visit 2).............................................................98
8.11.2.4. Visit 4 – 6-Month Follow-up Visit: (175 to 189 Days
After Visit 2)......................................................................................99
8.11.2.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 2)......................................................................................99

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8.11.2.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 2)....................................................................................100
8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction ......................100
8.13. COVID-19 Surveillance (All Participants) .........................................................101
8.13.1. Potential COVID-19 Illness Visit: (Optimally Within 3 Days After
Potential COVID-19 Illness Onset) ...............................................................103
8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After
Potential COVID-19 Illness Visit)................................................................104
8.14. Communication and Use of Technology.............................................................105
8.15. SARS-CoV-2 NAAT Results From Visits 1 and 2 and Potential COVID-19
Illness Visits ............................................................................................................105
9. STATISTICAL CONSIDERATIONS ..............................................................................106
9.1. Estimands and Statistical Hypotheses ...................................................................106
9.1.1. Estimands..................................................................................................106
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9.1.2. Statistical Hypotheses...............................................................................107
9.1.2.1. Statistical Hypothesis Evaluation for Efficacy........................107
9.1.2.2. Statistical Hypothesis Evaluation for Immunogenicity...........107
9.2. Sample Size Determination...................................................................................107
9.3. Analysis Sets .........................................................................................................109
9.4. Statistical Analyses ...............................................................................................110
9.4.1. Immunogenicity Analyses ........................................................................110
9.4.2. Efficacy Analyses .....................................................................................115
9.4.3. Safety Analyses ........................................................................................117
9.4.4. Other Analyses..........................................................................................118
9.5. Interim Analyses ...................................................................................................1199.5.1. Analysis Timing........................................................................................122
9.6. Data Monitoring Committee or Other Independent Oversight Committee...........122
10. SUPPORTING DOCUMENTATION AND OPERATIONALCONSIDERATIONS ........................................................................................................124
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .............124
10.1.1. Regulatory and Ethical Considerations ..................................................124
10.1.1.1. Reporting of Safety Issues and Serious Breaches of theProtocol or ICH GCP.......................................................................124
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10.1.2. Informed Consent Process ......................................................................125
10.1.3. Data Protection .......................................................................................126
10.1.4. Dissemination of Clinical Study Data ....................................................126
10.1.5. Data Quality Assurance ..........................................................................127
10.1.6. Source Documents ..................................................................................129
10.1.7. Study and Site Start and Closure ............................................................129
10.1.8. Sponsor’s Qualified Medical Personnel .................................................130
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................131
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting ....................................................................133
10.3.1. Definition of AE .....................................................................................133
10.3.2. Definition of SAE ...................................................................................134
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.....................136
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10.3.4. Reporting of SAEs..................................................................................139
10.4. Appendix 4: Contraceptive Guidance .................................................................140
10.4.1. Male Participant Reproductive Inclusion Criteria ..................................140
10.4.2. Female Participant Reproductive Inclusion Criteria...............................140
10.4.3. Woman of Childbearing Potential ..........................................................141
10.4.4. Contraception Methods...........................................................................142
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ......144
10.6. Appendix 6: Abbreviations .................................................................................146
10.7. Appendix 7: Stopping and Alert Rules for Enhanced COVID-19 ......................150
10.8. Appendix 8: Criteria for Allowing Inclusion of Participants With Chronic
Stable HIV, HCV, or HBV Infection ......................................................................153
11. REFERENCES ................................................................................................................154
LIST OF TABLES
Table 1.

Local Reaction Grading Scale ..................................................................69

Table 2.

Systemic Event Grading Scale..................................................................69

Table 3.

Scale for Fever..........................................................................................70

Table 4.

Power Analysis for Noninferiority Assessment .....................................108

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Table 5.

Probability of Observing at Least 1 AE by Assumed True Event
Rates With Different Sample Sizes ........................................................109

Table 6.

Interim Analysis Plan and Boundaries for Efficacy and Futility............120

Table 7.

Statistical Design Operating Characteristics: Probability of Successor Failure for Interim Analyses...............................................................121

Table 8.

Statistical Design Operating Characteristics: Probability of Successfor Final Analysis and Overall................................................................121

Table 9.

Laboratory Abnormality Grading Scale .................................................131

Table 10.

Stopping Rule: Enrollment Is Stopped if the Number of Severe
Cases in the Vaccine Group Is Greater Than or Equal to the
Prespecified Stopping Rule Value (S) ....................................................151

Table 11.

Alert Rule: Further Action Is Taken if the Number of Severe Casesin the Vaccine Group Is Greater Than or Equal to the Prespecified
Alert Rule Value (A) ..............................................................................152

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1. PROTOCOL SUMMARY
1.1. Synopsis
Short Title: A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, andEfficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Individuals
Rationale

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A pneumonia of unknown cause detected in Wuhan, China, was first reported in
December 2019. On 08 January 2020, the pathogen causing this outbreak was identified as anovel coronavirus 2019. The outbreak was declared a Public Health Emergency ofInternational Concern on 30 January 2020. On 12 February 2020, the virus was officiallynamed as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the WHO
officially named the disease caused by SARS-CoV-2 as coronavirus disease 2019
(COVID-19). On 11 March 2020, the WHO upgraded the status of the COVID-19 outbreakfrom epidemic to pandemic, which is now spreading globally at high speed.
There are currently no licensed vaccines to prevent infection with SARS-CoV-2 or
COVID-19. Given the rapid transmission of COVID-19 and incidence of disease in the
United States and elsewhere, the rapid development of an effective vaccine is of utmost
importance.
BioNTech has developed RNA-based vaccine candidates using a platform approach thatenables the rapid development of vaccines against emerging viral diseases, including
SARS-CoV-2. Each vaccine candidate is based on a platform of nucleoside-modified
messenger RNA (modRNA, BNT162b). Each vaccine candidate expresses 1 of 2 antigens:the SARS-CoV-2 full-length, P2 mutant, prefusion spike glycoprotein (P2 S) (version 9) or atrimerized SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) (version 5).
The 2 SARS-CoV-2 vaccine candidates that will be tested in this study are therefore:
BNT162b1 (variant RBP020.3): a modRNA encoding the RBD;
BNT162b2 (variant RBP020.2): a modRNA encoding P2 S.
All candidates are formulated in the same lipid nanoparticle (LNP) composition. This study
is intended to investigate the safety, immunogenicity, and efficacy of these prophylactic
BNT162 vaccines against COVID-19.

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Objectives, Estimands, and Endpoints

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)For Phase 1
Objectives

Estimands

Endpoints

Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Primary:
In participants receiving at least 1 doseof study intervention, the percentage ofparticipants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each doseAdverse events (AEs) from
Dose 1 to 1 month after the lastdose
 Serious AEs (SAEs) from Dose 1
to 6 months after the last dosePrimary:
Local reactions (pain at the
injection site, redness, andswelling)

Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs

Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

In addition, the percentage ofHematology and chemistry laboratory
participants with:parameters detailed in Section 10.2
Abnormal hematology andchemistry laboratory values 1 and7 days after Dose 1; and 7 days
after Dose 2
Grading shifts in hematology andchemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2
Secondary:
Secondary:In participants complying with the key
protocol criteria (evaluableparticipants) at the following time
points after receipt of study
intervention:
7 and 21 days after Dose 1; 7 and 14
days and 1, 6, 12, and 24 months after
Dose 2

Geometric mean titers (GMTs) at SARS-CoV-2 neutralizing titers
each time point
Geometric mean fold rise (GMFR)
from before vaccination to eachsubsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination

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Objectives

Estimands







Endpoints

S1-binding IgG levels andGeometric mean concentrations
RBD-binding IgG levels(GMCs) at each time point
GMFR from before vaccination toeach subsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
Geometric mean ratio (GMR),
SARS-CoV-2 neutralizing titers
estimated by the ratio of theS1-binding IgG levels
geometric mean of SARS-CoV-2 
RBD-binding IgG levels
neutralizing titers to the geometricmean of binding IgG levels at eachtime point

For Phase 2/3

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Objectivesa

Estimands
Primary Efficacy

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 occurring from
7 days after the second dose inparticipants without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 occurring from
7 days after the second dose inparticipants with and without
evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To define the safety profile ofprophylactic BNT162b2 in the first
360 participants randomized (Phase 2)

In participants receiving at least 1
dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 7 days after
the second dose
SAEs from Dose 1 to 7 days
after the second dose

Endpoints
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of thesecond dose) of past SARS-CoV-2
infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT

Primary Safety






Local reactions (pain at the
injection site, redness, andswelling)
Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened
muscle pain, and new orworsened joint pain)
AEs
SAEs

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Objectivesa

Estimands

To define the safety profile ofprophylactic BNT162b2 in allparticipants randomized in Phase 2/3

In participants receiving at least
1 dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the second dose
 SAEs from Dose 1 to 6 months
after the second dose

To define the safety profile ofprophylactic BNT162b2 inparticipants 12 to 15 years of age inPhase 3

In participants receiving at least
1 dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the second dose
 SAEs from Dose 1 to 6 months
after the second dose

Endpoints







AEs
SAEs
In a subset of at least 6000
participants:
o Local reactions (pain at the
injection site, redness, andswelling)o Systemic events (fever,fatigue, headache, chills,
vomiting, diarrhea, new orworsened muscle pain, andnew or worsened joint pain)
Local reactions (pain at the
injection site, redness, andswelling)
Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened
muscle pain, and new orworsened joint pain)
AEs
SAEs

Secondary Efficacy
To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 occurring from
14 days after the second dose inparticipants without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 14 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 occurring from
14 days after the second dose inparticipants with and without
evidence of infection before
vaccination
To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed severe COVID-19
occurring from 7 days and from
14 days after the second dose inparticipants without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 14 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants)
 at least 7 daysand
 at least 14 days
after receipt of the second dose of
study intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 14 days after receipt of thesecond dose) of past SARS-CoV-2
infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT

Confirmed severe COVID-19
incidence per 1000 person-years offollow-up in participants with noserological or virological evidence (upto 7 days and up to 14 days after
receipt of the second dose) of past
SARS-CoV-2 infection

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Objectivesa
To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed severe COVID-19
occurring from 7 days and from
14 days after the second dose inparticipants with and without
evidence of infection before
vaccination

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To describe the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms)
occurring from 7 days and from
14 days after the second dose inparticipants without evidence of
infection before vaccination

To describe the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms)
occurring from 7 days and from
14 days after the second dose inparticipants with and without
evidence of infection before
vaccination

Estimands
In participants complying with the
key protocol criteria (evaluableparticipants)
 at least 7 daysand
 at least 14 days
after receipt of the second dose of
study intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants)
 at least 7 daysand
 at least 14 days
after receipt of the second dose of
study intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants)
 at least 7 daysand
 at least 14 days
after receipt of the second dose of
study intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

Endpoints
Confirmed severe COVID-19
incidence per 1000 person-years offollow-up

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days and up to 14 days after
receipt of the second dose) of past
SARS-CoV-2 infection

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT

Secondary Immunogenicity
To demonstrate the noninferiority of
the immune response to prophylactic
BNT162b2 in participants 12 to 15
years of age compared to participants
16 to 25 years of age

GMR, estimated by the ratio of thegeometric mean of SARS-CoV-2
neutralizing titers in the 2 age groups(12-15 years of age to 16-25 years ofage) 1 month after completion of
vaccination

To evaluate the immune responseover time to prophylactic BNT162b2
and persistence of immune response
in participants with and without
serological or virological evidence of
SARS-CoV-2 infection before
vaccination
To evaluate the immune response(non-S) to SARS-CoV-2 inparticipants with and without
confirmed COVID-19 during thestudy
To describe the serological responses
to the BNT vaccine candidate in casesof:
Confirmed COVID-19

Confirmed severe COVID-19

SARS-CoV-2 infection without
confirmed COVID-19

GMC/GMT, GMFR, and percentageof participants with titers greater thandefined threshold(s), at baseline and1, 6, 12, and 24 months after
completion of vaccination

SARS-CoV-2 neutralizing titers inparticipants with no serological or
virological evidence (up to 1 monthafter receipt of the second dose) of
past SARS-CoV-2 infection

ExploratoryS1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titersN-binding antibody

S1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titers



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Objectivesa

Estimands

To describe the safety,
immunogenicity, and efficacy ofprophylactic BNT162b2 in
individuals with confirmed stable HIV
diseaseTo describe the safety andimmunogenicity of prophylactic
BNT162b2 in individuals 16 to 55
years of age vaccinated with study
intervention produced bymanufacturing “Process 1” or“Process 2”ba.

EndpointsAll safety, immunogenicity, andefficacy endpoints described
above



All safety endpoints describedabove
SARS-CoV-2 neutralizing titersHIV-positive participants in Phase 3 will not be included in analyses of the objectives, with the
exception of the specific exploratory objective.
See Section 6.1.1 for a description of the manufacturing process.

b.

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Overall Design
This is a Phase 1/2/3, multicenter, multinational, randomized, placebo-controlled,
observer-blind, dose-finding, vaccine candidate–selection, and efficacy study in healthy
individuals.
The study consists of 2 parts: Phase 1: to identify preferred vaccine candidate(s) and doselevel(s); Phase 2/3: an expanded cohort and efficacy part. These parts, and the progression
between them, are detailed in the schema (Section 1.2).
The study will evaluate the safety, tolerability, and immunogenicity of 2 different
SARS-CoV-2 RNA vaccine candidates against COVID-19 and the efficacy of 1 candidate:

As a 2-dose (separated by 21 days) schedule;At various different dose levels in Phase 1;



In 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3: ≥12years of age [stratified as 12-15, 16-55, or >55 years of age]).

Dependent upon safety and/or immunogenicity data generated during the course of thisstudy, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
in Phase 1 may be started at the next highest dose, groups may not be started, groups may beterminated early, and/or groups may be added with dose levels below the lowest stated doseor intermediate between the lowest and highest stated doses.
The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.

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Number of Participants
Each group in Phase 1 will comprise 15 participants (12 receiving active vaccine and3 receiving placebo). In this phase, 13 groups will be studied, corresponding to a total of
195 participants.
The vaccine candidate selected for Phase 2/3, BNT162b2 at a dose of 30 µg, will comprise
21,999 vaccine recipients. The 12- to 15-year stratum will comprise up to approximately
2000 participants (1000 vaccine recipients) enrolled at selected investigational sites. It is
intended that a minimum of 40% of participants will be in the >55-year stratum. An equal
number of participants will receive placebo, ie, randomized in a 1:1 ratio.
Intervention Groups and Duration

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)The study will evaluate a 2-dose (separated by 21 days) schedule of various different doselevels of 2 investigational RNA vaccine candidates for active immunization against
COVID-19 in 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3:
≥12 years of age [stratified as 12-15, 16-55, or >55 years of age]):

BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 20 µg, 30 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 20 µg, 30 µg

The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.
Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Phase 1
dosing arms that are not evaluated in Phase 2/3.
Data Monitoring Committee or Other Independent Oversight Committee
The study will utilize an IRC, an internal Pfizer committee that will review data to allow
dose escalation or changes to continuation of specific groups.
An external data monitoring committee (DMC) will be formed and will review cumulative
unblinded data throughout the study.
Statistical Methods
The sample size for Phase 1 of the study is not based on any statistical hypothesis testing.
For Phase 2/3, the VE evaluation will be the primary objective. The VE is defined as
VE = 100 × (1 – IRR), where IRR is calculated as the ratio of the first confirmed COVID-19
illness rate in the vaccine group to the corresponding illness rate in the placebo group. Withassumptions of a true VE of 60% and 4 IAs planned, 164 COVID-19 cases will provide 90%
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power to conclude true VE >30%. This would be achieved with a total 43,998 participants(21,999 vaccine recipients), based on the assumption of a 1.3% per year incidence in theplacebo group, accrual of 164 primary-endpoint cases within 6 months, and 20% of theparticipants being nonevaluable. If the attack rate is much higher, case accrual would be
expected to be more rapid, enabling the study’s primary endpoint to be evaluated muchsooner. The total number of participants enrolled in Phase 2/3 may vary depending on theincidence of COVID-19 at the time of the enrollment, the true underlying VE, and a potential
early stop for efficacy or futility.
VE will be evaluated using a beta-binomial model and the posterior probability of VE being>30% will be assessed.

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)In Phase 3, up to approximately 2000 participants are anticipated to be 12 to 15 years of age.
Noninferiority of immune response to prophylactic BNT162b2 in participants 12 to 15 yearsof age to response in participants 16 to 25 years of age will be assessed based on the GMR of
SARS-CoV-2 neutralizing titers using a 1.5-fold margin. A sample size of 200 evaluableparticipants (or 250 vaccine recipients) per age group will provide a power of 90.8% todeclare the noninferiority in terms of GMR (lower limit of 95% CI for GMR >0.67).
The primary safety objective will be evaluated by descriptive summary statistics for local
reactions, systemic events, AEs/SAEs, and abnormal hematology and chemistry laboratory
parameters (Phase 1 only), for each vaccine group. A 3-tier approach will be used tosummarize AEs in Phase 2/3.
Except for the objective to assess the noninferiority of immune response in participants 12 to
15 years of age compared to participants 16 to 25 years of age, the other immunogenicity
objectives will be evaluated descriptively by GMT, GMC, GMFR, percentage of participants
with ≥4-fold rise, percentage of participants with ≥ specified threshold, and GMC ratio, andthe associated 95% confidence intervals (CIs), for SARS-CoV-2 neutralizing titers,
S1-binding IgG levels, and/or RBD-binding IgG levels at the various time points.

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1.2. Schema
Phase 1For each vaccine candidate(4:1 randomization active:placebo)

Age: 18-55 yAge: 65-85 y

Low-dose-level 2-dose group (n=15)
IRC (safety)

IRC (safety

Low-dose-level 2-dose group (n=15)

after Dose 1)
Mid-dose-level 2-dose group (n=15)
IRC (safety)

IRC (safety

Mid-dose-level 2-dose group (n=15)

after Dose 1)
High-dose-level 2-dose group (n=15)
IRC (safety

High-dose-level 2-dose group (n=15)

after Dose 1)

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IRC choice of group(s) for Phase 2/3(safety & immunogenicity after Doses 1 and 2)

Phase 2/3
Single vaccine candidate
Safety and immunogenicity analysis of
Age: ≥12
Phase 2 data (first 360 participants)(Stratified 12-15, 16-55, or >55)
by unblinded team (these participants
BNT162b2 30 µg or placebo 2 doses
will also be included in Phase 3(n~21,999 per group, total n~43.998)
analyses)Abbreviation: IRC = internal review committee.

(1:1 randomization active:placebo)

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1.3. Schedule of Activities

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with theprotocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations orassessments required to protect the well-being of the participant.
1.3.1. Phase 1
An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 10 (24-month follow-up visit) that COVID-19 is suspected.
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

X

X

X

X

X

Obtain informed consent

X

Assign participant number

X

Obtain demography andmedical history data

X

Obtain details of medications
currently taken

X

Perform physical examination

X

2

3

4

5

6

7

8

10

Unplanned

Unplanned

12 to 16 28 to 35 175 to
350 to714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4COVID-19 Illness Visit
Illness
Onset

X

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Protocol Amendment 9, 29 October 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

Measure vital signs(including body temperature)

X

X

X

X

X

X

Collect blood sample forhematology and chemistrylaboratory testsb~10 mL~10 mL~10 mL~10 mL~10 mL

Collect screening blood
sample for HIV, HBsAg,
HBc Ab, and HCV Ab tests~10 mL

Serological test for prior
COVID-19 infection~20 mL

Perform urine pregnancy test
(if appropriate)X

Obtain nasal (midturbinate)swab(s)c

2

3

4

X

X

X

X

Collect nonstudy vaccine
information

X

X

Confirm eligibility

X

X

Collect prohibited medication
use

X

X

Review temporary delay
criteria

X

X

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 175 to
350 to714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4COVID-19 Illness Visit
Illness
Onset
X

X
X

X

X

X

X

X

X
X

Review hematology andchemistry results

X

5

X

X

X

X

X

X

X

X

X

X

X

X

X

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Protocol Amendment 9, 29 October 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

4

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

Confirm use of contraceptives(if appropriate)

X

X

X

X

X

X

~50 mL~50 mL

Obtain randomization number
and study intervention
allocation

X

Collect blood sample for
immunogenicity assessment~50 mL

Administer study intervention

X

X

Assess acute reactions for atleast 30 minutes after study
intervention administrationd

X

X

Explain participant
communication methods(including for e-diarycompletion), assist theparticipant with downloading
the app, or issue provisioned
device, if required

X

Provide thermometer andmeasuring device

X

5

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 175 to
350 to714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4COVID-19 Illness Visit
Illness
Onset
X

X~50 mL ~50 mL ~50 mL ~20 mL+++
optionale optionale optionale~170 mL ~170 mL ~170 mL~20 mL~20 mL~20 mL

X

Review reactogenicity e-diarydata (daily review is optimal
during the active diary period)

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Protocol Amendment 9, 29 October 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 46 to 8Days
After
Visit 1

Review ongoingreactogenicity e-diary
symptoms and obtain stopdatesCollect AEs and SAEs as
appropriate

4

5

X

X

X

X

X

X

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 175 to
350 to714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4COVID-19 Illness Visit
Illness
Onset
X

X

X

X

X

Collect e-diary or assist theparticipant to delete
application

X

X

X

X

X

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Protocol Amendment 9, 29 October 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 46 to 8Days
After
Visit 1

4

5

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 175 to
350 to714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4COVID-19 Illness Visit
Illness
Onset

Collection of
COVID-19–related clinicaland laboratory information(including local diagnosis)

X

X

Abbreviations: e-diary = electronic diary; HBc Ab = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HCV Ab = hepatitis C virus antibody;
HIV = human immunodeficiency virus; NAAT = nucleic acid amplification test; vax = vaccination.

a.
b.
c.
d.
e.

The COVID-19 illness visit may be conducted as an in-person or telehealth visit.
Hematology: hemoglobin, complete blood count with differential, and platelets. Blood chemistry: alanine aminotransferase (ALT), aspartate
aminotransferase (AST), alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), and creatinine.
Two swabs will be taken at Visits 1 and 4. One will be tested (if possible at the site, otherwise at the central laboratory) within 24 hours and vaccination will
only proceed if it is NAAT-negative for SARS-CoV-2 genomes. The second will be sent to the central laboratory for potential later testing.
The first 5 participants in in each group will be observed at the site for at least 4 hours after study intervention administration. Further vaccination willcommence no sooner than 24 hours after the fifth participant received his or her vaccination.
An optional blood draw of ~170 mL will be taken at 1 of the visits (from selected participants who consent) for exploratory COVID-19 research.

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1.3.2. Phase 2/3

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An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 6 (24-month follow-up visit) that potential COVID-19 symptoms are reported, including
MIS-C.
Visit Number

1

Visit Description

Day 1bVisit Window (Days)

Obtain informed consent

X

Assign participant number

X

Obtain demography and medical history data
Perform clinical assessment

2

3

4

5

6

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
Potential
COVID-19
COVID-19
Illness Visita ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2

175 to 189
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

X

X

X

Vaccination 1 Vaccination 2

X

For participants who are HIV-positive, record latest
CD4 count and HIV viral load

X

Measure height and weightX

Measure temperature (body)

X

X

Perform urine pregnancy test (if appropriate)

X

X

Confirm use of contraceptives (if appropriate)

X

X

X

Collect nonstudy vaccine information

X

X

X

X

X

X

X

X

X

~20 mL/~10 mL~20 mL/~10 mL~20 mL/~10 mL~20 mL/~10 mL

Collect prohibited medication use

X

Confirm eligibility

X

X

Review temporary delay criteria

X

X

Obtain nasal (midturbinate) swab

Unplanned

XcCollect blood sample for immunogenicity
assessmentd

Unplanned~20 mL/~10 mL
X

X

X

X~20 mL/~10 mLX

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Visit Number

1

Visit Description

Day 1bVisit Window (Days)

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2

3

4

5

6

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
Potential
COVID-19
COVID-19
Illness Visita ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2

175 to 189
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

Xf

Xf

Xf

Vaccination 1 Vaccination 2

Obtain randomization number and study
intervention allocation

X

Administer study intervention

X

X

Assess acute reactions for at least 30 minutes after
study intervention administration

X

X

Explain participant communication methods(including for e-diary completion), assist theparticipant with downloading the app, or issue
provisioned device, if required

X

Provide/ensure the participant has a thermometer(all participants) and measuring device(reactogenicity subset participants only)

X

Unplanned

Unplanned

X

Review reactogenicity e-diary data (daily review is
optimal during the active diary period)e
Review ongoing reactogenicity e-diary symptoms
and obtain stop dateseCollect AEs and SAEs as appropriate

X

X

X

X

X

Collect e-diary or assist the participant to delete
application

X

Xf

X

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Visit Number

1

Visit Description

Day 1bVisit Window (Days)

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2

3

4

5

6

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
Potential
COVID-19
COVID-19
Illness Visita ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2

175 to 189
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

Vaccination 1 Vaccination 2

Collection of COVID-19–related clinical andlaboratory information (including local diagnosis)

Unplanned

X

UnplannedX

Abbreviations: HIV = human immunodeficiency virus; e-diary = electronic diary.

a.
b.
c.
d.
e.
f.

The COVID-19 illness visit may be conducted as an in-person or telehealth visit.
The visit may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and exclusion criteria onwards must be conducted on thesame day.
Including, if indicated, a physical examination.
20 mL is to be collected from participants ≥16 years of age; 10 mL is to be collected from participants 12 to 15 years of age.
Reactogenicity subset participants only.
Any AEs occurring up to 48 hours after the blood draw must be recorded (see Section 8.3.1).

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2. INTRODUCTION
The BNT162 RNA-based COVID-19 vaccines are currently being investigated forprevention of COVID-19 in healthy individuals.
2.1. Study Rationale
The purpose of the study is to rapidly describe the safety, tolerability, and immunogenicity of
2 BNT162 RNA-based COVID-19 vaccine candidates against COVID-19, and the efficacyof 1 candidate, in healthy individuals. There are currently no licensed vaccines to prevent
infection with SARS-CoV-2 or COVID-19. Given the global crisis of COVID-19 and fast
expansion of the disease in the United States and elsewhere, the rapid development of aneffective vaccine is of utmost importance.

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)

2.2. Background
In December 2019, a pneumonia outbreak of unknown cause occurred in Wuhan, China.
In January 2020, it became clear that a novel coronavirus (2019-nCoV) was the underlying
cause. Later in January, the genetic sequence of the 2019-nCoV became available to theWorld Health Organization (WHO) and public (MN908947.3), and the virus was categorized
in the Betacoronavirus subfamily. By sequence analysis, the phylogenetic tree revealed acloser relationship to severe acute respiratory syndrome (SARS) virus isolates than to anothercoronavirus infecting humans, the Middle East respiratory syndrome (MERS) virus.
SARS-CoV-2 infections and the resulting disease, COVID-19, have spread globally,affecting a growing number of countries.
On 11 March 2020, the WHO characterized the COVID-19 outbreak as a pandemic.1
The WHO Situation Update Report dated 30 March 2020 noted 693,224 confirmed caseswith 33,106 deaths globally, including 142,081 confirmed cases with 2457 deaths in theAmericas.2 The United States currently has the most reported cases globally. At the time ofthis communication, the number of confirmed cases continues to rise globally. There are
currently no vaccines or effective antiviral drugs to treat SARS-CoV-2 infections or the
disease it causes, COVID-19.3
A prophylactic, RNA-based SARS-CoV-2 vaccine provides one of the most flexible andfastest approaches available to immunize against the emerging virus.4,5The development of an RNA-based vaccine encoding a viral antigen, which is then expressedby the vaccine recipient as a protein capable of eliciting protective immune responses,
provides significant advantages over more traditional vaccine approaches. Unlike live
attenuated vaccines, RNA vaccines do not carry the risks associated with infection and may
be given to people who cannot be administered live virus (eg, pregnant women andimmunocompromised persons). RNA-based vaccines are manufactured via a cell-free invitro transcription process, which allows an easy and rapid production and the prospect of
producing high numbers of vaccination doses within a shorter time period than achieved with

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traditional vaccine approaches. This capability is pivotal to enable the most effective
response in outbreak scenarios.
Two SARS-CoV-2–RNA lipid nanoparticle (RNA-LNP) vaccines based on a platform of
nucleoside-modified messenger RNA (modRNA, BNT162b) will be evaluated in this study.
Each vaccine candidate expresses 1 of 2 antigens: the SARS-CoV-2 full-length, P2 mutant,prefusion spike glycoprotein (P2 S) (version 9) or a trimerized SARS-CoV-2 spikeglycoprotein-receptor binding domain (RBD) (version 5). The 2 SARS-CoV-2 vaccine
candidates that will be tested in this study are therefore:

BNT162b1 (variant RBP020.3): nucleoside-modified messenger RNA (modRNA)with blunted innate immune sensor–activating capacity and augmented expression
encoding the RBD.



BNT162b2 (variant RBP020.2): nucleoside-modified messenger RNA (modRNA) as
above, but encoding P2 S.

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2.
2.2.1. Clinical Overview
Prior to this study, given clinical data from other similarly formulated uRNA liposomal
vaccines from BioNTech in oncology trials6 and recent published results from clinical trials
using modRNA influenza vaccines by Moderna,7 the BNT162 vaccines were expected tohave a favorable safety profile with mild, localized, and transient effects. BNT162 vaccines
based on modRNA have now been administered to humans for the first time in this study andthe BNT162-01 study conducted in Germany by BioNTech, at doses between 1 µg and100 µg. The currently available safety and immunogenicity data are presented in the BNT162
IB.
2.3. Benefit/Risk Assessment
There is an ongoing global pandemic of COVID-19 with no preventative or therapeutic
options available. While there were no data available from clinical trials on the use of
BNT162 vaccines in humans at the outset of this study, available nonclinical data with thesevaccines, and data from nonclinical studies and clinical trials with the same or related RNAcomponents, or antigens, supported a favorable risk/benefit profile. Anticipated AEs after
vaccination were expected to be manageable using routine symptom-driven standard of careas determined by the investigators and, as a result, the profile of these vaccine candidates
supported initiation of this Phase 1/2/3 clinical study.
Updates as part of protocol amendment 6:
In order for the overall Phase 3 study population to be as representative anddiverse as possible, the inclusion of participants with known chronic stable HIV,
HCV, or HBV infection is permitted. Individuals with chronic viral diseases are atincreased risk for COVID-19 complications and severe disease. In addition, with
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the currently available therapies for their treatment, many individuals with chronic
stable HIV, HCV, and HBV infections are unlikely to be at higher safety risk as aparticipant in this vaccine study than individuals with other chronic stable medical
conditions.
All participants with chronic stable HIV disease will be included in thereactogenicity subset (see Section 8.2.2).

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)

Updates as part of protocol amendment 7:
The minimum age for inclusion in Phase 3 is lowered to 12 years, therefore
allowing the inclusion of participants 12 to 15 years of age.



For individuals 12 to 15 years of age, the immune responses in this age group may
be higher and reactogenicity is expected to be similar to younger adults 18 to 25
years of age. Inclusion of individuals 12 to 15 years of age was based upon asatisfactory blinded safety profile in participants 18 to 25 years of age.

All participants 12 to 15 years of age will be included in the reactogenicity subset(see Section 8.2.2).

More detailed information about the known and expected benefits and risks and reasonably
expected AEs of BNT162 RNA-based COVID-19 vaccines may be found in the IB, which is
the SRSD for this study.

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2.3.1. Risk Assessment
Potential Risk of ClinicalSignificance

Summary of Data/Rationale for Risk

Mitigation Strategy

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Study Intervention: BNT162 RNA-Based COVID-19 Vaccine
Potential for local reactions (injection These are common adverse reactions seensite redness, injection site swelling, with other vaccines, as noted in the FDA
and injection site pain) and systemic Center for Biologics Evaluation andResearch (CBER) guidelines on toxicity
events (fever, fatigue, headache,
grading scales for healthy adult volunteers
chills, vomiting, diarrhea, muscle
pain, and joint pain) following
enrolled in preventive vaccine clinicalvaccination.
trials.8

The Phase 1 study design includes the use of controlled vaccination anddose escalation to closely monitor and limit the rate of enrollment to ensure
participant safety. The study employs the use of a reactogenicity e-diary tomonitor local reactions and systemic events in real time. Stopping rules arealso in place. The first 5 participants in each group in Phase 1 will beobserved for 4 hours after vaccination to assess any immediate AEs. Allother participants will be observed for at least 30 minutes after vaccination.

Unknown AEs and laboratory
abnormalities with a novel vaccine.

This study is one of the first 2
parallel-running clinical studies with the
BNT162 vaccine candidates and as suchthere are no clinical data available for this
vaccine.

The Phase 1 study design includes the use of controlled vaccination anddose escalation to closely monitor and limit the rate of enrollment to ensure
participant safety. An IRC (in Phase 1) and DMC (throughout the study)
will also review safety data. Stopping rules are also in place. The first 5
participants in each group in Phase 1 will be observed for 4 hours after
vaccination to assess any immediate AEs. All other participants will beobserved for at least 30 minutes after vaccination.

Potential for COVID-19
enhancement.

Disease enhancement has been seen
following vaccination with respiratorysyncytial virus (RSV), feline coronavirus,
and Dengue virus vaccines.

Phase 1 excludes participants with likely previous or current COVID-19. In
Phase 2/3, temporary delay criteria defer vaccination of participants withsymptoms of potential COVID-19. All participants are followed for any
potential COVID-19 illness, including markers of severity, and have blood
samples taken for potential measurement of SARS-CoV-2 antigen-specificantibody and SARS-CoV-2 neutralizing titers.

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Potential Risk of ClinicalSignificance

Summary of Data/Rationale for Risk

Mitigation Strategy

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Study Procedures
Participants will be required to attend Without appropriate social distancing andhealthcare facilities during the global PPE, there is a potential for increased
exposure to SARS-CoV-2.
SARS-CoV-2 pandemic.
Venipuncture will be performed
during the study.

There is the risk of bleeding, bruising,hematoma formation, and infection at the
venipuncture site.

Pfizer will work with sites to ensure an appropriate COVID-19 prevention
strategy. Potential COVID-19 illness visits can be conducted via telehealth,without the need for an in-person visit, if required, with the participant
performing a self-swab.
Only appropriately qualified personnel would obtain the blood draw.

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2.3.2. Benefit Assessment
Benefits to individual participants may include:Receipt of a potentially efficacious COVID-19 vaccine during a global pandemicAccess to COVID-19 diagnostic testingContributing to research to help others in a time of global pandemic

2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in thisstudy, the potential risks identified in association with BNT162 RNA-based COVID-19
vaccine are justified by the anticipated benefits that may be afforded to healthy participants.
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS

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3.1. For Phase 1
Objectives

Estimands

Endpoints

Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Primary:
In participants receiving at least 1 doseof study intervention, the percentage ofparticipants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each doseAdverse events (AEs) from
Dose 1 to 1 month after the lastdose
 Serious AEs (SAEs) from Dose 1
to 6 months after the last dosePrimary:
Local reactions (pain at the
injection site, redness, andswelling)

Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs

In addition, the percentage ofHematology and chemistry laboratory
participants with:parameters detailed in Section 10.2
Abnormal hematology andchemistry laboratory values 1 and7 days after Dose 1; and 7 days
after Dose 2
Grading shifts in hematology andchemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2

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Objectives

Estimands

Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Secondary:In participants complying with the key
protocol criteria (evaluableparticipants) at the following time
points after receipt of study
intervention: 7 and 21 days after Dose
1; 7 and 14 days and 1, 6, 12, and 24
months after Dose 2







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Endpoints
Secondary:

Geometric mean titers (GMTs) at SARS-CoV-2 neutralizing titers
each time point
Geometric mean fold rise (GMFR)
from before vaccination to eachsubsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
S1-binding IgG levels and RBDGeometric mean concentrations
binding IgG levels(GMCs) at each time point
GMFR from prior to first dose of
study intervention to eachsubsequent time point
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
Geometric mean ratio (GMR),estimated by the ratio of thegeometric mean of SARS-CoV-2 neutralizing titers to the geometric mean of binding IgG levels at
each time point

SARS-CoV-2 neutralizing titers
S1-binding IgG levels
RBD-binding IgG levels

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3.2. For Phase 2/3
Objectivesa

Estimands
Primary Efficacy

Endpoints

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 occurring from
7 days after the second dose inparticipants without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 occurring from
7 days after the second dose inparticipants with and without
evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To define the safety profile ofprophylactic BNT162b2 in the first
360 participants randomized (Phase 2)

In participants receiving at least 1
dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 7 days after
the second dose
SAEs from Dose 1 to 7 days
after the second dose

To define the safety profile ofprophylactic BNT162b2 in allparticipants randomized in Phase 2/3

In participants receiving at least
1 dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the second dose
SAEs from Dose 1 to 6 months
after the second dose





AEs
SAEs
In a subset of at least 6000
participants:
o Local reactions (pain at the
injection site, redness, andswelling)o Systemic events (fever,fatigue, headache, chills,
vomiting, diarrhea, new orworsened muscle pain, andnew or worsened joint pain)

To define the safety profile ofprophylactic BNT162b2 inparticipants 12 to 15 years of age inPhase 3

In participants receiving at least
1 dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the second dose

Local reactions (pain at the
injection site, redness, andswelling)
Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened
muscle pain, and new orworsened joint pain)
AEs
SAEs

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of thesecond dose) of past SARS-CoV-2
infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT

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Primary SafetySAEs from Dose 1 to 6
months after the second dose











Local reactions (pain at the
injection site, redness, andswelling)
Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened
muscle pain, and new orworsened joint pain)
AEs
SAEs

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Objectivesa

Estimands
Secondary Efficacy

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 occurring from
14 days after the second dose inparticipants without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 14 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 occurring from
14 days after the second dose inparticipants with and without
evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 14 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed severe COVID-19
occurring from 7 days and from 14days after the second dose inparticipants without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluableparticipants)
 at least 7 daysand
 at least 14 days
after receipt of the second dose of
study intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants)
 at least 7 daysand
 at least 14 days
after receipt of the second dose of
study intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants)
 at least 7 daysand
 at least 14 days
after receipt of the second dose of
study intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants)
 at least 7 daysand
 at least 14 days
after receipt of the second dose of
study intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed severe COVID-19
occurring from 7 days and from 14days after the second dose inparticipants with and without
evidence of infection before
vaccination

To describe the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms)
occurring from 7 days and from 14days after the second dose inparticipants without evidence of
infection before vaccination

To describe the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms)
occurring from 7 days and from 14days after the second dose inparticipants with and without
evidence of infection before
vaccination

Endpoints
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 14 days after receipt of thesecond dose) of past SARS-CoV-2
infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT

Confirmed severe COVID-19
incidence per 1000 person-years offollow-up in participants with noserological or virological evidence (upto 7 days and up to 14 days after
receipt of the second dose) of past
SARS-CoV-2 infection

Confirmed severe COVID-19
incidence per 1000 person-years offollow-up

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days and up to 14 days after
receipt of the second dose) of past
SARS-CoV-2 infection

COVID-19 incidence per 1000
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Objectivesa

Estimands
Secondary Immunogenicity

Endpoints

To demonstrate the noninferiority of
the immune response to prophylactic
BNT162b2 in participants 12 to 15
years of age compared to participants
16 to 25 years of age

GMR, estimated by the ratio of thegeometric mean of SARS-CoV-2
neutralizing titers in the 2 age groups(12-15 years of age to 16-25 years ofage) 1 month after completion of
vaccination

SARS-CoV-2 neutralizing titers inparticipants with no serological or
virological evidence (up to 1 monthafter receipt of the second dose) of
past SARS-CoV-2 infection

To evaluate the immune responseover time to prophylactic BNT162b2
and persistence of immune response
in participants with and without
serological or virological evidence of
SARS-CoV-2 infection before
vaccination

GMC/GMT, GMFR, and percentageof participants with titers greater thandefined threshold(s), at baseline and1, 6, 12, and 24 months after
completion of vaccination

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ExploratoryS1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titers

To evaluate the immune response(non-S) to SARS-CoV-2 inparticipants with and without
confirmed COVID-19 during the
study



N-binding antibody

To describe the serological responses
to the BNT vaccine candidate in casesof:
Confirmed COVID-19

Confirmed severe COVID-19

SARS-CoV-2 infection without
confirmed COVID-19
To describe the safety,
immunogenicity, and efficacy ofprophylactic BNT162b2 in
individuals with confirmed stable
HIV disease
To describe the safety andimmunogenicity of prophylactic
BNT162b2 in individuals 16 to 55
years of age vaccinated with study
intervention produced bymanufacturing “Process 1” or“Process 2”b

S1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titers

a.
b.





All safety, immunogenicity, andefficacy endpoints described
above



All safety endpoints describedabove
SARS-CoV-2 neutralizing titersHIV-positive participants in Phase 3 will not be included in analyses of the objectives, with the
exception of the specific exploratory objective.
See Section 6.1.1 for description of the manufacturing process.

This protocol will use a group of internal case reviewers to determine whether certain
investigator-reported events meet the definition of disease-related efficacy endpoints, using
predefined endpoint criteria.
For those AEs that are handled as disease-related efficacy endpoints (which may include
death), a DMC will conduct unblinded reviews on a regular basis throughout the trial(see Section 9.6).

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Any AE that is determined by the internal case reviewers NOT to meet endpoint criteria isreported back to the investigator site of incidence. Refer to Section 8.3.1.1 for instructions
on how to report any such AE that meets the criteria for seriousness to Pfizer Safety.
4. STUDY DESIGN
4.1. Overall Design
This is a multicenter, multinational, Phase 1/2/3, randomized, placebo-controlled,
observer-blind, dose-finding, vaccine candidate–selection, and efficacy study in healthy
individuals.
The study consists of 2 parts. Phase 1: to identify preferred vaccine candidate(s) and doselevel(s); Phase 2/3: an expanded cohort and efficacy part. These parts, and the progression
between them, are detailed in the schema (Section 1.2).

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)The study will evaluate the safety, tolerability, and immunogenicity of 2 different
SARS-CoV-2 RNA vaccine candidates against COVID-19 and the efficacy of 1 candidate:

As a 2-dose (separated by 21 days) schedule;At various different dose levels in Phase 1;



In 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3: ≥12years of age [stratified as 12-15, 16-55, or >55 years of age]).

Dependent upon safety and/or immunogenicity data generated during the course of thisstudy, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
in Phase 1 may be started at the next highest dose, groups may not be started, groups may beterminated early, and/or groups may be added with dose levels below the lowest stated doseor intermediate between the lowest and highest stated doses.
The study is observer-blinded, as the physical appearance of the investigational vaccine
candidates and the placebo may differ. The participant, investigator, study coordinator, andother site staff will be blinded. At the study site, only the dispenser(s)/administrator(s) are
unblinded.
To facilitate rapid review of data in real time, sponsor staff will be unblinded to vaccine
allocation for the participants in Phase 1.
4.1.1. Phase 1
Each group (vaccine candidate/dose level/age group) will comprise 15 participants;
12 participants will be randomized to receive active vaccine and 3 to receive placebo.
For each vaccine candidate/dose level/age group, the following apply:Additional safety assessments (see Section 8.2)
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Controlled enrollment (required only for the first candidate and/or dose level studied):No more than 5 participants (4 active, 1 placebo) can be vaccinated on the firstdayThe first 5 participants must be observed by blinded site staff for at least 4 hours
after vaccination for any acute reactions

Vaccination of the remaining participants will commence no sooner than 24 hours
after the fifth participant received his or her vaccination

Application of stopping rules

IRC review of safety data to determine escalation to the next dose level in the 18- to
55-year age cohort:Escalation between dose levels will be based on IRC review of at least 7-day
post–Dose 1 safety data in this study and/or the BioNTech study conducted inGermany (BNT162-01)

Note that, since both candidates are based upon the same RNA platform, dose
escalation for the second candidate studied may be based upon the safety profileof the first candidate studied being deemed acceptable at the same, or a higher,
dose level by the IRC

Groups of participants 65 to 85 years of age will not be started until safety data for the RNA
platform have been deemed acceptable at the same, or a higher, dose level in the 18- to
55-year age cohort by the IRC.
In this phase, 13 groups will be studied, corresponding to a total of 195 participants.
The IRC will select 1 vaccine candidate that, in Phase 1, has an established dose level per age
group based on induction of a post–Dose 2 immune response, including neutralizing
antibodies, which is expected to be associated with protection against COVID-19, forprogression into Phase 2/3.
4.1.2. Phase 2/3
On the basis of safety and/or immunogenicity data generated during the course of this study,
and/or the BioNTech study conducted in Germany (BNT162-01), 1 vaccine candidate wasselected to proceed into Phase 2/3. Participants in this phase will be ≥12 years of age,stratified as follows: 12 to 15 years, 16 to 55 years, or >55 years. The 12- to 15-year stratum
will comprise up to approximately 2000 participants enrolled at selected investigational sites.
It is intended that a minimum of 40% of participants will be in the >55-year stratum.
Commencement of each age stratum will be based upon satisfactory post–Dose 2 safety andimmunogenicity data from the 18- to 55-year and 65- to 85-year age groups in Phase 1,
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respectively. The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a doseof 30 µg.

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Phase 2/3 is event-driven. Under the assumption of a true VE rate of ≥60%, after the second
dose of investigational product, a target of 164 primary-endpoint cases of confirmed
COVID-19 due to SARS-CoV-2 occurring at least 7 days following the second dose of the
primary series of the candidate vaccine will be sufficient to provide 90% power to conclude
true VE >30% with high probability. The total number of participants enrolled in Phase 2/3
may vary depending on the incidence of COVID-19 at the time of the enrollment, the true
underlying VE, and a potential early stop for efficacy or futility.
Assuming a COVID-19 attack rate of 1.3% per year in the placebo group, accrual of 164 firstprimary-endpoint cases within 6 months, an estimated 20% nonevaluable rate, and 1:1
randomization, the BNT162b2 vaccine candidate selected for Phase 2/3 is expected tocomprise approximately 21,999 vaccine recipients. This is the number of participants
initially targeted for Phase 2/3 and may be adjusted based on advice from DMC analyses ofcase accumulation and the percentage of participants who are seropositive at baseline.
Dependent upon the evolution of the pandemic, it is possible that the COVID-19 attack rate
may be much higher, in which case accrual would be expected to be more rapid, enabling thestudy’s primary endpoint to be evaluated much sooner.
The first 360 participants enrolled (180 to active vaccine and 180 to placebo, stratified
equally between 18 to 55 years and >55 to 85 years) will comprise the “Phase 2” portion.
Safety data through 7 days after Dose 2 and immunogenicity data through 1 month after
Dose 2 from these 360 participants will be analyzed by the unblinded statistical team,reviewed by the DMC, and submitted to appropriate regulatory authorities for review.
Enrollment may continue during this period and these participants would be included in theefficacy evaluation in the “Phase 3” portion of the study.
In Phase 3, up to approximately 2000 participants, enrolled at selected sites, are anticipatedto be 12 to 15 years of age. Noninferiority of immune response to prophylactic BNT162b2
in participants 12 to 15 years of age to response in participants 16 to 25 years of age will beassessed based on the GMR of SARS-CoV-2 neutralizing titers using a 1.5-fold margin. A
sample size of 200 evaluable participants (or 250 vaccine recipients) per age group will
provide a power of 90.8% to declare the noninferiority in terms of GMR (lower limit of 95%
CI for GMR >0.67). A random sample of 250 participants from each of the 2 age groups(12 to 15 years and 16 to 25 years) will be selected as an immunogenicity subset for thenoninferiority assessment.
The initial BNT162b2 was manufactured using “Process 1”; however, “Process 2” wasdeveloped to support an increased scale of manufacture. In the study, each lot of“Process 2”-manufactured BNT162b2 will be administered to approximately 250 participants
16 to 55 years of age. The safety and immunogenicity of prophylactic BNT162b2 in
individuals 16 to 55 years of age vaccinated with “Process 1” and each lot of “Process 2”
study intervention will be described. A random sample of 250 participants from those
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vaccinated with study intervention produced by manufacturing “Process 1” will be selected
for this descriptive analysis.
Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Phase 1
dosing arms that are not evaluated in Phase 2/3.
4.2. Scientific Rationale for Study Design
Additional surveillance for COVID-19 will be conducted as part of the study, given thepotential risk of disease enhancement. If a participant experiences symptoms, as detailed in
Section 8.13, a COVID-19 illness and subsequent convalescent visit will occur. As part ofthese visits, samples (nasal [midturbinate] swab and blood) will be taken for antigen andantibody assessment as well as recording of COVID-19–related clinical and laboratory
information (including local diagnosis).

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Human reproductive safety data are not available for BNT162 RNA-based COVID-19
vaccines, but there is no suspicion of human teratogenicity based on the intended mechanismof action of the compound. Therefore, the use of a highly effective method of contraception
is required (see Appendix 4).
4.3. Justification for Dose
Because of the requirement for a rapid response to the newly emerged COVID-19 pandemic,
sufficient data were not available to experimentally validate the dose selection and initialstarting dose. Therefore, the original planned starting dose of 10 µg (for both BNT162b1 and
BNT162b2) in this study was based on nonclinical experience with the same RNAs encoding
other viral antigens (such as influenza and HIV antigens). The general safety andeffectiveness of uRNA and modRNA platforms have been demonstrated in oncologicalclinical trials with different administration routes (NCT02410733, NCT03871348). Doses of
up to 400 µg total uRNA have been administered IV as RNA lipoplex (RNA-LPX) and dosesof up to 1000 µg total naked modRNA have been administered intratumorally, both without
signs of unpredictable overstimulation of the immune system.
Based on nonclinical data of the RNA components, with other liposomes or in conjunction
with the lipid nanoparticles as will be tested clinically in this study, it was expected that
doses in the 1- to 5-µg range would be immunogenic and induce neutralizing antibodies;
however, it was anticipated that 3- to 10-fold higher doses would likely be required to elicit astronger antibody response. Based on previous clinical and nonclinical experience, it was
expected that doses of up to 100 µg would be well tolerated.
Update as part of protocol amendment 2: preliminary experience in this study and the
BioNTech study conducted in Germany (BNT162-01) suggests that, for vaccine candidates
based on the modRNA platform, a dose level between 30 µg and 100 µg warrants
consideration. Therefore, a 50-µg dose level is formally included for BNT162b1 and
BNT162b2.

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Update as part of protocol amendment 3: as data have become available from this study andthe BNT162-01 study in Germany, it was decided:

To not study the BNT162a1 and BNT162c2 vaccine candidates at this time, so thesecandidates have been removed from the protocol; andThat lower dose levels of BNT162b1 and BNT162b2 warrant consideration.
Therefore, a 20-µg dose level is formally included for both candidates.

Update as part of protocol amendment 4: the 50-µg dose level for BNT162b1 and BNT162b2
is removed and the 100-µg dose level for BNT162b2 is removed; similar dose levels of
BNT162b3 may be studied as for BNT162b1 and BNT162b2.
Update as part of protocol amendment 5: the vaccine candidate selected for Phase 2/3
evaluation is BNT162b2 at a dose of 30 µg. BNT162b3 will not be studied.

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4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases ofthe study, including the last visit. Note that participants enrolled in Phase 1 in groups that do
not proceed to Phase 2/3 may be followed for fewer than 24 months (but no less than
6 months after the last vaccination).
The end of the study is defined as the date of last visit of the last participant in the study.
5. STUDY POPULATIONThis study can fulfill its objectives only if appropriate participants are enrolled. The
following eligibility criteria are designed to select participants for whom participation in the
study is considered appropriate. All relevant medical and nonmedical conditions should betaken into consideration when deciding whether a particular participant is suitable for thisprotocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male or female participants between the ages of 18 and 55 years, inclusive, and 65 and85 years, inclusive (Phase 1), or ≥12 years (Phase 2/3), at randomization. Note thatparticipants <18 years of age cannot be enrolled in the EU.


Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female(Section 10.4.2) participants.
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Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, vaccination
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Healthy participants who are determined by medical history, physical examination(if required), and clinical judgment of the investigator to be eligible for inclusion in the
study.
Note: Healthy participants with preexisting stable disease, defined as disease notrequiring significant change in therapy or hospitalization for worsening disease during
the 6 weeks before enrollment, can be included. Specific criteria for Phase 3 participants
with known stable infection with human immunodeficiency virus (HIV), hepatitis C virus(HCV), or hepatitis B virus (HBV) can be found in Section 10.8.
4. Phase 2/3 only: Participants who, in the judgment of the investigator, are at higher risk
for acquiring COVID-19 (including, but not limited to, use of mass transportation,
relevant demographics, and frontline essential workers).
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Informed Consent:
5. Capable of giving personal signed informed consent/have parent(s)/legal guardiancapable of giving signed informed consent as described in Appendix 1, which includes
compliance with the requirements and restrictions listed in the ICD and in this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Other medical or psychiatric condition including recent (within the past year) or active
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study
participation or, in the investigator’s judgment, make the participant inappropriate for the
study.
2. Phases 1 and 2 only: Known infection with human immunodeficiency virus (HIV),hepatitis C virus (HCV), or hepatitis B virus (HBV).
3. History of severe adverse reaction associated with a vaccine and/or severe allergic
reaction (eg, anaphylaxis) to any component of the study intervention(s).
4. Receipt of medications intended to prevent COVID-19.
5. Previous clinical (based on COVID-19 symptoms/signs alone, if a SARS-CoV-2 NAAT
result was not available) or microbiological (based on COVID-19 symptoms/signs and apositive SARS-CoV-2 NAAT result) diagnosis of COVID-19.
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6. Phase 1 only: Individuals at high risk for severe COVID-19, including those with any of
the following risk factors:Hypertension

Diabetes mellitus

Chronic pulmonary diseaseAsthma

Current vaping or smoking

History of chronic smoking within the prior year

Chronic liver diseaseStage 3 or worse chronic kidney disease (glomerular filtration rate
<60 mL/min/1.73 m2)



Resident in a long-term facility

BMI >30 kg/m2

Anticipating the need for immunosuppressive treatment within the next 6 months

7. Phase 1 only: Individuals currently working in occupations with high risk of exposure to
SARS-CoV-2 (eg, healthcare worker, emergency response personnel).
8. Immunocompromised individuals with known or suspected immunodeficiency, as
determined by history and/or laboratory/physical examination.
9. Phase 1 only: Individuals with a history of autoimmune disease or an active autoimmune
disease requiring therapeutic intervention, including but not limited to: systemic or
cutaneous lupus erythematosus, autoimmune arthritis/rheumatoid arthritis, Guillain-Barré
syndrome, multiple sclerosis, Sjögren’s syndrome, idiopathic thrombocytopenia purpura,glomerulonephritis, autoimmune thyroiditis, giant cell arteritis (temporal arteritis),
psoriasis, and insulin-dependent diabetes mellitus (type 1).
10. Bleeding diathesis or condition associated with prolonged bleeding that would, in theopinion of the investigator, contraindicate intramuscular injection.
11. Women who are pregnant or breastfeeding.
Prior/Concomitant Therapy:
12. Previous vaccination with any coronavirus vaccine.
13. Individuals who receive treatment with immunosuppressive therapy, including cytotoxic
agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned
receipt throughout the study. If systemic corticosteroids have been administered short
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term (<14 days) for treatment of an acute illness, participants should not be enrolled into
the study until corticosteroid therapy has been discontinued for at least 28 days before
study intervention administration. Inhaled/nebulized (except for participants in
Phase 1 – see exclusion criterion 14), intra-articular, intrabursal, or topical (skin or eyes)corticosteroids are permitted.
14. Phase 1 only: Regular receipt of inhaled/nebulized corticosteroids.
15. Receipt of blood/plasma products or immunoglobulin, from 60 days before study
intervention administration or planned receipt throughout the study.
Prior/Concurrent Clinical Study Experience:
16. Participation in other studies involving study intervention within 28 days prior to study
entry and/or during study participation.
17. Previous participation in other studies involving study intervention containing lipid
nanoparticles.
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Diagnostic Assessments:
18. Phase 1 only: Positive serological test for SARS-CoV-2 IgM and/or IgG antibodies atthe screening visit.
19. Phase 1 only: Any screening hematology and/or blood chemistry laboratory value thatmeets the definition of a ≥ Grade 1 abnormality.
Note: With the exception of bilirubin, participants with any stable Grade 1 abnormalities(according to the toxicity grading scale) may be considered eligible at the discretion of
the investigator. (Note: A “stable” Grade 1 laboratory abnormality is defined as a reportof Grade 1 on an initial blood sample that remains ≤ Grade 1 upon repeat testing on asecond sample from the same participant.)
20. Phase 1 only: Positive test for HIV, hepatitis B surface antigen (HBsAg), hepatitis B
core antibodies (HBc Abs), or hepatitis C virus antibodies (HCV Abs) at the screening
visit.
21. Phase 1 only: SARS-CoV-2 NAAT-positive nasal swab within 24 hours before receipt ofstudy intervention.
Other Exclusions:
22. Investigator site staff or Pfizer/BioNTech employees directly involved in the conduct of
the study, site staff otherwise supervised by the investigator, and their respective family
members.

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5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm thatthe participant has selected an appropriate method of contraception for the individual
participant and his or her partner(s) from the permitted list of contraception methods(see Appendix 4, Section 10.4.4) and will confirm that the participant has been instructed inits consistent and correct use. At time points indicated in the SoA, the investigator ordesignee will inform the participant of the need to use highly effective contraception
consistently and correctly and document the conversation and the participant’s affirmation in
the participant’s chart (participants need to affirm their consistent and correct use of at least 1of the selected methods of contraception). In addition, the investigator or designee will
instruct the participant to call immediately if the selected contraception method is
discontinued or if pregnancy is known or suspected in the participant or partner.

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5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but
are not subsequently randomly assigned to study intervention. A minimal set of screen
failure information is required to ensure transparent reporting of screen failure participants tomeet the CONSORT publishing requirements and to respond to queries from regulatory
authorities. Minimal information includes demography, screen failure details, eligibility
criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may berescreened under a different participant number.
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention
Administration
The following conditions are temporary or self-limiting and a participant may be vaccinatedonce the condition(s) has/have resolved and no other exclusion criteria are met.
1. Current febrile illness (body temperature ≥100.4°F [≥38°C]) or other acute illness within
48 hours before study intervention administration. This includes current symptoms that
could represent a potential COVID-19 illness:

New or increased cough;

New or increased shortness of breath;Chills;

New or increased muscle pain;New loss of taste/smell;

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

Sore throat;

Diarrhea;Vomiting.

2. Receipt of any seasonal or pandemic influenza vaccine within 14 days, or any othernonstudy vaccine within 28 days, before study intervention administration.
3. Anticipated receipt of any seasonal or pandemic influenza vaccine within 14 days, or any
other nonstudy vaccine within 28 days, after study intervention administration.
4. Receipt of short-term (<14 days) systemic corticosteroids. Study intervention
administration should be delayed until systemic corticosteroid use has been discontinued
for at least 28 days. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin oreyes) corticosteroids are permitted.

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6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s),placebo, medical device(s), or study procedure(s) intended to be administered to a study
participant according to the study protocol.
The study will evaluate a 2-dose (separated by 21 days) schedule of various different doselevels of 2 investigational RNA vaccine candidates for active immunization against
COVID-19 in 3 age groups (18 to 55 years of age, 65 to 85 years of age, and ≥12 years ofage [stratified as 12-15, 16-55, or >55 years of age]).
These 2 investigational RNA vaccine candidates, with the addition of saline placebo, are the
3 potential study interventions that may be administered to a study participant:

BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 20 µg, 30 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 20 µg, 30 µgNormal saline (0.9% sodium chloride solution for injection)

The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.

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6.1. Study Intervention(s) Administered
Intervention Name

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Type
Dose Formulation

BNT162b1(BNT162 RNA-LNP
vaccine utilizing
modRNA)
VaccinemodRNA

BNT162b2(BNT162 RNA-LNP
vaccine utilizing
modRNA)
VaccinemodRNA

Saline Placebo

Placebo
Normal saline (0.9%sodium chloride solution
for injection)
Unit Dose Strength(s)250 µg/0.5 mL
250 µg/0.5 mL
N/A
Dosage Level(s)a10-, 20-, 30-, 100-µg
10-, 20-, 30-µg
N/A
Route of Administration Intramuscular injection
Intramuscular injection
Intramuscular injection
Use
Experimental
Experimental
Placebo
IMP or NIMP
IMP
IMP
IMP
Sourcing
Provided centrally by the Provided centrally by the Provided centrally by thesponsorsponsorsponsorPackaging and Labeling Study intervention will be Study intervention will be Study intervention will be
provided in a glass vial as provided in a glass vial as provided in a glass or
open-label supply. Each
open-label supply. Each
plastic vial as open-labelvial will be labeled asvial will be labeled as
supply. Each vial will be
required per country
required per country
labeled as required per
requirement
requirement
country requirementa. Dependent upon safety and/or immunogenicity data generated during the course of this study, or the
BioNTech study conducted in Germany (BNT162-01), it is possible that groups may be started at the next
highest dose, groups may not be started, groups may be terminated early, and/or groups may be addedwith dose levels below the lowest stated dose or intermediate between the lowest and highest stated doses.

The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.
6.1.1. Manufacturing Process
The scale of the BNT162b2 manufacturing has been increased to support future supply.
BNT162b2 generated using the manufacturing process supporting an increased supply(“Process 2”) will be administered to approximately 250 participants 16 to 55 years of age,per lot, in the study. The safety and immunogenicity of prophylactic BNT162b2 in
individuals 16 to 55 years of age vaccinated with material generated using the existing
manufacturing process “Process 1,” and with material from lots generated using the
manufacturing process supporting increased supply, “Process 2,” will be described.
In brief, the process changes relate to the method of production for the DNA template thatRNA drug substance is transcribed from, and the RNA drug substance purification method.
The BNT162b2 drug product is then produced using a scaled-up LNP manufacturing process.
6.1.2. Administration
Participants will receive 1 dose of study intervention as randomized at each vaccination visit(Visits 1 and 4 for Phase 1 participants, Visits 1 and 2 for Phase 2/3 participants) inaccordance with the study’s SoA. The volume to be administered may vary by vaccine
candidate and dose level; full details are described in the IP manual.
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Study intervention should be administered intramuscularly into the deltoid muscle, preferablyof the nondominant arm, by an unblinded administrator.
Standard vaccination practices must be observed and vaccine must not be injected into bloodvessels. Appropriate medication and other supportive measures for management of an acute
hypersensitivity reaction should be available in accordance with local guidelines for standard
immunization practices.
Administration of study interventions should be performed by an appropriately qualified,
GCP-trained, and vaccine-experienced member of the study staff (eg, physician, nurse,
physician’s assistant, nurse practitioner, pharmacist, or medical assistant) as allowed by
local, state, and institutional guidance.
Study intervention administration details will be recorded on the CRF.
6.2. Preparation/Handling/Storage/Accountability

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1. The investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study interventions received and any discrepancies arereported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only
authorized site staff may supply or administer study intervention. All study interventions
must be stored in a secure, environmentally controlled, and monitored (manual or
automated recording) area in accordance with the labeled storage conditions with accesslimited to the investigator and authorized site staff. At a minimum, daily minimum andmaximum temperatures for all site storage locations must be documented and available
upon request. Data for nonworking days must indicate the minimum and maximum
temperatures since previously documented for all site storage locations upon return tobusiness.
3. Any excursions from the study intervention label storage conditions should be reported to
Pfizer upon discovery along with any actions taken. The site should actively pursue
options for returning the study intervention to the storage conditions described in thelabeling, as soon as possible. Once an excursion is identified, the study intervention must
be quarantined and not used until Pfizer provides permission to use the study
intervention. Specific details regarding the definition of an excursion and information thesite should report for each excursion will be provided to the site in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage conditions
stated on the label.
5. Study interventions should be stored in their original containers.
6. See the IP manual for storage conditions of the study intervention.

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7. The investigator, institution, or the head of the medical institution (where applicable) is
responsible for study intervention accountability, reconciliation, and record maintenance(ie, receipt, reconciliation, and final disposition records), such as the IPAL orsponsor-approved equivalent. All study interventions will be accounted for using a study
intervention accountability form/record.
8. Further guidance and information for the final disposition of unused study interventions
are provided in the IP manual. All destruction must be adequately documented. If
destruction is authorized to take place at the investigator site, the investigator must ensurethat the materials are destroyed in compliance with applicable environmental regulations,institutional policy, and any special instructions provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of
discovery as described in the IP manual.

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6.2.1. Preparation and Dispensing
See the IP manual for instructions on how to prepare the study intervention foradministration. Study intervention should be prepared and dispensed by an appropriately
qualified and experienced member of the study staff (eg, physician, nurse, physician’s
assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as allowed by
local, state, and institutional guidance. A second staff member will verify the dispensing.
Study intervention and placebo will be prepared by qualified unblinded site personnel
according to the IP manual. The study intervention will be administered in such a way toensure the participants remain blinded.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
Allocation (randomization) of participants to vaccine groups will proceed through the use of
an IRT system (IWR). The site personnel (study coordinator or specified designee) will be
required to enter or select information including but not limited to the user’s ID andpassword, the protocol number, and the participant number. The site personnel will then be
provided with a vaccine assignment and randomization number. The IRT system will
provide a confirmation report containing the participant number, randomization number, andstudy intervention allocation assigned. The confirmation report must be stored in the site’s
files.
The study-specific IRT reference manual and IP manual will provide the contact informationand further details on the use of the IRT system.
6.3.2. Blinding of Site Personnel
In this observer blinded study, the study staff receiving, storing, dispensing, preparing, andadministering the study interventions will be unblinded. All other study and site personnel,
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including the investigator, investigator staff, and participants, will be blinded to study
intervention assignments. In particular, the individuals who evaluate participant safety willbe blinded. Because the BNT162 RNA-based COVID-19 vaccine candidates and placebo
are different in physical appearance, the study intervention syringes will be administered in amanner that prevents the study participants from identifying the study intervention type basedon its appearance.
The responsibility of the unblinded dispenser and administrator must be assigned to anindividual or individuals who will not participate in the evaluation of any study participants.
Contact between the unblinded dispenser and study participants and unblinded administrator
and study participants should be kept to a minimum. The remaining site personnel must notknow study intervention assignments.

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6.3.3. Blinding of the Sponsor
To facilitate rapid review of data in real time, sponsor staff will be unblinded to study
intervention allocation for the participants in Phase 1. The majority of sponsor staff will beblinded to study intervention allocation in Phase 2/3. All laboratory testing personnel
performing serology assays will remain blinded to study intervention assigned/received
throughout the study. The following sponsor staff, who will have no part in the blinded
conduct of the study, will be unblinded in Phase 2/3 (further details will be provided in a data
blinding plan):

Those study team members who are involved in ensuring that protocol requirements
for study intervention preparation, handling, allocation, and administration are
fulfilled at the site will be unblinded for the duration of the study (eg, unblinded study
manager, unblinded clinical research associate).

Unblinded clinician(s), who are not direct members of the study team and will notparticipate in any other study-related activities, will review unblinded protocol
deviations.

An unblinded team supporting interactions with, and analyses for, the DMC(see Section 9.6). This will comprise a statistician, programmer(s), a clinicalscientist, and a medical monitor who will review cases of severe COVID-19 as they
are received, and will review AEs at least weekly for additional potential cases ofsevere COVID-19 (see Section 8.2.3).

An unblinded submissions team will be responsible for preparing unblinded analyses
and documents to support regulatory activities that may be required while the study is
ongoing. This team will only be unblinded at the group level and not have access toindividual participant assignments. The programs that produce the summary tables
will be developed and validated by the blinded study team, and these programs will
be run by the unblinded DMC team. The submissions team will not have access tounblinded COVID-19 cases unless efficacy is achieved in either an interim analysis or
the final analysis, as determined by the DMC.
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6.3.4. Breaking the Blind
The IRT will be programmed with blind-breaking instructions. In case of an emergency, theinvestigator has the sole responsibility for determining if unblinding of a participant’s study
intervention assignment is warranted. Participant safety must always be the firstconsideration in making such a determination. If the investigator decides that unblinding iswarranted, the investigator should make every effort to contact the sponsor prior to
unblinding a participant’s vaccine assignment unless this could delay further management of
the participant. If a participant’s vaccine assignment is unblinded, the sponsor must be
notified within 24 hours after breaking the blind. The date and reason that the blind was
broken must be recorded in the source documentation and CRF.
The study-specific IRT reference manual and IP manual will provide the contact informationand further details on the use of the IRT system.

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6.4. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from theinvestigator or designee, under medical supervision. The date and time of each dose
administered in the clinic will be recorded in the source documents and recorded in the CRF.
The dose of study intervention and study participant identification will be confirmed at thetime of dosing by a member of the study site staff other than the person administering thestudy intervention.
6.5. Concomitant Therapy
The following concomitant medications and vaccinations will be recorded in the CRF:
All vaccinations received from 28 days prior to study enrollment until the 6-monthfollow-up visit (Visit 8 for Phase 1 participants, and Visit 4 for Phase 2/3
participants).

Prohibited medications listed in Section 6.5.1 will be recorded, to include start andstop dates, name of the medication, dose, unit, route, and frequency.

In addition, for participants enrolled in Phase 1, all current medication at baseline will
be recorded, to include start date, name of the medication, dose, unit, route, andfrequency.

6.5.1. Prohibited During the Study
Receipt of the following vaccines and medications during the time periods listed below may
exclude a participant from the per-protocol analysis from that point onwards, and may
require vaccinations to be discontinued in that participant; however, it is anticipated that theparticipant would not be withdrawn from the study (see Section 7). Medications should not
be withheld if required for a participant’s medical care.

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Unless considered medically necessary, no vaccines other than study intervention should be
administered within 28 days before and 28 days after each study vaccination. One exception
to this is that seasonal and pandemic influenza vaccine can be given at least 14 days after, orat least 14 days prior to, the administration of study intervention.
Receipt of chronic systemic treatment with known immunosuppressant medications, orradiotherapy, within 60 days before enrollment through conclusion of the study.
Receipt of systemic corticosteroids (≥20 mg/day of prednisone or equivalent) for ≥14 days is
prohibited from 28 days prior to enrollment to Visit 7 for Phase 1 participants, and Visit 3 forPhase 2/3 participants).
Receipt of inhaled/nebulized corticosteroids from 28 days prior to enrollment to Visit 7(1-month follow-up visit) for Phase 1 participants.
Receipt of blood/plasma products or immunoglobulins within 60 days before enrollment
through conclusion of the study.

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Receipt of any other (nonstudy) coronavirus vaccine at any time prior to or during study
participation is prohibited.
Prophylactic antipyretics and other pain medication to prevent symptoms associated withstudy intervention administration are not permitted. However, if a participant is taking a
medication for another condition, even if it may have antipyretic or pain-relieving properties,
it should not be withheld prior to study vaccination.
6.5.2. Permitted During the Study
The use of antipyretics and other pain medication to treat symptoms associated with study
intervention administration or ongoing conditions is permitted.
Medication other than that described as prohibited in Section 6.5.1 required for treatment ofpreexisting stable conditions is permitted.
Inhaled (except in Phase 1 participants – see Section 6.5.1), topical, or localized injections ofcorticosteroids (eg, intra-articular or intrabursal administration) are permitted.
6.6. Dose Modification
This protocol allows some alteration of vaccine dose for individual participants and/or dosegroups from the currently outlined dosing schedule. For reasons of reactogenicity,
tolerability, or safety, the IRC may recommend to reduce the second dose of study
intervention and/or increase the interval between doses.
If, due to a medication error, a participant receives 1 dose of BNT162b2 at Visit 1 and 1 doseof placebo at Visit 2 (or vice versa), the participant should be offered the possibility toreceive a second dose of BNT162b2 at an unscheduled visit. In this situation:
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Obtain informed consent for administration of the additional dose.

Measure the participant’s body temperature.

Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention
into the deltoid muscle of the preferably nondominant arm. Please refer to the IP
manual for further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of
the CRF, and on an SAE form as applicable.



The participant should continue to adhere to the normal visit schedule but must be
followed for nonserious AEs for 1 month and SAEs for 6 months after the second
dose of BNT162b2. This will require AEs to be elicited either by unscheduled
telephone contact(s) and/or in-person visit(s).

6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANTDISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study
intervention (definitive discontinuation). Reasons for definitive discontinuation of study
intervention may include the following: AEs; participant request; investigator request;
pregnancy; protocol deviation (including no longer meeting all the inclusion criteria, or
meeting 1 or more exclusion criteria). In general, unless the investigator considers it unsafe
to administer the second dose, or the participant does not wish to receive it, it is preferredthat the second dose be administered. Note that a positive SARS-CoV-2 NAAT result
without symptoms does not meet exclusion criterion 5 and should not result in
discontinuation of study intervention, whereas a COVID-19 diagnosis does meet exclusion
criterion 5 and should result in discontinuation of study intervention (see Section 8.15).
Note that discontinuation of study intervention does not represent withdrawal from the study.
Per the study estimands, if study intervention is definitively discontinued, the participant will
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remain in the study to be evaluated for safety, immunogenicity, and efficacy. See the SoA
for data to be collected at the time of discontinuation of study intervention and follow-up for
any further evaluations that need to be completed.
In the event of discontinuation of study intervention, it must be documented on theappropriate CRF/in the medical records whether the participant is discontinuing further
receipt of study intervention or also from study procedures, posttreatment study follow-up,
and/or future collection of additional information.
7.2. Participant Discontinuation/Withdrawal From the Study

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)A participant may withdraw from the study at any time at his/her own request. Reasons fordiscontinuation from the study may include the following:

Refused further follow-up;

Lost to follow-up;



Death;



Study terminated by sponsor;



AEs;



Participant request;

Investigator request;Protocol deviation.

If a participant does not return for a scheduled visit, every effort should be made to contact
the participant. All attempts to contact the participant and information received duringcontact attempts must be documented in the participant’s source document. In any
circumstance, every effort should be made to document participant outcome, if possible.
The investigator or his or her designee should capture the reason for withdrawal in the CRF
for all participants.
If a participant withdraws from the study, he/she may request destruction of any remaining
samples taken and not tested, and the investigator must document any such requests in thesite study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1)
for disclosure of future information, no further evaluations should be performed and no
additional data should be collected. The sponsor may retain and continue to use any datacollected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not beviewed as protocol deviations so long as the participant’s safety was preserved.

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7.2.1. Withdrawal of Consent
Participants who request to discontinue receipt of study intervention will remain in the study
and must continue to be followed for protocol-specified follow-up procedures. The only
exception to this is when a participant specifically withdraws consent for any further contact
with him or her or persons previously authorized by the participant to provide thisinformation. Participants should notify the investigator in writing of the decision towithdraw consent from future follow-up, whenever possible. The withdrawal of consent
should be explained in detail in the medical records by the investigator, as to whether thewithdrawal is only from further receipt of study intervention or also from study procedures
and/or posttreatment study follow-up, and entered on the appropriate CRF page. In the eventthat vital status (whether the participant is alive or dead) is being measured, publicly
available information should be used to determine vital status only as appropriately directedin accordance with local law.
7.3. Lost to Follow-up

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)A participant will be considered lost to follow-up if he or she repeatedly fails to return forscheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to attend a required study visit:The site must attempt to contact the participant and reschedule the missed visit assoon as possible and counsel the participant on the importance of maintaining theassigned visit schedule and ascertain whether or not the participant wishes to and/or
should continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must
make every effort to regain contact with the participant (where possible, 3 telephone
calls and, if necessary, a certified letter to the participant’s last known mailingaddress or local equivalent methods). These contact attempts should be documented
in the participant’s medical record;Should the participant continue to be unreachable, he/she will be considered to havewithdrawn from the study.

8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed anddated ICD before performing any study-specific procedures.
The full date of birth will be collected to critically evaluate the immune response and safety
profile by age.
Study procedures and their timing are summarized in the SoA. Protocol waivers or
exemptions are not allowed.

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Safety issues should be discussed with the sponsor immediately upon occurrence orawareness to determine whether the participant should continue or discontinue study
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential
and required for study conduct.

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All screening evaluations must be completed and reviewed to confirm that potential
participants meet all eligibility criteria. The investigator will maintain a screening log torecord details of all participants screened and to confirm eligibility or record reasons forscreening failure, as applicable.
Every effort should be made to ensure that protocol-required tests and procedures arecompleted as described. However, it is anticipated that from time to time there may becircumstances outside the control of the investigator that may make it unfeasible to performthe test. In these cases, the investigator must take all steps necessary to ensure the safety andwell-being of the participant. When a protocol-required test cannot be performed, theinvestigator will document the reason for the missed test and any corrective and preventive
actions that he or she has taken to ensure that required processes are adhered to as soon as
possible. The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, andshipment instructions and contact information will be provided to the investigator site prior
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately up
to: 515 mL for participants in Phase 1, 110 mL for Phase 2/3 participants ≥16 years of age,and 50 mL for participants in the 12- to 15-year age stratum. Additionally, 20 mL of bloodfor participants ≥16 years of age and 10 mL for participants in the 12- to 15-year age stratum
will be taken at an unplanned convalescent visit at any time a participant develops respiratory
symptoms indicating a potential COVID-19 infection. Select participants in Phase 1 will also
be asked to provide an additional blood sample of approximately 170 mL at either Visit 5, 6,
or 7. These participants would therefore have a total blood sampling volume of 700 mL
during the 24-month study period. Other additional blood samples may be taken for safetyassessments at times specified by Pfizer, provided the total volume taken during the study
does not exceed 550 mL during any period of 60 consecutive days.
8.1. Efficacy and/or Immunogenicity Assessments
Efficacy will be assessed throughout a participant’s involvement in the study throughsurveillance for potential cases of COVID-19. If, at any time, a participant develops acuterespiratory illness (see Section 8.13), for the purposes of the study he or she will beconsidered to potentially have COVID-19 illness.9 In this circumstance, the participant
should contact the site, an in-person or telehealth visit should occur, and assessments should
be conducted as specified in the SoA. The assessments will include a nasal (midturbinate)swab, which will be tested at a central laboratory using a reverse transcription–polymerase
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chain reaction (RT-PCR) test (Cepheid; FDA approved under EUA), or other equivalent
nucleic acid amplification–based test (ie, NAAT), to detect SARS-CoV-2. In addition,clinical information and results from local standard-of-care tests (as detailed in Section 8.13)
will be assessed. The central laboratory NAAT result will be used for the case definition,
unless no result is available from the central laboratory, in which case a local NAAT result
may be used if it was obtained using 1 of the following assays:


Cepheid Xpert Xpress SARS-CoV-2



Roche cobas SARS-CoV-2 real-time RT-PCR test (EUA200009/A001)



Abbott Molecular/RealTime SARS-CoV-2 assay (EUA200023/A001)

Two definitions of SARS-CoV-2–related cases, and SARS-CoV-2–related severe cases, will
be considered (for both, the onset date of the case will be the date that symptoms were firstexperienced by the participant; if new symptoms are reported within 4 days after resolutionof all previous symptoms, they will be considered as part of a single illness):

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Confirmed COVID-19: presence of at least 1 of the following symptoms and
SARS-CoV-2 NAAT-positive during, or within 4 days before or after, thesymptomatic period, either at the central laboratory or at a local testing facility (using
an acceptable test):Fever;

New or increased cough;

New or increased shortness of breath;Chills;

New or increased muscle pain;New loss of taste or smell;

Sore throat;

Diarrhea;Vomiting.

The second definition, which may be updated as more is learned about COVID-19, will
include the following additional symptoms defined by the CDC (listed athttps://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html):


Fatigue;
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Nasal congestion or runny nose;Nausea.

Confirmed severe COVID-19: confirmed COVID-19 and presence of at least 1 of thefollowing:Clinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per
minute, HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or
PaO2/FiO2 <300 mm Hg);

Respiratory failure (defined as needing high-flow oxygen, noninvasive
ventilation, mechanical ventilation, or ECMO);

Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiringvasopressors);

Significant acute renal, hepatic, or neurologic dysfunction*;Admission to an ICU;Death.

The DMC may recommend modification of the definition of severe disease according toemerging information.
* Three blinded case reviewers (medically qualified Pfizer staff members) will review all
potential COVID-19 illness events. If a NAAT-confirmed case in Phase 2/3 may beconsidered severe, or not, solely on the basis of this criterion, the blinded data will be
reviewed by the case reviewers to assess whether the criterion is met; the majority opinion
will prevail.
In addition, a serological definition will be used for participants without clinical presentationof COVID-19:


Confirmed seroconversion to SARS-CoV-2 without confirmed COVID-19: positive
N-binding antibody result in a participant with a prior negative N-binding antibody
resultSerum samples will be obtained for immunogenicity testing at the visits specified in the SoA.
The following assays will be performed:

SARS-CoV-2 neutralization assay

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

S1-binding IgG level assay

RBD-binding IgG level assay

N-binding antibody assay

Note that all immunogenicity analyses will be based upon samples analyzed at the central
laboratory; the rapid test will only be performed at screening by all sites recruiting
participants in Phase 1 (see Section 8.11.1.1) to determine eligibility.
Serum obtained from the additional ~170-mL blood sample from select participants in Phase
1 at either Visit 5, 6, or 7 will be used for exploratory COVID-19 research, intended toestablish a surrogate endpoint that is reasonably likely to predict clinical benefit.

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8.1.1. Biological Samples
Blood and nasal swab samples will be used only for scientific research. Each sample will belabeled with a code so that the laboratory personnel testing the samples will not know theparticipant’s identity. Samples that remain after performing assays outlined in the protocol
may be stored by Pfizer. Unless a time limitation is required by local regulations or ethicalrequirements, the samples will be stored for up to 15 years after the end of the study and thendestroyed. If allowed by the ICD, stored samples may be used for additional testing to better
understand the immune responses to the vaccine(s) under study in this protocol, to inform thedevelopment of other products, and/or for vaccine-related assay work supporting vaccine
programs. No testing of the participant’s DNA will be performed.
The participant may request that his or her samples, if still identifiable, be destroyed at any
time; however, any data already collected from those samples will still be used for thisresearch. The biological samples may be shared with other researchers as long asconfidentiality is maintained and no testing of the participant’s DNA is performed.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinicallaboratory measurements may be obtained at any time during the study to assess any
perceived safety issues.
A clinical assessment, including medical history, will be performed on all participants at
his/her first visit to establish a baseline. Significant medical history and observations fromany physical examination, if performed, will be documented in the CRF.
AEs and SAEs are collected, recorded, and reported as defined in Section 8.3.
Acute reactions within the first 4 hours after administration of the study intervention (for the
first 5 participants vaccinated in each Phase 1 group), and within the first 30 minutes (for theremainder of participants), will be assessed and documented in the AE CRF.

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The safety parameters also include reactogenicity e-diary reports of local reactions andsystemic events (including fever), and use of antipyretic medication that occur in the 7 days
after administration of the study intervention in a subset of participants. These prospectively
self-collected occurrences of local reactions and systemic events are graded as described in
Section 8.2.2. For participants who are not in the reactogenicity subset, these local reactions
and systemic events should be detected and reported as AEs, in accordance with
Section 8.3.2.
8.2.1. Clinical Safety Laboratory Assessments (Phase 1 Participants Only)

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See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for
the timing and frequency. All protocol-required laboratory assessments, as defined inAppendix 2, must be conducted in accordance with the laboratory manual and the SoA.
Unscheduled clinical laboratory measurements may be obtained at any time during the study
to assess any perceived safety issues.
The investigator must review the laboratory report, document this review, and record any
clinically relevant changes occurring during the study in the AE section of the CRF. See
Appendix 2 for the grading scale for assessment of clinically significant abnormal laboratory
findings. Clinically significant abnormal laboratory findings are those which are notassociated with the underlying disease, unless judged by the investigator to be more severe
than expected for the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during
participation in the study or within 28 days after the last dose of study intervention should be
repeated until the values return to normal or baseline or are no longer considered clinicallysignificant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 5 for suggested actions and follow-up assessments in the event of potential
drug-induced liver injury (DILI).
8.2.2. Electronic Diary
Participants will be required to complete a reactogenicity e-diary through an application(see Section 8.14) installed on a provisioned device or on the participant’s own personal
device. All participants in Phase 1, and a subset of at least the first 6000 randomized inPhase 2/3, will be asked to monitor and record local reactions, systemic events, andantipyretic medication usage for 7 days following administration of the study intervention.
All participants in Phase 3 who are HIV-positive or 12 to 15 years of age will be included inthis subset. In addition, participants 16 through 17 years of age enrolled under protocol
amendment 9 and onwards will be included in the reactogenicity subset. The reactogenicity
e-diary allows recording of these assessments only within a fixed time window, thus
providing the accurate representation of the participant’s experience at that time. Data on
local reactions and systemic events reported in the reactogenicity e-diary will be transferred
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electronically to a third-party vendor, where they will be available for review by investigatorsand the Pfizer clinicians at all times via an internet-based portal.
At intervals agreed to by the vendor and Pfizer, these data will be transferred electronicallyinto Pfizer's database for analysis and reporting. These data do not need to be reported by theinvestigator in the CRF as AEs.
Investigators (or designee) will be required to review the reactogenicity e-diary data online atfrequent intervals as part of the ongoing safety review.
The investigator or designee must obtain stop dates from the participant for any ongoing
local reactions, systemic events, or use of antipyretic medication on the last day that thereactogenicity e-diary was completed. The stop dates should be documented in the source
documents and the information entered in the CRF.

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8.2.2.1. Grading Scales
The grading scales used in this study to assess local reactions and systemic events as
described below are derived from the FDA Center for Biologics Evaluation and Research(CBER) guidelines on toxicity grading scales for healthy adult volunteers enrolled inpreventive vaccine clinical trials.8
8.2.2.2. Local Reactions
During the reactogenicity e-diary reporting period, participants will be asked to assess
redness, swelling, and pain at the injection site and to record the symptoms in thereactogenicity e-diary. If a local reaction persists beyond the end of the reactogenicity
e-diary period following vaccination, the participant will be requested to report that
information. The investigator will enter this additional information in the CRF.
Redness and swelling will be measured and recorded in measuring device units(range: 1 to 21) and then categorized during analysis as absent, mild, moderate, or severe
based on the grading scale in Table 1. Measuring device units can be converted tocentimeters according to the following formula: 1 measuring device unit = 0.5 cm. Pain at
the injection site will be assessed by the participant as absent, mild, moderate, or severe
according the grading scale in Table 1.
If a Grade 3 local reaction is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinicallyindicated. Only an investigator or medically qualified person is able to classify aparticipant’s local reaction as Grade 4. If a participant experiences a confirmed Grade 4 local
reaction, the investigator must immediately notify the sponsor and, if it is determined to berelated to the administration of the study intervention, further vaccinations will be
discontinued in that participant.

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Table 1.

Local Reaction Grading Scale
Mild(Grade 1)

Moderate(Grade 2)

Severe(Grade 3)

Pain at the
injection site

Does not interferewith activity

Interferes withactivity

Redness>2.0 cm to 5.0 cm(5 to 10 measuring
device units)>2.0 cm to 5.0 cm(5 to 10 measuring
device units)>5.0 cm to 10.0 cm(11 to 20 measuring
device units)>5.0 cm to 10.0 cm(11 to 20 measuring
device units)

Swelling

Potentially Life
Threatening(Grade 4)
Prevents daily activity Emergency room visit
or hospitalization forsevere pain
>10 cmNecrosis or(≥21 measuringexfoliative dermatitis
device units)>10 cmNecrosis(≥21 measuring
device units)

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8.2.2.3. Systemic Events
During the reactogenicity e-diary reporting period, participants will be asked to assess
vomiting, diarrhea, headache, fatigue, chills, new or worsened muscle pain, and new orworsened joint pain and to record the symptoms in the reactogenicity e-diary. The symptoms
will be assessed by the participant as absent, mild, moderate, or severe according to thegrading scale in Table 2.
If a Grade 3 systemic event is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinicallyindicated. Only an investigator or medically qualified person is able to classify aparticipant’s systemic event as Grade 4. If a participant experiences a confirmed Grade 4
systemic event, the investigator must immediately notify the sponsor and, if it is determined
to be related to the administration of the study intervention, further vaccinations will be
discontinued in that participant.
Table 2.

Systemic Event Grading Scale
Mild(Grade 1)

Moderate(Grade 2)>2 times in
24 hours

Severe(Grade 3)

Vomiting

1-2 times in
24 hours

Requires IV
hydration

Diarrhea

2 to 3 loose stools 4 to 5 loose stools
in 24 hours
in 24 hours

6 or more loosestools in 24 hours

Headache

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Fatigue/tiredness

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Potentially Life
Threatening(Grade 4)
Emergency room visit or
hospitalization for
hypotensive shock
Emergency room visit or
hospitalization for severe
diarrhea
Emergency room visit or
hospitalization for severe
headache
Emergency room visit or
hospitalization for severe
fatigue

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Table 2.

Systemic Event Grading Scale
Mild(Grade 1)

Moderate(Grade 2)

Severe(Grade 3)

Chills

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

New orworsened
muscle pain

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

New or
Does not interfere Some interference
worsenedwith activity
with activity
joint pain
Abbreviation: IV = intravenous.

Prevents daily
routine activity

Potentially Life
Threatening(Grade 4)
Emergency room visit or
hospitalization for severe
chillsEmergency room visit or
hospitalization for severe
new or worsened muscle
painEmergency room visit or
hospitalization for severe
new or worsened joint pain

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8.2.2.4. Fever
In order to record information on fever, a thermometer will be given to participants with
instructions on how to measure oral temperature at home. Temperature will be collected in
the reactogenicity e-diary in the evening daily during the reactogenicity e-diary reporting
period. It will also be collected at any time during the reactogenicity e-diary data collection
periods when fever is suspected. Fever is defined as an oral temperature of ≥38.0°C(100.4°F). The highest temperature for each day will be recorded in the reactogenicity
e-diary. Temperature will be measured and recorded to 1 decimal place and then categorized
during analysis according to the scale shown in Table 3.
If a fever of ≥39.0°C (102.1°F) is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinicallyindicated. Only an investigator or medically qualified person is able to confirm aparticipant’s fever as >40.0°C (>104.0°F). If a participant experiences a confirmed fever>40.0°C (>104.0°F), the investigator must immediately notify the sponsor and, if it isdetermined to be related to the administration of the study intervention, further vaccinations
will be discontinued in that participant.
Table 3.

Scale for Fever≥38.0-38.4°C (100.4-101.1°F)>38.4-38.9°C (101.2-102.0°F)>38.9-40.0°C (102.1-104.0°F)>40.0°C (>104.0°F)

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8.2.2.5. Antipyretic Medication
The use of antipyretic medication to treat symptoms associated with study intervention
administration will be recorded in the reactogenicity e-diary daily during the reporting period(Day 1 to Day 7).
8.2.3. Phase 1 Stopping Rules
The following stopping rules are in place for all Phase 1 participants, based on review of AE
data and e-diary reactogenicity data, until the start of Phase 2/3 or 30 days after the last doseof study intervention in Phase 1, whichever is later. These data will be monitored on an
ongoing basis by the investigator (or medically qualified designee) and sponsor in order topromptly identify and flag any event that potentially contributes to a stopping rule.
The sponsor study team will be unblinded during Phase 1, so will be able to assess whether
or not a stopping rule has been met on the basis of a participant’s individual study
intervention allocation.

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In the event that sponsor personnel confirm that a stopping rule is met, the following actions
will commence:The IRC will review all appropriate data.

The stopping rule will PAUSE randomization and study intervention administration
for the impacted vaccine candidate all dose levels and age groups.



The DMC will review all appropriate data.

For all participants vaccinated, all other routine study conduct activities, including
ongoing data entry, reporting of AEs, participant reactogenicity e-diary completion,
blood sample collection, and participant follow-up, will continue during the pause.

A stopping rule is met if any of the following rules occur after administration of
investigational BNT162 vaccine; data from placebo recipients will not contribute to thestopping rules. Reactogenicity e-diary data confirmed by the investigator as being entered by
the participant in error will not contribute toward a stopping rule.
The BNT162b RNA platform will be evaluated for contribution to stopping rules overall;
vaccine candidate dose levels within the platform and age groups will contribute to stopping
rules together. However, it is possible that the recommendations may include halting or
continuing randomization with any of the BNT162 vaccine candidates.
Stopping Rule Criteria for Each BNT162 Vaccine Candidate:
1. If any participant vaccinated with the BNT162 candidate (at any dose level) develops an
SAE that is assessed by the investigator as possibly related, or for which there is noalternative, plausible, attributable cause.
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2. If any participant vaccinated with the BNT162 candidate (at any dose level) develops a
Grade 4 local reaction or systemic event after vaccination (see Section 8.2.2) that is
assessed as possibly related by the investigator, or for which there is no alternative,plausible, attributable cause.
3. If any participant vaccinated with the BNT162 candidate (at any dose level) develops afever >40.0°C (>104.0°F) for at least 1 daily measurement after vaccination(see Section 8.2.2.4) that is assessed as possibly related by the investigator, or for which
there is no alternative, plausible, attributable cause.
4. If any 2 participants vaccinated with the BNT162 candidate (at any dose level) report thesame or similar severe (Grade 3) AE (including laboratory abnormalities) after
vaccination, assessed as possibly related by the investigator, or for which there is noalternative, plausible, attributable cause.

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5. If any participant dies or requires ICU admission due to SARS-CoV-2 infection; if thisstopping rule is met, all available clinical and preclinical safety and immunogenicity data
should be reviewed to evaluate for enhanced COVID-19.
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19 and Phase 2/3
Stopping Rule
Participants in all phases of the study will be surveilled for potential COVID-19 illness from
Visit 1 onwards (see Section 8.13).
As this is a sponsor open-label study during Phase 1, the sponsor will conduct unblinded
reviews of the data during the course of the study, including for the purpose of safetyassessment. All NAAT-confirmed cases in Phase 1 will be reviewed contemporaneously by
the IRC and the DMC (see Section 9.6).
In Phase 2/3, the unblinded team supporting the DMC, including an unblinded medical
monitor, will review cases of severe COVID-19 as they are received and will review AEs atleast weekly for additional potential cases of severe COVID-19. At any point, the unblinded
team may discuss with the DMC chair whether the DMC should review cases for an adverse
imbalance of cases of COVID-19 and/or severe COVID-19 between the vaccine and placebogroups.
The purpose of these reviews will be to identify whether any features of each case appear
unusual, in particular greater in severity, compared to available information at the time ofreview. Indicators of severity may include accelerated deterioration, need for hospitalization,need for ventilation, or death. Observed rates of these indicators will be compared with what
could be expected in a similar population to the study participants based upon available
information at the time of review.
Stopping and alert rules will be applied as follows. The stopping rule will be triggered whenthe 1-sided probability of observing the same or a more extreme case split is 5% or less when
the true incidence of severe disease is the same for vaccine and placebo participants, and alert
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criteria are triggered when this probability is less than 11%. In addition, when the total
number of severe cases is low (15 or less), the unblinded team supporting the DMC will
implement the alert rule when a reverse case split of 2:1 or worse is observed. For example,
at 3 cases 2:1, at 4 cases 3:1, etc. Below 15 cases, this rule is more rigorous than requiring
the probability of an observed adverse split or worse be <11%. Further details can be foundin Section 10.7.
8.2.5. Randomization and Vaccination After a Stopping Rule Is Met
Once the IRC (if in Phase 1) and DMC (all phases) have reviewed the safety data andprovided guidance, a notification will be sent from the sponsor to the sites with guidance on
how to proceed.

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8.2.6. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA,
immediately before the administration of each vaccine dose. A negative pregnancy test result
will be required prior to the participant’s receiving the study intervention. Pregnancy tests
may also be repeated if requested by IRBs/ECs or if required by local regulations. In thecase of a positive confirmed pregnancy, the participant will be withdrawn fromadministration of study intervention but may remain in the study.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or
the participant's parent(s)/legal guardian).
The investigator and any qualified designees are responsible for detecting, documenting, andrecording events that meet the definition of an AE or SAE and remain responsible to pursue
and obtain adequate information both to determine the outcome and to assess whether the
event meets the criteria for classification as an SAE or caused the participant to discontinue
the study intervention (see Section 7.1).
Each participant/parent(s)/legal guardian will be questioned about the occurrence of AEs in anonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection
period”) for each participant begins from the time the participant/parent(s)/legal guardian
provides informed consent, which is obtained before the participant’s participation in the
study (ie, before undergoing any study-related procedure and/or receiving study
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intervention), through and including Visit 7 for Phase 1 participants, and Visit 3 for Phase
2/3 participants. In addition, any AEs occurring up to 48 hours after each subsequent blooddraw must be recorded on the CRF.
SAEs will be collected from the time the participant/parent(s)/legal guardian provides
informed consent to approximately 6 months after the last dose of study intervention (Visit 8
for Phase 1 participants, and Visit 4 for Phase 2/3 participants).
Follow-up by the investigator continues throughout and after the active collection period anduntil the AE or SAE or its sequelae resolve or stabilize at a level acceptable to theinvestigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure
status is determined.

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If the participant withdraws from the study and also withdraws consent for the collection of
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervention
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE
reported using the Vaccine SAE Report Form.
Investigators are not obligated to actively seek AEs or SAEs after the participant has
concluded study participation. However, if the investigator learns of any SAE, including adeath, at any time after a participant has completed the study, and he/she considers the event
to be reasonably related to the study intervention, the investigator must promptly report the
SAE to Pfizer using the Vaccine SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in
Section 8.3.1 are reported to Pfizer Safety on the Vaccine SAE Report Form immediately
upon awareness and under no circumstance should this exceed 24 hours, as indicated inAppendix 3. The investigator will submit any updated SAE data to the sponsor within
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period,
which begins after obtaining informed consent as described in Section 8.3.1, will be recordedon the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported
AEs and SAEs reported by the participant.

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8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and theprocedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended andnonleading verbal questioning of the participant is the preferred method to inquire about
AE occurrences.
8.3.3. Follow-up of AEs and SAEs

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After the initial AE/SAE report, the investigator is required to proactively follow eachparticipant at subsequent visits/contacts. For each event, the investigator must pursue andobtain adequate information until resolution, stabilization, the event is otherwise explained,or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail toallow for a complete medical assessment of the case and independent determination of
possible causality. Any information relevant to the event, such as concomitant medications
and illnesses, must be provided. In the case of a participant death, a summary of available
autopsy findings must be submitted as soon as possible to Pfizer Safety.
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal
obligations and ethical responsibilities towards the safety of participants and the safety of astudy intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and otherregulatory agencies about the safety of a study intervention under clinical investigation. The
sponsor will comply with country-specific regulatory requirements relating to safety
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding andoccupational exposure are reportable to Pfizer Safety within 24 hours of investigatorawareness.

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8.3.5.1. Exposure During Pregnancy

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)An EDP occurs if:A female participant is found to be pregnant while receiving or after discontinuing
study intervention.



A male participant who is receiving or has discontinued study intervention exposes afemale partner prior to or around the time of conception.



A female is found to be pregnant while being exposed or having been exposed to
study intervention due to environmental exposure. Below are examples ofenvironmental exposure during pregnancy:

A female family member or healthcare provider reports that she is pregnant after
having been exposed to the study intervention by inhalation or skin contact.

A male family member or healthcare provider who has been exposed to the study
intervention by inhalation or skin contact then exposes his female partner prior to
or around the time of conception.

The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s
awareness, irrespective of whether an SAE has occurred. The initial information submitted
should include the anticipated date of delivery (see below for information related totermination of pregnancy).


If EDP occurs in a participant or a participant’s partner, the investigator must report
this information to Pfizer Safety on the Vaccine SAE Report Form and an EDP
Supplemental Form, regardless of whether an SAE has occurred. Details of thepregnancy will be collected after the start of study intervention and until 6 months
after the last dose of study intervention.



If EDP occurs in the setting of environmental exposure, the investigator must report
information to Pfizer Safety using the Vaccine SAE Report Form and EDP
Supplemental Form. Since the exposure information does not pertain to theparticipant enrolled in the study, the information is not recorded on a CRF; however,a copy of the completed Vaccine SAE Report Form is maintained in the investigatorsite file.

Follow-up is conducted to obtain general information on the pregnancy and its outcome for
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as afollow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural
integrity of the neonate can be assessed at the time of birth. In the event of a termination, thereason(s) for termination should be specified and, if clinically possible, the structural
integrity of the terminated fetus should be assessed by gross visual inspection (unless
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preprocedure test findings are conclusive for a congenital anomaly and the findings arereported).

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Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meetsthe criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal
demise, neonatal death, or congenital anomaly), the investigator should follow the procedures
for reporting SAEs. Additional information about pregnancy outcomes that are reported to
Pfizer Safety as SAEs follows:

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as
SAEs when the investigator assesses the infant death as related or possibly related to
exposure to the study intervention.

Additional information regarding the EDP may be requested by the sponsor. Further
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on
preterm infants to identify developmental delays). In the case of paternal exposure, theinvestigator will provide the participant with the Pregnant Partner Release of Information
Form to deliver to his partner. The investigator must document in the source documents thatthe participant was given the Pregnant Partner Release of Information Form to provide to his
partner.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if:A female participant is found to be breastfeeding while receiving or after
discontinuing study intervention.



A female is found to be breastfeeding while being exposed or having been exposed to
study intervention (ie, environmental exposure). An example of environmental
exposure during breastfeeding is a female family member or healthcare provider who
reports that she is breastfeeding after having been exposed to the study intervention
by inhalation or skin contact.

The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hoursof the investigator’s awareness, irrespective of whether an SAE has occurred. The
information must be reported using the Vaccine SAE Report Form. When exposure during
breastfeeding occurs in the setting of environmental exposure, the exposure information does
not pertain to the participant enrolled in the study, so the information is not recorded on a
CRF. However, a copy of the completed Vaccine SAE Report Form is maintained in theinvestigator site file.

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An exposure during breastfeeding report is not created when a Pfizer drug specificallyapproved for use in breastfeeding women (eg, vitamins) is administered in accord withauthorized use. However, if the infant experiences an SAE associated with such a drug, theSAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with thestudy intervention, which may or may not lead to the occurrence of an AE. Such persons
may include healthcare providers, family members, and other roles that are involved in thetrial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of theinvestigator’s awareness, regardless of whether there is an associated SAE. The informationmust be reported using the Vaccine SAE Report Form. Since the information does not
pertain to a participant enrolled in the study, the information is not recorded on a CRF;
however, a copy of the completed Vaccine SAE Report Form is maintained in theinvestigator site file.

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8.3.6. Cardiovascular and Death Events
Not applicable.
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs
or SAEs
Potential COVID-19 illnesses and their sequelae that are consistent with the clinical endpoint
definition should not be recorded as AEs. These data will be captured as efficacy assessment
data only on the relevant pages of the CRF, as these are expected endpoints.
Potential COVID-19 illnesses and their sequelae will not be reported according to thestandard process for expedited reporting of SAEs, even though the event may meet thedefinition of an SAE. These events will be recorded on the COVID-19 illness pages in theparticipant’s CRF within 1 day.
NOTE: However, if either of the following conditions applies, then the event must berecorded and reported as an SAE (instead of a disease-related event):
The event is, in the investigator’s opinion, of greater intensity, frequency, or duration than
expected for the individual participant.
OR
The investigator considers that there is a reasonable possibility that the event was related to
study intervention.
Potential COVID-19 illness events and their sequelae will be reviewed by a group of internal
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meet endpoint criteria is reported back to the investigator site of incidence. The investigatormust report the SAE to Pfizer Safety within 24 hours of being made aware that the SAE did
not meet endpoint criteria. The investigator’s SAE awareness date is the date on which theinvestigator site of incidence receives the SAE back from the internal case reviewers.
8.3.8. Adverse Events of Special Interest
Not applicable.
8.3.8.1. Lack of Efficacy
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.
8.3.9. Medical Device Deficiencies
Not applicable.
8.3.10. Medication Errors

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Medication errors may result from the administration or consumption of the study
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as
medication errors.
Safety Event

Recorded on the CRF

Reported on the Vaccine SAE Report
Form to Pfizer Safety Within 24 Hours
of Awareness

Medication errors

All (regardless of whether
associated with an AE)

Only if associated with an SAE

Medication errors include:Medication errors involving participant exposure to the study intervention;Potential medication errors or uses outside of what is foreseen in the protocol that do
or do not involve the study participant;The administration of expired study intervention;

The administration of an incorrect study intervention;

The administration of an incorrect dosage;

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The administration of study intervention that has undergone temperature excursion
from the specified storage range, unless it is determined by the sponsor that the study
intervention under question is acceptable for use.

Such medication errors occurring to a study participant are to be captured on the medication
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by theinvestigator, the medication error is recorded on the medication error page of the CRF and, if
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a Vaccine SAE
Report Form only when associated with an SAE.

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8.4. Treatment of Overdose
For this study, any dose of study intervention greater than 1 dose of study intervention within
a 24-hour time period will be considered an overdose.
Pfizer does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs.
3. Document the quantity of the excess dose as well as the duration of the overdose in the
CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7. Genetics
Genetics (specified analyses) are not evaluated in this study.
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8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.9. Immunogenicity Assessments
Immunogenicity assessments are described in Section 8.1.
8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are notevaluated in this study.
8.11. Study Procedures
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8.11.1.1. Screening: (0 to 28 Days Before Visit 1)
Before enrollment and before any study-related procedures are performed, voluntary, written
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.
It is anticipated that the procedures below will be conducted in a stepwise manner; however,the visit can occur over more than 1 day.
Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance.

Obtain details of any medications currently taken.

Perform physical examination including vital signs (weight, height, body temperature,pulse rate, and seated blood pressure), evaluating any clinically significant
abnormalities within the following body systems: general appearance; skin; head,eyes, ears, nose, and throat; heart; lungs; abdomen; musculoskeletal; extremities;
neurological; and lymph nodes.

Collect a blood sample (approximately 20 mL) for potential future serologicalassessment and to perform a rapid test for prior COVID-19 infection.

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

Collect a blood sample (approximately 10 mL) for hematology and chemistrylaboratory tests as described in Section 10.2.

Collect a blood sample (approximately 10 mL) for HIV, HBsAg, HBc Ab, and HCV
Ab tests.



Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion
criteria are met.



Record AEs as described in Section 8.3. AEs that occur prior to dosing should be
noted on the Medical History CRF.



Ask the participant to contact the site staff or investigator immediately if any
significant illness or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

Complete the CRF.

8.11.1.2. Visit 1 – Vaccination 1: (Day 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.
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

Record nonstudy vaccinations as described in Section 6.5.



Review screening laboratory results (hematology and chemistry, and HIV, HBsAg,
HBc Ab, and HCV Ab tests).

Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested(if possible at the site, otherwise at the central laboratory) within 24 hours andvaccination will proceed only if it is NAAT-negative for SARS-CoV-2 genomes.
The second will be sent to the central laboratory for potential later testing.

Ensure and document that all of the inclusion criteria and none of the exclusion
criteria are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Obtain the participant’s randomization number and study intervention allocation
using the IRT system. Only an unblinded site staff member may obtain thisinformation.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention
into the deltoid muscle of the preferably nondominant arm. Please refer to the IP
manual for further instruction on this process.



The first 5 participants vaccinated in each group must be observed by blinded site
staff for any acute reactions for at least 4 hours after vaccination. For participants
enrolled thereafter, blinded site staff must observe the participant for at least 30
minutes after study intervention administration for any acute reactions. Record any
acute reactions (including time of onset) in the participant’s source documents and on
the AE page of the CRF, and on an SAE form as applicable.

Issue a measuring device to measure local reactions at the injection site and athermometer for recording daily temperatures and provide instructions on their use.



Explain the e-diary technologies available for this study (see Section 8.14), and assist
the participant in downloading the study application onto the participant’s own device
or issue a provisioned device if required. Provide instructions on e-diary completion
and ask the participant to complete the reactogenicity e-diary from Day 1 to Day 7,
with Day 1 being the day of vaccination and, if utilized, the COVID-19 illness e-diary(to be completed if the participant is diagnosed with COVID-19 or has possible new
or increased symptoms, and when he/she receives a reminder, at least weekly).

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Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1
is the day of vaccination) to determine if an unscheduled reactogenicity visit isrequired:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the reactogenicity
e-diary data online following vaccination to evaluate participant compliance and as
part of the ongoing safety review. Daily review is optimal during the active diary
period.

8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1 to 3 Days After Visit 1)

Record AEs as described in Section 8.3.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

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

Collect a blood sample (approximately 10 mL) for hematology and chemistrylaboratory tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1
is the day of vaccination) to determine if an unscheduled reactogenicity visit isrequired:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the reactogenicity ediary data online following vaccination to evaluate participant compliance and as partof the ongoing safety review. Daily review is optimal during the active diary period.

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8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to 8 Days After Visit 1)

Record AEs as described in Section 8.3.



Review hematology and chemistry laboratory results and record any AEs inaccordance with Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistrylaboratory tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1
is the day of vaccination) to determine if an unscheduled reactogenicity visit isrequired:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

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Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the reactogenicity ediary data online following vaccination to evaluate participant compliance and as partof the ongoing safety review. Daily review is optimal during the active diary period.

8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1)

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It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary
was completed and record stop dates in the CRF if required.



Review hematology and chemistry laboratory results and record any AEs inaccordance with Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested (ifpossible at the site, otherwise at the central laboratory) within 24 hours andvaccination will only proceed if it is NAAT-negative for SARS-CoV-2 genomes.
The second will be sent to the central laboratory for potential later testing.
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Ensure and document that all of the inclusion criteria and none of the exclusion
criteria are met. If not, the participant should not receive further study intervention
but will remain in the study to be evaluated for safety, immunogenicity, and efficacy(see Section 7.1).

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Collect a blood sample (approximately 10 mL) for hematology and chemistrylaboratory tests as described in Section 10.2.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention
into the deltoid muscle of the preferably nondominant arm. Please refer to the IP
manual for further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of
the CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the
injection site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and ask the participant to complete thereactogenicity e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1
is the day of vaccination) to determine if an unscheduled reactogenicity visit isrequired:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.

Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.
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

Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the reactogenicity
e-diary data online following vaccination to evaluate participant compliance and as
part of the ongoing safety review. Daily review is optimal during the active diary
period.

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8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to 8 Days After Visit 4)

Record AEs as described in Section 8.3.



Review hematology and chemistry laboratory results and record any AEs inaccordance with Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistrylaboratory tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



If the participant (select participants only, details will be provided by the sponsor)
consents, collect an additional 170 mL blood sample for exploratory COVID-19
research.
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Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1
is the day of vaccination) to determine if an unscheduled reactogenicity visit isrequired:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the reactogenicity
e-diary data online following vaccination to evaluate participant compliance and as
part of the ongoing safety review. Daily review is optimal during the active diary
period.

8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to 16 Days After Visit 4)

Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary
was completed and record stop dates in the CRF if required.



Review hematology and chemistry laboratory results and record any AEs inaccordance with Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform a
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physical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.


Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



If not collected at Visit 5, and the participant (select participants only, details will be
provided by the sponsor) consents, collect an additional 170-mL blood sample for
exploratory COVID-19 research.



Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately (this could be
via the COVID-19 illness e-diary) if he or she experiences any respiratory symptoms
as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After Visit 4)

Record AEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



If not collected at Visit 5 or 6, and the participant (select participants only, details will
be provided by the sponsor) consents, collect an additional 170-mL blood sample for
exploratory COVID-19 research.
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

Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (175 to 189 Days After Visit 4)

Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Collect a blood sample (approximately 20 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.1.10. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 4)Collect a blood sample (approximately 20 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

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

Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.1.11. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 4)Collect a blood sample (approximately 20 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Collect the participant’s e-diary or assist the participant to remove the study
application from his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.2. Phase 2/3
8.11.2.1. Visit 1 – Vaccination 1: (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written,
study-specific informed consent will be obtained from the participant or his/herparent(s)/legal guardian, as appropriate. Each signature on the ICD must be personally dated
by the signatory. The investigator or his or her designee will also sign the ICD. A copy ofthe signed and dated ICD must be given to the participant/participant’s parent(s)/legal
guardian. The source data must reflect that the informed consent was obtained before
participation in the study.
It is anticipated that the procedures below will be conducted in a stepwise manner. The visit
may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion andexclusion criteria onwards must be conducted on the same day.
Assign a single participant number using the IRT system.
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Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance. For participants who are
HIV-positive, record HIV viral load and CD4 count results from the most recent test
performed in the previous 6 months.



Perform a clinical assessment. If the clinical assessment indicates that a physicalexamination is necessary to comprehensively evaluate the participant, perform aphysical examination and record any findings in the source documents and, if
clinically significant, record on the medical history CRF.

Measure the participant’s height and weight.

Measure the participant’s body temperature.

Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion
criteria are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.



Record AEs as described in Section 8.3.

Collect a blood sample (approximately 20 mL for participants ≥16 years of age andapproximately 10 mL for participants in the 12- to 15-year age stratum) for
immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Obtain the participant’s randomization number and study intervention allocation
number using the IRT system. Only an unblinded site staff member may obtain thisinformation.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention
into the deltoid muscle of the preferably nondominant arm. Please refer to the IP
manual for further instruction on this process.

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Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of
the CRF, and on an SAE form as applicable.

For participants in the reactogenicity subset, issue a measuring device to measure
local reactions at the injection site and a thermometer for recording daily
temperatures and provide instructions on their use.

For participants not in the reactogenicity subset, issue a thermometer to monitor for
fever (for COVID-19 surveillance) and provide instructions on its use.



Explain the e-diary technologies available for this study (see Section 8.14), and assist
the participant or his/her parent(s)/legal guardian, as appropriate, in downloading thestudy application onto the participant’s own device or issue a provisioned device if
required.

For participants in the reactogenicity subset, provide instructions onreactogenicity e-diary completion and ask the participant or his/her parent(s)/legal
guardian, as appropriate, to complete the reactogenicity e-diary from Day 1 to
Day 7, with Day 1 being the day of vaccination.

For all participants, provide instructions on COVID-19 illness e-diary completion
and ask the participant or his/her parent(s)/legal guardian, as appropriate, tocomplete the COVID-19 illness e-diary if the participant is diagnosed with
COVID-19 or has possible new or increased symptoms, and when he/she receivesa reminder, at least weekly. See Section 8.14 for further details.

If the participant is part of the reactogenicity subset, ask the participant or his/herparent(s)/legal guardian, as appropriate, to contact the site staff or investigator
immediately if the participant experiences any of the following from Day 1 to Day 7
after vaccination (where Day 1 is the day of vaccination) to determine if anunscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator if a medically attended event (eg, doctor’s visit, emergency
room visit) or hospitalization occurs.
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

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator (this could be via the COVID-19 illness e-diary) immediately
if he or she experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant or his/her parent(s)/legal guardian, as appropriate, to bring thee-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.

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If the participant is part of the reactogenicity subset, the investigator or appropriately
qualified designee reviews the reactogenicity e-diary data online following vaccination toevaluate participant compliance and as part of the ongoing safety review. Daily review is
optimal during the active diary period.
8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days After Visit 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



If the participant is part of the reactogenicity subset, review the participant’s
reactogenicity e-diary data. Collect stop dates of any reactogenicity e-diary events
ongoing on the last day that the reactogenicity e-diary was completed and record stop
dates in the CRF if required.



Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Ensure and document that all of the inclusion criteria and none of the exclusion
criteria are met. If not, the participant may not receive further study intervention but
will remain in the study to be evaluated for safety, immunogenicity, and efficacy(see Section 7.1).

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

Measure the participant’s body temperature.

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention
into the deltoid muscle of the preferably nondominant arm. Please refer to the IP
manual for further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of
the CRF, and on an SAE form as applicable.

Ensure the participant or his/her parent(s)/legal guardian, as appropriate, has ameasuring device to measure local reactions at the injection site and a thermometerfor recording daily temperatures.

Ensure the participant or his/her parent(s)/legal guardian, as appropriate, remains
comfortable with the chosen e-diary platform, confirm instructions on e-diarycompletion, and, if the participant is part of the reactogenicity subset, ask theparticipant or his/her parent(s)/legal guardian, as appropriate, to complete thereactogenicity e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination.



If the participant is part of the reactogenicity subset, ask the participant or his/herparent(s)/legal guardian, as appropriate, to contact the site staff or investigator
immediately if the participant experiences any of the following from Day 1 to Day 7
after vaccination (where Day 1 is the day of vaccination) to determine if anunscheduled reactogenicity visit is required:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator if a medically attended event (eg, doctor’s visit, emergency
room visit) or hospitalization occurs.

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

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator (this could be via the COVID-19 illness e-diary) immediately
if the participant experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant or his/her parent(s)/legal guardian, as appropriate, to bring thee-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.

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If the participant is part of the reactogenicity subset, the investigator or appropriately
qualified designee reviews the reactogenicity e-diary data online following vaccination toevaluate participant compliance and as part of the ongoing safety review. Daily review is
optimal during the active diary period.
8.11.2.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2): (28 to 35 Days After
Visit 2)


Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. If the participant is part of thereactogenicity subset, review the participant’s reactogenicity e-diary data. Collectstop dates of any reactogenicity e-diary events ongoing on the last day that thereactogenicity e-diary was completed and record stop dates in the CRF if required.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count resultsfrom the most recent test performed since Visit 1 (if any).

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 20 mL for participants ≥16 years of age, andapproximately 10 mL for participants in the 12- to 15-year age stratum) for
immunogenicity testing.



Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator if a medically attended event (eg, doctor’s visit, emergency
room visit) or hospitalization occurs.
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

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator (this could be via the COVID-19 illness e-diary) immediately
if the participant experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.2.4. Visit 4 – 6-Month Follow-up Visit: (175 to 189 Days After Visit 2)

Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.

For participants who are HIV-positive, record HIV viral load and CD4 count resultsfrom the most recent test performed since Visit 3 (if any).

Collect a blood sample (approximately 20 mL for participants ≥16 years of age andapproximately 10 mL for participants in the 12- to 15-year age stratum) for
immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.



Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator (this could be via the COVID-19 illness e-diary) immediately
if the participant experiences any respiratory symptoms as detailed in Section 8.3.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.2.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 2)Collect a blood sample (approximately 20 mL for participants ≥16 years of age andapproximately 10 mL for participants in the 12- to 15-year age stratum) for
immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.
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Protocol Amendment 9, 29 October 2020For participants who are HIV-positive, record HIV viral load and CD4 count resultsfrom the most recent test performed since Visit 4 (if any).



Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator (this could be via the COVID-19 illness e-diary) immediately
if the participant experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.2.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 2)Collect a blood sample (approximately 20 mL for participants ≥16 years of age andapproximately 10 mL for participants in the 12- to 15-year age stratum) for
immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count resultsfrom the most recent test performed since Visit 5 (if any).

Collect the participant’s e-diary or assist the participant to remove the study
application from his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction
If a Grade 3 local reaction (Section 8.2.2.2), systemic event (Section 8.2.2.3), or fever(Section 8.2.2.4) is reported in the reactogenicity e-diary, a telephone contact should occur toascertain further details and determine whether a site visit is clinically indicated. If suspected
Grade 4 local reaction (Section 8.2.2.2), systemic event (Section 8.2.2.3), or fever(Section 8.2.2.4) is reported in the reactogenicity e-diary, a telephone contact or site visit
should occur to confirm whether the event meets the criteria for Grade 4.

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A site visit must be scheduled as soon as possible to assess the participant unless any of thefollowing is true:The participant is unable to attend the unscheduled visit.

The local reaction/systemic event is no longer present at the time of the telephone
contact.



The participant or his/her parent(s)/legal guardian, as appropriate, recorded anincorrect value in the reactogenicity e-diary (confirmation of a reactogenicity e-diarydata entry error).



The PI or authorized designee determined it was not needed.

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)This telephone contact will be recorded in the participant’s source documentation and theCRF.
If the participant is unable to attend the unscheduled visit, or the PI or authorized designee
determined it was not needed, any ongoing local reactions/systemic events must be assessedat the next study visit.
During the unscheduled visit, the reactions should be assessed by the investigator or a
medically qualified member of the study staff such as a study physician or a study nurse, asapplicable to the investigator’s local practice, who will:Measure body temperature (°F/°C).

Measure minimum and maximum diameters of redness (if present).

Measure minimum and maximum diameters of swelling (if present).



Assess injection site pain (if present) in accordance with the grades provided in
Section 8.2.2.2.

Assess systemic events (if present) in accordance with the grades provided in
Section 8.2.2.3.

Assess for other findings associated with the reaction and record on the AE page of
the CRF, if appropriate.

The investigator or an authorized designee will complete the unscheduled visit assessment
page of the CRF.
8.13. COVID-19 Surveillance (All Participants)
If a participant experiences any of the following (irrespective of perceived etiology or
clinical significance), he or she is instructed to contact the site immediately and, if
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confirmed, participate in an in-person or telehealth visit as soon as possible, optimally within
3 days of symptom onset (and at the latest 4 days after symptom resolution). Note that:

If new symptoms are reported within 4 days after resolution of all previous symptoms,
they will be considered as part of a single illness and a second illness visit is not required;Surveillance of potential COVID-19 symptoms should continue even if a participant has
a positive SARS-CoV-2 test earlier in the study.

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During the 7 days following each vaccination, potential COVID-19 symptoms that overlap
with specific systemic events (ie, fever, chills, new or increased muscle pain, diarrhea,
vomiting) should not trigger a potential COVID-19 illness visit unless, in the investigator’sopinion, the clinical picture is more indicative of a possible COVID-19 illness than vaccine
reactogenicity. If, in the investigator’s opinion, the symptoms are considered more likely to
be vaccine reactogenicity, but a participant is required to demonstrate that they are
SARS-CoV-2–negative, a local SARS-CoV-2 test may be performed: if positive, thesymptoms should be recorded as a potential COVID-19 illness; if not, the symptoms should
be recorded as AEs (unless already captured in the reactogenicity e-diary).
Participants may utilize a COVID-19 illness e-diary through an application (see Section 8.14)
installed on a provisioned device or on the participant’s own personal device to prompt
him/her to report any symptoms. Note that this does not substitute for a participant’s routine
medical care. Therefore, participants should be encouraged to seek care, if appropriate, fromtheir usual provider.


A diagnosis of COVID-19;



Fever;

New or increased cough;

New or increased shortness of breath;Chills;

New or increased muscle pain;New loss of taste/smell;

Sore throat;

Diarrhea;Vomiting.

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8.13.1. Potential COVID-19 Illness Visit: (Optimally Within 3 Days After Potential
COVID-19 Illness Onset)
This visit may be conducted as an in-person or telehealth visit; a telehealth visit involves thesharing of healthcare information and services via telecommunication technologies(eg, audio, video, video-conferencing software) remotely, thus allowing the participant andinvestigator to communicate on aspects of clinical care.

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)As a participant’s COVID-19 illness may evolve over time, several contacts may be required
to obtain the following information:


Record AEs, as appropriate as described in Section 8.3. Note: Potential COVID-19
illnesses that are consistent with the clinical endpoint definition should not berecorded as AEs. These data will be captured as efficacy assessment data only on therelevant pages of the CRF, as these are expected endpoints.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.



If the visit is conducted in person, obtain a nasal (midturbinate) swab (collected bysite staff). Alternatively, if conducted by telehealth, instruct the participant toself-collect a nasal (midturbinate) swab and ship for assessment at the central
laboratory.

Collect COVID-19–related standard-of-care clinical and laboratory information. This
includes, but is not limited to:Symptoms and signs, includingClinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per
minute, HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or
PaO2/FiO2 <300 mm Hg)



Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiringvasopressors)Significant acute renal, hepatic, or neurologic dysfunction

Respiratory failure (defined as needing high-flow oxygen, noninvasive
ventilation, mechanical ventilation, or ECMO)

Clinical diagnosis

Local laboratory SARS-CoV-2 test result(s). Note that if it is routine practice toperform a repeat local SARS-CoV-2 test for any reason, then a repeat nasal

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

Full blood count

Blood chemistry, specifically creatinine, urea, liver function tests, and C-reactive
protein

Imaging results (eg, CT or MRI scan) to document neurologic dysfunction

Number and type of any healthcare contact; duration of hospitalization and ICU
stay



Death



Schedule an appointment for the participant to return for the potential COVID-19
convalescent visit once he or she has recovered.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After Potential
COVID-19 Illness Visit)

Record AEs, as appropriate as described in Section 8.3. Note: Potential COVID-19
illnesses that are consistent with the clinical endpoint definition should not berecorded as AEs. These data will be captured as efficacy assessment data only on therelevant pages of the CRF, as these are expected endpoints.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Collect a blood sample (approximately 20 mL for participants ≥16 years of age andapproximately 10 mL for participants in the 12- to 15-year age stratum) for
immunogenicity testing.

Collect/update COVID-19–related clinical and laboratory information (detailed in
Section 8.13.1).

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.
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8.14. Communication and Use of Technology

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In a study of this nature that requires illness events to be reported outside of scheduled study
visits, it is vital that communication between the study site and the participant or his/herparent(s)/legal guardian, as appropriate, is maintained to ensure that endpoint events are notmissed. This study will employ various methods, tailored to the individual participant, toensure that communication is maintained and study information can be transmitted securely.
Using appropriate technology, such as a study application, a communication pathway
between the participant or his/her parent(s)/legal guardian, as appropriate, and the study site
staff will be established. The participant or his/her parent(s)/legal guardian, as appropriate,
may be able to utilize his or her own devices to access this technology, or use a device
provided by the sponsor. Traditional methods of telephone communication will also be
available. The technology solution may facilitate the following:Contact with the investigator, including the ability of the participant or his/herparent(s)/legal guardian, as appropriate, to report whether or not the participant has
experienced symptoms that could represent a potential COVID-19 illness (COVID-19
illness e-diary; see Section 8.13).

An alert in the event that the participant is hospitalized.



Visit reminders.



Messages of thanks and encouragement from the study team.



A platform for recording local reactions and systemic events (reactogenicity e-diary)– see Section 8.2.2.

If a participant or his/her parent(s)/legal guardian, as appropriate, is not actively completing
either the reactogenicity or COVID-19 illness e-diary, the investigator or designee is required
to contact the participant or his/her parent(s)/legal guardian, as appropriate, to ascertain why
and also to obtain details of any missed events.
8.15. SARS-CoV-2 NAAT Results From Visits 1 and 2 and Potential COVID-19 Illness
VisitsNasal (midturbinate) swabs for SARS-CoV-2 NAAT are obtained at:Visits 1 and 2: To determine whether a participant will be included in efficacy analysesof those with no serological or virological evidence (up to 7 or 14 days after receipt of thesecond dose, depending on the objective) of past SARS-CoV-2 infection.

Potential COVID-19 illness visits: To determine whether symptoms experienced by theparticipant fulfill the COVID-19 case definition.

Research laboratory–generated positive results from the Visit 1 and Visit 2 swabs, and all
results from the illness visit swabs, will be provided to the site once available, but this will
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not be in real time and cannot be relied upon to direct clinical care. Therefore, the participant
should be directed to seek additional testing through his/her primary healthcare providers at alicensed clinical laboratory when exhibiting potential COVID-19 symptoms or otherwise
receiving a positive result and counseled on whether to take any precautionary measurespending confirmatory testing.
Participants who have a positive SARS-CoV-2 NAAT result prior to Visit 2 should be
handled as follows:Positive SARS-CoV-2 test with no symptoms, either at Visit 1 or any time between Visit
1 and Visit 2: A positive test in an asymptomatic participant does not meet exclusion
criterion 5; therefore, Vaccination 2 should proceed as normal.

Confirmed COVID-19 (ie, symptoms and positive SARS-CoV-2 test): This meets
exclusion criterion 5; therefore, Vaccination 2 should not be given but the participant
should remain in the study.

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9. STATISTICAL CONSIDERATIONS
Methodology for summary and statistical analyses of the data collected in this study is
described here and further detailed in a statistical analysis plan (SAP), which will bemaintained by the sponsor. The SAP may modify what is outlined in the protocol whereappropriate; however, any major modifications of the primary endpoint definitions or theiranalyses will also be reflected in a protocol amendment.
9.1. Estimands and Statistical Hypotheses
9.1.1. Estimands
The estimand corresponding to each primary, secondary, and tertiary/exploratory objective is
described in the table in Section 3.
In the primary safety objective evaluations, missing reactogenicity e-diary data will not be
imputed. Missing AE dates will be imputed according to Pfizer safety rules. No othermissing information will be imputed in the safety analysis.
The estimands to evaluate the immunogenicity objectives are based on evaluable populations
for immunogenicity (Section 9.3). These estimands estimate the vaccine effect in the
hypothetical setting where participants follow the study schedules and protocol requirements
as directed. Missing antibody results will not be imputed. Immunogenicity results that are
below the LLOQ will be set to 0.5 × LLOQ in the analysis; this may be adjusted once
additional data on the assay characteristics become available.
The estimands to evaluate the efficacy objectives are based on evaluable populations for
efficacy (Section 9.3). These estimands estimate the vaccine effect in the hypotheticalsetting where participants follow the study schedules and protocol requirements as directed.
In addition, VE will also be analyzed by all-available efficacy population. Missing laboratory
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results will not be imputed for the primary analysis, but missing data imputation for theefficacy endpoint may be performed as a sensitivity analysis.
9.1.2. Statistical Hypotheses
9.1.2.1. Statistical Hypothesis Evaluation for Efficacy

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Phase 2/3 of the study has 2 primary efficacy endpoints evaluating VE, which is defined as
VE = 100 × (1 – IRR). IRR is calculated as the ratio of first confirmed COVID-19 illness ratein the vaccine group to the corresponding illness rate in the placebo group. In Phase 2/3, theassessment of VE will be based on posterior probabilities of VE1 > 30% and VE2 > 30%.
VE1 represents VE for prophylactic BNT162b2 against confirmed COVID-19 in participants
without evidence of infection before vaccination, and VE2 represents VE for prophylactic
BNT162b2 against confirmed COVID-19 in all participants after vaccination.
For participants with multiple confirmed cases, only the first case will contribute to the VE
calculation for each hypothesis. VE1 and VE2 will be evaluated sequentially to control theoverall type I error to the desired level of 2.5%. VE is demonstrated if there is sufficientevidence (posterior probability) that either VE1 >30% or both VE1 and VE2 are >30%. The
assessment for the primary analysis will be based on posterior probability using a Bayesianmodel.
9.1.2.2. Statistical Hypothesis Evaluation for Immunogenicity
One of the secondary objectives in the Phase 3 part of the study is to evaluate noninferiorityof the immune response to prophylactic BNT162b2 in participants 12 to 15 years of age
compared to the response in participants 16 to 25 years of age at 1 month after Dose 2. The(Dose 2) evaluable immunogenicity population will be used for the following hypothesis
testing:
H0: ln(µ2) – ln(µ1) ≤ ln(0.67)
where ln (0.67) corresponds to a 1.5-fold margin for noninferiority, ln(µ2) and ln(µ1) are thenatural log of the geometric mean of SARS-CoV-2 neutralizing titers from BNT162b2
recipients 12 to 15 years of age and 16 to 25 years of age, respectively, measured 1 monthafter Dose 2. If the lower limit of the 95% CI for the GMR (12-15 years of age to 16-25
years of age) is >0.67, the noninferiority objective is met.
9.2. Sample Size Determination
The study sample size for Phase 1 of the study is not based on any statistical hypothesis
testing. Phase 1 comprises 15 participants (randomization ratio of 4:1 so that 12 receive
active vaccine and 3 receive placebo) per group; 13 vaccine groups are studied,corresponding to a total of 195 participants.
For Phase 2/3, with assumptions of a true VE of 60% after the second dose of investigational
product, a total of approximately 164 first confirmed COVID-19 illness cases will provide
90% power to conclude true VE >30% with high probability, allowing early stopping for
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efficacy at the IA. This would be achieved with 17,600 evaluable participants per group or
21,999 vaccine recipients randomized in a 1:1 ratio with placebo, for a total sample size of
43,998, based on the assumption of a 1.3% illness rate per year in the placebo group, accrualof 164 first primary-endpoint cases within 6 months, and 20% of the participants being
nonevaluable or having serological evidence of prior infection with SARS-CoV-2,
potentially making them immune to further infection. Dependent upon the evolution of thepandemic, it is possible that the COVID-19 attack rate may be much higher, in which caseaccrual would be expected to be more rapid, enabling the study’s primary endpoint to beevaluated much sooner. The total number of participants enrolled in Phase 2/3 may varydepending on the incidence of COVID-19 at the time of the enrollment, the true underlying
VE, and a potential early stop for efficacy or futility.
In Phase 3, approximately 2000 participants are anticipated to be 12 to 15 years of age. A
random sample of 250 participants will be selected for each of the 2 age groups (12 to 15
years and 16 to 25 years) as an immunogenicity subset for the noninferiority assessment.
With the standard deviation and observed GMT difference assumed in the power analysis
below, a sample size of 200 evaluable participants (or 250 vaccine recipients) per age groupwill provide a power of 90.8% to declare the noninferiority of adolescents to 16- to
25-year-olds in terms of neutralizing antibody GMR, 1 month after the second dose(see Table 4).
Table 4.
Criteria

Power Analysis for Noninferiority Assessment
Standard
Deviation(Log Value)a

AssumedObserved GMT
Difference (Log
Scale)-0.2

Number of
Evaluable
Participants per
Age Group
200

PowerbLower limit of 95%
0.623
90.8%
CI for GMR(12-15/16-25)>0.67
Abbreviation: GMR = geometric mean ratio.
a. Reference: 1 month after Dose 2, BNT162b2 (30 µg), 18- to 55-year age group (C4591001 Phase 1,
N=12). Calculation may be updated if additional information becomes available to better estimate thestandard deviation.
b. At 0.05 alpha level (2-sided).

For safety outcomes, Table 5 shows the probability of observing at least 1 AE for a given
true event rate of a particular AE, for various sample sizes. For example, if the true AE rate
is 10%, with 12 participants in a vaccine group, there is 72% probability of observing at least
1 AE.

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Table 5.

Probability of Observing at Least 1 AE by Assumed True Event Rates
With Different Sample Sizes

Assumed
N=12
N=45
True Event
Rate of an
AE
0.01%
0.00
0.00
0.02%
0.00
0.01
0.04%
0.00
0.02
0.06%
0.01
0.03
0.08%
0.01
0.04
0.10%
0.01
0.04
0.15%
0.02
0.07
0.20%
0.02
0.09
0.25%
0.03
0.11
0.30%
0.04
0.13
0.35%
0.04
0.15
0.50%
0.06
0.20
1.00%
0.11
0.36
2.00%
0.22
0.60
3.00%
0.31
0.75
5.00%
0.46
0.90
7.00%
0.58
0.96
10.00%
0.72
0.99
Note: N = number in sample.

N=180

N=1000N=3000N=6000N=9000N=15000

0.02
0.04
0.07
0.10
0.13
0.16
0.24
0.30
0.36
0.42
0.47
0.59
0.84
0.97
>0.99
>0.99
>0.99
>0.99

0.10
0.18
0.33
0.45
0.55
0.63
0.78
0.86
0.92
0.95
0.97
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

0.26
0.45
0.70
0.83
0.91
0.95
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

0.45
0.70
0.91
0.97
0.99
0.99
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

0.59
0.83
0.97
0.99
0.99
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

0.78
0.95
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

9.3. Analysis Sets
For purposes of analysis, the following populations are defined:
Population
Enrolled
Randomized
Dose 1 evaluable
immunogenicity

Dose 2 evaluable
immunogenicity

Description
All participants who have a signed ICD.
All participants who are assigned a randomization number in
the IWR system.
For Phase 1 only, all eligible randomized participants who
receive the vaccine to which they are randomly assigned at thefirst dose, have at least 1 valid and determinate
immunogenicity result after Dose 1, have blood collection
within an appropriate window after Dose 1, and have no otherimportant protocol deviations as determined by the clinician.
All eligible randomized participants who receive 2 doses ofthe vaccine to which they are randomly assigned, within thepredefined window, have at least 1 valid and determinate
immunogenicity result after Dose 2, have blood collection
within an appropriate window after Dose 2, and have no otherimportant protocol deviations as determined by the clinician.

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Population
Dose 1 all-available
immunogenicity
Dose 2 all-available
immunogenicity
Evaluable efficacy

All-available efficacy

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SafetyDescription
For Phase 1 only: all randomized participants who receive atleast 1 dose of the study intervention with at least 1 valid anddeterminate immunogenicity result after Dose 1 but before
Dose 2.
All randomized participants who receive at least 1 dose of thestudy intervention with at least 1 valid and determinate
immunogenicity result after Dose 2.
All eligible randomized participants who receive all
vaccination(s) as randomized within the predefined windowand have no other important protocol deviations as determinedby the clinician.
1. All randomized participants who receive at least
1 vaccination.
2. All randomized participants who complete 2 vaccination
doses.
All randomized participants who receive at least 1 dose of thestudy intervention.

9.4. Statistical Analyses
The SAP will be developed and finalized before database lock for any of the planned
analyses in Section 9.5.1. It will describe the participant populations to be included in theanalyses and the procedures for accounting for missing, unused, and spurious data. Thissection provides a summary of the planned statistical analyses of the primary, secondary, andtertiary/exploratory endpoints.
9.4.1. Immunogenicity Analyses
Immunogenicity samples will be drawn for all participants. Immunogenicity analyses will bebased upon results from appropriately sized subsets of samples, according to the purpose.
The statistical analysis of immunogenicity results will be primarily based on the evaluable
immunogenicity populations as defined in Section 9.3. Serology data after a postbaseline
positive SARS-CoV-2 test result will not be included in the analysis based on the evaluable
immunogenicity populations.
An additional analysis will be performed based on the all-available populations if there is alarge enough difference in sample size between the all-available immunogenicity populationand the evaluable immunogenicity population. Participants will be summarized according to
the vaccine group to which they were randomized.

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Endpoint
Secondaryimmunogenicity

Statistical Analysis Methods
Geometric mean titers/concentrations (GMTs/GMCs) of
SARS-CoV-2 neutralizing titers, S1-binding IgG level, andRBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, GMTs/GMCs and 2-sided 95% CIs will be
provided for each investigational product within each group before
vaccination and at each of the following time points:Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1, 6, 12
and 24 months after Dose 2090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)

Geometric means will be calculated as the mean of the assay results
after making the logarithm transformation and then exponentiating themean to express results on the original scale. Two-sided 95% CIs will
be obtained by taking natural log transforms of concentrations/titers,
calculating the 95% CI with reference to the t-distribution, and thenexponentiating the confidence limits.
GMFRs of SARS-CoV-2 neutralizing titers, S1-binding IgG level,
and RBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, the GMFRs and 2-sided 95% CIs will be
provided for each investigational product within each group at each of
the following time points:Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1, 6, 12,
and 24 months after Dose 2

GMFRs will be limited to participants with nonmissing values prior to
the first dose and at the postvaccination time point. The GMFR will becalculated as the mean of the difference of logarithmically transformed
assay results (later time point – earlier time point) and exponentiating
the mean. The associated 2-sided CIs will be obtained by calculating
CIs using Student’s t-distribution for the mean difference of thelogarithmically transformed assay results and exponentiating theconfidence limits.
Percentage of participants with ≥4-fold rise in SARS-CoV-2
neutralizing titers, S1-binding IgG level, and RBD-binding IgG
level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, percentages (and 2-sided 95% CIs) of
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Statistical Analysis Methods
participants with ≥4-fold rise will be provided for each investigational
product within each group at each of the following time points:Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1, 6, 12,
and 24 months after Dose 2

The Clopper-Pearson method will be used to calculate the CIs.
GMR of SARS-CoV-2 neutralizing titer to S1-binding IgG level
and to RBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, the GMRs and 2-sided 95% CIs will be
provided for each investigational product within each group at each of
the following time points:

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Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1, 6, 12,
and 24 months after Dose 2

GMRs will be limited to participants with nonmissing values for both
SARS-CoV-2 neutralizing titers and S1-binding IgG level/RBDbinding IgG level at each time point. The GMR will be calculated as
the mean of the difference of logarithmically transformed assay results(eg, SARS-CoV-2 neutralizing titers minus S1-binding IgG level foreach participant) and exponentiating the mean. Two-sided CIs will beobtained by calculating CIs using Student’s t-distribution for the meandifference of the logarithmically transformed assay results andexponentiating the confidence limits.
For all the immunogenicity endpoints, the analysis will be based on the
Dose 1 and Dose 2 evaluable immunogenicity populations. An
additional analysis will be performed based on the all-available
immunogenicity populations if there is a large enough difference insample size between the all-available immunogenicity populations andthe evaluable immunogenicity populations. Participants will besummarized according to the vaccine group to which they wererandomized. Missing serology data will not be imputed.
Secondaryimmunogenicity(noninferiority inthe 12- to 15-year
age groupcompared to the

GMR of SARS-CoV-2 neutralizing titers in participants 12 to 15
years of age to those 16 to 25 years of age
For participants with no serological or virological evidence (up to
1 month after receipt of the second dose) of past SARS-CoV-2
infection, the GMR of SARS-CoV-2 neutralizing titers in participants
12 to 15 years of age to those in participants 16 to 25 years of age and

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Endpoint
Statistical Analysis Methods
16- to 25-year age 2-sided 95% CIs will be provided at 1 month after Dose 2 forgroup)
noninferiority assessment.
The GMR and its 2-sided 95% CI will be derived by calculating
differences in means and CIs on the natural log scale of the titers basedon the Student’s t-distribution and then exponentiating the results. The
difference in means on the natural log scale will be 12 to 15 years
minus 16 to 25 years. Noninferiority will be declared if the lower
bound of the 2-sided 95% CI for the GMR is greater than 0.67.

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)This analysis will be based on Dose 2 evaluable immunogenicity
populations. An additional analysis may be performed based on the
Dose 2 all-available immunogenicity population if needed.
Participants will be summarized according to the vaccine group towhich they were randomized. Missing serology data will not be
imputed.
Exploratory
immunogenicity

Geometric mean titers/concentrations (GMTs/GMCs) of
SARS-CoV-2 neutralizing titers, S1-binding IgG level, andRBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, GMTs/GMCs and 2-sided 95% CIs will be
provided for each investigational product within each group before
vaccination and at each of the following time points in Phase 2/3:


1, 6, 12, and 24 months after completion of vaccination inparticipants with and without serological or virologicalevidence of SARS-CoV-2 infection before vaccination

Geometric means will be calculated as the mean of the assay results
after making the logarithm transformation and then exponentiating themean to express results on the original scale. Two-sided 95% CIs will
be obtained by taking natural log transforms of concentrations/titers,
calculating the 95% CI with reference to the t-distribution, and thenexponentiating the confidence limits.
GMFRs of SARS-CoV-2 neutralizing titers, S1-binding IgG level,
and RBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, the GMFRs and 2-sided 95% CIs will be
provided for each investigational product within each group at each of
the following time points in Phase 2/3:
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Endpoint

Statistical Analysis Methods
1, 6, 12, and 24 months after completion of vaccination inparticipants with and without serological or virologicalevidence of SARS-CoV-2 infection before vaccination

GMFRs will be limited to participants with nonmissing values prior to
the first dose and at the postvaccination time point. The GMFR will becalculated as the mean of the difference of logarithmically transformed
assay results (later time point – earlier time point) and exponentiating
the mean. The associated 2-sided CIs will be obtained by calculating
CIs using Student’s t-distribution for the mean difference of thelogarithmically transformed assay results and exponentiating theconfidence limits.

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Percentage of participants with antibody levels ≥ predefined
threshold(s) for SARS-CoV-2 serological parameters
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels and/or
RBD-binding IgG levels, N-binding antibody, and SARS-CoV-2
detection by NAAT, percentages (and 2-sided 95% CIs) of participants
with antibody levels ≥ predefined threshold(s) will be provided foreach investigational product within each group at baseline and each of
the following time points in Phase 2/3:


1, 6, 12, and 24 months after completion of vaccination inparticipants with and without serological or virologicalevidence of SARS-CoV-2 infection before vaccination

The Clopper-Pearson method will be used to calculate the CIs.
Percentage of participants with the immune response (non-S) to
SARS-CoV-2 for N-binding antibody at the time points when data
are available
The Clopper-Pearson method will be used to calculate the CIs.
For all of the immunogenicity endpoints, the analysis will be based on
the Dose 1 and Dose 2 evaluable immunogenicity populations. An
additional analysis will be performed based on the all-available
immunogenicity populations if there is a large enough difference insample size between the all-available immunogenicity populations andthe evaluable immunogenicity populations. Participants will besummarized according to the vaccine group to which they wererandomized. Missing serology data will not be imputed.

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Endpoint

Statistical Analysis Methods
RCDCs for immunogenicity results
Empirical RCDCs will be provided for SARS-CoV-2 neutralizing
titers, S1-binding IgG level, and RBD-binding IgG level after Dose 1
and after Dose 2.

9.4.2. Efficacy Analyses
The evaluable efficacy population will be the primary analysis population for all efficacy
analyses. Additional analyses based on the all-available efficacy population will be
performed.

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Endpoint
Primary efficacy

Statistical Analysis Methods
Ratio of confirmed COVID-19 illness from 7 days after the second
dose per 1000 person-years of follow-up in participants without
evidence of infection (prior to 7 days after receipt of the seconddose) for the active vaccine group to the placebo group
VE will be estimated by 100 × (1 – IRR), where IRR is the calculated
ratio of confirmed COVID-19 illness per 1000 person-years follow-up
in the active vaccine group to the corresponding illness rate in theplacebo group from 7 days after the second dose. VE will be analyzed
using a beta-binomial model.
After the above objective is met, the second primary endpoint will be
evaluated as below.
Ratio of confirmed COVID-19 illness from 7 days after the second
dose per 1000 person-years of follow-up in participants with andwithout evidence of infection (prior to 7 days after receipt of thesecond dose) for the active vaccine group to the placebo group
VE will be estimated by 100 × (1 – IRR), where IRR is the calculated
ratio of confirmed COVID-19 illness per 1000 person-years follow-up
in the active vaccine group to the corresponding illness rate in theplacebo group from 7 days after the second dose. VE will be analyzed
using a beta-binomial model.
The efficacy analysis for the first primary objective evaluation will bebased on the participants without evidence of infection before
vaccination and included in the evaluable efficacy population and in
the all-available efficacy population.

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Endpoint

Statistical Analysis Methods
The efficacy analysis for the second primary objective evaluation will
be based on all participants included in the evaluable efficacy
population and in the all-available efficacy population.
For the primary endpoint analysis, missing efficacy data will not be
imputed. A sensitivity analysis will be performed by imputing missing
values with the assumption of MAR. A missing efficacy endpoint may
be imputed based on predicted probability using the fully conditional
specification method. Other imputation methods without the MAR
assumption may be explored. The details will be provided in the SAP.

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SecondaryFirst: Ratio of confirmed COVID-19 illness from 14 days after thesecond dose per 1000 person-years of follow-up in participants
without evidence of infection (prior to 14 days after receipt of thesecond dose) for the active vaccine group to the placebo group
Second: Ratio of confirmed COVID-19 illness from 14 days after
the second dose per 1000 person-years of follow-up in participants
with and without evidence of infection (prior to 14 days after
receipt of the second dose) for the active vaccine group to theplacebo group
Third and fourth: Ratios of confirmed severe COVID-19 illness
from 7 days and from 14 days after the second dose per 1000
person-years of follow-up in participants without evidence of
infection (prior to 7 days or 14 days after receipt of the seconddose) for the active vaccine group to the placebo group
Fifth and sixth: Ratios of confirmed severe COVID-19 illness from
7 days and from 14 days after the second dose per 1000
person-years of follow-up in participants with and without
evidence of infection (prior to 7 days or 14 days after receipt of thesecond dose) for the active vaccine group to the placebo group
These secondary efficacy objectives will be evaluated sequentially inthe order specified above after the primary objectives are met. The
analysis will be based on the evaluable efficacy population and the allavailable efficacy population. The analysis methodology used for the
primary efficacy endpoints will be applied for the analysis of the above
secondary efficacy endpoints.
The following secondary efficacy endpoints will be evaluateddescriptively with 95% CIs.

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Endpoint

Statistical Analysis Methods
Ratios of confirmed COVID-19 illness (according to the
CDC-defined symptoms) from 7 days and from 14 days after thesecond dose per 1000 person-years of follow-up in participants
without evidence of infection (prior to 7 days or 14 days after
receipt of the second dose) for the active vaccine group to theplacebo group
Ratios of confirmed COVID-19 illness (according to the
CDC-defined symptoms) from 7 days and from 14 days after thesecond dose per 1000 person-years of follow-up in participants
with and without evidence of infection (prior to 7 days or 14 days
after receipt of the second dose) for the active vaccine group to theplacebo group

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VE = 100 × (1 – IRR) will be estimated with confirmed COVID-19
illness according to the CDC-defined symptoms from 7 days or from
14 days after the second dose. The 2-sided 95% CI for VE will bederived using the Clopper-Pearson method as described by Agresti.9
Missing efficacy data will not be imputed.

9.4.3. Safety Analyses
Endpoint
Primary

Statistical Analysis Methods
Descriptive statistics will be provided for each reactogenicity endpoint
for each dose and vaccine group. Local reactions and systemic eventsfrom Day 1 through Day 7 after each vaccination will be presented byseverity and cumulatively across severity levels. Descriptive
summary statistics will include counts and percentages of participants
with the indicated endpoint and the associated Clopper-Pearson 95%
CIs.
For Phase 1, descriptive statistics will be provided for abnormal
hematology and chemistry laboratory values at 1 and 7 days after
Dose 1 and 7 days after Dose 2, including grading shifts inhematology and chemistry laboratory assessments between baseline
and 1 and 7 days after Dose 1, and before Dose 2 and 7 days after
Dose 2. Descriptive summary statistics will include counts andpercentages of participants with the indicated endpoint and theassociated Clopper-Pearson 2-sided 95% CIs.
AEs will be categorized according to the Medical Dictionary forRegulatory Activities (MedDRA) terms. A 3-tier approach will be

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Endpoint

Statistical Analysis Methods
used to summarize AEs in Phase 2/3. Under this approach AEs areclassified into 1 of 3 tiers: (1) Tier 1 events are prespecified events ofclinical importance and are identified in a list in the product’s safety
review plan; (2) Tier 2 events are those that are not Tier 1 but areconsidered “relatively common”; a MedDRA preferred term is defined
as a Tier 2 event if there are at least 1% of participants in at least 1
vaccine group reporting the event; and (3) Tier 3 events are those thatare neither Tier 1 nor Tier 2 events. For both Tier 1 and Tier 2 events,
2-sided 95% CIs for the difference between the vaccine and placebogroups in the percentage of participants reporting the events based on
the Miettinen and Nurminen method10 will be provided. In addition,
for Tier 1 events, the asymptotic p-values will also be presented forthe difference between groups in the percentage of participants
reporting the events, based on the same test statistic and under theassumption that the test statistic is asymptotically normally
distributed.
Descriptive summary statistics (counts, percentages, and associatedClopper-Pearson 95% CIs) will be provided for any AE events foreach vaccine group.
SAEs will be categorized according to MedDRA terms. Counts,
percentages, and the associated Clopper-Pearson 95% CIs of SAEs
from Dose 1 to 6 months after the last dose will be provided for eachvaccine group.
The safety analyses are based on the safety population. Participants
will be summarized by vaccine group according to the investigational
products they actually received. Missing reactogenicity e-diary data
will not be imputed; missing AE dates will be handled according to
the Pfizer safety rules.

SecondaryNot applicable (N/A)

Exploratory

N/A

9.4.4. Other Analyses
The ratios of (GMFR A to GMFR B) and (GMFR A to GMFR C) may be explored, where
GMFR A is the geometric mean of the ratio of the SARS-CoV-2 neutralizing titer at the
postvaccination time point to the corresponding titer at the prevaccination time point,
GFMR B is the geometric mean of the ratio of the S1-binding IgG level at the
postvaccination time point to the corresponding IgG level at the prevaccination time point,
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and GMFR C is the geometric mean of the ratio of the RBD-binding IgG level at the
postvaccination time point to the corresponding antibody level at the prevaccination time
point.
The safety data and immunogenicity results for individuals with confirmed stable HIV
disease will be summarized descriptively. Furthermore, VE may be assessed if there is asufficient number of COVID-19 cases in this group of participants.
The safety and immunogenicity results for individuals 16 to 55 years of age vaccinated withstudy intervention produced by manufacturing “Process 1” and each lot of “Process 2” will
be summarized descriptively. A random sample of 250 participants from those vaccinatedwith study intervention produced by manufacturing “Process 1” will be selected randomly forthe analysis.
9.5. Interim Analyses

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)As this is a sponsor open-label study during Phase 1, the sponsor may conduct unblinded
reviews of the data during the course of the study for the purpose of safety assessment,
facilitating dose escalation decisions, and/or supporting clinical development.
During Phase 2/3, 4 IAs were planned to be performed by an unblinded statistical team after
accrual of at least 32, 62, 92, and 120 cases. However, for operational reasons, the firstplanned IA was not performed. Consequently, 3 IAs are now planned to be performed after
accrual of at least 62, 92, and 120 cases. At these IAs, futility and VE with respect to thefirst primary endpoint will be assessed as follows:VE for the first primary objective will be evaluated. Overwhelming efficacy will bedeclared if the first primary study objective is met. The criteria for success at aninterim analysis are based on the posterior probability (ie, P[VE >30%|data]) at thecurrent number of cases. Overwhelming efficacy will be declared if the posterior
probability is higher than the success threshold. The success threshold for eachinterim analysis will be calibrated to protect overall type I error at 2.5%. Additional
details about the success threshold or boundary calculation at each interim analysis
will be provided in the SAP.

The study will stop for lack of benefit (futility) if the predicted probability of successat the final analysis or study success is <5%. The posterior predictive POS will becalculated using a beta-binomial model. The futility assessment will be performed
for the first primary endpoint and the futility boundary may be subject to change toreflect subsequent program-related decisions by the sponsor.

Efficacy and futility boundaries will be applied in a nonbinding way.

Bayesian approaches require specification of a prior distribution for the possible values of theunknown vaccine effect, thereby accounting for uncertainty in its value. A minimally
informative beta prior, beta (0.700102, 1), is proposed for θ = (1-VE)/(2-VE). The prior is
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centered at θ = 0.4118 (VE=30%) which can be considered pessimistic. The prior allows
considerable uncertainty; the 95% interval for θ is (0.005, 0.964) and the corresponding 95%
interval for VE is (-26.2, 0.995).
Table 6 illustrates the boundary for efficacy and futility if, for example, IAs are performed
after accrual of 32, 62, 92, and 120 cases in participants without evidence of infection before
vaccination. Note that although the first IA was not performed, the statistical criterion for
demonstrating success (posterior probability threshold) at the interim (>0.995) and final(>0.986) analyses remains unchanged. Similarly, the futility boundaries are not changed.
Table 6.

Futility Boundary
Success Criteriaa
VE Point Estimate
VE Point Estimate(Case Split)(Case Split)
IA1
32
76.9% (6:26)
11.8% (15:17)
IA2
6268.1% (15:47)
27.8% (26:36)
IA3
92
62.7% (25:67)
38.6% (35:57)
IA4120
58.8% (35:85)
N/A
Final
164
52.3% (53:111)
Abbreviations: IA = interim analysis; N/A = not applicable; VE = vaccine efficacy.
Note: Case split = vaccine : placebo.
a. Interim efficacy claim: P(VE >30%|data) > 0.995; success at the final analysis: P(VE >30%|data)> 0.986.
Analysis090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)Interim Analysis Plan and Boundaries for Efficacy and Futility
Number of
Cases

Additional design operating characteristics (the boundary based on the number of cases
observed in the vaccine group; the probabilities for efficacy and futility given assumed
various VEs with a 1:1 randomization ratio) are listed in Table 7 and Table 8, for IAs
conducted at 32, 62, 92, and 120 cases and the final analysis at 164 cases. Although the IA at
32 cases was not performed, the overall Type I error (overall probability of success when true
VE=30%) will still be strictly controlled at 0.025 with the originally proposed success/futility
boundaries.

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Table 7.

Statistical Design Operating Characteristics: Probability of Success or
Failure for Interim Analyses

VaccineEfficacy(%)

Interim Analysis 1(Total Cases = 32)

30
50
60
70
80

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Table 8.

Probabilityof Success(Cases in
VaccineGroup ≤6)
0.006
0.054
0.150
0.368
0.722

Probabilityof Failure(Cases in
VaccineGroup ≥15)
0.315
0.078
0.021
0.003
<0.001

Interim Analysis 2(Total Cases = 62)
Probabilityof Success(Cases in
VaccineGroup ≤15)
0.003
0.051
0.160
0.310
0.238

Probabilityof Failure(Cases in
VaccineGroup ≥26)
0.231
0.056
0.010
<0.001<0.001

Interim Analysis 3(Total Cases = 92)
Probabilityof Success(Cases in
VaccineGroup ≤25)
0.002
0.063
0.175
0.195
0.037

Probabilityof Failure(Cases in
VaccineGroup ≥35)
0.239
0.103
0.019
0.001
<0.001

InterimAnalysis 4(Total Cases= 120)
Probability of
Success(CasesVaccineGroup ≤35)
0.002
0.075
0.160
0.085
0.003

Statistical Design Operating Characteristics: Probability of Success for
Final Analysis and Overall

Vaccine Efficacy (%)

30
50
60
70
80

Final Analysis(Total Cases = 164)
Probability of Success (Cases in Vaccine
Group ≤53)
0.007
0.196
0.220
0.036
<0.001

Overall Probability of Success

0.021
0.439
0.866
>0.999>0.999If neither success nor futility has been declared after all IAs, the final analysis will be
performed and the first primary objective will have been met if there are 53 or fewer cases
observed in the vaccine group out of a total of 164 first confirmed cases from 7 days after
receipt of the second dose of investigational product onwards.
Only the first primary endpoint will be analyzed at IA. If the first primary objective is met,
the second primary objective will be evaluated at the final analysis. After the primaryobjectives are met, the first 6 secondary VE endpoints (confirmed COVID-19 occurring from
14 days after the second dose in participants without evidence of infection and in allparticipants, confirmed severe COVID-19 occurring from 7 days and from 14 days after thesecond dose in participants without evidence of infection and in all participants) will be
evaluated sequentially in the stated order, by the same method used for the evaluation ofprimary VE endpoints. Success thresholds for secondary VE endpoints will be appropriately
chosen to control overall Type I error at 2.5%. Further details will be provided in the SAP.
The remaining secondary VE endpoints will be evaluated descriptively to calculate theobserved VE with 95% CIs.
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9.5.1. Analysis Timing

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Statistical analyses will be carried out when the following data are available:Complete safety and immunogenicity analysis approximately 1 month after Dose 2
for Phase 1.



Safety data through 7 days after Dose 2 and immunogenicity data through 1 monthafter Dose 2 from the first 360 participants enrolled (180 to active vaccine and 180 toplacebo, stratified equally between 18 to 55 years and >55 to 85 years) in Phase 2/3.



Safety data through 1 month after Dose 2 from at least 6000 participants enrolled(3000 to active vaccine and 3000 to placebo) in Phase 2/3. Additional analyses ofsafety data (with longer follow-up and/or additional participants) may be conducted if
required for regulatory purposes.



IAs for efficacy after accrual of at least 62, 92, and 120 cases and futility after accrualof at least 62 and 92 cases.

Safety data through 1 month after Dose 2 and noninferiority comparison of
SARS-CoV-2 neutralizing titers in participants 12 to 15 years of age compared tothose in participants 16 to 25 years of age, 1 month after Dose 2.



Descriptive analysis of immunogenicity and safety of “Process 1” and “Process 2”
material, 1 month after Dose 2.

Complete safety and immunogenicity analysis approximately 6 months after Dose 2
for all participants in Phase 2/3.

Complete efficacy and persistence-of-immunogenicity analysis after complete data
are available or at the end of the study.

All analyses conducted on Phase 2/3 data while the study is ongoing will be performed by an
unblinded statistical team.
9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will use an IRC, a DMC, and a group of internal case reviewers. The IRC is
independent of the study team and includes only internal members. The DMC is independentof the study team and includes only external members. The IRC and DMC charters describe
the role of the IRC and DMC in more detail.
The responsibilities of the IRC are only in Phase 1 and will include:

Review of safety data to permit dose escalations in the 18- to 55-year age cohort



Review of safety data in the case of a stopping rule being met
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

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Review of safety and/or immunogenicity data to:Allow groups of participants of 65 to 85 years of age to proceed

Select vaccine candidate/dose level(s) to proceed into Phase 2/3. Data supporting
the selection, including results for both binding antibody levels and neutralizing
titers, and the ratio between them, will also be submitted to the FDA for review

Review of any available safety and/or immunogenicity data generated during thecourse of this study, or the BioNTech study conducted in Germany, to determine:Whether any groups may not be started



Whether any groups may be terminated earlyWhether any groups may be added with dose levels below the lowest stated doseor intermediate between the lowest and highest stated doses

Contemporaneous review of all NAAT-confirmed COVID-19 illnesses in Phase 1

The DMC will be responsible for ongoing monitoring of the safety of participants in the
study according to the charter. This may include, but is not limited to:Contemporaneous review of related AEs up to 1 month after completion of thevaccination scheduleContemporaneous review of all SAEs up to 6 months after completion of thevaccination scheduleContemporaneous review of all NAAT-confirmed COVID-19 illnesses in Phase 1

At the time of the planned IAs, and ad hoc if requested by the unblinded team, review
of cases of COVID-19 for an adverse imbalance of cases of COVID-19 and/or severe
COVID-19 between the vaccine and placebo groups

The recommendations made by the DMC to alter the conduct of the study will be forwarded
to the appropriate Pfizer personnel for final decision. Pfizer will forward such decisions,which may include summaries of aggregate analyses of safety data, to regulatory authorities,
as appropriate.
Three blinded case reviewers (medically qualified Pfizer staff members) will review all
potential COVID-19 illness events. If a NAAT-confirmed case in Phase 2/3 may beconsidered severe, or not, solely on the basis of “significant acute renal, hepatic, orneurologic dysfunction,” the blinded data will be reviewed by the case reviewers to assess
whether the criterion is met; the majority opinion will prevail.

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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:Consensus ethical principles derived from international guidelines including the
Declaration of Helsinki and CIOMS International Ethical Guidelines;Applicable ICH GCP guidelines;Applicable laws and regulations, including applicable privacy laws.

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents(eg, advertisements) must be reviewed and approved by the sponsor and submitted to an
IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study is
initiated.
Any amendments to the protocol will require IRB/EC approval before implementation ofchanges made to the study design, except for changes necessary to eliminate an immediate
hazard to study participants.
The investigator will be responsible for the following:Providing written summaries of the status of the study to the IRB/EC annually or
more frequently in accordance with the requirements, policies, and procedures
established by the IRB/EC;



Notifying the IRB/EC of SAEs or other significant safety findings as required by
IRB/EC procedures;Providing oversight of the conduct of the study at the site and adherence torequirements of 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014
for clinical studies (if applicable), and all other applicable local regulations.

10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicableregulatory authority in any area of the world, or if the investigator is aware of any new
information that might influence the evaluation of the benefits and risks of the study
intervention, Pfizer should be informed immediately.
In addition, the investigator will inform Pfizer immediately of any urgent safety measurestaken by the investigator to protect the study participants against any immediate hazard, andof any serious breaches of this protocol or of ICH GCP that the investigator becomes awareof.
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10.1.2. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to theparticipant or his or her parent(s)/legal guardian and answer all questions regarding the study.
The participant or his or her parent(s)/legal guardian should be given sufficient time andopportunity to ask questions and to decide whether or not to participate in the trial.
Participants must be informed that their participation is voluntary. Participants or theirparent(s)/legal guardian will be required to sign a statement of informed consent that meetsthe requirements of 21 CFR 50, local regulations, ICH guidelines, HIPAA requirements,
where applicable, and the IRB/EC or study center.
The investigator must ensure that each study participant or his or her parent(s)/legal guardianis fully informed about the nature and objectives of the study, the sharing of data related tothe study, and possible risks associated with participation, including the risks associated withthe processing of the participant’s personal data.

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)The participant must be informed that his/her personal study-related data will be used by thesponsor in accordance with local data protection law. The level of disclosure must also be
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical
Quality Assurance auditors or other authorized personnel appointed by the sponsor, byappropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant or his or her parent(s)/legal
guardian is fully informed about his or her right to access and correct his or her personal data
and to withdraw consent for the processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their
participation in the study.
A copy of the ICD(s) must be provided to the participant or his or her parent(s)/legal
guardian. Participants who are rescreened are required to sign a new ICD.
Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate
section that addresses the use of samples for optional additional research. The optional
additional research does not require the collection of any further samples. The investigator
or authorized designee will explain to each participant the objectives of the additional
research. Participants will be told that they are free to refuse to participate and may
withdraw their consent at any time and for any reason during the storage period.

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10.1.3. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementationof organizational and technical measures to ensure protection of participant data.

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Participants’ personal data will be stored at the study site in encrypted electronic and/or paper
form and will be password protected or secured in a locked room to ensure that only
authorized study staff have access. The study site will implement appropriate technical andorganizational measures to ensure that the personal data can be recovered in the event ofdisaster. In the event of a potential personal data breach, the study site will be responsiblefor determining whether a personal data breach has in fact occurred and, if so, providing
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personaldata, participants will be assigned a single, participant-specific numerical code. Any
participant records or data sets that are transferred to the sponsor will contain the numericalcode; participant names will not be transferred. All other identifiable data transferred to thesponsor will be identified by this single, participant-specific code. The study site will
maintain a confidential list of participants who participated in the study, linking eachparticipant’s numerical code to his or her actual identity and medical record identification. In
case of data transfer, the sponsor will protect the confidentiality of participants’ personal dataconsistent with the clinical study agreement and applicable privacy laws.
10.1.4. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting theresults of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or
www.pfizer.com, and other public registries in accordance with applicable local
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, andcomplete manner and are reported regardless of the outcome of the study or the country inwhich the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional
studies (conducted in patients) that evaluate the safety and/or efficacy of a product,
regardless of the geographical location in which the study is conducted. These results are
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies inaccordance with the format and timelines set forth by EU requirements.

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www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used
to identify individual participants have been removed) on www.pfizer.com for
Pfizer-sponsored interventional studies at the same time the corresponding study results areposted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinicaldata to the EMA website. Clinical data, under Phase 1 of this policy, includes clinicaloverviews, clinical summaries, CSRs, and appendices containing the protocol and protocol
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of thispolicy, includes the publishing of individual participant data. Policy 0070 applies to newmarketing authorization applications submitted via the centralized procedure since
01 January 2015 and applications for line extensions and for new indications submitted via
the centralized procedure since 01 July 2015.

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Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposesof “bona-fide scientific research” that contributes to the scientific understanding of thedisease, target, or compound class. Pfizer will make available data from these trials
24 months after study completion. Patient-level data will be anonymized in accordance withapplicable privacy laws and regulations. CSRs will have personally identifiable information
redacted.
Data requests are considered from qualified researchers with the appropriate competencies toperform the proposed analyses. Research teams must include a biostatistician. Data will not
be provided to applicants with significant conflicts of interest, including individuals
requesting access for commercial/competitive or legal purposes.
10.1.5. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unlesstransmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is
responsible for verifying that data entries are accurate and correct by physically orelectronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports theinformation entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted
electronic and/or paper form and are password protected or secured in a locked room toprevent access by unauthorized third parties.

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The investigator must permit study-related monitoring, audits, IRB/EC review, andregulatory agency inspections and provide direct access to source data documents. This
verification may also occur after study completion. It is important that the investigator(s)and their relevant personnel are available during the monitoring visits and possible audits orinspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality
such as risk management and mitigation strategies and analytical risk-based monitoring),
methods, responsibilities, and requirements, including handling of noncompliance issues andmonitoring techniques (central, remote, or on-site monitoring), are provided in themonitoring plan.

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)The sponsor or designee is responsible for the data management of this study, including
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data enteredinto the CRF by authorized site personnel are accurate, complete, and verifiable from source
documents; that the safety and rights of participants are being protected; and that the study is
being conducted in accordance with the currently approved protocol and any other study
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must
be retained by the investigator for 15 years after study completion unless local regulations or
institutional policies require a longer retention period. No records may be destroyed during
the retention period without the written approval of the sponsor. No records may betransferred to another location or party without written notification to the sponsor. The
investigator must ensure that the records continue to be stored securely for as long as they are
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of suchdata are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory
inspection notification in relation to the study. Furthermore, the investigator will cooperatewith the sponsor or its agents to prepare the investigator site for the inspection and will allow
the sponsor or its agent, whenever feasible, to be present during the inspection. The
investigator site and investigator will promptly resolve any discrepancies that are identified
between the study data and the participant's medical records. The investigator will promptly
provide copies of the inspection findings to the sponsor or its agent. Before response
submission to the regulatory authorities, the investigator will provide the sponsor or its
agents with an opportunity to review and comment on responses to any such findings.

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10.1.6. Source Documents
Source documents provide evidence for the existence of the participant and substantiate theintegrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be
consistent with the source documents or the discrepancies must be explained. The
investigator may need to request previous medical records or transfer records, depending on
the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the study monitoring plan.
Description of the use of computerized system is documented in the Data Management Plan.
10.1.7. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment ofparticipants.

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)The first act of recruitment is the date of the first participant’s first visit and will be the study
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any
time for any reason at the sole discretion of the sponsor. Study sites will be closed uponstudy completion. A study site is considered closed when all required documents and study
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor
or designee if requested to do so by the responsible IRB/EC or if such termination is required
to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limitedto:

Failure of the investigator to comply with the protocol, the requirements of the
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.

If the study is prematurely terminated or suspended, the sponsor shall promptly inform theinvestigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of
the reason for termination or suspension, as specified by the applicable regulatory
requirements. The investigator shall promptly inform the participant and should assure
appropriate participant therapy and/or follow-up.

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Study termination is also provided for in the clinical study agreement. If there is any conflict
between the contract and this protocol, the contract will control as to termination rights.
10.1.8. Sponsor’s Qualified Medical Personnel

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)The contact information for the sponsor's appropriately qualified medical personnel for the
study is documented in the study contact list located in the supporting study documentation.
To facilitate access to appropriately qualified medical personnel on study-related medical
questions or problems, participants are provided with a contact card at the time of informed
consent. The contact card contains, at a minimum, protocol and study intervention
identifiers, participant numbers, contact information for the investigator site, and contact
details for a contact center in the event that the investigator site staff cannot be reached toprovide advice on a medical question or problem originating from another healthcare
professional not involved in the participant’s participation in the study. The contact number
can also be used by investigator staff if they are seeking advice on medical questions or
problems; however, it should be used only in the event that the established communication
pathways between the investigator site and the study team are not available. It is therefore
intended to augment, but not replace, the established communication pathways between theinvestigator site and the study team for advice on medical questions or problems that may
arise during the study. The contact number is not intended for use by the participant directly,
and if a participant calls that number, he or she will be directed back to the investigator site.

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10.2. Appendix 2: Clinical Laboratory Tests

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)The following safety laboratory tests will be performed at times defined in the SoA section ofthis protocol. Additional laboratory results may be reported on these samples as a result of
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived
from calculated values. These additional tests would not require additional collection ofblood. Unscheduled clinical laboratory measurements may be obtained at any time during
the study to assess any perceived safety issues.
Hematology
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet countWBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)Basophils (Abs)
Lymphocytes (Abs)

Chemistry
BUN and creatinine
AST, ALT
Total bilirubin
Alkaline phosphatase

Other Urine pregnancy test (β-hCG)
At screening only: Hepatitis B core antibody
 Hepatitis B surface antigen
 Hepatitis C antibody
 Human immunodeficiency virus

Investigators must document their review of each laboratory safety report.
Clinically significant abnormal laboratory findings should be recorded in the AE CRF in
accordance with the following grading scale (Table 9).
Table 9.

Laboratory Abnormality Grading Scale

Hematology

Mild (Grade 1)

Hemoglobin
11.0 – 12.0
(Female) - g/dL
Hemoglobin
12.5 – 13.5
(Male) - g/dL
WBC increase 10,800 – 15,000
cells/mm3
WBC decrease 2,500 – 3,500
cells/mm3
Lymphocytes
750 – 1,000
decrease - cells/mm3
Neutrophils decrease 1,500 – 2,000- cells/mm3
Eosinophils 650 – 1500
cells/mm3
Platelets decreased - 125,000 – 140,000
cells/mm3

Moderate(Grade 2)

Severe (Grade 3)

9.5 – 10.9

8.0 – 9.4

Potentially Life
Threatening(Grade 4)<8.0

10.5 – 12.4

8.5 – 10.4

<8.5

15,001 – 20,000

20,001 – 25, 000>25,000

1,500 – 2,499

1,000 – 1,499<1,000500 – 749

250 – 499

<250

1,000 – 1,499

500 – 999

<500

1501 - 5000

>5000

Hypereosinophilic

100,000 – 124,000

25,000 – 99,000<25,000

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Table 9.

Laboratory Abnormality Grading Scale

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Chemistry

Mild (Grade 1)

Moderate(Grade 2)

Severe(Grade 3)

BUN - mg/dL
Creatinine – mg/dL

23 – 26
1.5 – 1.7

27 – 31
1.8 – 2.0> 31
2.1 – 2.5

Alkaline
phosphate –increase by factor
Liver function tests– ALT, AST
increase by factor
Bilirubin – whenaccompanied
by any increase inliver function test increase by factor
Bilirubin – whenliver function test is
normal - increase byfactor

1.1 – 2.0 x ULN

2.1 – 3.0 x ULN

3.1 – 10 x ULN

Potentially Life
Threatening(Grade 4)
Requires dialysis> 2.5 or requires
dialysis>10 x ULN

1.1 – 2.5 x ULN

2.6 – 5.0 x ULN

5.1 – 10 x ULN>10 x ULN

1.1 – 1.25 x ULN

1.26 – 1.5 x ULN

1.51 – 1.75 x ULN>1.75 x ULN

1.1 – 1.5 x ULN

1.6 – 2.0 x ULN

2.0 – 3.0 x ULN>3.0 x ULN

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen;
ULN = upper limit of normal; WBC = white blood cell.

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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition


An AE is any untoward medical occurrence in a patient or clinical study participant,temporally associated with the use of study intervention, whether or not consideredrelated to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including anabnormal laboratory finding), symptom, or disease (new or exacerbated) temporally
associated with the use of study intervention.

Events Meeting the AE Definition

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Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis)or other safety assessments (eg, ECG, radiological scans, vital sign measurements),
including those that worsen from baseline, considered clinically significant in the
medical and scientific judgment of the investigator Any abnormal laboratory test
results that meet any of the conditions below must be recorded as an AE:
Is associated with accompanying symptoms.



Requires additional diagnostic testing or medical/surgical intervention.



Leads to a change in study dosing (outside of any protocol-specified dose
adjustments) or discontinuation from the study, significant additional
concomitant drug treatment, or other therapy.



Exacerbation of a chronic or intermittent preexisting condition including either anincrease in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration eventhough it may have been present before the start of the study.



Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.



Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
intervention or a concomitant medication. Overdose per se will not be reported as
an AE/SAE unless it is an intentional overdose taken with possible
suicidal/self-harming intent. Such overdoses should be reported regardless ofsequelae.
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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safetyassessments which are associated with the underlying disease, unless judged by theinvestigator to be more severe than expected for the participant’s condition.



The disease/disorder being studied or expected progression, signs, or symptoms ofthe disease/disorder being studied, unless more severe than expected for theparticipant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).



Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present
or detected at the start of the study that do not worsen.

10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:a. Results in deathb. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which theparticipant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.
c. Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving
at least an overnight stay) at the hospital or emergency ward for observation and/or
treatment that would not have been appropriate in the physician’s office or outpatientsetting. Complications that occur during hospitalization are AEs. If a complication
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in
doubt as to whether “hospitalization” occurred or was necessary, the AE should beconsidered serious.
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Hospitalization for elective treatment of a preexisting condition that did not worsen frombaseline is not considered an AE.
d. Results in persistent disability/incapacity


The term disability means a substantial disruption of a person’s ability to conduct
normal life functions.

This definition is not intended to include experiences of relatively minor medicalsignificance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza,
and accidental trauma (eg, sprained ankle) which may interfere with or prevent
everyday life functions but do not constitute a substantial disruption.

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f. Other situations:Medical or scientific judgment should be exercised in deciding whether SAE
reporting is appropriate in other situations such as important medical events that
may not be immediately life-threatening or result in death or hospitalization but may
jeopardize the participant or may require medical or surgical intervention to prevent
one of the other outcomes listed in the above definition. These events should
usually be considered serious.



Examples of such events include invasive or malignant cancers, intensive treatment
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or
convulsions that do not result in hospitalization, or development of drug dependency
or drug abuse.

Suspected transmission via a Pfizer product of an infectious agent, pathogenic or
nonpathogenic, is considered serious. The event may be suspected from clinicalsymptoms or laboratory findings indicating an infection in a patient exposed to a
Pfizer product. The terms “suspected transmission” and “transmission” areconsidered synonymous. These cases are considered unexpected and handled asserious expedited cases by pharmacovigilance personnel. Such cases are also
considered for reporting as product defects, if appropriate.

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10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF andfor reporting serious adverse events on the Vaccine SAE Report Form to Pfizer Safety.
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious adverse
events (AEs); and (3) exposure to the study intervention under study during pregnancy orbreastfeeding, and occupational exposure.

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)It should be noted that the Vaccine SAE Report Form for reporting of SAE information is
not the same as the AE page of the CRF. When the same data are collected, the forms must
be completed in a consistent manner. AEs should be recorded using concise medical
terminology and the same AE term should be used on both the CRF and the Vaccine SAE
Report Form for reporting of SAE information.
Safety Event

Recorded on the CRF

SAE
Nonserious AE
Exposure to the study
intervention under study
during pregnancy orbreastfeeding, andoccupational exposure

All
All
All AEs/SAEs associatedwith exposure during
pregnancy or breastfeeding

Reported on the Vaccine
SAE Report Form to
Pfizer Safety Within 24
Hours of Awareness

All
None
All (and EDP supplemental
form for EDP)
Note: Include all SAEs
associated with exposure
Occupational exposure is not during pregnancy orbreastfeeding. Include allrecorded.
AEs/SAEs associated withoccupational exposure.

When an AE/SAE occurs, it is the responsibility of the investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostic
reports) related to the event.



The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s
medical records to Pfizer Safety in lieu of completion of the Vaccine SAE Report
Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases arerequested by Pfizer Safety. In this case, all participant identifiers, with the
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exception of the participant number, will be redacted on the copies of the medical
records before submission to Pfizer Safety.


The investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. Whenever possible, the diagnosis(not the individual signs/symptoms) will be documented as the AE/SAE.

Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during
the study and assign it to 1 of the following categories:

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)GRADE If required on the AE page of the CRF, the investigator will use theadjectives MILD, MODERATE, SEVERE, or LIFE-THREATENING todescribe the maximum intensity of the AE. For purposes of consistency,
these intensity grades are defined as follows:
1

MILD

Does not interfere with participant's usualfunction.

2

MODERATE

Interferes to some extent with participant's usualfunction.

3

SEVEREInterferes significantly with participant's usualfunction.

4

LIFE-THREATENING Life-threatening consequences; urgent
intervention indicated.

Assessment of Causality

The investigator is obligated to assess the relationship between study intervention
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence,
and/or arguments to suggest a causal relationship, rather than a relationship cannot
be ruled out.

The investigator will use clinical judgment to determine the relationship.



Alternative causes, such as underlying disease(s), concomitant therapy, and otherrisk factors, as well as the temporal relationship of the event to study intervention
administration, will be considered and investigated.

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The investigator will also consult the IB and/or product information, for marketed
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she
has reviewed the AE/SAE and has provided an assessment of causality.



There may be situations in which an SAE has occurred and the investigator has
minimal information to include in the initial report to the sponsor. However, it isvery important that the investigator always make an assessment of causality forevery event before the initial transmission of the SAE data to the sponsor.



The investigator may change his/her opinion of causality in light of follow-up
information and send an SAE follow-up report with the updated causality
assessment.



The causality assessment is one of the criteria used when determining regulatory
reporting requirements.



If the investigator does not know whether or not the study intervention caused theevent, then the event will be handled as “related to study intervention” for reporting
purposes, as defined by the sponsor. In addition, if the investigator determines thatan SAE is associated with study procedures, the investigator must record this causal
relationship in the source documents and CRF, and report such an assessment in the
dedicated section of the Vaccine SAE Report Form and in accordance with the SAE
reporting requirements.

Follow-up of AEs and SAEs


The investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by thesponsor to elucidate the nature and/or causality of the AE or SAE as fully as
possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other healthcare providers.



If a participant dies during participation in the study or during a recognizedfollow-up period, the investigator will provide Pfizer Safety with a copy of any
postmortem findings including histopathology.



New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours ofreceipt of the information.

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10.3.4. Reporting of SAEs

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SAE Reporting to Pfizer Safety via Vaccine SAE Report Form

Facsimile transmission of the Vaccine SAE Report Form is the preferred method totransmit this information to Pfizer Safety.



In circumstances when the facsimile is not working, notification by telephone isacceptable with a copy of the Vaccine SAE Report Form sent by overnight mail orcourier service.

Initial notification via telephone does not replace the need for the investigator tocomplete and sign the Vaccine SAE Report Form pages within the designatedreporting time frames.

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10.4. Appendix 4: Contraceptive Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during
the intervention period and for at least 28 days after the last dose of study intervention, whichcorresponds to the time needed to eliminate reproductive safety risk of the study
intervention(s):Refrain from donating sperm.

PLUS either:Be abstinent from heterosexual intercourse with a female of childbearing potential as
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) andagree to remain abstinent.

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)OR

Must agree to use a male condom when engaging in any activity that allows forpassage of ejaculate to another person.



In addition to male condom use, a highly effective method of contraception may beconsidered in WOCBP partners of male participants (refer to the list of highly
effective methods below in Section 10.4.4).

10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).

OR

Is a WOCBP and using an acceptable contraceptive method as described below
during the intervention period (for a minimum of 28 days after the last dose of study
intervention). The investigator should evaluate the effectiveness of the contraceptive
method in relationship to the first dose of study intervention.

The investigator is responsible for review of medical history, menstrual history, and recent
sexual activity to decrease the risk for inclusion of a woman with an early undetected
pregnancy.

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10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot
be confirmed before the first dose of study intervention, additional evaluation should beconsidered.
Women in the following categories are not considered WOCBP:
1. Premenarchal.

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2. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.

For individuals with permanent infertility due to an alternate medical cause other than theabove, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should beapplied to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s
review of the participant’s medical records, medical examination, or medical history
interview. The method of documentation should be recorded in the participant’s medical
record for the study.
3. Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause. In addition, ahigh FSH level in the postmenopausal range must be used to confirm apostmenopausal state in women under 60 years of age and not using hormonal
contraception or HRT.



Female on HRT and whose menopausal status is in doubt will be required to use
one of the nonestrogen hormonal highly effective contraception methods if theywish to continue their HRT during the study. Otherwise, they must discontinue
HRT to allow confirmation of postmenopausal status before study enrollment.

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10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations
regarding the use of contraceptive methods for those participating in clinical trials.
1. Implantable progestogen-only hormone contraception associated with inhibition ofovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner:

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)

Vasectomized partner is a highly effective contraceptive method provided that thepartner is the sole sexual partner of the woman of childbearing potential and theabsence of sperm has been confirmed. If not, an additional highly effective methodof contraception should be used. The spermatogenesis cycle is approximately
90 days.

6. Combined (estrogen- and progestogen-containing) hormonal contraception associatedwith inhibition of ovulation:


Oral;



Intravaginal;Transdermal;



Injectable.

7. Progestogen-only hormone contraception associated with inhibition of ovulation:


Oral;



Injectable.

8. Sexual abstinence:Sexual abstinence is considered a highly effective method only if defined as
refraining from heterosexual intercourse during the entire period of risk associatedwith the study intervention. The reliability of sexual abstinence needs to be evaluatedin relation to the duration of the study and the preferred and usual lifestyle of theparticipant.

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9. Progestogen-only oral hormonal contraception where inhibition of ovulation is not the
primary mode of action.
10. Male or female condom with or without spermicide.
11. Cervical cap, diaphragm, or sponge with spermicide.

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12. A combination of male condom with either cervical cap, diaphragm, or sponge with
spermicide (double-barrier methods).

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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations intransaminases) are termed “tolerators,” while those who show transient liver injury, but adapt
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of amore serious potential outcome. These participants fail to adapt and therefore are"susceptible" to progressive and serious liver injury, commonly referred to as DILI.
Participants who experience a transaminase elevation above 3 × ULN should be monitored
more frequently to determine if they are an “adaptor” or are “susceptible.”

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LFTs are not required as a routine safety monitoring procedure for all participants in thisstudy. However, should an investigator deem it necessary to assess LFTs because aparticipant presents with clinical signs/symptoms, such LFT results should be managed andfollowed as described below.
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will beelevated within the same laboratory sample). In rare instances, by the time TBili elevations
are detected, AST/ALT values might have decreased. This occurrence is still regarded as apotential DILI. Therefore, abnormal elevations in either AST OR ALT in addition to TBili
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law
criteria) cases and should always be considered important medical events, even before allother possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on theparticipant’s individual baseline values and underlying conditions. Participants who present
with the following laboratory abnormalities should be evaluated further as potential DILI
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:Participants with AST/ALT and TBili baseline values within the normal range who
subsequently present with AST OR ALT values >3 × ULN AND a TBili value>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value<2 × ULN or not available.

For participants with baseline AST OR ALT OR TBili values above the ULN, thefollowing threshold values are used in the definition mentioned above, as needed,
depending on which values are above the ULN at baseline:Preexisting AST or ALT baseline values above the normal range: AST or ALT
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever issmaller).

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Rises in AST/ALT and TBili separated by more than a few weeks should be assessedindividually based on clinical judgment; any case where uncertainty remains as to whether it
represents a potential Hy’s law case should be reviewed with the sponsor.

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)The participant should return to the investigator site and be evaluated as soon as possible,
preferably within 48 hours from awareness of the abnormal results. This evaluation should
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili for suspected cases ofHy’s law, additional laboratory tests should include albumin, CK, direct and indirect
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should
also be given to drawing a separate tube of clotted blood and an anticoagulated tube of bloodfor further testing, as needed, for further contemporaneous analyses at the time of therecognized initial abnormalities to determine etiology. A detailed history, including relevant
information, such as review of ethanol, acetaminophen/paracetamol (either by itself or as a
coformulated product in prescription or over-the-counter medications), recreational drug,
supplement (herbal) use and consumption, family history, sexual history, travel history,
history of contact with a jaundiced person, surgery, blood transfusion, history of liver orallergic disease, and potential occupational exposure to chemicals, should be collected.
Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary
tract) and collection of serum samples for acetaminophen/paracetamol drug and/or protein
adduct levels may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if noother reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law)cases are to be reported as SAEs, irrespective of availability of all the results of theinvestigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results ofreasonable investigations have been received and have excluded an alternative etiology.

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10.6. Appendix 6: Abbreviations

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)The following is a list of abbreviations that may be used in the protocol.
Abbreviation
2019-nCoV
Abs
AE
ALT
AST
-hCG
BMI
BUN
CBER
CDC
CFR
CI
CIOMS
CLIA
CONSORT
COVID-19
CRF
CRO
CSR
CT
DBP
DILI
DMC
DNA
DU
EC
ECMO
ECG
eCRF
e-diary
EDP
EMA
EU
EUA
EudraCT
FDA
FiO2
FSH
GCP

Term
novel coronavirus 2019absolute (in Appendix 2)
adverse event
alanine aminotransferase
aspartate aminotransferase
beta-human chorionic gonadotropin
body mass index
blood urea nitrogen
Center for Biologics Evaluation and ResearchCenters for Disease Control and Prevention (United States)
Code of Federal Regulations
confidence interval
Council for International Organizations of Medical Sciences
Clinical Laboratory Improvement Amendments
Consolidated Standards of Reporting Trials
coronavirus disease 2019case report form
contract research organization
clinical study reportcomputed tomography
diastolic blood pressuredrug-induced liver injury
data monitoring committee
deoxyribonucleic aciddosing unit
ethics committee
extracorporeal membrane oxygenationelectrocardiogram
electronic case report form
electronic diary
exposure during pregnancy
European Medicines Agency
European Union
emergency use authorization
European Clinical Trials Database
Food and Drug Administration
fraction of inspired oxygenfollicle-stimulating hormone
Good Clinical Practice

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Abbreviation
GGT
GMC
GMFR
GMR
GMT
HBc Ab
HBe
HBeAg
HBsAg
HBV
HCV
HCV Ab
HIPAA
HIV
HR
HRT
IA
IB
ICD
ICH
ICU
ID
Ig
IgG
IgM
IMP
IND
INR
IP manual
IPAL
IRB
IRC
IRR
IRT
ISO
IV
IWR
LFT
LL
LLOQ
LNP
LPX

Term
gamma-glutamyl transferase
geometric mean concentrationgeometric mean fold risegeometric mean ratio
geometric mean titerhepatitis B core antibody
hepatitis B ehepatitis B e antigen
hepatitis B surface antigen
hepatitis B virus
hepatitis C virus
hepatitis C virus antibody
Health Insurance Portability and Accountability Act
human immunodeficiency virus
heart rate
hormone replacement therapy
interim analysis
investigator’s brochure
informed consent document
International Council for Harmonisation
intensive care unit
identification
immunoglobulin
immunoglobulin G
immunoglobulin M
investigational medicinal productinvestigational new druginternational normalized ratio
investigational product manual
Investigational Product Accountability Log
institutional review board
internal review committee
illness rate ratio
interactive response technology
International Organization for Standardization
intravenous(ly)interactive Web-based response
liver function test
lower limit
lower limit of quantitation
lipid nanoparticle
lipoplex

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Abbreviation
MAR
MCH
MCHC
MCV
MedDRA
MERS
MIS-C
modRNA
MRI
N
N/A
NAAT
non-S
P2 S
PaO2
PCR
PI
POS
PPE
PT
RBC
RBD
RCDC
RNA
RR
RSV
RT-PCR
S1
SAE
SAP
saRNA
SARS
SARS-CoV-2
SBP
SoA
SOP
SpO2
SRSD
SUSAR
TBD
TBili
ULN

Term
missing at randommean corpuscular hemoglobinmean corpuscular hemoglobin concentration
mean corpuscular volume
Medical Dictionary for Regulatory Activities
Middle East respiratory syndrome
multisystem inflammatory syndrome in children
nucleoside-modified messenger ribonucleic acidmagnetic resonance imaging
SARS-CoV-2 nucleoprotein
not applicable
nucleic acid amplification test
nonspike protein
SARS-CoV-2 full-length, P2 mutant, prefusion spike glycoprotein
partial pressure of oxygen, arterial
polymerase chain reaction
principal investigatorprobability of successpersonal protective equipment
prothrombin time
red blood cell
receptor-binding domain
reverse cumulative distribution curve
ribonucleic acidrespiratory rate
respiratory syncytial virus
reverse transcription–polymerase chain reaction
spike protein S1 subunit
serious adverse event
statistical analysis planself-amplifying messenger ribonucleic acidsevere acute respiratory syndrome
severe acute respiratory syndrome coronavirus 2
systolic blood pressureschedule of activities
standard operating procedureoxygen saturation as measured by pulse oximetry
single reference safety document
suspected unexpected serious adverse reaction
to be determinedtotal bilirubin
upper limit of normal

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Abbreviation
uRNA
US
vax
VE
WBC
WHO
WOCBP

Term
unmodified messenger ribonucleic acid
United States
vaccination
vaccine efficacy
white blood cell
World Health Organization
woman/women of childbearing potential

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10.7. Appendix 7: Stopping and Alert Rules for Enhanced COVID-19
In Phase 2/3, the unblinded team supporting the DMC (reporting team), including an
unblinded medical monitor, will review cases of severe COVID-19 as they are received, andwill review AEs at least weekly for additional potential cases of severe COVID-19 and willcontact the DMC in the event that the stopping rule or an alert is met. Specifically, theunblinded reporting team will contact the DMC chair, who will then convene the full DMC
as soon as possible. The DMC will review all available safety and/or efficacy data at thetime of the review. The DMC will make one of the following recommendations to Pfizer:
withhold final recommendation until further information/data are provided, continue thestudy as designed, modify the study and continue, or stop the study. The final decision toaccept or reject the committee’s recommendation resides with Pfizer management and will be
communicated to the committee chairperson in writing.

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At any point the unblinded team may discuss with the DMC chair whether the DMC should
review cases for an adverse imbalance of cases of COVID-19 and/or severe COVID-19
between the vaccine and placebo groups (see Section 9.6). In addition, at the time of the IAs
after accrual of at least 62, 92, and 120 cases, the number of severe COVID-19 cases in thevaccine and placebo groups will be assessed.
Stopping and alert rules will be applied as follows. The stopping rule will be triggered whenthe 1-sided probability of observing the same or a more extreme case split is 5% or less when
the true incidence of severe disease is the same for vaccine and placebo participants, and alert
criteria are triggered when this probability is less than 11%. In addition, when the total
number of severe cases is low (15 or less), the unblinded team supporting the DMC will
implement the alert rule when a reverse case split of 2:1 or worse is observed. For example,
at 3 cases 2:1, at 4 cases 3:1, etc. Below 15 cases, this rule is more rigorous than requiring
the probability of an observed adverse split or worse be <11%.
The stopping rule and alert rules are illustrated in Table 10 and Table 11, respectively, when
the total number of severe cases is 20 or less. For example, when there are 7 severe cases,
the adverse split has to be 7:0 to stop the study, but a split of 5:2 would trigger the alert rule.
Similarly, when there is a total of 9 severe cases, an adverse split of 9:0 triggers the stopping
rule, while a split of 6:3 or worse triggers the alert rule. The alert rule may be triggered withas few as 2 cases, with a split of 2:0.

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Table 10. Stopping Rule: Enrollment Is Stopped if the Number of Severe Cases inthe Vaccine Group Is Greater Than or Equal to the Prespecified Stopping
Rule Value (S)090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)

Total Severe Cases

Prespecified Stopping Rule Value(S): Number of Severe Cases in the
Vaccine Group to Stop

4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Abbreviation: N/A = not applicable.

4
5
6
7
7
8
9
9
10
10
11
12
12
13
13
14
15

If the True Ratio of Severe Cases
Between Vaccine and PlaceboGroups Is 1:1, Probability of S or
More Being Observed in the Vaccine
Group
N/A
3.13%
1.56%
0.78%
3.52%
1.95%
1.07%
3.27%
1.93%
4.61%
2.87%
1.76%
3.84%
2.45%
4.81%
3.18%
2.07%

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Table 11. Alert Rule: Further Action Is Taken if the Number of Severe Cases in the
Vaccine Group Is Greater Than or Equal to the Prespecified Alert Rule
Value (A)
Total
SevereCases

Prespecified AlertRule Value(A):
Number of
SevereCases in the
VaccineGroup toTrigger
Further
ActionIf the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
1:1,
Probabilityof A Being
Observed inthe Vaccine
Group

2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20

2
2
3
4
4
5
6
6
7
8
8
9
10
10
11
12
13
13
14

25.00%
37.50%
25.00%
15.63%
23.44%
16.41%
10.94%
16.41%
11.72%
8.06%
12.08%
8.73%
6.11%
9.16%
6.67%
4.72%
3.27%
5.18%
3.70%

If the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
1:1,
Probabilityof A or More
Being
Observed inthe Vaccine
Group
25.00%
50.00%
31.25%
18.75%
34.38%
22.66%
14.45%
25.39%
17.19%
11.33%
19.38%
13.34%
8.98%
15.09%
10.51%
7.17%
4.81%
8.35%
5.77%

If the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
2:1,
Probabilityof A or More
Being
Observed inthe Vaccine
Group44.49%
74.12%
59.32%
46.16%
68.10%
57.14%
46.90%
65.11%
56.02%
47.35%
63.25%
55.31%
47.66%
61.94%
54.81%
47.88%
41.34%
54.43%
48.06%

If the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
3:1,
Probabilityof A or More
Being
Observed inthe Vaccine
Group56.25%
84.38%
73.83%
63.28%
83.06%
75.64%
67.85%
83.43%
77.59%
71.33%
84.24%
79.40%
74.15%
85.16%
81.03%
76.53%
71.75%
82.51%
78.58%

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If the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
4:1,
Probabilityof A or More
Being
Observed inthe VaccineGroup64.00%
89.60%
81.92%
73.73%
90.11%
85.20%
79.69%
91.44%
87.91%
83.89%
92.74%
90.09%
87.02%
93.89%
91.83%
89.43%
86.71%
93.24%
91.33%

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10.8. Appendix 8: Criteria for Allowing Inclusion of Participants With Chronic Stable
HIV, HCV, or HBV Infection
Potential participants with chronic stable HIV, HCV, or HBV infection may be considered
for inclusion if they fulfill the following respective criteria.
Known HIV infection
Confirmed stable HIV disease defined as documented viral load <50 copies/mL andCD4 count >200 cells/mm3 within 6 months before enrollment, and on stable
antiretroviral therapy for at least 6 months.

Known HCV infection
History of chronic HCV with evidence of sustained virological response (defined asundetectable HCV RNA) for ≥12 weeks following HCV treatment or without
evidence of HCV RNA viremia (undetectable HCV viral load).

090177e195653bd7\Approved\Approved On: 30-Oct-2020 13:40 (GMT)

Known HBV infection
Confirmed inactive chronic HBV infection, defined as HBsAg present for ≥6 months and thefollowing:

HBeAg negative, anti-HBe positive

Serum HBV DNA <2000 IU/mLPersistently normal ALT and/or AST levels

In those who have had a liver biopsy performed, findings that confirm the absence ofsignificant necroinflammation.

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11. REFERENCES
1

World Health Organization. WHO Director-General's opening remarks at the media
briefing on COVID-19. Available from: https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19--11-march-2020. Published: 11 Mar 2020. Accessed: 01 Apr 2020.

2

World Health Organization. Coronavirus disease 2019 (COVID-19) situation report - 70.
In: Data as reported by national authorities by 10:00 CET 30 March 2020. Geneva,
Switzerland: World Health Organization; 2020.

3

Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19):
information for clinicians on investigational therapeutics for patients with COVID-19.
Available from: https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeuticoptions.html. Updated: 25 Apr 2020. Accessed: 26 Jun 2020.

4

Rauch S, Jasny E, Schmidt KE, et al. New vaccine technologies to combat outbreaksituations. Front Immunol 2018;9:1963.

5

Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics—developing a new class ofdrugs. Nat Rev Drug Discov 2014;13(10):759-80.

6

BioNTech RNA Pharmaceuticals GmbH. CorVAC/BNT162 Investigator’s Brochure.
Mainz, Germany: BioNTech RNA Pharmaceuticals GmbH; 25 Mar 2020.

7

Feldman RA, Fuhr R, Smolenov I, et al. mRNA vaccines against H10N8 and H7N9
influenza viruses of pandemic potential are immunogenic and well tolerated in healthy
adults in phase 1 randomized clinical trials. Vaccine 2019;37(25):3326-34.

8

US Food and Drug Administration. Guidance for industry: toxicity grading scale forhealthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials.
Rockville, MD: Center for Biologics Evaluation and Research; September 2007.

9

Agresti A. Introduction: distributions and inference for categorical data. In: Agresti A,
ed. Categorical data analysis. 2nd ed. Hoboken, NJ: John Wiley & Sons; 2002:1-35.

10

Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med
1985;4(2):213-26.

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Document Approval Record
Document Name:

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Signing Capacity

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FDA-CBER-2021-5683-0014208

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Protocol Amendment 8, 15 October 2020090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)A PHASE 1/2/3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLIND,
DOSE-FINDING STUDY TO EVALUATE THE SAFETY, TOLERABILITY,IMMUNOGENICITY, AND EFFICACY OF SARS-COV-2 RNA VACCINECANDIDATES AGAINST COVID-19 IN HEALTHY INDIVIDUALS

Study Sponsor:

BioNTechStudy Conducted By:

PfizerStudy Intervention Number:

PF-07302048

Study Intervention Name:

RNA-Based COVID-19 Vaccines

US IND Number:

19736

EudraCT Number:2020-002641-42

Protocol Number:

C4591001

Phase:
1/2/3
Short Title: A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, andEfficacy of RNA Vaccine Candidates Against COVID-19 in Healthy IndividualsThis document and accompanying materials contain confidential information belonging to Pfizer. Except asotherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold thisinformation in confidence and not copy or disclose it to others (except where required by applicable law) or
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer
must be promptly notified.

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Protocol Amendment Summary of Changes Table
Document History
Document
Protocol amendment 8

Version Date
15 October 2020

Summary and Rationale for Changes

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)
Protocol amendment 7

06 October 2020













Removed “N-binding antibody” and“SARS-CoV-2 detection by NAAT” asendpoints from the third exploratory objective,
as these results are used for the determination of
the population, and are not endpoints.
Clarified that the “Process 1” participants
included in the descriptive analysis of“Process 1”- and “Process 2”-manufactured
study interventions will be selected randomly.
Clarified that surveillance of potential
COVID-19 symptoms should continue even if aparticipant has a positive SARS-CoV-2 testearlier in the study.
Further modified the circumstances in which a
local NAAT result may be used in the
COVID-19 case definition.
Clarified that for participants who are not in thereactogenicity subset, local reactions andsystemic events following vaccination should be
detected and reported as AEs.
Clarified that premenarchal females are not
WOCBP.
Made various editorial changes.
Reduced the lower age range to include
adolescents 12 to 15 years of age and added
corresponding objectives.
Removed reference to COVID-19 antibody
testing in Section 2.3.2.
Clarified with efficacy estimands and endpoints
that last dose refers to second dose.
Added an additional exploratory objective todescribe safety and immunogenicity inparticipants 16 to 55 years of age vaccinatedwith study intervention produced bymanufacturing “Process 1” or “Process 2.”
Clarified exclusion criterion 5.
Added Section 6.1.1 to describe manufacturing“Process 1” and “Process 2.”
Clarified the degree of unblinding on the
unblinded submissions team in Section 6.3.3.
Made provision for a second dose of BNT162b2
in participants who were affected by a
medication error at Visit 2 in Section 6.6.
Provided further clarification regarding
discontinuation of study intervention in
Section 7.1.

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Version Date

Summary and Rationale for Changes






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Protocol amendment 6(Germany-specific)

23 September 2020

Protocol amendment 6

08 September 2020









Modified the circumstances in which a local
NAAT result may be used in the COVID-19
case definition.
Added that 2 periods of potential COVID-19
symptoms within 4 days will be considered as asingle illness.
Provided guidance in Section 8.13 regarding
circumstances in which a SARS-CoV-2 test
might be required even if symptoms within 7days following each vaccination are consideredmore likely due to vaccine reactogenicity.
Made allowance in Section 8.13 for a second
SARS-CoV-2 test to be performed within thesame potential COVID-19 illness if it is inaccordance with routine practice.
Added Section 8.15 to describe the reporting of
SARS-CoV-2 test results and their implications
for participants receiving a second vaccine dose.
Added statistical hypothesis and power analysis
for evaluation of noninferiority of the immune
response to BNT162b2 in participants 12 to 15
years of age to the response in participants 16 to
25 years of age.
Amended scope of analyses of safety data in
Section 9.5.1.
Made various editorial changes.
According to regulatory request, inclusion
criterion 1 now specifies that participants lessthan 18 years of age will not be enrolled in theEU.
Reordered some procedures in the Phase 2/3
schedule of activities for consistency with themain body of the protocol.
Corrected the window for the 6-month follow-up
visit to be approximately 6 months after
Vaccination 2.
Reduced the volume of blood draws to ~20 mL.
Removed the need to have safety data reported
for participants to be included in the safety
objective assessment.
Added an exploratory objective to describe
safety, immunogenicity, and efficacy inparticipants with stable HIV disease.
Increased the sample size for Phase 2/3 to~43,998.
Clarified that inclusion criterion 4 (ie,participants at higher risk for acquiring COVID19) is applicable for Phase 2/3 only, andprovided some examples.

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Protocol amendment 5

24 July 2020

Removed exclusion criterion 2 (ie, known
infection with HIV, HCV, or HBV) for Phase 3
and added criteria for HIV-positive participants.
 Decreased the lower age limit and removed theupper age limit for inclusion in Phase 2/3 inorder to evaluate BNT162b2 30 µg in older
adolescents and those over 85 years of age;
updated the title and other references to adults toalign with this change.
 Renamed the immunological assays to alignwith other program-level documents.
 Removed reference to the SARS-CoV-2 fulllength, P2 mutant, prefusion spike glycoprotein(P2 S) being “heads up.” Clarified that a positive SARS-CoV-2 NAAT
result without symptoms should not result in
discontinuation of study intervention.
 Added clarification that potential COVID-19
illnesses that are consistent with the clinicalendpoint definition should not be recorded asAEs.
 Updated the analysis population descriptions toalign with the study SAP.
Following regulatory feedback: Renamed Stage 1 to Phase 1, removed Stage 2,
and renamed Stage 3 to Phase 2/3.
 Clarified that a single vaccine candidate,administered as 2 doses 21 days apart, will be
studied in Phase 2/3.
 Stated that the vaccine candidate selected forPhase 2/3 evaluation is BNT162b2 at a dose of
30 µg.
 Removed the potential to study BNT162b3.
 Immunogenicity data will be summarized for the
first 360 participants through 1 month after Dose2, rather than through 21 days after Dose 1.
 Provided further details of sponsor staff that will
be unblinded in Phase 2/3.
 Clarified which stopping rules apply to which
phase of the study.
In addition:
 Clarified the AE reporting requirements forpotential COVID-19 illnesses.
 Updated that Visit 1 may be conducted across 2
consecutive days in Phase 2/3.
 Moved the immunogenicity objectives inPhase 2/3 to become exploratory.

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Protocol amendment 4

30 June 2020

Added an additional inclusion criterion to enroll
participants who, in the judgment of theinvestigator, are at risk for acquiring COVID-19.
 Modified exclusion criterion 5, so thatparticipants with a previous clinical or
microbiological diagnosis of COVID-19 are
excluded from all phases of the study.
 Clarified that there will be 2 all-available
efficacy populations.
 Clarified that immunogenicity samples will bedrawn for all participants; analyses will be based
upon results from subsets of samples, according
to the purpose.
 Updated that the 3-tier approach to summarizing
AEs will only be performed in Phase 2/3.
 Updated that at each interim analysis for
efficacy, only the first primary objective will be
evaluated.
 Changed to use the same posterior probability(99.5%) for all interim analyses, resulting incase split changes in Tables 5, 6, and 7.
 Updated the stopping and alert rule parameters
for enhanced COVID-19.
Given the rapidly evolving pandemic situation, andthe need to demonstrate VE as soon as possible, theprotocol has been amended to be powered to meet
new efficacy objectives. These new efficacy
objectives and corresponding endpoints have been
added to Section 3.
Further nonclinical data are available to support the
study of the BNT162b3 candidate in humans, and thecandidate has been added to the protocol.
The 6-month safety follow-up telephone contact has
been changed to an in-person visit for Stage 3
participants, to allow collection of an
immunogenicity blood sample.
The COVID-19 illness visit has now added
flexibility to permit a remote or in-person visit.
The COVID-19 illness symptoms have been updated
to align with the FDA-accepted definitions; thischange is also reflected in the criteria for temporary
delay of enrollment.
AEs that occur between consent and dosing will now
be reported on the AE (rather than Medical History)

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Summary and Rationale for Changes
CRF, to align with the latest Pfizer protocol
template.
Changes have been made to the headings to alignwith the latest Pfizer protocol template.
Clarified that only an unblinded site staff member
may obtain the participant’s randomization number
and study intervention allocation.
Additional interim analyses have been added toevaluate VE and futility during the study.

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)

Protocol amendment 3

10 June 2020

As a result of regulatory feedback, an appendix has
been added to outline the stopping and alert rules tomonitor for potential enhanced COVID-19.
As data have become available from this study andthe BNT162-01 study in Germany, the following
decisions were made: Not to study the BNT162a1 and BNT162c2
vaccine candidates at this time. Therefore, thesecandidates have been removed from theprotocol.
 To study further lower dose levels of the
modRNA candidates. Therefore, a 20-µg doselevel is formally included for BNT162b1 and
BNT162b2.
 To permit individual and group dosing
alterations for the second dose of study
intervention.
Following regulatory feedback, the BNT162b3
vaccine candidate has been removed from theprotocol until further nonclinical data are available tosupport study in humans.
Given the rapidly evolving pandemic situation,
additional blood draws for exploratory COVID-19
research, intended to establish an immunologicalsurrogate of protection, will be taken from selectedparticipants who consent.
In order to increase flexibility enrolling participants,
an extended screening window (increased from 14 to
28 days) for sentinel participants in Stage 1 has been
added. This is considered acceptable since eligible
participants are expected to be either healthy or havestable medical conditions.

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To increase the number of doses that can be obtained
from available vaccine vials, not all dose levels will
result in a dosing volume of 0.5 mL. Precise dosing
instructions will be provided in the IP manual.

Protocol amendment 2

27 May 2020

Protocol amendment 1

13 May 2020

To facilitate the reporting of COVID-19 illness
diagnoses and potential symptoms to theinvestigator, participants may utilize a COVID-19
illness e-diary.
Given the urgent nature of the pandemic situation,
the following changes allow determination of theappropriate human dose level for both younger andolder adults to move speedily into the next phase ofclinical evaluation:
 Added a new vaccine candidate, BNT162b3,
modRNA encoding a membrane-anchored RBD
 Added a 50-µg dose level for vaccine candidates
based on the modRNA platform (ie, BNT162b1,
BNT162b2, and BNT162b3)
 Modified the criteria required for the IRC todetermine dose escalation in the 18- to 55-year
age cohort and advancement to groups ofparticipants 65 to 85 years of age
In addition:
 Removed hemoglobin change-from-baseline
abnormalities from the laboratory abnormality
grading scale as abnormalities should be gradedbased upon absolute values
 Following regulatory feedback: Modified exclusion criteria and prohibitedinhaled/nebulized corticosteroids for sentinel
participants in Stage 1
 Clarified that the rapid test for prior COVID-19
infection for sentinel participants in Stage 1 will
be used only for screening purposes Removed time frames for stopping rules
 Stated that data supporting the selection of
vaccine candidate(s)/dose level(s) andschedule(s) for Stages 2 and 3 will be submitted
to the FDA for review

Following preliminary experience in the
BioNTech study conducted in Germany(BNT162-01):
Decreased the dose levels for BNT162a1 and
BNT162c2

Additionally: Clarified the roles of BioNTech and Pfizer
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Document History
Document

Version Date

Summary and Rationale for Changes
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Amended text so that the IRC decision toprogress group(s) into Stages 2 and 3 can bebased upon safety and immunogenicity data
after Dose 1 or 2
Clarified safety data requirements to permit dose
escalation
Amended text so that the progression toparticipants 65 to 85 years of age can be based
upon data from the same RNA platform
Incorporated a protocol administrative change tocorrect the variant designation and the encoded
antigen to BNT162c2
Clarified that the SARS-CoV-2 neutralizing
assay does not employ wild-type virus
Clarified that the SARS-CoV-2 spike protein–binding antibody assay is specific for the S1subunitClarified that efficacy against COVID-19 isbased upon illness (not infection) rate ratio
Incorporated a protocol administrative change tostate that the study placebo may be supplied in a
glass or plastic vial
Corrected a typographical error in Section 6.5.1
regarding the time frame for prior receipt ofblood/plasma products or immunoglobulins
Corrected a typographical error in Table 2
regarding the lower limit of diameter (cm) for
mild redness and swelling
Updated the °C fever scale in Table 4 to ensurethat all potential °F values are correctly assigned
Incorporated a protocol administrative change toclarify that a rapid test for prior COVID-19
infection will be performed for sentinel
participants in Stage 1, and a serum sample will
be drawn for potential future assessment
Clarified that, after screening, physicalexaminations in sentinel participants in Stage 1
will be directed
Clarified the descriptions of the populations foranalysis to align with the statistical analysis plan
Added a complete safety and immunogenicity
analysis approximately 6 months after Dose 2
for all participants in Stage 3
Amended text so that the stopping rules apply to
an RNA platform rather than a specific vaccine
candidate

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Document History
Document
Original protocol

Version Date
15 April 2020

Summary and Rationale for Changes
N/A090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)This amendment incorporates all revisions to date, including amendments made at therequest of country health authorities and IRBs/ECs.

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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................15
1. PROTOCOL SUMMARY...................................................................................................17
1.1. Synopsis ..................................................................................................................17
1.2. Schema ....................................................................................................................24
1.3. Schedule of Activities .............................................................................................25
1.3.1. Phase 1 ........................................................................................................25
1.3.2. Phase 2/3.....................................................................................................30
2. INTRODUCTION ...............................................................................................................33
2.1. Study Rationale .......................................................................................................33
2.2. Background .............................................................................................................33
2.2.1. Clinical Overview.......................................................................................34

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2.3. Benefit/Risk Assessment.........................................................................................34
2.3.1. Risk Assessment .........................................................................................36
2.3.2. Benefit Assessment.....................................................................................38
2.3.3. Overall Benefit/Risk Conclusion................................................................38
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................38
3.1. For Phase 1 ..............................................................................................................38
3.2. For Phase 2/3 ...........................................................................................................40
4. STUDY DESIGN.................................................................................................................424.1. Overall Design.........................................................................................................424.1.1. Phase 1 ........................................................................................................43
4.1.2. Phase 2/3.....................................................................................................44
4.2. Scientific Rationale for Study Design .....................................................................45
4.3. Justification for Dose ..............................................................................................45
4.4. End of Study Definition ..........................................................................................46
5. STUDY POPULATION ......................................................................................................47
5.1. Inclusion Criteria.....................................................................................................47
5.2. Exclusion Criteria....................................................................................................48
5.3. Lifestyle Considerations..........................................................................................50
5.3.1. Contraception..............................................................................................50

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5.4. Screen Failures ........................................................................................................50
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study
Intervention Administration ......................................................................................51
6. STUDY INTERVENTION..................................................................................................51
6.1. Study Intervention(s) Administered ........................................................................52
6.1.1. Manufacturing Process ...............................................................................53
6.1.2. Administration ............................................................................................53
6.2. Preparation/Handling/Storage/Accountability ........................................................53
6.2.1. Preparation and Dispensing ........................................................................54
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................55
6.3.1. Allocation to Study Intervention ................................................................55
6.3.2. Blinding of Site Personnel ..........................................................................55
6.3.3. Blinding of the Sponsor ..............................................................................55
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6.3.4. Breaking the Blind......................................................................................56
6.4. Study Intervention Compliance...............................................................................56
6.5. Concomitant Therapy..............................................................................................57
6.5.1. Prohibited During the Study .......................................................................57
6.5.2. Permitted During the Study ........................................................................58
6.6. Dose Modification...................................................................................................58
6.7. Intervention After the End of the Study ..................................................................59
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANTDISCONTINUATION/WITHDRAWAL...........................................................................59
7.1. Discontinuation of Study Intervention ....................................................................59
7.2. Participant Discontinuation/Withdrawal From the Study .......................................59
7.2.1. Withdrawal of Consent ...............................................................................60
7.3. Lost to Follow-up ....................................................................................................60
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................61
8.1. Efficacy and/or Immunogenicity Assessments .......................................................62
8.1.1. Biological Samples .....................................................................................64
8.2. Safety Assessments .................................................................................................65
8.2.1. Clinical Safety Laboratory Assessments (Phase 1 Participants Only) .......65
8.2.2. Electronic Diary..........................................................................................66
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8.2.2.1. Grading Scales...........................................................................66
8.2.2.2. Local Reactions .........................................................................66
8.2.2.3. Systemic Events ........................................................................67
8.2.2.4. Fever..........................................................................................68
8.2.2.5. Antipyretic Medication .............................................................69
8.2.3. Phase 1 Stopping Rules ..............................................................................69
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19
and Phase 2/3 Stopping Rule ...........................................................................70
8.2.5. Randomization and Vaccination After a Stopping Rule Is Met .................71
8.2.6. Pregnancy Testing ......................................................................................71
8.3. Adverse Events and Serious Adverse Events..........................................................72
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......72
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................73
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8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................73
8.3.2. Method of Detecting AEs and SAEs ..........................................................73
8.3.3. Follow-up of AEs and SAEs.......................................................................73
8.3.4. Regulatory Reporting Requirements for SAEs...........................................74
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational
Exposure ..........................................................................................................74
8.3.5.1. Exposure During Pregnancy......................................................74
8.3.5.2. Exposure During Breastfeeding ................................................76
8.3.5.3. Occupational Exposure .............................................................76
8.3.6. Cardiovascular and Death Events...............................................................76
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not
Qualifying as AEs or SAEs..............................................................................77
8.3.8. Adverse Events of Special Interest .............................................................77
8.3.8.1. Lack of Efficacy ........................................................................77
8.3.9. Medical Device Deficiencies......................................................................77
8.3.10. Medication Errors .....................................................................................77
8.4. Treatment of Overdose............................................................................................78
8.5. Pharmacokinetics ....................................................................................................79
8.6. Pharmacodynamics..................................................................................................79
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8.7. Genetics ...................................................................................................................79
8.8. Biomarkers ..............................................................................................................79
8.9. Immunogenicity Assessments .................................................................................79
8.10. Health Economics .................................................................................................79
8.11. Study Procedures...................................................................................................79
8.11.1. Phase 1 ......................................................................................................79
8.11.1.1. Screening: (0 to 28 Days Before Visit 1) ................................79
8.11.1.2. Visit 1 – Vaccination 1: (Day 1) .............................................81
8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1to 3 Days After Visit 1) .....................................................................83
8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to
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8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1) ...........85
8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to
8 Days After Visit 4) .........................................................................87
8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to
16 Days After Visit 4) .......................................................................89
8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After
Visit 4) ...............................................................................................90
8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (175 to 189 Days
After Visit 4)......................................................................................90
8.11.1.10. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 4)......................................................................................91
8.11.1.11. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 4)......................................................................................91
8.11.2. Phase 2/3...................................................................................................92
8.11.2.1. Visit 1 – Vaccination 1: (Day 1) .............................................92
8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days After Visit 1) ...........94
8.11.2.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2):(28 to 35 Days After Visit 2).............................................................96
8.11.2.4. Visit 4 – 6-Month Follow-up Visit: (175 to 189 Days
After Visit 2)......................................................................................97
8.11.2.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 2)......................................................................................98

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8.11.2.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 2)......................................................................................98
8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction ........................99
8.13. COVID-19 Surveillance (All Participants) .........................................................100
8.13.1. Potential COVID-19 Illness Visit: (Optimally Within 3 Days After
Potential COVID-19 Illness Onset) ...............................................................101
8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After
Potential COVID-19 Illness Visit)................................................................102
8.14. Communication and Use of Technology.............................................................103
8.15. SARS-CoV-2 NAAT Results From Visits 1 and 2 and Potential COVID-19
Illness Visits ............................................................................................................104
9. STATISTICAL CONSIDERATIONS ..............................................................................104
9.1. Estimands and Statistical Hypotheses ...................................................................105
9.1.1. Estimands..................................................................................................105
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9.1.2. Statistical Hypotheses...............................................................................105
9.1.2.1. Statistical Hypothesis Evaluation for Efficacy........................105
9.1.2.2. Statistical Hypothesis Evaluation for Immunogenicity...........105
9.2. Sample Size Determination...................................................................................106
9.3. Analysis Sets .........................................................................................................1089.4. Statistical Analyses ...............................................................................................1089.4.1. Immunogenicity Analyses ........................................................................109
9.4.2. Efficacy Analyses .....................................................................................114
9.4.3. Safety Analyses ........................................................................................115
9.4.4. Other Analyses..........................................................................................117
9.5. Interim Analyses ...................................................................................................117
9.5.1. Analysis Timing........................................................................................120
9.6. Data Monitoring Committee or Other Independent Oversight Committee...........120
10. SUPPORTING DOCUMENTATION AND OPERATIONALCONSIDERATIONS ........................................................................................................122
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .............122
10.1.1. Regulatory and Ethical Considerations ..................................................122
10.1.1.1. Reporting of Safety Issues and Serious Breaches of theProtocol or ICH GCP.......................................................................122
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10.1.2. Informed Consent Process ......................................................................123
10.1.3. Data Protection .......................................................................................124
10.1.4. Dissemination of Clinical Study Data ....................................................124
10.1.5. Data Quality Assurance ..........................................................................125
10.1.6. Source Documents ..................................................................................127
10.1.7. Study and Site Start and Closure ............................................................127
10.1.8. Sponsor’s Qualified Medical Personnel .................................................128
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................129
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting ....................................................................131
10.3.1. Definition of AE .....................................................................................131
10.3.2. Definition of SAE ...................................................................................132
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.....................134
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10.3.4. Reporting of SAEs..................................................................................137
10.4. Appendix 4: Contraceptive Guidance .................................................................138
10.4.1. Male Participant Reproductive Inclusion Criteria ..................................138
10.4.2. Female Participant Reproductive Inclusion Criteria...............................138
10.4.3. Woman of Childbearing Potential ..........................................................139
10.4.4. Contraception Methods...........................................................................140
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ......142
10.6. Appendix 6: Abbreviations .................................................................................144
10.7. Appendix 7: Stopping and Alert Rules for Enhanced COVID-19 ......................148
10.8. Appendix 8: Criteria for Allowing Inclusion of Participants With Chronic
Stable HIV, HCV, or HBV Infection ......................................................................151
11. REFERENCES ................................................................................................................152
LIST OF TABLES
Table 1.

Local Reaction Grading Scale ..................................................................67

Table 2.

Systemic Event Grading Scale..................................................................68

Table 3.

Scale for Fever..........................................................................................69

Table 4.

Power Analysis for Noninferiority Assessment .....................................107

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Table 5.

Probability of Observing at Least 1 AE by Assumed True Event
Rates With Different Sample Sizes ........................................................107

Table 6.

Interim Analysis Plan and Boundaries for Efficacy and Futility............118

Table 7.

Statistical Design Operating Characteristics: Probability of Successor Failure for Interim Analyses...............................................................119

Table 8.

Statistical Design Operating Characteristics: Probability of Successfor Final Analysis and Overall................................................................119

Table 9.

Laboratory Abnormality Grading Scale .................................................129

Table 10.

Stopping Rule: Enrollment Is Stopped if the Number of Severe
Cases in the Vaccine Group Is Greater Than or Equal to the
Prespecified Stopping Rule Value (S) ....................................................149

Table 11.

Alert Rule: Further Action Is Taken if the Number of Severe Casesin the Vaccine Group Is Greater Than or Equal to the Prespecified
Alert Rule Value (A) ..............................................................................150

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1. PROTOCOL SUMMARY
1.1. Synopsis
Short Title: A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, andEfficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Individuals
Rationale

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A pneumonia of unknown cause detected in Wuhan, China, was first reported in
December 2019. On 08 January 2020, the pathogen causing this outbreak was identified as anovel coronavirus 2019. The outbreak was declared a Public Health Emergency ofInternational Concern on 30 January 2020. On 12 February 2020, the virus was officiallynamed as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the WHO
officially named the disease caused by SARS-CoV-2 as coronavirus disease 2019
(COVID-19). On 11 March 2020, the WHO upgraded the status of the COVID-19 outbreakfrom epidemic to pandemic, which is now spreading globally at high speed.
There are currently no licensed vaccines to prevent infection with SARS-CoV-2 or
COVID-19. Given the rapid transmission of COVID-19 and incidence of disease in the
United States and elsewhere, the rapid development of an effective vaccine is of utmost
importance.
BioNTech has developed RNA-based vaccine candidates using a platform approach thatenables the rapid development of vaccines against emerging viral diseases, including
SARS-CoV-2. Each vaccine candidate is based on a platform of nucleoside-modified
messenger RNA (modRNA, BNT162b). Each vaccine candidate expresses 1 of 2 antigens:the SARS-CoV-2 full-length, P2 mutant, prefusion spike glycoprotein (P2 S) (version 9) or atrimerized SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) (version 5).
The 2 SARS-CoV-2 vaccine candidates that will be tested in this study are therefore:
BNT162b1 (variant RBP020.3): a modRNA encoding the RBD;
BNT162b2 (variant RBP020.2): a modRNA encoding P2 S.
All candidates are formulated in the same lipid nanoparticle (LNP) composition. This study
is intended to investigate the safety, immunogenicity, and efficacy of these prophylactic
BNT162 vaccines against COVID-19.

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Objectives, Estimands, and Endpoints

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Objectives

Estimands

Endpoints

Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Primary:
In participants receiving at least 1 doseof study intervention, the percentage ofparticipants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each doseAdverse events (AEs) from
Dose 1 to 1 month after the lastdose
 Serious AEs (SAEs) from Dose 1
to 6 months after the last doseIn addition, the percentage ofparticipants with:
Abnormal hematology andchemistry laboratory values 1 and7 days after Dose 1; and 7 days
after Dose 2
Grading shifts in hematology andchemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2
Secondary:In participants complying with the key
protocol criteria (evaluableparticipants) at the following time
points after receipt of study
intervention:

Primary:
Local reactions (pain at the
injection site, redness, andswelling)

Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs

Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Hematology and chemistry laboratory
parameters detailed in Section 10.2

Secondary:

7 and 21 days after Dose 1; 7 and 14
days and 1, 6, 12, and 24 months after
Dose 2

Geometric mean titers (GMTs) at SARS-CoV-2 neutralizing titers
each time point
Geometric mean fold rise (GMFR)
from before vaccination to eachsubsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination

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Objectives

Estimands







Endpoints

S1-binding IgG levels andGeometric mean concentrations
RBD-binding IgG levels(GMCs) at each time point
GMFR from before vaccination toeach subsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
Geometric mean ratio (GMR),
SARS-CoV-2 neutralizing titers
estimated by the ratio of theS1-binding IgG levels
geometric mean of SARS-CoV-2 
RBD-binding IgG levels
neutralizing titers to the geometricmean of binding IgG levels at eachtime point

For Phase 2/3

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Objectivesa

Estimands
Primary Efficacy

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 in participants
without evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 in participants
with and without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To define the safety profile ofprophylactic BNT162b2 in the first
360 participants randomized (Phase 2)

In participants receiving at least 1
dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 7 days after
the last dose
SAEs from Dose 1 to 7 days
after the last dose

Endpoints
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of thesecond dose) of past SARS-CoV-2
infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT

Primary Safety






Local reactions (pain at the
injection site, redness, andswelling)
Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened
muscle pain, and new orworsened joint pain)
AEs
SAEs

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Objectivesa

Estimands

To define the safety profile ofprophylactic BNT162b2 in allparticipants randomized in Phase 2/3

In participants receiving at least
1 dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the last dose
 SAEs from Dose 1 to 6 months
after the last dose

To define the safety profile ofprophylactic BNT162b2 inparticipants 12 to 15 years of age inPhase 3

In participants receiving at least
1 dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the last dose
 SAEs from Dose 1 to 6 months
after the last dose

Endpoints







AEs
SAEs
In a subset of at least 6000
participants:
o Local reactions (pain at the
injection site, redness, andswelling)o Systemic events (fever,fatigue, headache, chills,
vomiting, diarrhea, new orworsened muscle pain, andnew or worsened joint pain)
Local reactions (pain at the
injection site, redness, andswelling)
Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened
muscle pain, and new orworsened joint pain)
AEs
SAEs

Secondary Efficacy
To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed severe COVID-19 inparticipants without evidence of
infection before vaccination
To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed severe COVID-19 inparticipants with and without
evidence of infection before
vaccination
To describe the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms) inparticipants without evidence of
infection before vaccination
To describe the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms) inparticipants with and without
evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

Confirmed severe COVID-19
incidence per 1000 person-years offollow-up in participants with noserological or virological evidence of
past SARS-CoV-2 infection
Confirmed severe COVID-19
incidence per 1000 person-years offollow-up

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of thesecond dose) of past SARS-CoV-2
infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAATCONFIDENTIAL
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Objectivesa

Estimands
Secondary Immunogenicity

Endpoints

To demonstrate the noninferiority of
the immune response to prophylactic
BNT162b2 in participants 12 to 15
years of age compared to participants
16 to 25 years of age

GMR, estimated by the ratio of thegeometric mean of SARS-CoV-2
neutralizing titers in the 2 age groups(12-15 years of age to 16-25 years ofage) 1 month after completion of
vaccination

SARS-CoV-2 neutralizing titers inparticipants with no serological or
virological evidence (up to 1 monthafter receipt of the second dose) of
past SARS-CoV-2 infection

To evaluate the immune responseover time to prophylactic BNT162b2
and persistence of immune response
in participants with and without
serological or virological evidence of
SARS-CoV-2 infection before
vaccination
To evaluate the immune response(non-S) to SARS-CoV-2 inparticipants with and without
confirmed COVID-19 during thestudy
To describe the serological responses
to the BNT vaccine candidate in casesof:
Confirmed COVID-19

Confirmed severe COVID-19

SARS-CoV-2 infection without
confirmed COVID-19
To describe the safety,
immunogenicity, and efficacy ofprophylactic BNT162b2 in
individuals with confirmed stable HIV
diseaseTo describe the safety andimmunogenicity of prophylactic
BNT162b2 in individuals 16 to 55
years of age vaccinated with study
intervention produced bymanufacturing “Process 1” or“Process 2”b

GMC/GMT, GMFR, and percentageof participants with titers greater thandefined threshold(s), at baseline and1, 6, 12, and 24 months after
completion of vaccination

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Exploratory

a.
b.





S1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titersN-binding antibody

S1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titersAll safety, immunogenicity, andefficacy endpoints described
above



All safety endpoints describedabove
SARS-CoV-2 neutralizing titersHIV-positive participants in Phase 3 will not be included in analyses of the objectives, with the
exception of the specific exploratory objective.
See Section 6.1.1 for a description of the manufacturing process.

Overall Design
This is a Phase 1/2/3, multicenter, multinational, randomized, placebo-controlled,
observer-blind, dose-finding, vaccine candidate–selection, and efficacy study in healthy
individuals.
The study consists of 2 parts: Phase 1: to identify preferred vaccine candidate(s) and doselevel(s); Phase 2/3: an expanded cohort and efficacy part. These parts, and the progression
between them, are detailed in the schema (Section 1.2).
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The study will evaluate the safety, tolerability, and immunogenicity of 2 different
SARS-CoV-2 RNA vaccine candidates against COVID-19 and the efficacy of 1 candidate:

As a 2-dose (separated by 21 days) schedule;At various different dose levels in Phase 1;



In 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3: ≥12years of age [stratified as 12-15, 16-55, or >55 years of age]).

Dependent upon safety and/or immunogenicity data generated during the course of thisstudy, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
in Phase 1 may be started at the next highest dose, groups may not be started, groups may beterminated early, and/or groups may be added with dose levels below the lowest stated doseor intermediate between the lowest and highest stated doses.
The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.

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Number of Participants
Each group in Phase 1 will comprise 15 participants (12 receiving active vaccine and3 receiving placebo). In this phase, 13 groups will be studied, corresponding to a total of
195 participants.
The vaccine candidate selected for Phase 2/3, BNT162b2 at a dose of 30 µg, will comprise
21,999 vaccine recipients. The 12- to 15-year stratum will comprise up to approximately
2000 participants (1000 vaccine recipients) enrolled at selected investigational sites. It is
intended that a minimum of 40% of participants will be in the >55-year stratum. An equal
number of participants will receive placebo, ie, randomized in a 1:1 ratio.
Intervention Groups and Duration
The study will evaluate a 2-dose (separated by 21 days) schedule of various different doselevels of 2 investigational RNA vaccine candidates for active immunization against
COVID-19 in 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3:
≥12 years of age [stratified as 12-15, 16-55, or >55 years of age]):

BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 20 µg, 30 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 20 µg, 30 µg

The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.

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Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Phase 1
dosing arms that are not evaluated in Phase 2/3.
Data Monitoring Committee or Other Independent Oversight Committee
The study will utilize an IRC, an internal Pfizer committee that will review data to allow
dose escalation or changes to continuation of specific groups.
An external data monitoring committee (DMC) will be formed and will review cumulative
unblinded data throughout the study.
Statistical Methods

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)The sample size for Phase 1 of the study is not based on any statistical hypothesis testing.
For Phase 2/3, the VE evaluation will be the primary objective. The VE is defined as
VE = 100 × (1 – IRR), where IRR is calculated as the ratio of the first confirmed COVID-19
illness rate in the vaccine group to the corresponding illness rate in the placebo group. Withassumptions of a true VE of 60% and 4 IAs planned, 164 COVID-19 cases will provide 90%
power to conclude true VE >30%. This would be achieved with a total 43,998 participants(21,999 vaccine recipients), based on the assumption of a 1.3% per year incidence in theplacebo group, accrual of 164 primary-endpoint cases within 6 months, and 20% of theparticipants being nonevaluable. If the attack rate is much higher, case accrual would be
expected to be more rapid, enabling the study’s primary endpoint to be evaluated muchsooner. The total number of participants enrolled in Phase 2/3 may vary depending on theincidence of COVID-19 at the time of the enrollment, the true underlying VE, and a potential
early stop for efficacy or futility.
VE will be evaluated using a beta-binomial model and the posterior probability of VE being>30% will be assessed.
In Phase 3, up to approximately 2000 participants are anticipated to be 12 to 15 years of age.
Noninferiority of immune response to prophylactic BNT162b2 in participants 12 to 15 yearsof age to response in participants 16 to 25 years of age will be assessed based on the GMR of
SARS-CoV-2 neutralizing titers using a 1.5-fold margin. A sample size of 200 evaluableparticipants (or 250 vaccine recipients) per age group will provide a power of 90.8% todeclare the noninferiority in terms of GMR (lower limit of 95% CI for GMR >0.67).
The primary safety objective will be evaluated by descriptive summary statistics for local
reactions, systemic events, AEs/SAEs, and abnormal hematology and chemistry laboratory
parameters (Phase 1 only), for each vaccine group. A 3-tier approach will be used tosummarize AEs in Phase 2/3.
Except for the objective to assess the noninferiority of immune response in participants 12 to
15 years of age compared to participants 16 to 25 years of age, the other immunogenicity
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objectives will be evaluated descriptively by GMT, GMC, GMFR, percentage of participants
with ≥4-fold rise, percentage of participants with ≥ specified threshold, and GMC ratio, andthe associated 95% confidence intervals (CIs), for SARS-CoV-2 neutralizing titers,
S1-binding IgG levels, and/or RBD-binding IgG levels at the various time points.
1.2. Schema
Phase 1For each vaccine candidate(4:1 randomization active:placebo)

Age: 18-55 yAge: 65-85 y

Low-dose-level 2-dose group (n=15)
IRC (safety)

IRC (safety

Low-dose-level 2-dose group (n=15)

after Dose 1)
Mid-dose-level 2-dose group (n=15)
IRC (safety)

IRC (safety

Mid-dose-level 2-dose group (n=15)

after Dose 1)
High-dose-level 2-dose group (n=15)
IRC (safety

High-dose-level 2-dose group (n=15)

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after Dose 1)
IRC choice of group(s) for Phase 2/3(safety & immunogenicity after Doses 1 and 2)

Phase 2/3
Single vaccine candidate
Safety and immunogenicity analysis of
Age: ≥12
Phase 2 data (first 360 participants)(Stratified 12-15, 16-55, or >55)
BNT162b2 30 µg or placebo 2 doses
by unblinded team (these participants(n~21,999 per group, total n~43.998)
will also be included in Phase 3
analyses)Abbreviation: IRC = internal review committee.

(1:1 randomization active:placebo)

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1.3. Schedule of Activities

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with theprotocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations orassessments required to protect the well-being of the participant.
1.3.1. Phase 1
An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 10 (24-month follow-up visit) that COVID-19 is suspected.
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

X

X

X

X

X

Obtain informed consent

X

Assign participant number

X

Obtain demography andmedical history data

X

Obtain details of medications
currently taken

X

Perform physical examination

X

2

3

4

5

6

7

8

10

Unplanned

Unplanned

12 to 16 28 to 35 175 to
350 to714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4COVID-19 Illness Visit
Illness
Onset

X

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Protocol Amendment 8, 15 October 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

Measure vital signs(including body temperature)

X

X

X

X

X

X

Collect blood sample forhematology and chemistrylaboratory testsb~10 mL~10 mL~10 mL~10 mL~10 mL

Collect screening blood
sample for HIV, HBsAg,
HBc Ab, and HCV Ab tests~10 mL

Serological test for prior
COVID-19 infection~20 mL

Perform urine pregnancy test
(if appropriate)X

Obtain nasal (midturbinate)swab(s)c

2

3

4

X

X

X

X

Collect nonstudy vaccine
information

X

X

Confirm eligibility

X

X

Collect prohibited medication
use

X

X

Review temporary delay
criteria

X

X

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 175 to
350 to714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4COVID-19 Illness Visit
Illness
Onset
X

X
X

X

X

X

X

X

X
X

Review hematology andchemistry results

X

5

X

X

X

X

X

X

X

X

X

X

X

X

X

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Protocol Amendment 8, 15 October 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

4

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

Confirm use of contraceptives(if appropriate)

X

X

X

X

X

X

~50 mL~50 mL

Obtain randomization number
and study intervention
allocation

X

Collect blood sample for
immunogenicity assessment~50 mL

Administer study intervention

X

X

Assess acute reactions for atleast 30 minutes after study
intervention administrationd

X

X

Explain participant
communication methods(including for e-diarycompletion), assist theparticipant with downloading
the app, or issue provisioned
device, if required

X

Provide thermometer andmeasuring device

X

5

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 175 to
350 to714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4COVID-19 Illness Visit
Illness
Onset
X

X~50 mL ~50 mL ~50 mL ~20 mL+++
optionale optionale optionale~170 mL ~170 mL ~170 mL~20 mL~20 mL~20 mL

X

Review reactogenicity e-diarydata (daily review is optimal
during the active diary period)

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Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 46 to 8Days
After
Visit 1

Review ongoingreactogenicity e-diary
symptoms and obtain stopdatesCollect AEs and SAEs as
appropriate

4

5

X

X

X

X

X

X

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 175 to
350 to714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4COVID-19 Illness Visit
Illness
Onset
X

X

X

X

X

Collect e-diary or assist theparticipant to delete
application

X

X

X

X

X

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Protocol Amendment 8, 15 October 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 46 to 8Days
After
Visit 1

4

5

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 175 to
350 to714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4COVID-19 Illness Visit
Illness
Onset

Collection of
COVID-19–related clinicaland laboratory information(including local diagnosis)

X

X

Abbreviations: e-diary = electronic diary; HBc Ab = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HCV Ab = hepatitis C virus antibody;
HIV = human immunodeficiency virus; NAAT = nucleic acid amplification test; vax = vaccination.

a.
b.
c.
d.
e.

The COVID-19 illness visit may be conducted as an in-person or telehealth visit.
Hematology: hemoglobin, complete blood count with differential, and platelets. Blood chemistry: alanine aminotransferase (ALT), aspartate
aminotransferase (AST), alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), and creatinine.
Two swabs will be taken at Visits 1 and 4. One will be tested (if possible at the site, otherwise at the central laboratory) within 24 hours and vaccination will
only proceed if it is NAAT-negative for SARS-CoV-2 genomes. The second will be sent to the central laboratory for potential later testing.
The first 5 participants in in each group will be observed at the site for at least 4 hours after study intervention administration. Further vaccination willcommence no sooner than 24 hours after the fifth participant received his or her vaccination.
An optional blood draw of ~170 mL will be taken at 1 of the visits (from selected participants who consent) for exploratory COVID-19 research.

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1.3.2. Phase 2/3

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An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 6 (24-month follow-up visit) that potential COVID-19 symptoms are reported, including
MIS-C.
Visit Number

1

Visit Description

Day 1bVisit Window (Days)

Obtain informed consent

X

Assign participant number

X

Obtain demography and medical history data
Perform clinical assessment

2

3

4

5

6

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
Potential
COVID-19
COVID-19
Illness Visita ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2

175 to 189
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

X

X

X

Vaccination 1 Vaccination 2

X

For participants who are HIV-positive, record latest
CD4 count and HIV viral load

X

Measure height and weightX

Measure temperature (body)

X

X

Perform urine pregnancy test (if appropriate)

X

X

Confirm use of contraceptives (if appropriate)

X

X

X

Collect nonstudy vaccine information

X

X

X

X

X

X

X

X

X

~20 mL/~10 mL~20 mL/~10 mL~20 mL/~10 mL~20 mL/~10 mL

Collect prohibited medication use

X

Confirm eligibility

X

X

Review temporary delay criteria

X

X

Obtain nasal (midturbinate) swab

Unplanned

XcCollect blood sample for immunogenicity
assessmentd

Unplanned~20 mL/~10 mL
X

X

X

X~20 mL/~10 mLX

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Visit Number

1

Visit Description

Day 1bVisit Window (Days)

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2

3

4

5

6

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
Potential
COVID-19
COVID-19
Illness Visita ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2

175 to 189
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

Xf

Xf

Xf

Vaccination 1 Vaccination 2

Obtain randomization number and study
intervention allocation

X

Administer study intervention

X

X

Assess acute reactions for at least 30 minutes after
study intervention administration

X

X

Explain participant communication methods(including for e-diary completion), assist theparticipant with downloading the app, or issue
provisioned device, if required

X

Provide/ensure the participant has a thermometer(all participants) and measuring device(reactogenicity subset participants only)

X

Unplanned

Unplanned

X

Review reactogenicity e-diary data (daily review is
optimal during the active diary period)e
Review ongoing reactogenicity e-diary symptoms
and obtain stop dateseCollect AEs and SAEs as appropriate

X

X

X

X

X

Collect e-diary or assist the participant to delete
application

X

Xf

X

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Visit Number

1

Visit Description

Day 1bVisit Window (Days)

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2

3

4

5

6

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
Potential
COVID-19
COVID-19
Illness Visita ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2

175 to 189
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

Vaccination 1 Vaccination 2

Collection of COVID-19–related clinical andlaboratory information (including local diagnosis)

Unplanned

X

UnplannedX

Abbreviations: HIV = human immunodeficiency virus; e-diary = electronic diary.

a.
b.
c.
d.
e.
f.

The COVID-19 illness visit may be conducted as an in-person or telehealth visit.
The visit may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and exclusion criteria onwards must be conducted on thesame day.
Including, if indicated, a physical examination.
20 mL is to be collected from participants ≥16 years of age; 10 mL is to be collected from participants 12 to 15 years of age.
Reactogenicity subset participants only.
Any AEs occurring up to 48 hours after the blood draw must be recorded (see Section 8.3.1).

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2. INTRODUCTION
The BNT162 RNA-based COVID-19 vaccines are currently being investigated forprevention of COVID-19 in healthy individuals.
2.1. Study Rationale
The purpose of the study is to rapidly describe the safety, tolerability, and immunogenicity of
2 BNT162 RNA-based COVID-19 vaccine candidates against COVID-19, and the efficacyof 1 candidate, in healthy individuals. There are currently no licensed vaccines to prevent
infection with SARS-CoV-2 or COVID-19. Given the global crisis of COVID-19 and fast
expansion of the disease in the United States and elsewhere, the rapid development of aneffective vaccine is of utmost importance.

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2.2. Background
In December 2019, a pneumonia outbreak of unknown cause occurred in Wuhan, China.
In January 2020, it became clear that a novel coronavirus (2019-nCoV) was the underlying
cause. Later in January, the genetic sequence of the 2019-nCoV became available to theWorld Health Organization (WHO) and public (MN908947.3), and the virus was categorized
in the Betacoronavirus subfamily. By sequence analysis, the phylogenetic tree revealed acloser relationship to severe acute respiratory syndrome (SARS) virus isolates than to anothercoronavirus infecting humans, the Middle East respiratory syndrome (MERS) virus.
SARS-CoV-2 infections and the resulting disease, COVID-19, have spread globally,affecting a growing number of countries.
On 11 March 2020, the WHO characterized the COVID-19 outbreak as a pandemic.1
The WHO Situation Update Report dated 30 March 2020 noted 693,224 confirmed caseswith 33,106 deaths globally, including 142,081 confirmed cases with 2457 deaths in theAmericas.2 The United States currently has the most reported cases globally. At the time ofthis communication, the number of confirmed cases continues to rise globally. There are
currently no vaccines or effective antiviral drugs to treat SARS-CoV-2 infections or the
disease it causes, COVID-19.3
A prophylactic, RNA-based SARS-CoV-2 vaccine provides one of the most flexible andfastest approaches available to immunize against the emerging virus.4,5The development of an RNA-based vaccine encoding a viral antigen, which is then expressedby the vaccine recipient as a protein capable of eliciting protective immune responses,
provides significant advantages over more traditional vaccine approaches. Unlike live
attenuated vaccines, RNA vaccines do not carry the risks associated with infection and may
be given to people who cannot be administered live virus (eg, pregnant women andimmunocompromised persons). RNA-based vaccines are manufactured via a cell-free invitro transcription process, which allows an easy and rapid production and the prospect of
producing high numbers of vaccination doses within a shorter time period than achieved with

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traditional vaccine approaches. This capability is pivotal to enable the most effective
response in outbreak scenarios.
Two SARS-CoV-2–RNA lipid nanoparticle (RNA-LNP) vaccines based on a platform of
nucleoside-modified messenger RNA (modRNA, BNT162b) will be evaluated in this study.
Each vaccine candidate expresses 1 of 2 antigens: the SARS-CoV-2 full-length, P2 mutant,prefusion spike glycoprotein (P2 S) (version 9) or a trimerized SARS-CoV-2 spikeglycoprotein-receptor binding domain (RBD) (version 5). The 2 SARS-CoV-2 vaccine
candidates that will be tested in this study are therefore:

BNT162b1 (variant RBP020.3): nucleoside-modified messenger RNA (modRNA)with blunted innate immune sensor–activating capacity and augmented expression
encoding the RBD.



BNT162b2 (variant RBP020.2): nucleoside-modified messenger RNA (modRNA) as
above, but encoding P2 S.

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2.
2.2.1. Clinical Overview
Prior to this study, given clinical data from other similarly formulated uRNA liposomal
vaccines from BioNTech in oncology trials6 and recent published results from clinical trials
using modRNA influenza vaccines by Moderna,7 the BNT162 vaccines were expected tohave a favorable safety profile with mild, localized, and transient effects. BNT162 vaccines
based on modRNA have now been administered to humans for the first time in this study andthe BNT162-01 study conducted in Germany by BioNTech, at doses between 1 µg and100 µg. The currently available safety and immunogenicity data are presented in the BNT162
IB.
2.3. Benefit/Risk Assessment
There is an ongoing global pandemic of COVID-19 with no preventative or therapeutic
options available. While there were no data available from clinical trials on the use of
BNT162 vaccines in humans at the outset of this study, available nonclinical data with thesevaccines, and data from nonclinical studies and clinical trials with the same or related RNAcomponents, or antigens, supported a favorable risk/benefit profile. Anticipated AEs after
vaccination were expected to be manageable using routine symptom-driven standard of careas determined by the investigators and, as a result, the profile of these vaccine candidates
supported initiation of this Phase 1/2/3 clinical study.
Updates as part of protocol amendment 6:
In order for the overall Phase 3 study population to be as representative anddiverse as possible, the inclusion of participants with known chronic stable HIV,
HCV, or HBV infection is permitted. Individuals with chronic viral diseases are atincreased risk for COVID-19 complications and severe disease. In addition, with
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the currently available therapies for their treatment, many individuals with chronic
stable HIV, HCV, and HBV infections are unlikely to be at higher safety risk as aparticipant in this vaccine study than individuals with other chronic stable medical
conditions.
All participants with chronic stable HIV disease will be included in thereactogenicity subset (see Section 8.2.2).

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Updates as part of protocol amendment 7:
The minimum age for inclusion in Phase 3 is lowered to 12 years, therefore
allowing the inclusion of participants 12 to 15 years of age.



For individuals 12 to 15 years of age, the immune responses in this age group may
be higher and reactogenicity is expected to be similar to younger adults 18 to 25
years of age. Inclusion of individuals 12 to 15 years of age was based upon asatisfactory blinded safety profile in participants 18 to 25 years of age.

All participants 12 to 15 years of age will be included in the reactogenicity subset(see Section 8.2.2).

More detailed information about the known and expected benefits and risks and reasonably
expected AEs of BNT162 RNA-based COVID-19 vaccines may be found in the IB, which is
the SRSD for this study.

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2.3.1. Risk Assessment
Potential Risk of ClinicalSignificance

Summary of Data/Rationale for Risk

Mitigation Strategy

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Study Intervention: BNT162 RNA-Based COVID-19 Vaccine
Potential for local reactions (injection These are common adverse reactions seensite redness, injection site swelling, with other vaccines, as noted in the FDA
and injection site pain) and systemic Center for Biologics Evaluation andResearch (CBER) guidelines on toxicity
events (fever, fatigue, headache,
grading scales for healthy adult volunteers
chills, vomiting, diarrhea, muscle
pain, and joint pain) following
enrolled in preventive vaccine clinicalvaccination.
trials.8

The Phase 1 study design includes the use of controlled vaccination anddose escalation to closely monitor and limit the rate of enrollment to ensure
participant safety. The study employs the use of a reactogenicity e-diary tomonitor local reactions and systemic events in real time. Stopping rules arealso in place. The first 5 participants in each group in Phase 1 will beobserved for 4 hours after vaccination to assess any immediate AEs. Allother participants will be observed for at least 30 minutes after vaccination.

Unknown AEs and laboratory
abnormalities with a novel vaccine.

This study is one of the first 2
parallel-running clinical studies with the
BNT162 vaccine candidates and as suchthere are no clinical data available for this
vaccine.

The Phase 1 study design includes the use of controlled vaccination anddose escalation to closely monitor and limit the rate of enrollment to ensure
participant safety. An IRC (in Phase 1) and DMC (throughout the study)
will also review safety data. Stopping rules are also in place. The first 5
participants in each group in Phase 1 will be observed for 4 hours after
vaccination to assess any immediate AEs. All other participants will beobserved for at least 30 minutes after vaccination.

Potential for COVID-19
enhancement.

Disease enhancement has been seen
following vaccination with respiratorysyncytial virus (RSV), feline coronavirus,
and Dengue virus vaccines.

Phase 1 excludes participants with likely previous or current COVID-19. In
Phase 2/3, temporary delay criteria defer vaccination of participants withsymptoms of potential COVID-19. All participants are followed for any
potential COVID-19 illness, including markers of severity, and have blood
samples taken for potential measurement of SARS-CoV-2 antigen-specificantibody and SARS-CoV-2 neutralizing titers.

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Potential Risk of ClinicalSignificance

Summary of Data/Rationale for Risk

Mitigation Strategy

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Study Procedures
Participants will be required to attend Without appropriate social distancing andhealthcare facilities during the global PPE, there is a potential for increased
exposure to SARS-CoV-2.
SARS-CoV-2 pandemic.
Venipuncture will be performed
during the study.

There is the risk of bleeding, bruising,hematoma formation, and infection at the
venipuncture site.

Pfizer will work with sites to ensure an appropriate COVID-19 prevention
strategy. Potential COVID-19 illness visits can be conducted via telehealth,without the need for an in-person visit, if required, with the participant
performing a self-swab.
Only appropriately qualified personnel would obtain the blood draw.

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2.3.2. Benefit Assessment
Benefits to individual participants may include:Receipt of a potentially efficacious COVID-19 vaccine during a global pandemicAccess to COVID-19 diagnostic testingContributing to research to help others in a time of global pandemic

2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in thisstudy, the potential risks identified in association with BNT162 RNA-based COVID-19
vaccine are justified by the anticipated benefits that may be afforded to healthy participants.
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS

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3.1. For Phase 1
Objectives

Estimands

Endpoints

Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Primary:
In participants receiving at least 1 doseof study intervention, the percentage ofparticipants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each doseAdverse events (AEs) from
Dose 1 to 1 month after the lastdose
 Serious AEs (SAEs) from Dose 1
to 6 months after the last dosePrimary:
Local reactions (pain at the
injection site, redness, andswelling)

Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs

In addition, the percentage ofHematology and chemistry laboratory
participants with:parameters detailed in Section 10.2
Abnormal hematology andchemistry laboratory values 1 and7 days after Dose 1; and 7 days
after Dose 2
Grading shifts in hematology andchemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2

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Objectives

Estimands

Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Secondary:In participants complying with the key
protocol criteria (evaluableparticipants) at the following time
points after receipt of study
intervention: 7 and 21 days after Dose
1; 7 and 14 days and 1, 6, 12, and 24
months after Dose 2







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Endpoints
Secondary:

Geometric mean titers (GMTs) at SARS-CoV-2 neutralizing titers
each time point
Geometric mean fold rise (GMFR)
from before vaccination to eachsubsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
S1-binding IgG levels and RBDGeometric mean concentrations
binding IgG levels(GMCs) at each time point
GMFR from prior to first dose of
study intervention to eachsubsequent time point
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
Geometric mean ratio (GMR),estimated by the ratio of thegeometric mean of SARS-CoV-2 neutralizing titers to the geometric mean of binding IgG levels at
each time point

SARS-CoV-2 neutralizing titers
S1-binding IgG levels
RBD-binding IgG levels

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3.2. For Phase 2/3
Objectivesa

Estimands
Primary Efficacy

Endpoints

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 in participants
without evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 in participants
with and without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To define the safety profile ofprophylactic BNT162b2 in the first
360 participants randomized (Phase 2)

In participants receiving at least 1
dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 7 days after
the last dose
SAEs from Dose 1 to 7 days
after the last dose

To define the safety profile ofprophylactic BNT162b2 in allparticipants randomized in Phase 2/3

In participants receiving at least
1 dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the last dose
SAEs from Dose 1 to 6 months
after the last dose





AEs
SAEs
In a subset of at least 6000
participants:
o Local reactions (pain at the
injection site, redness, andswelling)o Systemic events (fever,fatigue, headache, chills,
vomiting, diarrhea, new orworsened muscle pain, andnew or worsened joint pain)

To define the safety profile ofprophylactic BNT162b2 inparticipants 12 to 15 years of age inPhase 3

In participants receiving at least
1 dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the last dose

Local reactions (pain at the
injection site, redness, andswelling)
Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened
muscle pain, and new orworsened joint pain)
AEs
SAEs

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of thesecond dose) of past SARS-CoV-2
infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT

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Primary SafetySAEs from Dose 1 to 6
months after the last dose











Local reactions (pain at the
injection site, redness, andswelling)
Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened
muscle pain, and new orworsened joint pain)
AEs
SAEs

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Objectivesa
To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed severe COVID-19 inparticipants without evidence of
infection before vaccination

Endpoints

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

Confirmed severe COVID-19
incidence per 1000 person-years offollow-up in participants with noserological or virological evidence of
past SARS-CoV-2 infection

To describe the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms) inparticipants without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To describe the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms) inparticipants with and without
evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of thesecond dose) of past SARS-CoV-2
infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT

To demonstrate the noninferiority of
the immune response to prophylactic
BNT162b2 in participants 12 to 15
years of age compared to participants
16 to 25 years of age

GMR, estimated by the ratio of thegeometric mean of SARS-CoV-2
neutralizing titers in the 2 age groups(12-15 years of age to 16-25 years ofage) 1 month after completion of
vaccination

To evaluate the immune responseover time to prophylactic BNT162b2
and persistence of immune response
in participants with and without
serological or virological evidence of
SARS-CoV-2 infection before
vaccination

GMC/GMT, GMFR, and percentageof participants with titers greater thandefined threshold(s), at baseline and1, 6, 12, and 24 months after
completion of vaccination

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed severe COVID-19 inparticipants with and without
evidence of infection before
vaccination

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Estimands
Secondary Efficacy

Confirmed severe COVID-19
incidence per 1000 person-years offollow-up

Secondary Immunogenicity
SARS-CoV-2 neutralizing titers inparticipants with no serological or
virological evidence (up to 1 monthafter receipt of the second dose) of
past SARS-CoV-2 infection

ExploratoryS1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titers

To evaluate the immune response(non-S) to SARS-CoV-2 inparticipants with and without
confirmed COVID-19 during the
study



N-binding antibody

To describe the serological responses
to the BNT vaccine candidate in casesof:
Confirmed COVID-19

Confirmed severe COVID-19

SARS-CoV-2 infection without
confirmed COVID-19



S1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titers



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Objectivesa

Estimands

To describe the safety,
immunogenicity, and efficacy ofprophylactic BNT162b2 in
individuals with confirmed stable
HIV disease
To describe the safety andimmunogenicity of prophylactic
BNT162b2 in individuals 16 to 55
years of age vaccinated with study
intervention produced bymanufacturing “Process 1” or“Process 2”ba.

EndpointsAll safety, immunogenicity, andefficacy endpoints described
above



All safety endpoints describedabove
SARS-CoV-2 neutralizing titersHIV-positive participants in Phase 3 will not be included in analyses of the objectives, with the
exception of the specific exploratory objective.
See Section 6.1.1 for description of the manufacturing process.

b.

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)This protocol will use a group of internal case reviewers to determine whether certain
investigator-reported events meet the definition of disease-related efficacy endpoints, using
predefined endpoint criteria.
For those AEs that are handled as disease-related efficacy endpoints (which may include
death), a DMC will conduct unblinded reviews on a regular basis throughout the trial(see Section 9.6).
Any AE that is determined by the internal case reviewers NOT to meet endpoint criteria isreported back to the investigator site of incidence. Refer to Section 8.3.1.1 for instructions
on how to report any such AE that meets the criteria for seriousness to Pfizer Safety.
4. STUDY DESIGN
4.1. Overall Design
This is a multicenter, multinational, Phase 1/2/3, randomized, placebo-controlled,
observer-blind, dose-finding, vaccine candidate–selection, and efficacy study in healthy
individuals.
The study consists of 2 parts. Phase 1: to identify preferred vaccine candidate(s) and doselevel(s); Phase 2/3: an expanded cohort and efficacy part. These parts, and the progression
between them, are detailed in the schema (Section 1.2).
The study will evaluate the safety, tolerability, and immunogenicity of 2 different
SARS-CoV-2 RNA vaccine candidates against COVID-19 and the efficacy of 1 candidate:

As a 2-dose (separated by 21 days) schedule;At various different dose levels in Phase 1;



In 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3: ≥12years of age [stratified as 12-15, 16-55, or >55 years of age]).
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Dependent upon safety and/or immunogenicity data generated during the course of thisstudy, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
in Phase 1 may be started at the next highest dose, groups may not be started, groups may beterminated early, and/or groups may be added with dose levels below the lowest stated doseor intermediate between the lowest and highest stated doses.
The study is observer-blinded, as the physical appearance of the investigational vaccine
candidates and the placebo may differ. The participant, investigator, study coordinator, andother site staff will be blinded. At the study site, only the dispenser(s)/administrator(s) are
unblinded.
To facilitate rapid review of data in real time, sponsor staff will be unblinded to vaccine
allocation for the participants in Phase 1.
4.1.1. Phase 1
Each group (vaccine candidate/dose level/age group) will comprise 15 participants;
12 participants will be randomized to receive active vaccine and 3 to receive placebo.

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)For each vaccine candidate/dose level/age group, the following apply:Additional safety assessments (see Section 8.2)

Controlled enrollment (required only for the first candidate and/or dose level studied):No more than 5 participants (4 active, 1 placebo) can be vaccinated on the firstdayThe first 5 participants must be observed by blinded site staff for at least 4 hours
after vaccination for any acute reactions

Vaccination of the remaining participants will commence no sooner than 24 hours
after the fifth participant received his or her vaccination

Application of stopping rules

IRC review of safety data to determine escalation to the next dose level in the 18- to
55-year age cohort:Escalation between dose levels will be based on IRC review of at least 7-day
post–Dose 1 safety data in this study and/or the BioNTech study conducted inGermany (BNT162-01)

Note that, since both candidates are based upon the same RNA platform, dose
escalation for the second candidate studied may be based upon the safety profileof the first candidate studied being deemed acceptable at the same, or a higher,
dose level by the IRC
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Groups of participants 65 to 85 years of age will not be started until safety data for the RNA
platform have been deemed acceptable at the same, or a higher, dose level in the 18- to
55-year age cohort by the IRC.
In this phase, 13 groups will be studied, corresponding to a total of 195 participants.
The IRC will select 1 vaccine candidate that, in Phase 1, has an established dose level per age
group based on induction of a post–Dose 2 immune response, including neutralizing
antibodies, which is expected to be associated with protection against COVID-19, forprogression into Phase 2/3.

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4.1.2. Phase 2/3
On the basis of safety and/or immunogenicity data generated during the course of this study,
and/or the BioNTech study conducted in Germany (BNT162-01), 1 vaccine candidate wasselected to proceed into Phase 2/3. Participants in this phase will be ≥12 years of age,stratified as follows: 12 to 15 years, 16 to 55 years, or >55 years. The 12- to 15-year stratum
will comprise up to approximately 2000 participants enrolled at selected investigational sites.
It is intended that a minimum of 40% of participants will be in the >55-year stratum.
Commencement of each age stratum will be based upon satisfactory post–Dose 2 safety andimmunogenicity data from the 18- to 55-year and 65- to 85-year age groups in Phase 1,
respectively. The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a doseof 30 µg.
Phase 2/3 is event-driven. Under the assumption of a true VE rate of ≥60%, after the second
dose of investigational product, a target of 164 primary-endpoint cases of confirmed
COVID-19 due to SARS-CoV-2 occurring at least 7 days following the second dose of the
primary series of the candidate vaccine will be sufficient to provide 90% power to conclude
true VE >30% with high probability. The total number of participants enrolled in Phase 2/3
may vary depending on the incidence of COVID-19 at the time of the enrollment, the true
underlying VE, and a potential early stop for efficacy or futility.
Assuming a COVID-19 attack rate of 1.3% per year in the placebo group, accrual of 164
primary-endpoint cases within 6 months, an estimated 20% nonevaluable rate, and 1:1
randomization, the BNT162b2 vaccine candidate selected for Phase 2/3 is expected tocomprise approximately 21,999 vaccine recipients. This is the number of participants
initially targeted for Phase 2/3 and may be adjusted based on advice from DMC analyses ofcase accumulation and the percentage of participants who are seropositive at baseline.
Dependent upon the evolution of the pandemic, it is possible that the COVID-19 attack rate
may be much higher, in which case accrual would be expected to be more rapid, enabling thestudy’s primary endpoint to be evaluated much sooner.
The first 360 participants enrolled (180 to active vaccine and 180 to placebo, stratified
equally between 18 to 55 years and >55 to 85 years) will comprise the “Phase 2” portion.
Safety data through 7 days after Dose 2 and immunogenicity data through 1 month after
Dose 2 from these 360 participants will be analyzed by the unblinded statistical team,
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reviewed by the DMC, and submitted to appropriate regulatory authorities for review.
Enrollment may continue during this period and these participants would be included in theefficacy evaluation in the “Phase 3” portion of the study.

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)In Phase 3, up to approximately 2000 participants, enrolled at selected sites, are anticipatedto be 12 to 15 years of age. Noninferiority of immune response to prophylactic BNT162b2
in participants 12 to 15 years of age to response in participants 16 to 25 years of age will beassessed based on the GMR of SARS-CoV-2 neutralizing titers using a 1.5-fold margin. A
sample size of 200 evaluable participants (or 250 vaccine recipients) per age group will
provide a power of 90.8% to declare the noninferiority in terms of GMR (lower limit of 95%
CI for GMR >0.67). A random sample of 250 participants from each of the 2 age groups(12 to 15 years and 16 to 25 years) will be selected as an immunogenicity subset for thenoninferiority assessment.
The initial BNT162b2 was manufactured using “Process 1”; however, “Process 2” wasdeveloped to support an increased scale of manufacture. In the study, each lot of“Process 2”-manufactured BNT162b2 will be administered to approximately 250 participants
16 to 55 years of age. The safety and immunogenicity of prophylactic BNT162b2 in
individuals 16 to 55 years of age vaccinated with “Process 1” and each lot of “Process 2”
study intervention will be described. A random sample of 250 participants from thosevaccinated with study intervention produced by manufacturing “Process 1” will be selected
for this descriptive analysis.
Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Phase 1
dosing arms that are not evaluated in Phase 2/3.
4.2. Scientific Rationale for Study Design
Additional surveillance for COVID-19 will be conducted as part of the study, given thepotential risk of disease enhancement. If a participant experiences symptoms, as detailed in
Section 8.13, a COVID-19 illness and subsequent convalescent visit will occur. As part ofthese visits, samples (nasal [midturbinate] swab and blood) will be taken for antigen andantibody assessment as well as recording of COVID-19–related clinical and laboratory
information (including local diagnosis).
Human reproductive safety data are not available for BNT162 RNA-based COVID-19
vaccines, but there is no suspicion of human teratogenicity based on the intended mechanismof action of the compound. Therefore, the use of a highly effective method of contraception
is required (see Appendix 4).
4.3. Justification for Dose
Because of the requirement for a rapid response to the newly emerged COVID-19 pandemic,
sufficient data were not available to experimentally validate the dose selection and initialstarting dose. Therefore, the original planned starting dose of 10 µg (for both BNT162b1 and
BNT162b2) in this study was based on nonclinical experience with the same RNAs encoding
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other viral antigens (such as influenza and HIV antigens). The general safety andeffectiveness of uRNA and modRNA platforms have been demonstrated in oncologicalclinical trials with different administration routes (NCT02410733, NCT03871348). Doses of
up to 400 µg total uRNA have been administered IV as RNA lipoplex (RNA-LPX) and dosesof up to 1000 µg total naked modRNA have been administered intratumorally, both without
signs of unpredictable overstimulation of the immune system.
Based on nonclinical data of the RNA components, with other liposomes or in conjunction
with the lipid nanoparticles as will be tested clinically in this study, it was expected that
doses in the 1- to 5-µg range would be immunogenic and induce neutralizing antibodies;
however, it was anticipated that 3- to 10-fold higher doses would likely be required to elicit astronger antibody response. Based on previous clinical and nonclinical experience, it was
expected that doses of up to 100 µg would be well tolerated.

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Update as part of protocol amendment 2: preliminary experience in this study and the
BioNTech study conducted in Germany (BNT162-01) suggests that, for vaccine candidates
based on the modRNA platform, a dose level between 30 µg and 100 µg warrants
consideration. Therefore, a 50-µg dose level is formally included for BNT162b1 and
BNT162b2.
Update as part of protocol amendment 3: as data have become available from this study andthe BNT162-01 study in Germany, it was decided:

To not study the BNT162a1 and BNT162c2 vaccine candidates at this time, so thesecandidates have been removed from the protocol; andThat lower dose levels of BNT162b1 and BNT162b2 warrant consideration.
Therefore, a 20-µg dose level is formally included for both candidates.

Update as part of protocol amendment 4: the 50-µg dose level for BNT162b1 and BNT162b2
is removed and the 100-µg dose level for BNT162b2 is removed; similar dose levels of
BNT162b3 may be studied as for BNT162b1 and BNT162b2.
Update as part of protocol amendment 5: the vaccine candidate selected for Phase 2/3
evaluation is BNT162b2 at a dose of 30 µg. BNT162b3 will not be studied.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases ofthe study, including the last visit. Note that participants enrolled in Phase 1 in groups that do
not proceed to Phase 2/3 may be followed for fewer than 24 months (but no less than
6 months after the last vaccination).
The end of the study is defined as the date of last visit of the last participant in the study.

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5. STUDY POPULATIONThis study can fulfill its objectives only if appropriate participants are enrolled. The
following eligibility criteria are designed to select participants for whom participation in the
study is considered appropriate. All relevant medical and nonmedical conditions should betaken into consideration when deciding whether a particular participant is suitable for thisprotocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:

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1. Male or female participants between the ages of 18 and 55 years, inclusive, and 65 and85 years, inclusive (Phase 1), or ≥12 years (Phase 2/3), at randomization. Note thatparticipants <18 years of age cannot be enrolled in the EU.


Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female(Section 10.4.2) participants.

Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, vaccination
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Healthy participants who are determined by medical history, physical examination(if required), and clinical judgment of the investigator to be eligible for inclusion in the
study.
Note: Healthy participants with preexisting stable disease, defined as disease notrequiring significant change in therapy or hospitalization for worsening disease during
the 6 weeks before enrollment, can be included. Specific criteria for Phase 3 participants
with known stable infection with human immunodeficiency virus (HIV), hepatitis C virus(HCV), or hepatitis B virus (HBV) can be found in Section 10.8.
4. Phase 2/3 only: Participants who, in the judgment of the investigator, are at higher risk
for acquiring COVID-19 (including, but not limited to, use of mass transportation,
relevant demographics, and frontline essential workers).
Informed Consent:
5. Capable of giving personal signed informed consent/have parent(s)/legal guardiancapable of giving signed informed consent as described in Appendix 1, which includes
compliance with the requirements and restrictions listed in the ICD and in this protocol.
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5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Other medical or psychiatric condition including recent (within the past year) or active
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study
participation or, in the investigator’s judgment, make the participant inappropriate for the
study.
2. Phases 1 and 2 only: Known infection with human immunodeficiency virus (HIV),hepatitis C virus (HCV), or hepatitis B virus (HBV).
3. History of severe adverse reaction associated with a vaccine and/or severe allergic
reaction (eg, anaphylaxis) to any component of the study intervention(s).

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4. Receipt of medications intended to prevent COVID-19.
5. Previous clinical (based on COVID-19 symptoms/signs alone, if a SARS-CoV-2 NAAT
result was not available) or microbiological (based on COVID-19 symptoms/signs and apositive SARS-CoV-2 NAAT result) diagnosis of COVID-19.
6. Phase 1 only: Individuals at high risk for severe COVID-19, including those with any of
the following risk factors:Hypertension

Diabetes mellitus

Chronic pulmonary diseaseAsthma

Current vaping or smoking

History of chronic smoking within the prior year

Chronic liver diseaseStage 3 or worse chronic kidney disease (glomerular filtration rate
<60 mL/min/1.73 m2)



Resident in a long-term facility

BMI >30 kg/m2

Anticipating the need for immunosuppressive treatment within the next 6 months

7. Phase 1 only: Individuals currently working in occupations with high risk of exposure to
SARS-CoV-2 (eg, healthcare worker, emergency response personnel).

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8. Immunocompromised individuals with known or suspected immunodeficiency, as
determined by history and/or laboratory/physical examination.
9. Phase 1 only: Individuals with a history of autoimmune disease or an active autoimmune
disease requiring therapeutic intervention, including but not limited to: systemic or
cutaneous lupus erythematosus, autoimmune arthritis/rheumatoid arthritis, Guillain-Barré
syndrome, multiple sclerosis, Sjögren’s syndrome, idiopathic thrombocytopenia purpura,glomerulonephritis, autoimmune thyroiditis, giant cell arteritis (temporal arteritis),
psoriasis, and insulin-dependent diabetes mellitus (type 1).
10. Bleeding diathesis or condition associated with prolonged bleeding that would, in theopinion of the investigator, contraindicate intramuscular injection.
11. Women who are pregnant or breastfeeding.
Prior/Concomitant Therapy:

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12. Previous vaccination with any coronavirus vaccine.
13. Individuals who receive treatment with immunosuppressive therapy, including cytotoxic
agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned
receipt throughout the study. If systemic corticosteroids have been administered shortterm (<14 days) for treatment of an acute illness, participants should not be enrolled into
the study until corticosteroid therapy has been discontinued for at least 28 days before
study intervention administration. Inhaled/nebulized (except for participants in
Phase 1 – see exclusion criterion 14), intra-articular, intrabursal, or topical (skin or eyes)corticosteroids are permitted.
14. Phase 1 only: Regular receipt of inhaled/nebulized corticosteroids.
15. Receipt of blood/plasma products or immunoglobulin, from 60 days before study
intervention administration or planned receipt throughout the study.
Prior/Concurrent Clinical Study Experience:
16. Participation in other studies involving study intervention within 28 days prior to study
entry and/or during study participation.
17. Previous participation in other studies involving study intervention containing lipid
nanoparticles.
Diagnostic Assessments:
18. Phase 1 only: Positive serological test for SARS-CoV-2 IgM and/or IgG antibodies atthe screening visit.

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19. Phase 1 only: Any screening hematology and/or blood chemistry laboratory value thatmeets the definition of a ≥ Grade 1 abnormality.
Note: With the exception of bilirubin, participants with any stable Grade 1 abnormalities(according to the toxicity grading scale) may be considered eligible at the discretion of
the investigator. (Note: A “stable” Grade 1 laboratory abnormality is defined as a reportof Grade 1 on an initial blood sample that remains ≤ Grade 1 upon repeat testing on asecond sample from the same participant.)
20. Phase 1 only: Positive test for HIV, hepatitis B surface antigen (HBsAg), hepatitis B
core antibodies (HBc Abs), or hepatitis C virus antibodies (HCV Abs) at the screening
visit.
21. Phase 1 only: SARS-CoV-2 NAAT-positive nasal swab within 24 hours before receipt ofstudy intervention.

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Other Exclusions:
22. Investigator site staff or Pfizer/BioNTech employees directly involved in the conduct of
the study, site staff otherwise supervised by the investigator, and their respective family
members.
5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm thatthe participant has selected an appropriate method of contraception for the individual
participant and his or her partner(s) from the permitted list of contraception methods(see Appendix 4, Section 10.4.4) and will confirm that the participant has been instructed inits consistent and correct use. At time points indicated in the SoA, the investigator ordesignee will inform the participant of the need to use highly effective contraception
consistently and correctly and document the conversation and the participant’s affirmation in
the participant’s chart (participants need to affirm their consistent and correct use of at least 1of the selected methods of contraception). In addition, the investigator or designee will
instruct the participant to call immediately if the selected contraception method is
discontinued or if pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but
are not subsequently randomly assigned to study intervention. A minimal set of screen
failure information is required to ensure transparent reporting of screen failure participants tomeet the CONSORT publishing requirements and to respond to queries from regulatory
authorities. Minimal information includes demography, screen failure details, eligibility
criteria, and any SAE.

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Individuals who do not meet the criteria for participation in this study (screen failure) may berescreened under a different participant number.
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention
Administration
The following conditions are temporary or self-limiting and a participant may be vaccinatedonce the condition(s) has/have resolved and no other exclusion criteria are met.

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1. Current febrile illness (body temperature ≥100.4°F [≥38°C]) or other acute illness within
48 hours before study intervention administration. This includes current symptoms that
could represent a potential COVID-19 illness:

New or increased cough;

New or increased shortness of breath;Chills;

New or increased muscle pain;New loss of taste/smell;

Sore throat;

Diarrhea;Vomiting.

2. Receipt of any seasonal or pandemic influenza vaccine within 14 days, or any othernonstudy vaccine within 28 days, before study intervention administration.
3. Anticipated receipt of any seasonal or pandemic influenza vaccine within 14 days, or any
other nonstudy vaccine within 28 days, after study intervention administration.
4. Receipt of short-term (<14 days) systemic corticosteroids. Study intervention
administration should be delayed until systemic corticosteroid use has been discontinued
for at least 28 days. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin oreyes) corticosteroids are permitted.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s),placebo, medical device(s), or study procedure(s) intended to be administered to a study
participant according to the study protocol.

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The study will evaluate a 2-dose (separated by 21 days) schedule of various different doselevels of 2 investigational RNA vaccine candidates for active immunization against
COVID-19 in 3 age groups (18 to 55 years of age, 65 to 85 years of age, and ≥12 years ofage [stratified as 12-15, 16-55, or >55 years of age]).
These 2 investigational RNA vaccine candidates, with the addition of saline placebo, are the
3 potential study interventions that may be administered to a study participant:

BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 20 µg, 30 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 20 µg, 30 µgNormal saline (0.9% sodium chloride solution for injection)

The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.

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6.1. Study Intervention(s) Administered
Intervention NameType
Dose Formulation

BNT162b1(BNT162 RNA-LNP
vaccine utilizing
modRNA)
VaccinemodRNA

BNT162b2(BNT162 RNA-LNP
vaccine utilizing
modRNA)
VaccinemodRNA

Saline Placebo

Placebo
Normal saline (0.9%sodium chloride solution
for injection)
Unit Dose Strength(s)250 µg/0.5 mL
250 µg/0.5 mL
N/A
Dosage Level(s)a10-, 20-, 30-, 100-µg
10-, 20-, 30-µg
N/A
Route of Administration Intramuscular injection
Intramuscular injection
Intramuscular injection
Use
Experimental
Experimental
Placebo
IMP or NIMP
IMP
IMP
IMP
Sourcing
Provided centrally by the Provided centrally by the Provided centrally by thesponsorsponsorsponsorPackaging and Labeling Study intervention will be Study intervention will be Study intervention will be
provided in a glass vial as provided in a glass vial as provided in a glass or
open-label supply. Each
open-label supply. Each
plastic vial as open-labelvial will be labeled asvial will be labeled as
supply. Each vial will be
required per country
required per country
labeled as required per
requirement
requirement
country requirementa. Dependent upon safety and/or immunogenicity data generated during the course of this study, or the
BioNTech study conducted in Germany (BNT162-01), it is possible that groups may be started at the next
highest dose, groups may not be started, groups may be terminated early, and/or groups may be addedwith dose levels below the lowest stated dose or intermediate between the lowest and highest stated doses.

The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.

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6.1.1. Manufacturing Process
The scale of the BNT162b2 manufacturing has been increased to support future supply.
BNT162b2 generated using the manufacturing process supporting an increased supply(“Process 2”) will be administered to approximately 250 participants 16 to 55 years of age,per lot, in the study. The safety and immunogenicity of prophylactic BNT162b2 in
individuals 16 to 55 years of age vaccinated with material generated using the existing
manufacturing process “Process 1,” and with material from lots generated using the
manufacturing process supporting increased supply, “Process 2,” will be described.
In brief, the process changes relate to the method of production for the DNA template thatRNA drug substance is transcribed from, and the RNA drug substance purification method.
The BNT162b2 drug product is then produced using a scaled-up LNP manufacturing process.
6.1.2. Administration

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Participants will receive 1 dose of study intervention as randomized at each vaccination visit(Visits 1 and 4 for Phase 1 participants, Visits 1 and 2 for Phase 2/3 participants) inaccordance with the study’s SoA. The volume to be administered may vary by vaccine
candidate and dose level; full details are described in the IP manual.
Study intervention should be administered intramuscularly into the deltoid muscle, preferablyof the nondominant arm, by an unblinded administrator.
Standard vaccination practices must be observed and vaccine must not be injected into bloodvessels. Appropriate medication and other supportive measures for management of an acute
hypersensitivity reaction should be available in accordance with local guidelines for standard
immunization practices.
Administration of study interventions should be performed by an appropriately qualified,
GCP-trained, and vaccine-experienced member of the study staff (eg, physician, nurse,
physician’s assistant, nurse practitioner, pharmacist, or medical assistant) as allowed by
local, state, and institutional guidance.
Study intervention administration details will be recorded on the CRF.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study interventions received and any discrepancies arereported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only
authorized site staff may supply or administer study intervention. All study interventions
must be stored in a secure, environmentally controlled, and monitored (manual or
automated recording) area in accordance with the labeled storage conditions with accesslimited to the investigator and authorized site staff. At a minimum, daily minimum andmaximum temperatures for all site storage locations must be documented and available
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upon request. Data for nonworking days must indicate the minimum and maximum
temperatures since previously documented for all site storage locations upon return tobusiness.
3. Any excursions from the study intervention label storage conditions should be reported to
Pfizer upon discovery along with any actions taken. The site should actively pursue
options for returning the study intervention to the storage conditions described in thelabeling, as soon as possible. Once an excursion is identified, the study intervention must
be quarantined and not used until Pfizer provides permission to use the study
intervention. Specific details regarding the definition of an excursion and information thesite should report for each excursion will be provided to the site in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage conditions
stated on the label.
5. Study interventions should be stored in their original containers.

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6. See the IP manual for storage conditions of the study intervention.
7. The investigator, institution, or the head of the medical institution (where applicable) is
responsible for study intervention accountability, reconciliation, and record maintenance(ie, receipt, reconciliation, and final disposition records), such as the IPAL orsponsor-approved equivalent. All study interventions will be accounted for using a study
intervention accountability form/record.
8. Further guidance and information for the final disposition of unused study interventions
are provided in the IP manual. All destruction must be adequately documented. If
destruction is authorized to take place at the investigator site, the investigator must ensurethat the materials are destroyed in compliance with applicable environmental regulations,institutional policy, and any special instructions provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of
discovery as described in the IP manual.
6.2.1. Preparation and Dispensing
See the IP manual for instructions on how to prepare the study intervention foradministration. Study intervention should be prepared and dispensed by an appropriately
qualified and experienced member of the study staff (eg, physician, nurse, physician’s
assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as allowed by
local, state, and institutional guidance. A second staff member will verify the dispensing.
Study intervention and placebo will be prepared by qualified unblinded site personnel
according to the IP manual. The study intervention will be administered in such a way toensure the participants remain blinded.

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6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
Allocation (randomization) of participants to vaccine groups will proceed through the use of
an IRT system (IWR). The site personnel (study coordinator or specified designee) will be
required to enter or select information including but not limited to the user’s ID andpassword, the protocol number, and the participant number. The site personnel will then be
provided with a vaccine assignment and randomization number. The IRT system will
provide a confirmation report containing the participant number, randomization number, andstudy intervention allocation assigned. The confirmation report must be stored in the site’s
files.
The study-specific IRT reference manual and IP manual will provide the contact informationand further details on the use of the IRT system.

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6.3.2. Blinding of Site Personnel
In this observer blinded study, the study staff receiving, storing, dispensing, preparing, andadministering the study interventions will be unblinded. All other study and site personnel,
including the investigator, investigator staff, and participants, will be blinded to study
intervention assignments. In particular, the individuals who evaluate participant safety willbe blinded. Because the BNT162 RNA-based COVID-19 vaccine candidates and placebo
are different in physical appearance, the study intervention syringes will be administered in amanner that prevents the study participants from identifying the study intervention type basedon its appearance.
The responsibility of the unblinded dispenser and administrator must be assigned to anindividual or individuals who will not participate in the evaluation of any study participants.
Contact between the unblinded dispenser and study participants and unblinded administrator
and study participants should be kept to a minimum. The remaining site personnel must notknow study intervention assignments.
6.3.3. Blinding of the Sponsor
To facilitate rapid review of data in real time, sponsor staff will be unblinded to study
intervention allocation for the participants in Phase 1. The majority of sponsor staff will beblinded to study intervention allocation in Phase 2/3. All laboratory testing personnel
performing serology assays will remain blinded to study intervention assigned/received
throughout the study. The following sponsor staff, who will have no part in the blinded
conduct of the study, will be unblinded in Phase 2/3 (further details will be provided in a data
blinding plan):

Those study team members who are involved in ensuring that protocol requirements
for study intervention preparation, handling, allocation, and administration are
fulfilled at the site will be unblinded for the duration of the study (eg, unblinded study
manager, unblinded clinical research associate).
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Unblinded clinician(s), who are not direct members of the study team and will notparticipate in any other study-related activities, will review unblinded protocol
deviations.

An unblinded team supporting interactions with, and analyses for, the DMC(see Section 9.6). This will comprise a statistician, programmer(s), and a medical
monitor who will review cases of severe COVID-19 as they are received, and will
review AEs at least weekly for additional potential cases of severe COVID-19(see Section 8.2.3).

An unblinded submissions team will be responsible for preparing unblinded analyses
and documents to support regulatory activities that may be required while the study is
ongoing. This team will only be unblinded at the group level and not have access toindividual subject assignments. The programs that produce the summary tables will
be developed and validated by the blinded study team, and these programs will be runby the unblinded DMC team. The submissions team will not have access tounblinded COVID-19 cases unless efficacy is achieved in either an interim analysis or
the final analysis, as determined by the DMC.

6.3.4. Breaking the Blind
The IRT will be programmed with blind-breaking instructions. In case of an emergency, theinvestigator has the sole responsibility for determining if unblinding of a participant’s study
intervention assignment is warranted. Participant safety must always be the firstconsideration in making such a determination. If the investigator decides that unblinding iswarranted, the investigator should make every effort to contact the sponsor prior to
unblinding a participant’s vaccine assignment unless this could delay further management of
the participant. If a participant’s vaccine assignment is unblinded, the sponsor must be
notified within 24 hours after breaking the blind. The date and reason that the blind was
broken must be recorded in the source documentation and CRF.
The study-specific IRT reference manual and IP manual will provide the contact informationand further details on the use of the IRT system.
6.4. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from theinvestigator or designee, under medical supervision. The date and time of each dose
administered in the clinic will be recorded in the source documents and recorded in the CRF.
The dose of study intervention and study participant identification will be confirmed at thetime of dosing by a member of the study site staff other than the person administering thestudy intervention.

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6.5. Concomitant Therapy
The following concomitant medications and vaccinations will be recorded in the CRF:
All vaccinations received from 28 days prior to study enrollment until the 6-monthfollow-up visit (Visit 8 for Phase 1 participants, and Visit 4 for Phase 2/3
participants).

Prohibited medications listed in Section 6.5.1 will be recorded, to include start andstop dates, name of the medication, dose, unit, route, and frequency.

In addition, for participants enrolled in Phase 1, all current medication at baseline will
be recorded, to include start date, name of the medication, dose, unit, route, andfrequency.

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6.5.1. Prohibited During the Study
Receipt of the following vaccines and medications during the time periods listed below may
exclude a participant from the per-protocol analysis from that point onwards, and may
require vaccinations to be discontinued in that participant; however, it is anticipated that theparticipant would not be withdrawn from the study (see Section 7). Medications should not
be withheld if required for a participant’s medical care.
Unless considered medically necessary, no vaccines other than study intervention should be
administered within 28 days before and 28 days after each study vaccination. One exception
to this is that seasonal and pandemic influenza vaccine can be given at least 14 days after, orat least 14 days prior to, the administration of study intervention.
Receipt of chronic systemic treatment with known immunosuppressant medications, orradiotherapy, within 60 days before enrollment through conclusion of the study.
Receipt of systemic corticosteroids (≥20 mg/day of prednisone or equivalent) for ≥14 days is
prohibited from 28 days prior to enrollment to Visit 7 for Phase 1 participants, and Visit 3 forPhase 2/3 participants).
Receipt of inhaled/nebulized corticosteroids from 28 days prior to enrollment to Visit 7(1-month follow-up visit) for Phase 1 participants.
Receipt of blood/plasma products or immunoglobulins within 60 days before enrollment
through conclusion of the study.
Receipt of any other (nonstudy) coronavirus vaccine at any time prior to or during study
participation is prohibited.
Prophylactic antipyretics and other pain medication to prevent symptoms associated withstudy intervention administration are not permitted. However, if a participant is taking a

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medication for another condition, even if it may have antipyretic or pain-relieving properties,
it should not be withheld prior to study vaccination.
6.5.2. Permitted During the Study
The use of antipyretics and other pain medication to treat symptoms associated with study
intervention administration or ongoing conditions is permitted.
Medication other than that described as prohibited in Section 6.5.1 required for treatment ofpreexisting stable conditions is permitted.
Inhaled (except in Phase 1 participants – see Section 6.5.1), topical, or localized injections ofcorticosteroids (eg, intra-articular or intrabursal administration) are permitted.
6.6. Dose Modification

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)This protocol allows some alteration of vaccine dose for individual participants and/or dosegroups from the currently outlined dosing schedule. For reasons of reactogenicity,
tolerability, or safety, the IRC may recommend to reduce the second dose of study
intervention and/or increase the interval between doses.
If, due to a medication error, a participant receives 1 dose of BNT162b2 at Visit 1 and 1 doseof placebo at Visit 2 (or vice versa), the participant should be offered the possibility toreceive a second dose of BNT162b2 at an unscheduled visit. In this situation:
Obtain informed consent for administration of the additional dose.

Measure the participant’s body temperature.

Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention
into the deltoid muscle of the preferably nondominant arm. Please refer to the IP
manual for further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of
the CRF, and on an SAE form as applicable.



The participant should continue to adhere to the normal visit schedule but must be
followed for nonserious AEs for 1 month and SAEs for 6 months after the second
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dose of BNT162b2. This will require AEs to be elicited either by unscheduled
telephone contact(s) and/or in-person visit(s).
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANTDISCONTINUATION/WITHDRAWAL

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7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study
intervention (definitive discontinuation). Reasons for definitive discontinuation of study
intervention may include the following: AEs; participant request; investigator request;
pregnancy; protocol deviation (including no longer meeting all the inclusion criteria, or
meeting 1 or more exclusion criteria). In general, unless the investigator considers it unsafe
to administer the second dose, or the participant does not wish to receive it, it is preferredthat the second dose be administered. Note that a positive SARS-CoV-2 NAAT result
without symptoms does not meet exclusion criterion 5 and should not result in
discontinuation of study intervention, whereas a COVID-19 diagnosis does meet exclusion
criterion 5 and should result in discontinuation of study intervention (see Section 8.15).
Note that discontinuation of study intervention does not represent withdrawal from the study.
Per the study estimands, if study intervention is definitively discontinued, the participant willremain in the study to be evaluated for safety, immunogenicity, and efficacy. See the SoA
for data to be collected at the time of discontinuation of study intervention and follow-up for
any further evaluations that need to be completed.
In the event of discontinuation of study intervention, it must be documented on theappropriate CRF/in the medical records whether the participant is discontinuing further
receipt of study intervention or also from study procedures, posttreatment study follow-up,
and/or future collection of additional information.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request. Reasons fordiscontinuation from the study may include the following:

Refused further follow-up;

Lost to follow-up;



Death;



Study terminated by sponsor;



AEs;



Participant request;
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Investigator request;Protocol deviation.

If a participant does not return for a scheduled visit, every effort should be made to contact
the participant. All attempts to contact the participant and information received duringcontact attempts must be documented in the participant’s source document. In any
circumstance, every effort should be made to document participant outcome, if possible.
The investigator or his or her designee should capture the reason for withdrawal in the CRF
for all participants.
If a participant withdraws from the study, he/she may request destruction of any remaining
samples taken and not tested, and the investigator must document any such requests in thesite study records and notify the sponsor accordingly.

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If the participant withdraws from the study and also withdraws consent (see Section 7.2.1)
for disclosure of future information, no further evaluations should be performed and no
additional data should be collected. The sponsor may retain and continue to use any datacollected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not beviewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent
Participants who request to discontinue receipt of study intervention will remain in the study
and must continue to be followed for protocol-specified follow-up procedures. The only
exception to this is when a participant specifically withdraws consent for any further contact
with him or her or persons previously authorized by the participant to provide thisinformation. Participants should notify the investigator in writing of the decision towithdraw consent from future follow-up, whenever possible. The withdrawal of consent
should be explained in detail in the medical records by the investigator, as to whether thewithdrawal is only from further receipt of study intervention or also from study procedures
and/or posttreatment study follow-up, and entered on the appropriate CRF page. In the eventthat vital status (whether the participant is alive or dead) is being measured, publicly
available information should be used to determine vital status only as appropriately directedin accordance with local law.
7.3. Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return forscheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to attend a required study visit:The site must attempt to contact the participant and reschedule the missed visit assoon as possible and counsel the participant on the importance of maintaining the
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assigned visit schedule and ascertain whether or not the participant wishes to and/or
should continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must
make every effort to regain contact with the participant (where possible, 3 telephone
calls and, if necessary, a certified letter to the participant’s last known mailingaddress or local equivalent methods). These contact attempts should be documented
in the participant’s medical record;Should the participant continue to be unreachable, he/she will be considered to havewithdrawn from the study.

8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed anddated ICD before performing any study-specific procedures.

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)The full date of birth will be collected to critically evaluate the immune response and safety
profile by age.
Study procedures and their timing are summarized in the SoA. Protocol waivers or
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence orawareness to determine whether the participant should continue or discontinue study
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential
participants meet all eligibility criteria. The investigator will maintain a screening log torecord details of all participants screened and to confirm eligibility or record reasons forscreening failure, as applicable.
Every effort should be made to ensure that protocol-required tests and procedures arecompleted as described. However, it is anticipated that from time to time there may becircumstances outside the control of the investigator that may make it unfeasible to performthe test. In these cases, the investigator must take all steps necessary to ensure the safety andwell-being of the participant. When a protocol-required test cannot be performed, theinvestigator will document the reason for the missed test and any corrective and preventive
actions that he or she has taken to ensure that required processes are adhered to as soon as
possible. The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, andshipment instructions and contact information will be provided to the investigator site prior
to initiation of the study.
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The total blood sampling volume for individual participants in this study is approximately up
to: 515 mL for participants in Phase 1, 110 mL for Phase 2/3 participants ≥16 years of age,and 50 mL for participants in the 12- to 15-year age stratum. Additionally, 20 mL of bloodfor participants ≥16 years of age and 10 mL for participants in the 12- to 15-year age stratum
will be taken at an unplanned convalescent visit at any time a participant develops respiratory
symptoms indicating a potential COVID-19 infection. Select participants in Phase 1 will also
be asked to provide an additional blood sample of approximately 170 mL at either Visit 5, 6,
or 7. These participants would therefore have a total blood sampling volume of 700 mL
during the 24-month study period. Other additional blood samples may be taken for safetyassessments at times specified by Pfizer, provided the total volume taken during the study
does not exceed 550 mL during any period of 60 consecutive days.

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8.1. Efficacy and/or Immunogenicity Assessments
Efficacy will be assessed throughout a participant’s involvement in the study throughsurveillance for potential cases of COVID-19. If, at any time, a participant develops acuterespiratory illness (see Section 8.13), for the purposes of the study he or she will beconsidered to potentially have COVID-19 illness.9 In this circumstance, the participant
should contact the site, an in-person or telehealth visit should occur, and assessments should
be conducted as specified in the SoA. The assessments will include a nasal (midturbinate)swab, which will be tested at a central laboratory using a reverse transcription–polymerase
chain reaction (RT-PCR) test (Cepheid; FDA approved under EUA), or other equivalent
nucleic acid amplification–based test (ie, NAAT), to detect SARS-CoV-2. In addition,clinical information and results from local standard-of-care tests (as detailed in Section 8.13)
will be assessed. The central laboratory NAAT result will be used for the case definition,
unless no result is available from the central laboratory, in which case a local NAAT result
may be used if it was obtained using 1 of the following assays:


Cepheid Xpert Xpress SARS-CoV-2



Roche cobas SARS-CoV-2 real-time RT-PCR test (EUA200009/A001)



Abbott Molecular/RealTime SARS-CoV-2 assay (EUA200023/A001)

Two definitions of SARS-CoV-2–related cases, and SARS-CoV-2–related severe cases, will
be considered (for both, the onset date of the case will be the date that symptoms were firstexperienced by the participant; if new symptoms are reported within 4 days after resolutionof all previous symptoms, they will be considered as part of a single illness):Confirmed COVID-19: presence of at least 1 of the following symptoms and
SARS-CoV-2 NAAT-positive during, or within 4 days before or after, thesymptomatic period, either at the central laboratory or at a local testing facility (using
an acceptable test):Fever;

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New or increased cough;

New or increased shortness of breath;Chills;

New or increased muscle pain;New loss of taste or smell;

Sore throat;

Diarrhea;Vomiting.

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)The second definition, which may be updated as more is learned about COVID-19, will
include the following additional symptoms defined by the CDC (listed athttps://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html):



Fatigue;Headache;

Nasal congestion or runny nose;Nausea.

Confirmed severe COVID-19: confirmed COVID-19 and presence of at least 1 of thefollowing:Clinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per
minute, HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or
PaO2/FiO2 <300 mm Hg);

Respiratory failure (defined as needing high-flow oxygen, noninvasive
ventilation, mechanical ventilation, or ECMO);

Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiringvasopressors);

Significant acute renal, hepatic, or neurologic dysfunction*;Admission to an ICU;Death.
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The DMC may recommend modification of the definition of severe disease according toemerging information.
* Three blinded case reviewers (medically qualified Pfizer staff members) will review all
potential COVID-19 illness events. If a NAAT-confirmed case in Phase 2/3 may beconsidered severe, or not, solely on the basis of this criterion, the blinded data will be
reviewed by the case reviewers to assess whether the criterion is met; the majority opinion
will prevail.
In addition, a serological definition will be used for participants without clinical presentationof COVID-19:


Confirmed seroconversion to SARS-CoV-2 without confirmed COVID-19: positive
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Serum samples will be obtained for immunogenicity testing at the visits specified in the SoA.
The following assays will be performed:

SARS-CoV-2 neutralization assay

S1-binding IgG level assay

RBD-binding IgG level assay

N-binding antibody assay

Note that all immunogenicity analyses will be based upon samples analyzed at the central
laboratory; the rapid test will only be performed at screening by all sites recruiting
participants in Phase 1 (see Section 8.11.1.1) to determine eligibility.
Serum obtained from the additional ~170-mL blood sample from select participants in Phase
1 at either Visit 5, 6, or 7 will be used for exploratory COVID-19 research, intended toestablish a surrogate endpoint that is reasonably likely to predict clinical benefit.
8.1.1. Biological Samples
Blood and nasal swab samples will be used only for scientific research. Each sample will belabeled with a code so that the laboratory personnel testing the samples will not know theparticipant’s identity. Samples that remain after performing assays outlined in the protocol
may be stored by Pfizer. Unless a time limitation is required by local regulations or ethicalrequirements, the samples will be stored for up to 15 years after the end of the study and thendestroyed. If allowed by the ICD, stored samples may be used for additional testing to better
understand the immune responses to the vaccine(s) under study in this protocol, to inform thedevelopment of other products, and/or for vaccine-related assay work supporting vaccine
programs. No testing of the participant’s DNA will be performed.
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The participant may request that his or her samples, if still identifiable, be destroyed at any
time; however, any data already collected from those samples will still be used for thisresearch. The biological samples may be shared with other researchers as long asconfidentiality is maintained and no testing of the participant’s DNA is performed.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinicallaboratory measurements may be obtained at any time during the study to assess any
perceived safety issues.
A clinical assessment, including medical history, will be performed on all participants at
his/her first visit to establish a baseline. Significant medical history and observations fromany physical examination, if performed, will be documented in the CRF.
AEs and SAEs are collected, recorded, and reported as defined in Section 8.3.

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Acute reactions within the first 4 hours after administration of the study intervention (for the
first 5 participants vaccinated in each Phase 1 group), and within the first 30 minutes (for theremainder of participants), will be assessed and documented in the AE CRF.
The safety parameters also include reactogenicity e-diary reports of local reactions andsystemic events (including fever), and use of antipyretic medication that occur in the 7 days
after administration of the study intervention in a subset of participants. These prospectively
self-collected occurrences of local reactions and systemic events are graded as described in
Section 8.2.2. For participants who are not in the reactogenicity subset, these local reactions
and systemic events should be detected and reported as AEs, in accordance with
Section 8.3.2.
8.2.1. Clinical Safety Laboratory Assessments (Phase 1 Participants Only)
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for
the timing and frequency. All protocol-required laboratory assessments, as defined inAppendix 2, must be conducted in accordance with the laboratory manual and the SoA.
Unscheduled clinical laboratory measurements may be obtained at any time during the study
to assess any perceived safety issues.
The investigator must review the laboratory report, document this review, and record any
clinically relevant changes occurring during the study in the AE section of the CRF. See
Appendix 2 for the grading scale for assessment of clinically significant abnormal laboratory
findings. Clinically significant abnormal laboratory findings are those which are notassociated with the underlying disease, unless judged by the investigator to be more severe
than expected for the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during
participation in the study or within 28 days after the last dose of study intervention should be

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repeated until the values return to normal or baseline or are no longer considered clinicallysignificant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 5 for suggested actions and follow-up assessments in the event of potential
drug-induced liver injury (DILI).

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8.2.2. Electronic Diary
Participants will be required to complete a reactogenicity e-diary through an application(see Section 8.14) installed on a provisioned device or on the participant’s own personal
device. All participants in Phase 1, and a subset of at least the first 6000 randomized inPhase 2/3, will be asked to monitor and record local reactions, systemic events, andantipyretic medication usage for 7 days following administration of the study intervention.
All participants in Phase 3 who are HIV-positive or 12 to 15 years of age will be included inthis subset. The reactogenicity e-diary allows recording of these assessments only within afixed time window, thus providing the accurate representation of the participant’s experienceat that time. Data on local reactions and systemic events reported in the reactogenicity
e-diary will be transferred electronically to a third-party vendor, where they will be available
for review by investigators and the Pfizer clinicians at all times via an internet-based portal.
At intervals agreed to by the vendor and Pfizer, these data will be transferred electronicallyinto Pfizer's database for analysis and reporting. These data do not need to be reported by theinvestigator in the CRF as AEs.
Investigators (or designee) will be required to review the reactogenicity e-diary data online atfrequent intervals as part of the ongoing safety review.
The investigator or designee must obtain stop dates from the participant for any ongoing
local reactions, systemic events, or use of antipyretic medication on the last day that thereactogenicity e-diary was completed. The stop dates should be documented in the source
documents and the information entered in the CRF.
8.2.2.1. Grading Scales
The grading scales used in this study to assess local reactions and systemic events as
described below are derived from the FDA Center for Biologics Evaluation and Research(CBER) guidelines on toxicity grading scales for healthy adult volunteers enrolled inpreventive vaccine clinical trials.8
8.2.2.2. Local Reactions
During the reactogenicity e-diary reporting period, participants will be asked to assess
redness, swelling, and pain at the injection site and to record the symptoms in thereactogenicity e-diary. If a local reaction persists beyond the end of the reactogenicity
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e-diary period following vaccination, the participant will be requested to report that
information. The investigator will enter this additional information in the CRF.
Redness and swelling will be measured and recorded in measuring device units(range: 1 to 21) and then categorized during analysis as absent, mild, moderate, or severe
based on the grading scale in Table 1. Measuring device units can be converted tocentimeters according to the following formula: 1 measuring device unit = 0.5 cm. Pain at
the injection site will be assessed by the participant as absent, mild, moderate, or severe
according the grading scale in Table 1.
If a Grade 3 local reaction is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinicallyindicated. Only an investigator or medically qualified person is able to classify aparticipant’s local reaction as Grade 4. If a participant experiences a confirmed Grade 4 local
reaction, the investigator must immediately notify the sponsor and, if it is determined to berelated to the administration of the study intervention, further vaccinations will be
discontinued in that participant.

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Table 1.

Local Reaction Grading Scale
Mild(Grade 1)

Moderate(Grade 2)

Pain at the
injection site

Does not interferewith activity

Interferes withactivity

Redness>2.0 cm to 5.0 cm(5 to 10 measuring
device units)>2.0 cm to 5.0 cm(5 to 10 measuring
device units)>5.0 cm to 10.0 cm(11 to 20 measuring
device units)>5.0 cm to 10.0 cm(11 to 20 measuring
device units)

Swelling

Severe(Grade 3)

Potentially Life
Threatening(Grade 4)
Prevents daily activity Emergency room visit
or hospitalization forsevere pain
>10 cmNecrosis or(≥21 measuringexfoliative dermatitis
device units)>10 cmNecrosis(≥21 measuring
device units)

8.2.2.3. Systemic Events
During the reactogenicity e-diary reporting period, participants will be asked to assess
vomiting, diarrhea, headache, fatigue, chills, new or worsened muscle pain, and new orworsened joint pain and to record the symptoms in the reactogenicity e-diary. The symptoms
will be assessed by the participant as absent, mild, moderate, or severe according to thegrading scale in Table 2.
If a Grade 3 systemic event is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinicallyindicated. Only an investigator or medically qualified person is able to classify aparticipant’s systemic event as Grade 4. If a participant experiences a confirmed Grade 4
systemic event, the investigator must immediately notify the sponsor and, if it is determined

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to be related to the administration of the study intervention, further vaccinations will be
discontinued in that participant.
Table 2.

Systemic Event Grading Scale

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Mild(Grade 1)

Moderate(Grade 2)>2 times in
24 hours

Severe(Grade 3)

Vomiting

1-2 times in
24 hours

Requires IV
hydration

Diarrhea

2 to 3 loose stools 4 to 5 loose stools
in 24 hours
in 24 hours

6 or more loosestools in 24 hours

Headache

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Fatigue/tiredness

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Chills

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

New orworsened
muscle pain

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Does not interfere Some interference
New orwith activity
with activity
worsened
joint pain
Abbreviation: IV = intravenous.

Prevents daily
routine activity

Potentially Life
Threatening(Grade 4)
Emergency room visit or
hospitalization for
hypotensive shock
Emergency room visit or
hospitalization for severe
diarrhea
Emergency room visit or
hospitalization for severe
headache
Emergency room visit or
hospitalization for severe
fatigue
Emergency room visit or
hospitalization for severe
chillsEmergency room visit or
hospitalization for severe
new or worsened muscle
painEmergency room visit or
hospitalization for severe
new or worsened joint pain

8.2.2.4. Fever
In order to record information on fever, a thermometer will be given to participants with
instructions on how to measure oral temperature at home. Temperature will be collected in
the reactogenicity e-diary in the evening daily during the reactogenicity e-diary reporting
period. It will also be collected at any time during the reactogenicity e-diary data collection
periods when fever is suspected. Fever is defined as an oral temperature of ≥38.0°C(100.4°F). The highest temperature for each day will be recorded in the reactogenicity
e-diary. Temperature will be measured and recorded to 1 decimal place and then categorized
during analysis according to the scale shown in Table 3.
If a fever of ≥39.0°C (102.1°F) is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinicallyindicated. Only an investigator or medically qualified person is able to confirm aparticipant’s fever as >40.0°C (>104.0°F). If a participant experiences a confirmed fever>40.0°C (>104.0°F), the investigator must immediately notify the sponsor and, if it is
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determined to be related to the administration of the study intervention, further vaccinations
will be discontinued in that participant.
Table 3.

Scale for Fever≥38.0-38.4°C (100.4-101.1°F)>38.4-38.9°C (101.2-102.0°F)>38.9-40.0°C (102.1-104.0°F)>40.0°C (>104.0°F)

8.2.2.5. Antipyretic Medication
The use of antipyretic medication to treat symptoms associated with study intervention
administration will be recorded in the reactogenicity e-diary daily during the reporting period(Day 1 to Day 7).

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8.2.3. Phase 1 Stopping Rules
The following stopping rules are in place for all Phase 1 participants, based on review of AE
data and e-diary reactogenicity data, until the start of Phase 2/3 or 30 days after the last doseof study intervention in Phase 1, whichever is later. These data will be monitored on an
ongoing basis by the investigator (or medically qualified designee) and sponsor in order topromptly identify and flag any event that potentially contributes to a stopping rule.
The sponsor study team will be unblinded during Phase 1, so will be able to assess whether
or not a stopping rule has been met on the basis of a participant’s individual study
intervention allocation.
In the event that sponsor personnel confirm that a stopping rule is met, the following actions
will commence:The IRC will review all appropriate data.

The stopping rule will PAUSE randomization and study intervention administration
for the impacted vaccine candidate all dose levels and age groups.



The DMC will review all appropriate data.

For all participants vaccinated, all other routine study conduct activities, including
ongoing data entry, reporting of AEs, participant reactogenicity e-diary completion,
blood sample collection, and participant follow-up, will continue during the pause.

A stopping rule is met if any of the following rules occur after administration of
investigational BNT162 vaccine; data from placebo recipients will not contribute to thestopping rules. Reactogenicity e-diary data confirmed by the investigator as being entered by
the participant in error will not contribute toward a stopping rule.
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The BNT162b RNA platform will be evaluated for contribution to stopping rules overall;
vaccine candidate dose levels within the platform and age groups will contribute to stopping
rules together. However, it is possible that the recommendations may include halting or
continuing randomization with any of the BNT162 vaccine candidates.
Stopping Rule Criteria for Each BNT162 Vaccine Candidate:
1. If any participant vaccinated with the BNT162 candidate (at any dose level) develops an
SAE that is assessed by the investigator as possibly related, or for which there is noalternative, plausible, attributable cause.

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2. If any participant vaccinated with the BNT162 candidate (at any dose level) develops a
Grade 4 local reaction or systemic event after vaccination (see Section 8.2.2) that is
assessed as possibly related by the investigator, or for which there is no alternative,plausible, attributable cause.
3. If any participant vaccinated with the BNT162 candidate (at any dose level) develops afever >40.0°C (>104.0°F) for at least 1 daily measurement after vaccination(see Section 8.2.2.4) that is assessed as possibly related by the investigator, or for which
there is no alternative, plausible, attributable cause.
4. If any 2 participants vaccinated with the BNT162 candidate (at any dose level) report thesame or similar severe (Grade 3) AE (including laboratory abnormalities) after
vaccination, assessed as possibly related by the investigator, or for which there is noalternative, plausible, attributable cause.
5. If any participant dies or requires ICU admission due to SARS-CoV-2 infection; if thisstopping rule is met, all available clinical and preclinical safety and immunogenicity data
should be reviewed to evaluate for enhanced COVID-19.
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19 and Phase 2/3
Stopping Rule
Participants in all phases of the study will be surveilled for potential COVID-19 illness from
Visit 1 onwards (see Section 8.13).
As this is a sponsor open-label study during Phase 1, the sponsor will conduct unblinded
reviews of the data during the course of the study, including for the purpose of safetyassessment. All NAAT-confirmed cases in Phase 1 will be reviewed contemporaneously by
the IRC and the DMC (see Section 9.6).
In Phase 2/3, the unblinded team supporting the DMC, including an unblinded medical
monitor, will review cases of severe COVID-19 as they are received and will review AEs atleast weekly for additional potential cases of severe COVID-19. At any point, the unblinded
team may discuss with the DMC chair whether the DMC should review cases for an adverse
imbalance of cases of COVID-19 and/or severe COVID-19 between the vaccine and placebogroups.
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The purpose of these reviews will be to identify whether any features of each case appear
unusual, in particular greater in severity, compared to available information at the time ofreview. Indicators of severity may include accelerated deterioration, need for hospitalization,need for ventilation, or death. Observed rates of these indicators will be compared with what
could be expected in a similar population to the study participants based upon available
information at the time of review.
Stopping and alert rules will be applied as follows. The stopping rule will be triggered whenthe 1-sided probability of observing the same or a more extreme case split is 5% or less when
the true incidence of severe disease is the same for vaccine and placebo participants, and alert
criteria are triggered when this probability is less than 11%. In addition, when the total
number of severe cases is low (15 or less), the unblinded team supporting the DMC will
implement the alert rule when a reverse case split of 2:1 or worse is observed. For example,
at 3 cases 2:1, at 4 cases 3:1, etc. Below 15 cases, this rule is more rigorous than requiring
the probability of an observed adverse split or worse be <11%. Further details can be foundin Section 10.7.

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8.2.5. Randomization and Vaccination After a Stopping Rule Is Met
Once the IRC (if in Phase 1) and DMC (all phases) have reviewed the safety data andprovided guidance, a notification will be sent from the sponsor to the sites with guidance on
how to proceed.
8.2.6. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA,
immediately before the administration of each vaccine dose. A negative pregnancy test result
will be required prior to the participant’s receiving the study intervention. Pregnancy tests
may also be repeated if requested by IRBs/ECs or if required by local regulations. In thecase of a positive confirmed pregnancy, the participant will be withdrawn fromadministration of study intervention but may remain in the study.

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8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or
the participant's parent(s)/legal guardian).
The investigator and any qualified designees are responsible for detecting, documenting, andrecording events that meet the definition of an AE or SAE and remain responsible to pursue
and obtain adequate information both to determine the outcome and to assess whether the
event meets the criteria for classification as an SAE or caused the participant to discontinue
the study intervention (see Section 7.1).
Each participant/parent(s)/legal guardian will be questioned about the occurrence of AEs in anonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up
information in an expedited fashion.

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8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection
period”) for each participant begins from the time the participant/parent(s)/legal guardian
provides informed consent, which is obtained before the participant’s participation in the
study (ie, before undergoing any study-related procedure and/or receiving study
intervention), through and including Visit 7 for Phase 1 participants, and Visit 3 for Phase
2/3 participants. In addition, any AEs occurring up to 48 hours after each subsequent blooddraw must be recorded on the CRF.
SAEs will be collected from the time the participant/parent(s)/legal guardian provides
informed consent to approximately 6 months after the last dose of study intervention (Visit 8
for Phase 1 participants, and Visit 4 for Phase 2/3 participants).
Follow-up by the investigator continues throughout and after the active collection period anduntil the AE or SAE or its sequelae resolve or stabilize at a level acceptable to theinvestigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervention
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE
reported using the Vaccines SAE Report Form.

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Investigators are not obligated to actively seek AEs or SAEs after the participant has
concluded study participation. However, if the investigator learns of any SAE, including adeath, at any time after a participant has completed the study, and he/she considers the event
to be reasonably related to the study intervention, the investigator must promptly report the
SAE to Pfizer using the Vaccines SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in
Section 8.3.1 are reported to Pfizer Safety on the Vaccines SAE Report Form immediately
upon awareness and under no circumstance should this exceed 24 hours, as indicated inAppendix 3. The investigator will submit any updated SAE data to the sponsor within
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF

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All nonserious AEs and SAEs occurring in a participant during the active collection period,
which begins after obtaining informed consent as described in Section 8.3.1, will be recordedon the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and theprocedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended andnonleading verbal questioning of the participant is the preferred method to inquire about
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow eachparticipant at subsequent visits/contacts. For each event, the investigator must pursue andobtain adequate information until resolution, stabilization, the event is otherwise explained,or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail toallow for a complete medical assessment of the case and independent determination of
possible causality. Any information relevant to the event, such as concomitant medications
and illnesses, must be provided. In the case of a participant death, a summary of available
autopsy findings must be submitted as soon as possible to Pfizer Safety.
Further information on follow-up procedures is given in Appendix 3.

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8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal
obligations and ethical responsibilities towards the safety of participants and the safety of astudy intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and otherregulatory agencies about the safety of a study intervention under clinical investigation. The
sponsor will comply with country-specific regulatory requirements relating to safety
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the
study and will notify the IRB/EC, if appropriate according to local requirements.

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8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding andoccupational exposure are reportable to Pfizer Safety within 24 hours of investigatorawareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if:A female participant is found to be pregnant while receiving or after discontinuing
study intervention.



A male participant who is receiving or has discontinued study intervention exposes afemale partner prior to or around the time of conception.



A female is found to be pregnant while being exposed or having been exposed to
study intervention due to environmental exposure. Below are examples ofenvironmental exposure during pregnancy:

A female family member or healthcare provider reports that she is pregnant after
having been exposed to the study intervention by inhalation or skin contact.

A male family member or healthcare provider who has been exposed to the study
intervention by inhalation or skin contact then exposes his female partner prior to
or around the time of conception.

The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s
awareness, irrespective of whether an SAE has occurred. The initial information submitted
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should include the anticipated date of delivery (see below for information related totermination of pregnancy).


If EDP occurs in a participant or a participant’s partner, the investigator must report
this information to Pfizer Safety on the Vaccines SAE Report Form and an EDP
Supplemental Form, regardless of whether an SAE has occurred. Details of thepregnancy will be collected after the start of study intervention and until 6 months
after the last dose of study intervention.



If EDP occurs in the setting of environmental exposure, the investigator must report
information to Pfizer Safety using the Vaccines SAE Report Form and EDP
Supplemental Form. Since the exposure information does not pertain to theparticipant enrolled in the study, the information is not recorded on a CRF; however,a copy of the completed Vaccines SAE Report Form is maintained in the investigatorsite file.

Follow-up is conducted to obtain general information on the pregnancy and its outcome for
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as afollow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural
integrity of the neonate can be assessed at the time of birth. In the event of a termination, thereason(s) for termination should be specified and, if clinically possible, the structural
integrity of the terminated fetus should be assessed by gross visual inspection (unlesspreprocedure test findings are conclusive for a congenital anomaly and the findings arereported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meetsthe criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal
demise, neonatal death, or congenital anomaly), the investigator should follow the procedures
for reporting SAEs. Additional information about pregnancy outcomes that are reported to
Pfizer Safety as SAEs follows:

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as
SAEs when the investigator assesses the infant death as related or possibly related to
exposure to the study intervention.

Additional information regarding the EDP may be requested by the sponsor. Further
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on
preterm infants to identify developmental delays). In the case of paternal exposure, theinvestigator will provide the participant with the Pregnant Partner Release of Information
Form to deliver to his partner. The investigator must document in the source documents thatthe participant was given the Pregnant Partner Release of Information Form to provide to his
partner.
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8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if:A female participant is found to be breastfeeding while receiving or after
discontinuing study intervention.



A female is found to be breastfeeding while being exposed or having been exposed to
study intervention (ie, environmental exposure). An example of environmental
exposure during breastfeeding is a female family member or healthcare provider who
reports that she is breastfeeding after having been exposed to the study intervention
by inhalation or skin contact.

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hoursof the investigator’s awareness, irrespective of whether an SAE has occurred. The
information must be reported using the Vaccines SAE Report Form. When exposure during
breastfeeding occurs in the setting of environmental exposure, the exposure information does
not pertain to the participant enrolled in the study, so the information is not recorded on a
CRF. However, a copy of the completed Vaccines SAE Report Form is maintained in theinvestigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specificallyapproved for use in breastfeeding women (eg, vitamins) is administered in accord withauthorized use. However, if the infant experiences an SAE associated with such a drug, theSAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with thestudy intervention, which may or may not lead to the occurrence of an AE. Such persons
may include healthcare providers, family members, and other roles that are involved in thetrial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of theinvestigator’s awareness, regardless of whether there is an associated SAE. The informationmust be reported using the Vaccines SAE Report Form. Since the information does not
pertain to a participant enrolled in the study, the information is not recorded on a CRF;
however, a copy of the completed Vaccines SAE Report Form is maintained in theinvestigator site file.
8.3.6. Cardiovascular and Death Events
Not applicable.

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8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs
or SAEs
Potential COVID-19 illnesses and their sequelae that are consistent with the clinical endpoint
definition should not be recorded as AEs. These data will be captured as efficacy assessment
data only on the relevant pages of the CRF, as these are expected endpoints.
Potential COVID-19 illnesses and their sequelae will not be reported according to thestandard process for expedited reporting of SAEs, even though the event may meet thedefinition of an SAE. These events will be recorded on the COVID-19 illness pages in theparticipant’s CRF within 1 day.
NOTE: However, if either of the following conditions applies, then the event must berecorded and reported as an SAE (instead of a disease-related event):
The event is, in the investigator’s opinion, of greater intensity, frequency, or duration than
expected for the individual participant.

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The investigator considers that there is a reasonable possibility that the event was related to
study intervention.
Potential COVID-19 illness events and their sequelae will be reviewed by a group of internal
blinded case reviewers. Any SAE that is determined by the internal case reviewers NOT tomeet endpoint criteria is reported back to the investigator site of incidence. The investigatormust report the SAE to Pfizer Safety within 24 hours of being made aware that the SAE did
not meet endpoint criteria. The investigator’s SAE awareness date is the date on which theinvestigator site of incidence receives the SAE back from the internal case reviewers.
8.3.8. Adverse Events of Special Interest
Not applicable.
8.3.8.1. Lack of Efficacy
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.
8.3.9. Medical Device Deficiencies
Not applicable.
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as
medication errors.
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Safety Event

Recorded on the CRF

Reported on the Vaccines SAE Report
Form to Pfizer Safety Within 24 Hours
of Awareness

Medication errors

All (regardless of whether
associated with an AE)

Only if associated with an SAE

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Medication errors include:Medication errors involving participant exposure to the study intervention;Potential medication errors or uses outside of what is foreseen in the protocol that do
or do not involve the study participant;The administration of expired study intervention;

The administration of an incorrect study intervention;

The administration of an incorrect dosage;The administration of study intervention that has undergone temperature excursion
from the specified storage range, unless it is determined by the sponsor that the study
intervention under question is acceptable for use.

Such medication errors occurring to a study participant are to be captured on the medication
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by theinvestigator, the medication error is recorded on the medication error page of the CRF and, if
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a Vaccines SAE
Report Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of study intervention greater than 1 dose of study intervention within
a 24-hour time period will be considered an overdose.
Pfizer does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
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9. Contact the medical monitor within 24 hours.
10. Closely monitor the participant for any AEs/SAEs.
11. Document the quantity of the excess dose as well as the duration of the overdose in the
CRF.
12. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.

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8.7. Genetics
Genetics (specified analyses) are not evaluated in this study.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.9. Immunogenicity Assessments
Immunogenicity assessments are described in Section 8.1.
8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are notevaluated in this study.
8.11. Study Procedures
8.11.1. Phase 1
8.11.1.1. Screening: (0 to 28 Days Before Visit 1)
Before enrollment and before any study-related procedures are performed, voluntary, written
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.
It is anticipated that the procedures below will be conducted in a stepwise manner; however,the visit can occur over more than 1 day.
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Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance.

Obtain details of any medications currently taken.

Perform physical examination including vital signs (weight, height, body temperature,pulse rate, and seated blood pressure), evaluating any clinically significant
abnormalities within the following body systems: general appearance; skin; head,eyes, ears, nose, and throat; heart; lungs; abdomen; musculoskeletal; extremities;
neurological; and lymph nodes.

Collect a blood sample (approximately 20 mL) for potential future serologicalassessment and to perform a rapid test for prior COVID-19 infection.

Collect a blood sample (approximately 10 mL) for hematology and chemistrylaboratory tests as described in Section 10.2.

Collect a blood sample (approximately 10 mL) for HIV, HBsAg, HBc Ab, and HCV
Ab tests.



Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion
criteria are met.



Record AEs as described in Section 8.3. AEs that occur prior to dosing should be
noted on the Medical History CRF.



Ask the participant to contact the site staff or investigator immediately if any
significant illness or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.
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Complete the CRF.

8.11.1.2. Visit 1 – Vaccination 1: (Day 1)

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It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Review screening laboratory results (hematology and chemistry, and HIV, HBsAg,
HBc Ab, and HCV Ab tests).

Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested(if possible at the site, otherwise at the central laboratory) within 24 hours andvaccination will proceed only if it is NAAT-negative for SARS-CoV-2 genomes.
The second will be sent to the central laboratory for potential later testing.

Ensure and document that all of the inclusion criteria and none of the exclusion
criteria are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Obtain the participant’s randomization number and study intervention allocation
using the IRT system. Only an unblinded site staff member may obtain thisinformation.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention
into the deltoid muscle of the preferably nondominant arm. Please refer to the IP
manual for further instruction on this process.

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The first 5 participants vaccinated in each group must be observed by blinded site
staff for any acute reactions for at least 4 hours after vaccination. For participants
enrolled thereafter, blinded site staff must observe the participant for at least 30
minutes after study intervention administration for any acute reactions. Record any
acute reactions (including time of onset) in the participant’s source documents and on
the AE page of the CRF, and on an SAE form as applicable.

Issue a measuring device to measure local reactions at the injection site and athermometer for recording daily temperatures and provide instructions on their use.



Explain the e-diary technologies available for this study (see Section 8.14), and assist
the participant in downloading the study application onto the participant’s own device
or issue a provisioned device if required. Provide instructions on e-diary completion
and ask the participant to complete the reactogenicity e-diary from Day 1 to Day 7,
with Day 1 being the day of vaccination and, if utilized, the COVID-19 illness e-diary(to be completed if the participant is diagnosed with COVID-19 or has possible new
or increased symptoms, and when he/she receives a reminder, at least weekly).



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1
is the day of vaccination) to determine if an unscheduled reactogenicity visit isrequired:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.

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The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the reactogenicity ediary data online following vaccination to evaluate participant compliance and as partof the ongoing safety review. Daily review is optimal during the active diary period.

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8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1 to 3 Days After Visit 1)

Record AEs as described in Section 8.3.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistrylaboratory tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1
is the day of vaccination) to determine if an unscheduled reactogenicity visit isrequired:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.

Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.

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

Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the reactogenicity ediary data online following vaccination to evaluate participant compliance and as partof the ongoing safety review. Daily review is optimal during the active diary period.

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8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to 8 Days After Visit 1)

Record AEs as described in Section 8.3.



Review hematology and chemistry laboratory results and record any AEs inaccordance with Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistrylaboratory tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1
is the day of vaccination) to determine if an unscheduled reactogenicity visit isrequired:

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Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the reactogenicity ediary data online following vaccination to evaluate participant compliance and as partof the ongoing safety review. Daily review is optimal during the active diary period.

8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary
was completed and record stop dates in the CRF if required.



Review hematology and chemistry laboratory results and record any AEs inaccordance with Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within the
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following body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.


Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested (ifpossible at the site, otherwise at the central laboratory) within 24 hours andvaccination will only proceed if it is NAAT-negative for SARS-CoV-2 genomes.
The second will be sent to the central laboratory for potential later testing.

Ensure and document that all of the inclusion criteria and none of the exclusion
criteria are met. If not, the participant should not receive further study intervention
but will remain in the study to be evaluated for safety, immunogenicity, and efficacy(see Section 7.1).

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Collect a blood sample (approximately 10 mL) for hematology and chemistrylaboratory tests as described in Section 10.2.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention
into the deltoid muscle of the preferably nondominant arm. Please refer to the IP
manual for further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of
the CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the
injection site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and ask the participant to complete thereactogenicity e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination.
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Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1
is the day of vaccination) to determine if an unscheduled reactogenicity visit isrequired:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the reactogenicity ediary data online following vaccination to evaluate participant compliance and as partof the ongoing safety review. Daily review is optimal during the active diary period.

8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to 8 Days After Visit 4)

Record AEs as described in Section 8.3.



Review hematology and chemistry laboratory results and record any AEs inaccordance with Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.
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

Collect a blood sample (approximately 10 mL) for hematology and chemistrylaboratory tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



If the participant (select participants only, details will be provided by the sponsor)
consents, collect an additional 170 mL blood sample for exploratory COVID-19
research.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1
is the day of vaccination) to determine if an unscheduled reactogenicity visit isrequired:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the reactogenicity
e-diary data online following vaccination to evaluate participant compliance and as
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part of the ongoing safety review. Daily review is optimal during the active diary
period.

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8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to 16 Days After Visit 4)

Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary
was completed and record stop dates in the CRF if required.



Review hematology and chemistry laboratory results and record any AEs inaccordance with Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



If not collected at Visit 5, and the participant (select participants only, details will be
provided by the sponsor) consents, collect an additional 170-mL blood sample for
exploratory COVID-19 research.



Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately (this could be
via the COVID-19 illness e-diary) if he or she experiences any respiratory symptoms
as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After Visit 4)

Record AEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



If not collected at Visit 5 or 6, and the participant (select participants only, details will
be provided by the sponsor) consents, collect an additional 170-mL blood sample for
exploratory COVID-19 research.



Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (175 to 189 Days After Visit 4)

Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Collect a blood sample (approximately 20 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.
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Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.1.10. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 4)Collect a blood sample (approximately 20 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.1.11. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 4)Collect a blood sample (approximately 20 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Collect the participant’s e-diary or assist the participant to remove the study
application from his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.2. Phase 2/3
8.11.2.1. Visit 1 – Vaccination 1: (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written,
study-specific informed consent will be obtained from the participant or his/herparent(s)/legal guardian, as appropriate. Each signature on the ICD must be personally dated
by the signatory. The investigator or his or her designee will also sign the ICD. A copy ofthe signed and dated ICD must be given to the participant/participant’s parent(s)/legal
guardian. The source data must reflect that the informed consent was obtained before
participation in the study.

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It is anticipated that the procedures below will be conducted in a stepwise manner. The visit
may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion andexclusion criteria onwards must be conducted on the same day.
Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance. For participants who are
HIV-positive, record HIV viral load and CD4 count results from the most recent test
performed in the previous 6 months.



Perform a clinical assessment. If the clinical assessment indicates that a physicalexamination is necessary to comprehensively evaluate the participant, perform aphysical examination and record any findings in the source documents and, if
clinically significant, record on the medical history CRF.

Measure the participant’s height and weight.

Measure the participant’s body temperature.

Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion
criteria are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

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

Record AEs as described in Section 8.3.

Collect a blood sample (approximately 20 mL for participants ≥16 years of age andapproximately 10 mL for participants in the 12- to 15-year age stratum) for
immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Obtain the participant’s randomization number and study intervention allocation
number using the IRT system. Only an unblinded site staff member may obtain thisinformation.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention
into the deltoid muscle of the preferably nondominant arm. Please refer to the IP
manual for further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of
the CRF, and on an SAE form as applicable.

For participants in the reactogenicity subset, issue a measuring device to measure
local reactions at the injection site and a thermometer for recording daily
temperatures and provide instructions on their use.

For participants not in the reactogenicity subset, issue a thermometer to monitor for
fever (for COVID-19 surveillance) and provide instructions on its use.



Explain the e-diary technologies available for this study (see Section 8.14), and assist
the participant or his/her parent(s)/legal guardian, as appropriate, in downloading thestudy application onto the participant’s own device or issue a provisioned device if
required.

For participants in the reactogenicity subset, provide instructions onreactogenicity e-diary completion and ask the participant or his/her parent(s)/legal
guardian, as appropriate, to complete the reactogenicity e-diary from Day 1 to
Day 7, with Day 1 being the day of vaccination.

For all participants, provide instructions on COVID-19 illness e-diary completion
and ask the participant or his/her parent(s)/legal guardian, as appropriate, tocomplete the COVID-19 illness e-diary if the participant is diagnosed with
COVID-19 or has possible new or increased symptoms, and when he/she receivesa reminder, at least weekly. See Section 8.14 for further details.

If the participant is part of the reactogenicity subset, ask the participant or his/herparent(s)/legal guardian, as appropriate, to contact the site staff or investigator
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immediately if the participant experiences any of the following from Day 1 to Day 7
after vaccination (where Day 1 is the day of vaccination) to determine if anunscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator if a medically attended event (eg, doctor’s visit, emergency
room visit) or hospitalization occurs.



Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator (this could be via the COVID-19 illness e-diary) immediately
if he or she experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant or his/her parent(s)/legal guardian, as appropriate, to bring thee-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.

If the participant is part of the reactogenicity subset, the investigator or appropriately
qualified designee reviews the reactogenicity e-diary data online following vaccination toevaluate participant compliance and as part of the ongoing safety review. Daily review is
optimal during the active diary period.
8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days After Visit 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



If the participant is part of the reactogenicity subset, review the participant’s
reactogenicity e-diary data. Collect stop dates of any reactogenicity e-diary events
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ongoing on the last day that the reactogenicity e-diary was completed and record stop
dates in the CRF if required.


Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Ensure and document that all of the inclusion criteria and none of the exclusion
criteria are met. If not, the participant may not receive further study intervention but
will remain in the study to be evaluated for safety, immunogenicity, and efficacy(see Section 7.1).

Measure the participant’s body temperature.

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention
into the deltoid muscle of the preferably nondominant arm. Please refer to the IP
manual for further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of
the CRF, and on an SAE form as applicable.

Ensure the participant or his/her parent(s)/legal guardian, as appropriate, has ameasuring device to measure local reactions at the injection site and a thermometerfor recording daily temperatures.

Ensure the participant or his/her parent(s)/legal guardian, as appropriate, remains
comfortable with the chosen e-diary platform, confirm instructions on e-diarycompletion, and, if the participant is part of the reactogenicity subset, ask theparticipant or his/her parent(s)/legal guardian, as appropriate, to complete thereactogenicity e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination.



If the participant is part of the reactogenicity subset, ask the participant or his/herparent(s)/legal guardian, as appropriate, to contact the site staff or investigator
immediately if the participant experiences any of the following from Day 1 to Day 7
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after vaccination (where Day 1 is the day of vaccination) to determine if anunscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator if a medically attended event (eg, doctor’s visit, emergency
room visit) or hospitalization occurs.



Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator (this could be via the COVID-19 illness e-diary) immediately
if the participant experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant or his/her parent(s)/legal guardian, as appropriate, to bring thee-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.

If the participant is part of the reactogenicity subset, the investigator or appropriately
qualified designee reviews the reactogenicity e-diary data online following vaccination toevaluate participant compliance and as part of the ongoing safety review. Daily review is
optimal during the active diary period.
8.11.2.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2): (28 to 35 Days After
Visit 2)


Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. If the participant is part of thereactogenicity subset, review the participant’s reactogenicity e-diary data. Collectstop dates of any reactogenicity e-diary events ongoing on the last day that thereactogenicity e-diary was completed and record stop dates in the CRF if required.



Record nonstudy vaccinations as described in Section 6.5.
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

Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count resultsfrom the most recent test performed since Visit 1 (if any).

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 20 mL for participants ≥16 years of age, andapproximately 10 mL for participants in the 12- to 15-year age stratum) for
immunogenicity testing.



Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator if a medically attended event (eg, doctor’s visit, emergency
room visit) or hospitalization occurs.



Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator (this could be via the COVID-19 illness e-diary) immediately
if the participant experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.11.2.4. Visit 4 – 6-Month Follow-up Visit: (175 to 189 Days After Visit 2)

Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.

For participants who are HIV-positive, record HIV viral load and CD4 count resultsfrom the most recent test performed since Visit 3 (if any).

Collect a blood sample (approximately 20 mL for participants ≥16 years of age andapproximately 10 mL for participants in the 12- to 15-year age stratum) for
immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.



Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator (this could be via the COVID-19 illness e-diary) immediately
if the participant experiences any respiratory symptoms as detailed in Section 8.3.

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Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.2.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 2)Collect a blood sample (approximately 20 mL for participants ≥16 years of age andapproximately 10 mL for participants in the 12- to 15-year age stratum) for
immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count resultsfrom the most recent test performed since Visit 4 (if any).



Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator (this could be via the COVID-19 illness e-diary) immediately
if the participant experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.2.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 2)Collect a blood sample (approximately 20 mL for participants ≥16 years of age andapproximately 10 mL for participants in the 12- to 15-year age stratum) for
immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count resultsfrom the most recent test performed since Visit 5 (if any).

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

Collect the participant’s e-diary or assist the participant to remove the study
application from his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction

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If a Grade 3 local reaction (Section 8.2.2.2), systemic event (Section 8.2.2.3), or fever(Section 8.2.2.4) is reported in the reactogenicity e-diary, a telephone contact should occur toascertain further details and determine whether a site visit is clinically indicated. If suspected
Grade 4 local reaction (Section 8.2.2.2), systemic event (Section 8.2.2.3), or fever(Section 8.2.2.4) is reported in the reactogenicity e-diary, a telephone contact or site visit
should occur to confirm whether the event meets the criteria for Grade 4.
A site visit must be scheduled as soon as possible to assess the participant unless any of thefollowing is true:The participant is unable to attend the unscheduled visit.

The local reaction/systemic event is no longer present at the time of the telephone
contact.



The participant or his/her parent(s)/legal guardian, as appropriate, recorded anincorrect value in the reactogenicity e-diary (confirmation of a reactogenicity e-diarydata entry error).



The PI or authorized designee determined it was not needed.

This telephone contact will be recorded in the participant’s source documentation and theCRF.
If the participant is unable to attend the unscheduled visit, or the PI or authorized designee
determined it was not needed, any ongoing local reactions/systemic events must be assessedat the next study visit.
During the unscheduled visit, the reactions should be assessed by the investigator or a
medically qualified member of the study staff such as a study physician or a study nurse, asapplicable to the investigator’s local practice, who will:Measure body temperature (°F/°C).

Measure minimum and maximum diameters of redness (if present).
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

Measure minimum and maximum diameters of swelling (if present).



Assess injection site pain (if present) in accordance with the grades provided in
Section 8.2.2.2.

Assess systemic events (if present) in accordance with the grades provided in
Section 8.2.2.3.

Assess for other findings associated with the reaction and record on the AE page of
the CRF, if appropriate.

The investigator or an authorized designee will complete the unscheduled visit assessment
page of the CRF.
8.13. COVID-19 Surveillance (All Participants)

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If a participant experiences any of the following (irrespective of perceived etiology or
clinical significance), he or she is instructed to contact the site immediately and, if
confirmed, participate in an in-person or telehealth visit as soon as possible, optimally within
3 days of symptom onset (and at the latest 4 days after symptom resolution). Note that:

If new symptoms are reported within 4 days after resolution of all previous symptoms,
they will be considered as part of a single illness and a second illness visit is not required;Surveillance of potential COVID-19 symptoms should continue even if a participant has
a positive SARS-CoV-2 test earlier in the study.

During the 7 days following each vaccination, potential COVID-19 symptoms that overlap
with specific systemic events (ie, fever, chills, new or increased muscle pain, diarrhea,
vomiting) should not trigger a potential COVID-19 illness visit unless, in the investigator’sopinion, the clinical picture is more indicative of a possible COVID-19 illness than vaccine
reactogenicity. If, in the investigator’s opinion, the symptoms are considered more likely to
be vaccine reactogenicity, but a participant is required to demonstrate that they are
SARS-CoV-2–negative, a local SARS-CoV-2 test may be performed: if positive, thesymptoms should be recorded as a potential COVID-19 illness; if not, the symptoms should
be recorded as AEs (unless already captured in the reactogenicity e-diary).
Participants may utilize a COVID-19 illness e-diary through an application (see Section 8.14)
installed on a provisioned device or on the participant’s own personal device to prompt
him/her to report any symptoms. Note that this does not substitute for a participant’s routine
medical care. Therefore, participants should be encouraged to seek care, if appropriate, fromtheir usual provider.


A diagnosis of COVID-19;



Fever;
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New or increased cough;

New or increased shortness of breath;Chills;

New or increased muscle pain;New loss of taste/smell;

Sore throat;

Diarrhea;Vomiting.

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8.13.1. Potential COVID-19 Illness Visit: (Optimally Within 3 Days After Potential
COVID-19 Illness Onset)
This visit may be conducted as an in-person or telehealth visit; a telehealth visit involves thesharing of healthcare information and services via telecommunication technologies(eg, audio, video, video-conferencing software) remotely, thus allowing the participant andinvestigator to communicate on aspects of clinical care.
As a participant’s COVID-19 illness may evolve over time, several contacts may be required
to obtain the following information:


Record AEs, as appropriate as described in Section 8.3. Note: Potential COVID-19
illnesses that are consistent with the clinical endpoint definition should not berecorded as AEs. These data will be captured as efficacy assessment data only on therelevant pages of the CRF, as these are expected endpoints.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.



If the visit is conducted in person, obtain a nasal (midturbinate) swab (collected bysite staff). Alternatively, if conducted by telehealth, instruct the participant toself-collect a nasal (midturbinate) swab and ship for assessment at the central
laboratory.

Collect COVID-19–related standard-of-care clinical and laboratory information. This
includes, but is not limited to:Symptoms and signs, including

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Clinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per
minute, HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or
PaO2/FiO2 <300 mm Hg)



Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiringvasopressors)Significant acute renal, hepatic, or neurologic dysfunction

Respiratory failure (defined as needing high-flow oxygen, noninvasive
ventilation, mechanical ventilation, or ECMO)

Clinical diagnosis

Local laboratory SARS-CoV-2 test result(s). Note that if it is routine practice toperform a repeat local SARS-CoV-2 test for any reason, then a repeat nasal(midturbinate) swab should also be obtained and shipped for assessment at thecentral laboratory.



Full blood count

Blood chemistry, specifically creatinine, urea, liver function tests, and C-reactive
protein

Imaging results (eg, CT or MRI scan) to document neurologic dysfunction

Number and type of any healthcare contact; duration of hospitalization and ICU
stay



Death



Schedule an appointment for the participant to return for the potential COVID-19
convalescent visit once he or she has recovered.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After Potential
COVID-19 Illness Visit)

Record AEs, as appropriate as described in Section 8.3. Note: Potential COVID-19
illnesses that are consistent with the clinical endpoint definition should not berecorded as AEs. These data will be captured as efficacy assessment data only on therelevant pages of the CRF, as these are expected endpoints.

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

Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Collect a blood sample (approximately 20 mL for participants ≥16 years of age andapproximately 10 mL for participants in the 12- to 15-year age stratum) for
immunogenicity testing.

Collect/update COVID-19–related clinical and laboratory information (detailed in
Section 8.13.1).

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.14. Communication and Use of Technology
In a study of this nature that requires illness events to be reported outside of scheduled study
visits, it is vital that communication between the study site and the participant or his/herparent(s)/legal guardian, as appropriate, is maintained to ensure that endpoint events are notmissed. This study will employ various methods, tailored to the individual participant, toensure that communication is maintained and study information can be transmitted securely.
Using appropriate technology, such as a study application, a communication pathway
between the participant or his/her parent(s)/legal guardian, as appropriate, and the study site
staff will be established. The participant or his/her parent(s)/legal guardian, as appropriate,
may be able to utilize his or her own devices to access this technology, or use a device
provided by the sponsor. Traditional methods of telephone communication will also be
available. The technology solution may facilitate the following:Contact with the investigator, including the ability of the participant or his/herparent(s)/legal guardian, as appropriate, to report whether or not the participant has
experienced symptoms that could represent a potential COVID-19 illness (COVID-19
illness e-diary; see Section 8.13).

An alert in the event that the participant is hospitalized.



Visit reminders.



Messages of thanks and encouragement from the study team.



A platform for recording local reactions and systemic events (reactogenicity e-diary)– see Section 8.2.2.

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If a participant or his/her parent(s)/legal guardian, as appropriate, is not actively completing
either the reactogenicity or COVID-19 illness e-diary, the investigator or designee is required
to contact the participant or his/her parent(s)/legal guardian, as appropriate, to ascertain why
and also to obtain details of any missed events.
8.15. SARS-CoV-2 NAAT Results From Visits 1 and 2 and Potential COVID-19 Illness
Visits

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Nasal (midturbinate) swabs for SARS-CoV-2 NAAT are obtained at:Visits 1 and 2: To determine whether a participant will be included in efficacy analysesof those with no serological or virological evidence (up to 7 days after receipt of thesecond dose) of past SARS-CoV-2 infection.

Potential COVID-19 illness visits: To determine whether symptoms experienced by theparticipant fulfill the COVID-19 case definition.

Research laboratory–generated positive results from the Visit 1 and Visit 2 swabs, and all
results from the illness visit swabs, will be provided to the site once available, but this will
not be in real time and cannot be relied upon to direct clinical care. Therefore, the participant
should be directed to seek additional testing through his/her primary healthcare providers at alicensed clinical laboratory when exhibiting potential COVID-19 symptoms or otherwise
receiving a positive result and counseled on whether to take any precautionary measurespending confirmatory testing.
Participants who have a positive SARS-CoV-2 NAAT result prior to Visit 2 should be
handled as follows:Positive SARS-CoV-2 test with no symptoms, either at Visit 1 or any time between Visit
1 and Visit 2: A positive test in an asymptomatic participant does not meet exclusion
criterion 5; therefore, Vaccination 2 should proceed as normal.

Confirmed COVID-19 (ie, symptoms and positive SARS-CoV-2 test): This meets
exclusion criterion 5; therefore, Vaccination 2 should not be given but the participant
should remain in the study.

9. STATISTICAL CONSIDERATIONS
Methodology for summary and statistical analyses of the data collected in this study is
described here and further detailed in a statistical analysis plan (SAP), which will bemaintained by the sponsor. The SAP may modify what is outlined in the protocol whereappropriate; however, any major modifications of the primary endpoint definitions or theiranalyses will also be reflected in a protocol amendment.

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9.1. Estimands and Statistical Hypotheses
9.1.1. Estimands
The estimand corresponding to each primary, secondary, and tertiary/exploratory objective is
described in the table in Section 3.
In the primary safety objective evaluations, missing reactogenicity e-diary data will not be
imputed. Missing AE dates will be imputed according to Pfizer safety rules. No othermissing information will be imputed in the safety analysis.

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)The estimands to evaluate the immunogenicity objectives are based on evaluable populations
for immunogenicity (Section 9.3). These estimands estimate the vaccine effect in the
hypothetical setting where participants follow the study schedules and protocol requirements
as directed. Missing antibody results will not be imputed. Immunogenicity results that are
below the LLOQ will be set to 0.5 × LLOQ in the analysis; this may be adjusted once
additional data on the assay characteristics become available.
The estimands to evaluate the efficacy objectives are based on evaluable populations for
efficacy (Section 9.3). These estimands estimate the vaccine effect in the hypotheticalsetting where participants follow the study schedules and protocol requirements as directed.
In addition, VE will be analyzed by all--available efficacy population. Missing laboratory
results will not be imputed for the primary analysis, but missing data imputation for theefficacy endpoint may be performed as a sensitivity analysis.
9.1.2. Statistical Hypotheses
9.1.2.1. Statistical Hypothesis Evaluation for Efficacy
Phase 2/3 of the study has 2 primary efficacy endpoints evaluating VE, which is defined as
VE = 100 × (1 – IRR). IRR is calculated as the ratio of first confirmed COVID-19 illness ratein the vaccine group to the corresponding illness rate in the placebo group. In Phase 2/3, theassessment of VE will be based on posterior probabilities of VE1 > 30% and VE2 > 30%.
VE1 represents VE for prophylactic BNT162b2 against confirmed COVID-19 in participants
without evidence of infection before vaccination, and VE2 represents VE for prophylactic
BNT162b2 against confirmed COVID-19 in all participants after vaccination.
For participants with multiple confirmed cases, only the first case will contribute to the VE
calculation for each hypothesis. VE1 and VE2 will be evaluated sequentially to control theoverall type I error to the desired level of 2.5%. VE is demonstrated if there is sufficientevidence (posterior probability) that either VE1 >30% or both VE1 and VE2 are >30%. The
assessment for the primary analysis will be based on posterior probability using a Bayesianmodel.
9.1.2.2. Statistical Hypothesis Evaluation for Immunogenicity
One of the secondary objectives in the Phase 3 part of the study is to evaluate noninferiorityof the immune response to prophylactic BNT162b2 in participants 12 to 15 years of age
compared to the response in participants 16 to 25 years of age at 1 month after Dose 2. The
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(Dose 2) evaluable immunogenicity population will be used for the following hypothesis
testing:
H0: ln(µ2) – ln(µ1) ≤ ln(0.67)
where ln (0.67) corresponds to a 1.5-fold margin for noninferiority, ln(µ2) and ln(µ1) are thenatural log of the geometric mean of SARS-CoV-2 neutralizing titers from BNT162b2
recipients 12 to 15 years of age and 16 to 25 years of age, respectively, measured 1 monthafter Dose 2. If the lower limit of the 95% CI for the GMR (12-15 years of age to 16-25
years of age) is >0.67, the noninferiority objective is met.
9.2. Sample Size Determination

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)The study sample size for Phase 1 of the study is not based on any statistical hypothesis
testing. Phase 1 comprises 15 participants (randomization ratio of 4:1 so that 12 receive
active vaccine and 3 receive placebo) per group; 13 vaccine groups are studied,corresponding to a total of 195 participants.
For Phase 2/3, with assumptions of a true VE of 60% after the second dose of investigational
product, a total of approximately 164 first confirmed COVID-19 illness cases will provide
90% power to conclude true VE >30% with high probability, allowing early stopping for
efficacy at the IA. This would be achieved with 17,600 evaluable participants per group or
21,999 vaccine recipients randomized in a 1:1 ratio with placebo, for a total sample size of
43,998, based on the assumption of a 1.3% illness rate per year in the placebo group, accrualof 164 primary-endpoint cases within 6 months, and 20% of the participants being
nonevaluable or having serological evidence of prior infection with SARS-CoV-2,
potentially making them immune to further infection. Dependent upon the evolution of thepandemic, it is possible that the COVID-19 attack rate may be much higher, in which caseaccrual would be expected to be more rapid, enabling the study’s primary endpoint to beevaluated much sooner. The total number of participants enrolled in Phase 2/3 may varydepending on the incidence of COVID-19 at the time of the enrollment, the true underlying
VE, and a potential early stop for efficacy or futility.
In Phase 3, approximately 2000 participants are anticipated to be 12 to 15 years of age. A
random sample of 250 participants will be selected for each of the 2 age groups (12 to 15
years and 16 to 25 years) as an immunogenicity subset for the noninferiority assessment.
With the standard deviation and observed GMT difference assumed in the power analysis
below, a sample size of 200 evaluable participants (or 250 vaccine recipients) per age groupwill provide a power of 90.8% to declare the noninferiority of adolescents to 16- to
25-year-olds in terms of neutralizing antibody GMR, 1 month after the second dose(see Table 4).

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Table 4.

Power Analysis for Noninferiority Assessment

Criteria

Standard
Deviation(Log Value)a

AssumedObserved GMT
Difference (Log
Scale)-0.2

Powerb

Number of
Evaluable
Participants per
Age Group
200

Lower limit of 95%
0.623
90.8%
CI for GMR(12-15/16-25)>0.67
Abbreviation: GMR = geometric mean ratio.
a. Reference: 1 month after Dose 2, BNT162b2 (30 µg), 18- to 55-year age group (C4591001 Phase 1,
N=12). Calculation may be updated if additional information becomes available to better estimate thestandard deviation.
b. At 0.05 alpha level (2-sided).

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For safety outcomes, Table 5 shows the probability of observing at least 1 AE for a given
true event rate of a particular AE, for various sample sizes. For example, if the true AE rate
is 10%, with 12 participants in a vaccine group, there is 72% probability of observing at least
1 AE.
Table 5.

Probability of Observing at Least 1 AE by Assumed True Event Rates
With Different Sample Sizes

N=12
N=45
Assumed
True Event
Rate of an
AE
0.01%
0.00
0.00
0.02%
0.00
0.01
0.04%
0.00
0.02
0.06%
0.01
0.03
0.08%
0.01
0.04
0.10%
0.01
0.04
0.15%
0.02
0.07
0.20%
0.02
0.09
0.25%
0.03
0.11
0.30%
0.04
0.13
0.35%
0.04
0.15
0.50%
0.06
0.20
1.00%
0.11
0.36
2.00%
0.22
0.60
3.00%
0.31
0.75
5.00%
0.46
0.90
7.00%
0.58
0.96
10.00%
0.72
0.99
Note: N = number in sample.

N=180

N=1000N=3000N=6000N=9000N=15000

0.02
0.04
0.07
0.10
0.13
0.16
0.24
0.30
0.36
0.42
0.47
0.59
0.84
0.97
>0.99
>0.99
>0.99
>0.99

0.10
0.18
0.33
0.45
0.55
0.63
0.78
0.86
0.92
0.95
0.97
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

0.26
0.45
0.70
0.83
0.91
0.95
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

0.45
0.70
0.91
0.97
0.99
0.99
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

0.59
0.83
0.97
0.99
0.99
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

0.78
0.95
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

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9.3. Analysis Sets
For purposes of analysis, the following populations are defined:
Population
Enrolled
Randomized
Dose 1 evaluable
immunogenicity

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Dose 2 evaluable
immunogenicity

Dose 1 all-available
immunogenicity
Dose 2 all-available
immunogenicity
Evaluable efficacy

All-available efficacy

SafetyDescription
All participants who have a signed ICD.
All participants who are assigned a randomization number in
the IWR system.
For Phase 1 only, all eligible randomized participants who
receive the vaccine to which they are randomly assigned at thefirst dose, have at least 1 valid and determinate
immunogenicity result after Dose 1, have blood collection
within an appropriate window after Dose 1, and have no otherimportant protocol deviations as determined by the clinician.
All eligible randomized participants who receive 2 doses ofthe vaccine to which they are randomly assigned, within thepredefined window, have at least 1 valid and determinate
immunogenicity result after Dose 2, have blood collection
within an appropriate window after Dose 2, and have no otherimportant protocol deviations as determined by the clinician.
For Phase 1 only: all randomized participants who receive atleast 1 dose of the study intervention with at least 1 valid anddeterminate immunogenicity result after Dose 1 but before
Dose 2.
All randomized participants who receive at least 1 dose of thestudy intervention with at least 1 valid and determinate
immunogenicity result after Dose 2.
All eligible randomized participants who receive all
vaccination(s) as randomized within the predefined windowand have no other important protocol deviations as determinedby the clinician.
1. All randomized participants who receive at least
1 vaccination.
2. All randomized participants who complete 2 vaccination
doses.
All randomized participants who receive at least 1 dose of thestudy intervention.

9.4. Statistical Analyses
The SAP will be developed and finalized before database lock for any of the planned
analyses in Section 9.5.1. It will describe the participant populations to be included in theanalyses and the procedures for accounting for missing, unused, and spurious data. Thissection provides a summary of the planned statistical analyses of the primary, secondary, andtertiary/exploratory endpoints.
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9.4.1. Immunogenicity Analyses
Immunogenicity samples will be drawn for all participants. Immunogenicity analyses will bebased upon results from appropriately sized subsets of samples, according to the purpose.
The statistical analysis of immunogenicity results will be primarily based on the evaluable
immunogenicity populations as defined in Section 9.3.
An additional analysis will be performed based on the all-available populations if there is alarge enough difference in sample size between the all-available immunogenicity populationand the evaluable immunogenicity population. Participants will be summarized according to
the vaccine group to which they were randomized.

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Endpoint
Secondaryimmunogenicity

Statistical Analysis Methods
Geometric mean titers/concentrations (GMTs/GMCs) of
SARS-CoV-2 neutralizing titers, S1-binding IgG level, andRBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, GMTs/GMCs and 2-sided 95% CIs will be
provided for each investigational product within each group before
vaccination and at each of the following time points:Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1, 6, 12
and 24 months after Dose 2

Geometric means will be calculated as the mean of the assay results
after making the logarithm transformation and then exponentiating themean to express results on the original scale. Two-sided 95% CIs will
be obtained by taking natural log transforms of concentrations/titers,
calculating the 95% CI with reference to the t-distribution, and thenexponentiating the confidence limits.
GMFRs of SARS-CoV-2 neutralizing titers, S1-binding IgG level,
and RBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, the GMFRs and 2-sided 95% CIs will be
provided for each investigational product within each group at each of
the following time points:Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1, 6, 12,
and 24 months after Dose 2

GMFRs will be limited to participants with nonmissing values prior to
the first dose and at the postvaccination time point. The GMFR will becalculated as the mean of the difference of logarithmically transformed
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Statistical Analysis Methods
assay results (later time point – earlier time point) and exponentiating
the mean. The associated 2-sided CIs will be obtained by calculating
CIs using Student’s t-distribution for the mean difference of thelogarithmically transformed assay results and exponentiating theconfidence limits.
Percentage of participants with ≥4-fold rise in SARS-CoV-2
neutralizing titers, S1-binding IgG level, and RBD-binding IgG
level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, percentages (and 2-sided 95% CIs) ofparticipants with ≥4-fold rise will be provided for each investigational
product within each group at each of the following time points:

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Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1, 6, 12,
and 24 months after Dose 2

The Clopper-Pearson method will be used to calculate the CIs.
GMR of SARS-CoV-2 neutralizing titer to S1-binding IgG level
and to RBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, the GMRs and 2-sided 95% CIs will be
provided for each investigational product within each group at each of
the following time points:Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1, 6, 12,
and 24 months after Dose 2

GMRs will be limited to participants with nonmissing values for both
SARS-CoV-2 neutralizing titers and S1-binding IgG level/RBDbinding IgG level at each time point. The GMR will be calculated as
the mean of the difference of logarithmically transformed assay results(eg, SARS-CoV-2 neutralizing titers minus S1-binding IgG level foreach participant) and exponentiating the mean. Two-sided CIs will beobtained by calculating CIs using Student’s t-distribution for the meandifference of the logarithmically transformed assay results andexponentiating the confidence limits.
For all the immunogenicity endpoints, the analysis will be based on the
Dose 1 and Dose 2 evaluable immunogenicity populations. An
additional analysis will be performed based on the all-available
immunogenicity populations if there is a large enough difference in
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Endpoint

Statistical Analysis Methods
sample size between the all-available immunogenicity populations andthe evaluable immunogenicity populations. Participants will besummarized according to the vaccine group to which they wererandomized. Missing serology data will not be imputed.

Secondaryimmunogenicity(noninferiority inthe 12- to 15-year
age groupcompared to the
16- to 25-year age
group)

GMR of SARS-CoV-2 neutralizing titers in participants 12 to 15
years of age to those 16 to 25 years of age
For participants with no serological or virological evidence (up to
1 month after receipt of the second dose) of past SARS-CoV-2
infection, the GMR of SARS-CoV-2 neutralizing titers in participants
12 to 15 years of age to those in participants 16 to 25 years of age and2-sided 95% CIs will be provided at 1 month after Dose 2 fornoninferiority assessment.
The GMR and its 2-sided 95% CI will be derived by calculating
differences in means and CIs on the natural log scale of the titers basedon the Student’s t-distribution and then exponentiating the results. The
difference in means on the natural log scale will be 12 to 15 years
minus 16 to 25 years. Noninferiority will be declared if the lower
bound of the 2-sided 95% CI for the GMR is greater than 0.67.
This analysis will be based on Dose 2 evaluable immunogenicity
populations. An additional analysis may be performed based on the
Dose 2 all-available immunogenicity population if needed.
Participants will be summarized according to the vaccine group towhich they were randomized. Missing serology data will not be
imputed.

Exploratory
immunogenicity

Geometric mean titers/concentrations (GMTs/GMCs) of
SARS-CoV-2 neutralizing titers, S1-binding IgG level, andRBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, GMTs/GMCs and 2-sided 95% CIs will be
provided for each investigational product within each group before
vaccination and at each of the following time points in Phase 2/3:


1, 6, 12, and 24 months after completion of vaccination inparticipants with and without serological or virologicalevidence of SARS-CoV-2 infection before vaccination

Geometric means will be calculated as the mean of the assay results
after making the logarithm transformation and then exponentiating themean to express results on the original scale. Two-sided 95% CIs will
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Statistical Analysis Methods
be obtained by taking natural log transforms of concentrations/titers,
calculating the 95% CI with reference to the t-distribution, and thenexponentiating the confidence limits.
GMFRs of SARS-CoV-2 neutralizing titers, S1-binding IgG level,
and RBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, the GMFRs and 2-sided 95% CIs will be
provided for each investigational product within each group at each of
the following time points in Phase 2/3:

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1, 6, 12, and 24 months after completion of vaccination inparticipants with and without serological or virologicalevidence of SARS-CoV-2 infection before vaccination

GMFRs will be limited to participants with nonmissing values prior to
the first dose and at the postvaccination time point. The GMFR will becalculated as the mean of the difference of logarithmically transformed
assay results (later time point – earlier time point) and exponentiating
the mean. The associated 2-sided CIs will be obtained by calculating
CIs using Student’s t-distribution for the mean difference of thelogarithmically transformed assay results and exponentiating theconfidence limits.
Percentage of participants with antibody levels ≥ predefined
threshold(s) for SARS-CoV-2 serological parameters
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels and/or
RBD-binding IgG levels, N-binding antibody, and SARS-CoV-2
detection by NAAT, percentages (and 2-sided 95% CIs) of participants
with antibody levels ≥ predefined threshold(s) will be provided foreach investigational product within each group at baseline and each of
the following time points in Phase 2/3:


1, 6, 12, and 24 months after completion of vaccination inparticipants with and without serological or virologicalevidence of SARS-CoV-2 infection before vaccination

The Clopper-Pearson method will be used to calculate the CIs.
Percentage of participants with the immune response (non-S) to
SARS-CoV-2 for N-binding antibody at the time points when data
are available
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Statistical Analysis Methods
The Clopper-Pearson method will be used to calculate the CIs.
For all of the immunogenicity endpoints, the analysis will be based on
the Dose 1 and Dose 2 evaluable immunogenicity populations. An
additional analysis will be performed based on the all-available
immunogenicity populations if there is a large enough difference insample size between the all-available immunogenicity populations andthe evaluable immunogenicity populations. Participants will besummarized according to the vaccine group to which they wererandomized. Missing serology data will not be imputed.
RCDCs for immunogenicity results

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Empirical RCDCs will be provided for SARS-CoV-2 neutralizing
titers, S1-binding IgG level, and RBD-binding IgG level after Dose 1
and after Dose 2.

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9.4.2. Efficacy Analyses
The statistical analysis of efficacy will be based on the evaluable efficacy population(primary analysis) and the all-available efficacy population as defined in Section 9.3.
Endpoint
Primary efficacy

Statistical Analysis Methods
Ratio of confirmed COVID-19 illness per 1000 person-years offollow-up in participants without evidence of infection before
vaccination for the active vaccine group to the placebo group
VE will be estimated by 100 × (1 – IRR), where IRR is the calculated
ratio of confirmed COVID-19 illness per 1000 person-years follow-up
in the active vaccine group to the corresponding illness rate in theplacebo group 7 days after the second dose. VE will be analyzed using
a beta-binomial model.

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After the above objective is met, the second primary endpoint will be
evaluated as below.
Ratio of confirmed COVID-19 illness per 1000 person-years offollow-up in participants with and without evidence of infection
before vaccination for the active vaccine group to the placebogroup
VE will be estimated by 100 × (1 – IRR), where IRR is the calculated
ratio of confirmed COVID-19 illness per 1000 person-years follow-up
in the active vaccine group to the corresponding illness rate in theplacebo group after 7 days after the second dose. VE will be analyzed
using a beta-binomial model.
The efficacy analysis for the first primary objective evaluation will bebased on the participants without evidence of infection before
vaccination and included in the evaluable efficacy population and in
the all-available efficacy population.
The efficacy analysis for the second primary objective evaluation will
be based on all participants included in the evaluable efficacy
population and in the all-available efficacy population.
For the primary endpoint analysis, missing efficacy data will not be
imputed. A sensitivity analysis will be performed by imputing missing
values with the assumption of MAR. A missing efficacy endpoint may
be imputed based on predicted probability using the fully conditional
specification method. Other imputation methods without the MAR
assumption may be explored. The details will be provided in the SAP.

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Endpoint
Secondary

Statistical Analysis Methods
Ratio of confirmed severe COVID-19 illness per 1000 person-years
of follow-up in participants without evidence of infection before
vaccination for the active vaccine group to the placebo group
Ratio of confirmed severe COVID-19 illness per 1000 person-years
of follow-up for the active vaccine group to the placebo group
These secondary efficacy objectives will be evaluated after the primaryobjectives are met. The analysis will be based on the evaluable
efficacy population and the all-available efficacy population. The
analysis methodology used for the primary efficacy endpoints will beapplied for the analysis of the above secondary efficacy endpoints.

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)The following secondary efficacy endpoints will be evaluateddescriptively with 95% CIs.
Ratio of confirmed COVID-19 illness (according to the
CDC-defined symptoms) per 1000 person-years of follow-up inparticipants without evidence of infection before vaccination for
the active vaccine group to the placebo group
Ratio of confirmed COVID-19 illness (according to the
CDC-defined symptoms) per 1000 person-years of follow-up inparticipants with and without evidence of infection before
vaccination for the active vaccine group to the placebo group
VE = 100 × (1 – IRR) will be estimated with confirmed COVID-19
illness according to the CDC-defined symptoms after 7 days after thesecond dose. The 2-sided 95% CI for VE will be derived using the
Clopper-Pearson method as described by Agresti.9
Missing efficacy data will not be imputed.

9.4.3. Safety Analyses
Endpoint
Primary

Statistical Analysis Methods
Descriptive statistics will be provided for each reactogenicity endpoint
for each dose and vaccine group. Local reactions and systemic eventsfrom Day 1 through Day 7 after each vaccination will be presented byseverity cumulatively across severity levels. Descriptive summary
statistics will include counts and percentages of participants with theindicated endpoint and the associated Clopper-Pearson 95% CIs.

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Endpoint

Statistical Analysis Methods
For Phase 1, descriptive statistics will be provided for abnormal
hematology and chemistry laboratory values at 1 and 7 days after
Dose 1 and 7 days after Dose 2, including grading shifts inhematology and chemistry laboratory assessments between baseline
and 1 and 7 days after Dose 1, and before Dose 2 and 7 days after
Dose 2. Descriptive summary statistics will include counts andpercentages of participants with the indicated endpoint and theassociated Clopper-Pearson 2-sided 95% CIs.
AEs will be categorized according to the Medical Dictionary forRegulatory Activities (MedDRA) terms. A 3-tier approach will be
used to summarize AEs in Phase 2/3. Under this approach AEs areclassified into 1 of 3 tiers: (1) Tier 1 events are prespecified events ofclinical importance and are identified in a list in the product’s safety
review plan; (2) Tier 2 events are those that are not Tier 1 but areconsidered “relatively common”; a MedDRA preferred term is defined
as a Tier 2 event if there are at least 1% of participants in at least 1
vaccine group reporting the event; and (3) Tier 3 events are those thatare neither Tier 1 nor Tier 2 events. For both Tier 1 and Tier 2 events,
2-sided 95% CIs for the difference between the vaccine and placebogroups in the percentage of participants reporting the events based on
the Miettinen and Nurminen method10 will be provided. In addition,
for Tier 1 events, the asymptotic p-values will also be presented forthe difference between groups in the percentage of participants
reporting the events, based on the same test statistic and under theassumption that the test statistic is asymptotically normally
distributed.
Descriptive summary statistics (counts, percentages, and associatedClopper-Pearson 95% CIs) will be provided for any AE events foreach vaccine group.
SAEs will be categorized according to MedDRA terms. Counts,
percentages, and the associated Clopper-Pearson 95% CIs of SAEs
from Dose 1 to 6 months after last dose will be provided for eachvaccine group.
The safety analyses are based on the safety population. Participants
will be summarized by vaccine group according to the investigational
products they actually received. Missing reactogenicity e-diary data
will not be imputed; missing AE dates will be handled according to
the Pfizer safety rules.

SecondaryNot applicable (N/A)
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Endpoint
Exploratory

Statistical Analysis Methods
N/A

9.4.4. Other Analyses
The ratios of (GMFR A to GMFR B) and (GMFR A to GMFR C) may be explored, where
GMFR A is the geometric mean of the ratio of the SARS-CoV-2 neutralizing titer at the
postvaccination time point to the corresponding titer at the prevaccination time point,
GFMR B is the geometric mean of the ratio of the S1-binding IgG level at the
postvaccination time point to the corresponding IgG level at the prevaccination time point,
and GMFR C is the geometric mean of the ratio of the RBD-binding IgG level at the
postvaccination time point to the corresponding antibody level at the prevaccination time
point.

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)The safety data and immunogenicity results for individuals with confirmed stable HIV
disease will be summarized descriptively. Furthermore, VE may be assessed if there is asufficient number of COVID-19 cases in this group of participants.
The safety and immunogenicity results for individuals 16 to 55 years of age vaccinated withstudy intervention produced by manufacturing “Process 1” and each lot of “Process 2” will
be summarized descriptively. A random sample of 250 participants from those vaccinatedwith study intervention produced by manufacturing “Process 1” will be selected randomly forthe analysis.
9.5. Interim Analyses
As this is a sponsor open-label study during Phase 1, the sponsor may conduct unblinded
reviews of the data during the course of the study for the purpose of safety assessment,
facilitating dose escalation decisions, and/or supporting clinical development.
During Phase 2/3, 4 IAs are planned and will be performed by an unblinded statistical teamafter accrual of 32, 62, 92, and 120 cases. At each IA:

VE for the first primary objective will be evaluated. Overwhelming efficacy will bedeclared if the first primary study objective is met. The criteria for success at aninterim analysis are based on the posterior probability (ie, P[VE >30%|data]) at thecurrent number of cases. Overwhelming efficacy will be declared if the posterior
probability is higher than the success threshold. The success threshold for eachinterim analysis will be calibrated to protect overall type I error at 2.5%. Additional
details about the success threshold or boundary calculation at each interim analysis
will be provided in the SAP.

The study will stop for lack of benefit (futility) if the predicted probability of successat the final analysis or study success is <5%. The posterior predictive POS will becalculated using a beta-binomial model. The futility assessment will be performed
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for the first primary endpoint and the futility boundary may be subject to change toreflect subsequent program-related decisions by the sponsor.
Efficacy and futility boundaries will be applied in a nonbinding way.

Bayesian approaches require specification of a prior distribution for the possible values of theunknown vaccine effect, thereby accounting for uncertainty in its value. A minimally
informative beta prior, beta (0.700102, 1), is proposed for θ = (1-VE)/(2-VE). The prior iscentered at θ = 0.4118 (VE=30%) which can be considered pessimistic. The prior allows
considerable uncertainty; the 95% interval for θ is (0.005, 0.964) and the corresponding 95%
interval for VE is (-26.2, 0.995).
Table 6 illustrates the boundary for efficacy and futility if IAs are performed after accrual of
32 62, 92, and 120 cases in participants without evidence of infection before vaccination.
Table 6.

Success Criteriaa
Futility Boundary
VE Point Estimate
VE Point Estimate(Case Split)(Case Split)
IA1
32
76.9% (6:26)
11.8% (15:17)
IA2
6268.1% (15:47)
27.8% (26:36)
IA3
92
62.7% (25:67)
38.6% (35:57)
IA4120
58.8% (35:85)
N/A
Final
164
52.3% (53:111)
Abbreviations: IA = interim analysis; N/A = not applicable; VE = vaccine efficacy.
Note: Case split = vaccine : placebo.
a. Interim efficacy claim: P(VE >30%|data) > 0.995; success at the final analysis: P(VE >30%|data)> 0.986.
Analysis090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)Interim Analysis Plan and Boundaries for Efficacy and Futility
Number of
Cases

Additional design operating characteristics (the boundary based on the number of cases
observed in the vaccine group; the probabilities for efficacy and futility given assumed
various VEs with a 1:1 randomization ratio) are listed in Table 7 and Table 8.

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Table 7.

Statistical Design Operating Characteristics: Probability of Success or
Failure for Interim Analyses

VaccineEfficacy(%)

Interim Analysis 1(Total Cases = 32)

30
50
60
70
80

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Table 8.

Probabilityof Success(Cases in
VaccineGroup ≤6)
0.006
0.054
0.150
0.368
0.722

Probabilityof Failure(Cases in
VaccineGroup ≥15)
0.315
0.078
0.021
0.003
<0.001

Interim Analysis 2(Total Cases = 62)
Probabilityof Success(Cases in
VaccineGroup ≤15)
0.003
0.051
0.160
0.310
0.238

Probabilityof Failure(Cases in
VaccineGroup ≥26)
0.231
0.056
0.010
<0.001<0.001

Interim Analysis 3(Total Cases = 92)
Probabilityof Success(Cases in
VaccineGroup ≤25)
0.002
0.063
0.175
0.195
0.037

Probabilityof Failure(Cases in
VaccineGroup ≥35)
0.239
0.103
0.019
0.001
<0.001

InterimAnalysis 4(Total Cases= 120)
Probability of
Success(CasesVaccineGroup ≤35)
0.002
0.075
0.160
0.085
0.003

Statistical Design Operating Characteristics: Probability of Success for
Final Analysis and Overall

Vaccine Efficacy (%)

30
50
60
70
80

Final Analysis(Total Cases = 164)
Probability of Success (Cases in Vaccine
Group ≤53)
0.007
0.196
0.220
0.036
<0.001

Overall Probability of Success

0.021
0.439
0.866
>0.999>0.999If neither success nor futility has been declared after all IAs, the final analysis will be
performed and the first primary objective will have been met if there are 53 or fewer cases
observed in the vaccine group out of a total of 164 first confirmed cases from 7 days after
receipt of the second dose of investigational product onwards.
After the primary objectives are met, the secondary VE endpoints (confirmed severe
COVID-19 in participants without evidence of infection before vaccination and confirmed
severe COVID-19 in all participants) will be evaluated sequentially, by the same method
used for the primary VE endpoint evaluation. Success thresholds for secondary VE will beappropriately chosen to control overall Type I error at 2.5%. Further details will be provided
in the SAP. The remaining secondary VE endpoints will be evaluated descriptively to
calculate the observed VE with 95% CIs.

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9.5.1. Analysis Timing

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Statistical analyses will be carried out when the following data are available:Complete safety and immunogenicity analysis approximately 1 month after Dose 2
for Phase 1.



Safety data through 7 days after Dose 2 and immunogenicity data through 1 monthafter Dose 2 from the first 360 participants enrolled (180 to active vaccine and 180 toplacebo, stratified equally between 18 to 55 years and >55 to 85 years) in Phase 2/3.



Safety data through 1 month after Dose 2 from at least 6000 participants enrolled(3000 to active vaccine and 3000 to placebo) in Phase 2/3. Additional analyses ofsafety data (with longer follow-up and/or additional participants) may be conducted if
required for regulatory purposes.



IAs for efficacy at 32, 62, 92, and 120 cases and futility at 32, 62, and 92 cases.

Safety data through 1 month after Dose 2 and noninferiority comparison of
SARS-CoV-2 neutralizing titers in participants 12 to 15 years of age compared tothose in participants 16 to 25 years of age, 1 month after Dose 2Descriptive analysis of immunogenicity and safety of “Process 1” and “Process 2”
material, 1 month after Dose 2Complete safety and immunogenicity analysis approximately 6 months after Dose 2
for all participants in Phase 2/3.

Complete efficacy and persistence-of-immunogenicity analysis after complete data
are available or at the end of the study.

All analyses conducted on Phase 2/3 data while the study is ongoing will be performed by an
unblinded statistical team.
9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will use an IRC, a DMC, and a group of internal case reviewers. The IRC is
independent of the study team and includes only internal members. The DMC is independentof the study team and includes only external members. The IRC and DMC charters describe
the role of the IRC and DMC in more detail.
The responsibilities of the IRC are only in Phase 1 and will include:

Review of safety data to permit dose escalations in the 18- to 55-year age cohort



Review of safety data in the case of a stopping rule being met

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

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Review of safety and/or immunogenicity data to:Allow groups of participants of 65 to 85 years of age to proceed

Select vaccine candidate/dose level(s) to proceed into Phase 2/3. Data supporting
the selection, including results for both binding antibody levels and neutralizing
titers, and the ratio between them, will also be submitted to the FDA for review

Review of any available safety and/or immunogenicity data generated during thecourse of this study, or the BioNTech study conducted in Germany, to determine:Whether any groups may not be started



Whether any groups may be terminated earlyWhether any groups may be added with dose levels below the lowest stated doseor intermediate between the lowest and highest stated doses

Contemporaneous review of all NAAT-confirmed COVID-19 illnesses in Phase 1

The DMC will be responsible for ongoing monitoring of the safety of participants in the
study according to the charter. This may include, but is not limited to:Contemporaneous review of related AEs up to 1 month after completion of thevaccination scheduleContemporaneous review of all SAEs up to 6 months after completion of thevaccination scheduleContemporaneous review of all NAAT-confirmed COVID-19 illnesses in Phase 1

At the time of the planned IAs, and ad hoc if requested by the unblinded team, review
of cases of COVID-19 for an adverse imbalance of cases of COVID-19 and/or severe
COVID-19 between the vaccine and placebo groups

The recommendations made by the DMC to alter the conduct of the study will be forwarded
to the appropriate Pfizer personnel for final decision. Pfizer will forward such decisions,which may include summaries of aggregate analyses of safety data, to regulatory authorities,
as appropriate.
Three blinded case reviewers (medically qualified Pfizer staff members) will review all
potential COVID-19 illness events. If a NAAT-confirmed case in Phase 2/3 may beconsidered severe, or not, solely on the basis of “significant acute renal, hepatic, orneurologic dysfunction,” the blinded data will be reviewed by the case reviewers to assess
whether the criterion is met; the majority opinion will prevail.

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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:Consensus ethical principles derived from international guidelines including the
Declaration of Helsinki and CIOMS International Ethical Guidelines;Applicable ICH GCP guidelines;Applicable laws and regulations, including applicable privacy laws.

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents(eg, advertisements) must be reviewed and approved by the sponsor and submitted to an
IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study is
initiated.
Any amendments to the protocol will require IRB/EC approval before implementation ofchanges made to the study design, except for changes necessary to eliminate an immediate
hazard to study participants.
The investigator will be responsible for the following:Providing written summaries of the status of the study to the IRB/EC annually or
more frequently in accordance with the requirements, policies, and procedures
established by the IRB/EC;



Notifying the IRB/EC of SAEs or other significant safety findings as required by
IRB/EC procedures;Providing oversight of the conduct of the study at the site and adherence torequirements of 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014
for clinical studies (if applicable), and all other applicable local regulations.

10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicableregulatory authority in any area of the world, or if the investigator is aware of any new
information that might influence the evaluation of the benefits and risks of the study
intervention, Pfizer should be informed immediately.
In addition, the investigator will inform Pfizer immediately of any urgent safety measurestaken by the investigator to protect the study participants against any immediate hazard, andof any serious breaches of this protocol or of ICH GCP that the investigator becomes awareof.
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10.1.2. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to theparticipant or his or her parent(s)/legal guardian and answer all questions regarding the study.
The participant or his or her parent(s)/legal guardian should be given sufficient time andopportunity to ask questions and to decide whether or not to participate in the trial.
Participants must be informed that their participation is voluntary. Participants or theirparent(s)/legal guardian will be required to sign a statement of informed consent that meetsthe requirements of 21 CFR 50, local regulations, ICH guidelines, HIPAA requirements,
where applicable, and the IRB/EC or study center.
The investigator must ensure that each study participant or his or her parent(s)/legal guardianis fully informed about the nature and objectives of the study, the sharing of data related tothe study, and possible risks associated with participation, including the risks associated withthe processing of the participant’s personal data.

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)The participant must be informed that his/her personal study-related data will be used by thesponsor in accordance with local data protection law. The level of disclosure must also be
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical
Quality Assurance auditors or other authorized personnel appointed by the sponsor, byappropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant or his or her parent(s)/legal
guardian is fully informed about his or her right to access and correct his or her personal data
and to withdraw consent for the processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their
participation in the study.
A copy of the ICD(s) must be provided to the participant or his or her parent(s)/legal
guardian. Participants who are rescreened are required to sign a new ICD.
Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate
section that addresses the use of samples for optional additional research. The optional
additional research does not require the collection of any further samples. The investigator
or authorized designee will explain to each participant the objectives of the additional
research. Participants will be told that they are free to refuse to participate and may
withdraw their consent at any time and for any reason during the storage period.

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10.1.3. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementationof organizational and technical measures to ensure protection of participant data.

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Participants’ personal data will be stored at the study site in encrypted electronic and/or paper
form and will be password protected or secured in a locked room to ensure that only
authorized study staff have access. The study site will implement appropriate technical andorganizational measures to ensure that the personal data can be recovered in the event ofdisaster. In the event of a potential personal data breach, the study site will be responsiblefor determining whether a personal data breach has in fact occurred and, if so, providing
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personaldata, participants will be assigned a single, participant-specific numerical code. Any
participant records or data sets that are transferred to the sponsor will contain the numericalcode; participant names will not be transferred. All other identifiable data transferred to thesponsor will be identified by this single, participant-specific code. The study site will
maintain a confidential list of participants who participated in the study, linking eachparticipant’s numerical code to his or her actual identity and medical record identification. In
case of data transfer, the sponsor will protect the confidentiality of participants’ personal dataconsistent with the clinical study agreement and applicable privacy laws.
10.1.4. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting theresults of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or
www.pfizer.com, and other public registries in accordance with applicable local
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, andcomplete manner and are reported regardless of the outcome of the study or the country inwhich the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional
studies (conducted in patients) that evaluate the safety and/or efficacy of a product,
regardless of the geographical location in which the study is conducted. These results are
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies inaccordance with the format and timelines set forth by EU requirements.

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www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used
to identify individual participants have been removed) on www.pfizer.com for
Pfizer-sponsored interventional studies at the same time the corresponding study results areposted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinicaldata to the EMA website. Clinical data, under Phase 1 of this policy, includes clinicaloverviews, clinical summaries, CSRs, and appendices containing the protocol and protocol
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of thispolicy, includes the publishing of individual participant data. Policy 0070 applies to newmarketing authorization applications submitted via the centralized procedure since
01 January 2015 and applications for line extensions and for new indications submitted via
the centralized procedure since 01 July 2015.

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Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposesof “bona-fide scientific research” that contributes to the scientific understanding of thedisease, target, or compound class. Pfizer will make available data from these trials
24 months after study completion. Patient-level data will be anonymized in accordance withapplicable privacy laws and regulations. CSRs will have personally identifiable information
redacted.
Data requests are considered from qualified researchers with the appropriate competencies toperform the proposed analyses. Research teams must include a biostatistician. Data will not
be provided to applicants with significant conflicts of interest, including individuals
requesting access for commercial/competitive or legal purposes.
10.1.5. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unlesstransmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is
responsible for verifying that data entries are accurate and correct by physically orelectronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports theinformation entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted
electronic and/or paper form and are password protected or secured in a locked room toprevent access by unauthorized third parties.

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The investigator must permit study-related monitoring, audits, IRB/EC review, andregulatory agency inspections and provide direct access to source data documents. This
verification may also occur after study completion. It is important that the investigator(s)and their relevant personnel are available during the monitoring visits and possible audits orinspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality
such as risk management and mitigation strategies and analytical risk-based monitoring),
methods, responsibilities, and requirements, including handling of noncompliance issues andmonitoring techniques (central, remote, or on-site monitoring), are provided in themonitoring plan.

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)The sponsor or designee is responsible for the data management of this study, including
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data enteredinto the CRF by authorized site personnel are accurate, complete, and verifiable from source
documents; that the safety and rights of participants are being protected; and that the study is
being conducted in accordance with the currently approved protocol and any other study
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must
be retained by the investigator for 15 years after study completion unless local regulations or
institutional policies require a longer retention period. No records may be destroyed during
the retention period without the written approval of the sponsor. No records may betransferred to another location or party without written notification to the sponsor. The
investigator must ensure that the records continue to be stored securely for as long as they are
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of suchdata are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory
inspection notification in relation to the study. Furthermore, the investigator will cooperatewith the sponsor or its agents to prepare the investigator site for the inspection and will allow
the sponsor or its agent, whenever feasible, to be present during the inspection. The
investigator site and investigator will promptly resolve any discrepancies that are identified
between the study data and the participant's medical records. The investigator will promptly
provide copies of the inspection findings to the sponsor or its agent. Before response
submission to the regulatory authorities, the investigator will provide the sponsor or its
agents with an opportunity to review and comment on responses to any such findings.

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10.1.6. Source Documents
Source documents provide evidence for the existence of the participant and substantiate theintegrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be
consistent with the source documents or the discrepancies must be explained. The
investigator may need to request previous medical records or transfer records, depending on
the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the study monitoring plan.
Description of the use of computerized system is documented in the Data Management Plan.
10.1.7. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment ofparticipants.

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)The first act of recruitment is the date of the first participant’s first visit and will be the study
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any
time for any reason at the sole discretion of the sponsor. Study sites will be closed uponstudy completion. A study site is considered closed when all required documents and study
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor
or designee if requested to do so by the responsible IRB/EC or if such termination is required
to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limitedto:

Failure of the investigator to comply with the protocol, the requirements of the
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.

If the study is prematurely terminated or suspended, the sponsor shall promptly inform theinvestigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of
the reason for termination or suspension, as specified by the applicable regulatory
requirements. The investigator shall promptly inform the participant and should assure
appropriate participant therapy and/or follow-up.

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Study termination is also provided for in the clinical study agreement. If there is any conflict
between the contract and this protocol, the contract will control as to termination rights.
10.1.8. Sponsor’s Qualified Medical Personnel

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)The contact information for the sponsor's appropriately qualified medical personnel for the
study is documented in the study contact list located in the supporting study documentation.
To facilitate access to appropriately qualified medical personnel on study-related medical
questions or problems, participants are provided with a contact card at the time of informed
consent. The contact card contains, at a minimum, protocol and study intervention
identifiers, participant numbers, contact information for the investigator site, and contact
details for a contact center in the event that the investigator site staff cannot be reached toprovide advice on a medical question or problem originating from another healthcare
professional not involved in the participant’s participation in the study. The contact number
can also be used by investigator staff if they are seeking advice on medical questions or
problems; however, it should be used only in the event that the established communication
pathways between the investigator site and the study team are not available. It is therefore
intended to augment, but not replace, the established communication pathways between theinvestigator site and the study team for advice on medical questions or problems that may
arise during the study. The contact number is not intended for use by the participant directly,
and if a participant calls that number, he or she will be directed back to the investigator site.

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10.2. Appendix 2: Clinical Laboratory Tests

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)The following safety laboratory tests will be performed at times defined in the SoA section ofthis protocol. Additional laboratory results may be reported on these samples as a result of
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived
from calculated values. These additional tests would not require additional collection ofblood. Unscheduled clinical laboratory measurements may be obtained at any time during
the study to assess any perceived safety issues.
Hematology
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet countWBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)Basophils (Abs)
Lymphocytes (Abs)

Chemistry
BUN and creatinine
AST, ALT
Total bilirubin
Alkaline phosphatase

Other Urine pregnancy test (β-hCG)
At screening only: Hepatitis B core antibody
 Hepatitis B surface antigen
 Hepatitis C antibody
 Human immunodeficiency virus

Investigators must document their review of each laboratory safety report.
Clinically significant abnormal laboratory findings should be recorded in the AE CRF in
accordance with the following grading scale (Table 9).
Table 9.

Laboratory Abnormality Grading Scale

Hematology

Mild (Grade 1)

Hemoglobin
11.0 – 12.0
(Female) - g/dL
Hemoglobin
12.5 – 13.5
(Male) - g/dL
WBC increase 10,800 – 15,000
cells/mm3
WBC decrease 2,500 – 3,500
cells/mm3
Lymphocytes
750 – 1,000
decrease - cells/mm3
Neutrophils decrease 1,500 – 2,000- cells/mm3
Eosinophils 650 – 1500
cells/mm3
Platelets decreased - 125,000 – 140,000
cells/mm3

Moderate(Grade 2)

Severe (Grade 3)

9.5 – 10.9

8.0 – 9.4

Potentially Life
Threatening(Grade 4)<8.0

10.5 – 12.4

8.5 – 10.4

<8.5

15,001 – 20,000

20,001 – 25, 000>25,000

1,500 – 2,499

1,000 – 1,499<1,000500 – 749

250 – 499

<250

1,000 – 1,499

500 – 999

<500

1501 - 5000

>5000

Hypereosinophilic

100,000 – 124,000

25,000 – 99,000<25,000

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Table 9.

Laboratory Abnormality Grading Scale

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Chemistry

Mild (Grade 1)

Moderate(Grade 2)

Severe(Grade 3)

BUN - mg/dL
Creatinine – mg/dL

23 – 26
1.5 – 1.7

27 – 31
1.8 – 2.0> 31
2.1 – 2.5

Alkaline
phosphate –increase by factor
Liver function tests– ALT, AST
increase by factor
Bilirubin – whenaccompanied
by any increase inliver function test increase by factor
Bilirubin – whenliver function test is
normal - increase byfactor

1.1 – 2.0 x ULN

2.1 – 3.0 x ULN

3.1 – 10 x ULN

Potentially Life
Threatening(Grade 4)
Requires dialysis> 2.5 or requires
dialysis>10 x ULN

1.1 – 2.5 x ULN

2.6 – 5.0 x ULN

5.1 – 10 x ULN>10 x ULN

1.1 – 1.25 x ULN

1.26 – 1.5 x ULN

1.51 – 1.75 x ULN>1.75 x ULN

1.1 – 1.5 x ULN

1.6 – 2.0 x ULN

2.0 – 3.0 x ULN>3.0 x ULN

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen;
ULN = upper limit of normal; WBC = white blood cell.

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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition


An AE is any untoward medical occurrence in a patient or clinical study participant,temporally associated with the use of study intervention, whether or not consideredrelated to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including anabnormal laboratory finding), symptom, or disease (new or exacerbated) temporally
associated with the use of study intervention.

Events Meeting the AE Definition

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis)or other safety assessments (eg, ECG, radiological scans, vital sign measurements),
including those that worsen from baseline, considered clinically significant in the
medical and scientific judgment of the investigator Any abnormal laboratory test
results that meet any of the conditions below must be recorded as an AE:
Is associated with accompanying symptoms.



Requires additional diagnostic testing or medical/surgical intervention.



Leads to a change in study dosing (outside of any protocol-specified dose
adjustments) or discontinuation from the study, significant additional
concomitant drug treatment, or other therapy.



Exacerbation of a chronic or intermittent preexisting condition including either anincrease in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration eventhough it may have been present before the start of the study.



Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.



Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
intervention or a concomitant medication. Overdose per se will not be reported as
an AE/SAE unless it is an intentional overdose taken with possible
suicidal/self-harming intent. Such overdoses should be reported regardless ofsequelae.
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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safetyassessments which are associated with the underlying disease, unless judged by theinvestigator to be more severe than expected for the participant’s condition.



The disease/disorder being studied or expected progression, signs, or symptoms ofthe disease/disorder being studied, unless more severe than expected for theparticipant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).



Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present
or detected at the start of the study that do not worsen.

10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:a. Results in deathb. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which theparticipant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.
c. Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving
at least an overnight stay) at the hospital or emergency ward for observation and/or
treatment that would not have been appropriate in the physician’s office or outpatientsetting. Complications that occur during hospitalization are AEs. If a complication
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in
doubt as to whether “hospitalization” occurred or was necessary, the AE should beconsidered serious.
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Hospitalization for elective treatment of a preexisting condition that did not worsen frombaseline is not considered an AE.
d. Results in persistent disability/incapacity


The term disability means a substantial disruption of a person’s ability to conduct
normal life functions.

This definition is not intended to include experiences of relatively minor medicalsignificance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza,
and accidental trauma (eg, sprained ankle) which may interfere with or prevent
everyday life functions but do not constitute a substantial disruption.

e. Is a congenital anomaly/birth defect090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)

f. Other situations:Medical or scientific judgment should be exercised in deciding whether SAE
reporting is appropriate in other situations such as important medical events that
may not be immediately life-threatening or result in death or hospitalization but may
jeopardize the participant or may require medical or surgical intervention to prevent
one of the other outcomes listed in the above definition. These events should
usually be considered serious.



Examples of such events include invasive or malignant cancers, intensive treatment
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or
convulsions that do not result in hospitalization, or development of drug dependency
or drug abuse.

Suspected transmission via a Pfizer product of an infectious agent, pathogenic or
nonpathogenic, is considered serious. The event may be suspected from clinicalsymptoms or laboratory findings indicating an infection in a patient exposed to a
Pfizer product. The terms “suspected transmission” and “transmission” areconsidered synonymous. These cases are considered unexpected and handled asserious expedited cases by pharmacovigilance personnel. Such cases are also
considered for reporting as product defects, if appropriate.

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10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF andfor reporting serious adverse events on the Vaccines SAE Report Form to Pfizer Safety.
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious adverse
events (AEs); and (3) exposure to the study intervention under study during pregnancy orbreastfeeding, and occupational exposure.

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)It should be noted that the Vaccines SAE Report Form for reporting of SAE information is
not the same as the AE page of the CRF. When the same data are collected, the forms must
be completed in a consistent manner. AEs should be recorded using concise medical
terminology and the same AE term should be used on both the CRF and the Vaccines SAE
Report Form for reporting of SAE information.
Safety Event

Recorded on the CRF

SAE
Nonserious AE
Exposure to the study
intervention under study
during pregnancy orbreastfeeding, andoccupational exposure

All
All
All AEs/SAEs associatedwith exposure during
pregnancy or breastfeeding

Reported on the Vaccines
SAE Report Form to
Pfizer Safety Within 24
Hours of Awareness

All
None
All (and EDP supplemental
form for EDP)
Note: Include all SAEs
associated with exposure
Occupational exposure is not during pregnancy orbreastfeeding. Include allrecorded.
AEs/SAEs associated withoccupational exposure.

When an AE/SAE occurs, it is the responsibility of the investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostic
reports) related to the event.



The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s
medical records to Pfizer Safety in lieu of completion of the Vaccines SAE Report
Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases arerequested by Pfizer Safety. In this case, all participant identifiers, with the
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exception of the participant number, will be redacted on the copies of the medical
records before submission to Pfizer Safety.


The investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. Whenever possible, the diagnosis(not the individual signs/symptoms) will be documented as the AE/SAE.

Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during
the study and assign it to 1 of the following categories:

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)GRADE If required on the AE page of the CRF, the investigator will use theadjectives MILD, MODERATE, SEVERE, or LIFE-THREATENING todescribe the maximum intensity of the AE. For purposes of consistency,
these intensity grades are defined as follows:
1

MILD

Does not interfere with participant's usualfunction.

2

MODERATE

Interferes to some extent with participant's usualfunction.

3

SEVEREInterferes significantly with participant's usualfunction.

4

LIFE-THREATENING Life-threatening consequences; urgent
intervention indicated.

Assessment of Causality

The investigator is obligated to assess the relationship between study intervention
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence,
and/or arguments to suggest a causal relationship, rather than a relationship cannot
be ruled out.

The investigator will use clinical judgment to determine the relationship.



Alternative causes, such as underlying disease(s), concomitant therapy, and otherrisk factors, as well as the temporal relationship of the event to study intervention
administration, will be considered and investigated.

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The investigator will also consult the IB and/or product information, for marketed
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she
has reviewed the AE/SAE and has provided an assessment of causality.



There may be situations in which an SAE has occurred and the investigator has
minimal information to include in the initial report to the sponsor. However, it isvery important that the investigator always make an assessment of causality forevery event before the initial transmission of the SAE data to the sponsor.



The investigator may change his/her opinion of causality in light of follow-up
information and send an SAE follow-up report with the updated causality
assessment.



The causality assessment is one of the criteria used when determining regulatory
reporting requirements.



If the investigator does not know whether or not the study intervention caused theevent, then the event will be handled as “related to study intervention” for reporting
purposes, as defined by the sponsor. In addition, if the investigator determines thatan SAE is associated with study procedures, the investigator must record this causal
relationship in the source documents and CRF, and report such an assessment in the
dedicated section of the Vaccines SAE Report Form and in accordance with the
SAE reporting requirements.

Follow-up of AEs and SAEs


The investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by thesponsor to elucidate the nature and/or causality of the AE or SAE as fully as
possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other healthcare providers.



If a participant dies during participation in the study or during a recognizedfollow-up period, the investigator will provide Pfizer Safety with a copy of any
postmortem findings including histopathology.



New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours ofreceipt of the information.

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10.3.4. Reporting of SAEs

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SAE Reporting to Pfizer Safety via Vaccines SAE Report Form

Facsimile transmission of the Vaccines SAE Report Form is the preferred method totransmit this information to Pfizer Safety.



In circumstances when the facsimile is not working, notification by telephone isacceptable with a copy of the Vaccines SAE Report Form sent by overnight mail orcourier service.

Initial notification via telephone does not replace the need for the investigator tocomplete and sign the Vaccines SAE Report Form pages within the designatedreporting time frames.

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10.4. Appendix 4: Contraceptive Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during
the intervention period and for at least 28 days after the last dose of study intervention, whichcorresponds to the time needed to eliminate reproductive safety risk of the study
intervention(s):Refrain from donating sperm.

PLUS either:Be abstinent from heterosexual intercourse with a female of childbearing potential as
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) andagree to remain abstinent.

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)OR

Must agree to use a male condom when engaging in any activity that allows forpassage of ejaculate to another person.



In addition to male condom use, a highly effective method of contraception may beconsidered in WOCBP partners of male participants (refer to the list of highly
effective methods below in Section 10.4.4).

10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).

OR

Is a WOCBP and using an acceptable contraceptive method as described below
during the intervention period (for a minimum of 28 days after the last dose of study
intervention). The investigator should evaluate the effectiveness of the contraceptive
method in relationship to the first dose of study intervention.

The investigator is responsible for review of medical history, menstrual history, and recent
sexual activity to decrease the risk for inclusion of a woman with an early undetected
pregnancy.

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10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot
be confirmed before the first dose of study intervention, additional evaluation should beconsidered.
Women in the following categories are not considered WOCBP:
1. Premenarchal.

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2. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.

For individuals with permanent infertility due to an alternate medical cause other than theabove, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should beapplied to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s
review of the participant’s medical records, medical examination, or medical history
interview. The method of documentation should be recorded in the participant’s medical
record for the study.
3. Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause. In addition, ahigh FSH level in the postmenopausal range must be used to confirm apostmenopausal state in women under 60 years of age and not using hormonal
contraception or HRT.



Female on HRT and whose menopausal status is in doubt will be required to use
one of the nonestrogen hormonal highly effective contraception methods if theywish to continue their HRT during the study. Otherwise, they must discontinue
HRT to allow confirmation of postmenopausal status before study enrollment.

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10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations
regarding the use of contraceptive methods for those participating in clinical trials.
1. Implantable progestogen-only hormone contraception associated with inhibition ofovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner:

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Vasectomized partner is a highly effective contraceptive method provided that thepartner is the sole sexual partner of the woman of childbearing potential and theabsence of sperm has been confirmed. If not, an additional highly effective methodof contraception should be used. The spermatogenesis cycle is approximately
90 days.

6. Combined (estrogen- and progestogen-containing) hormonal contraception associatedwith inhibition of ovulation:


Oral;



Intravaginal;Transdermal;



Injectable.

7. Progestogen-only hormone contraception associated with inhibition of ovulation:


Oral;



Injectable.

8. Sexual abstinence:Sexual abstinence is considered a highly effective method only if defined as
refraining from heterosexual intercourse during the entire period of risk associatedwith the study intervention. The reliability of sexual abstinence needs to be evaluatedin relation to the duration of the study and the preferred and usual lifestyle of theparticipant.

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9. Progestogen-only oral hormonal contraception where inhibition of ovulation is not the
primary mode of action.
10. Male or female condom with or without spermicide.
11. Cervical cap, diaphragm, or sponge with spermicide.

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12. A combination of male condom with either cervical cap, diaphragm, or sponge with
spermicide (double-barrier methods).

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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations intransaminases) are termed “tolerators,” while those who show transient liver injury, but adapt
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of amore serious potential outcome. These participants fail to adapt and therefore are"susceptible" to progressive and serious liver injury, commonly referred to as DILI.
Participants who experience a transaminase elevation above 3 × ULN should be monitored
more frequently to determine if they are an “adaptor” or are “susceptible.”

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LFTs are not required as a routine safety monitoring procedure for all participants in thisstudy. However, should an investigator deem it necessary to assess LFTs because aparticipant presents with clinical signs/symptoms, such LFT results should be managed andfollowed as described below.
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will beelevated within the same laboratory sample). In rare instances, by the time TBili elevations
are detected, AST/ALT values might have decreased. This occurrence is still regarded as apotential DILI. Therefore, abnormal elevations in either AST OR ALT in addition to TBili
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law
criteria) cases and should always be considered important medical events, even before allother possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on theparticipant’s individual baseline values and underlying conditions. Participants who present
with the following laboratory abnormalities should be evaluated further as potential DILI
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:Participants with AST/ALT and TBili baseline values within the normal range who
subsequently present with AST OR ALT values >3 × ULN AND a TBili value>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value<2 × ULN or not available.

For participants with baseline AST OR ALT OR TBili values above the ULN, thefollowing threshold values are used in the definition mentioned above, as needed,
depending on which values are above the ULN at baseline:Preexisting AST or ALT baseline values above the normal range: AST or ALT
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever issmaller).

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Rises in AST/ALT and TBili separated by more than a few weeks should be assessedindividually based on clinical judgment; any case where uncertainty remains as to whether it
represents a potential Hy’s law case should be reviewed with the sponsor.

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)The participant should return to the investigator site and be evaluated as soon as possible,
preferably within 48 hours from awareness of the abnormal results. This evaluation should
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili for suspected cases ofHy’s law, additional laboratory tests should include albumin, CK, direct and indirect
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should
also be given to drawing a separate tube of clotted blood and an anticoagulated tube of bloodfor further testing, as needed, for further contemporaneous analyses at the time of therecognized initial abnormalities to determine etiology. A detailed history, including relevant
information, such as review of ethanol, acetaminophen/paracetamol (either by itself or as a
coformulated product in prescription or over-the-counter medications), recreational drug,
supplement (herbal) use and consumption, family history, sexual history, travel history,
history of contact with a jaundiced person, surgery, blood transfusion, history of liver orallergic disease, and potential occupational exposure to chemicals, should be collected.
Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary
tract) and collection of serum samples for acetaminophen/paracetamol drug and/or protein
adduct levels may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if noother reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law)cases are to be reported as SAEs, irrespective of availability of all the results of theinvestigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results ofreasonable investigations have been received and have excluded an alternative etiology.

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10.6. Appendix 6: Abbreviations

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)The following is a list of abbreviations that may be used in the protocol.
Abbreviation
2019-nCoV
Abs
AE
ALT
AST
-hCG
BMI
BUN
CBER
CDC
CFR
CI
CIOMS
CLIA
CONSORT
COVID-19
CRF
CRO
CSR
CT
DBP
DILI
DMC
DNA
DU
EC
ECMO
ECG
eCRF
e-diary
EDP
EMA
EU
EUA
EudraCT
FDA
FiO2
FSH
GCP

Term
novel coronavirus 2019absolute (in Appendix 2)
adverse event
alanine aminotransferase
aspartate aminotransferase
beta-human chorionic gonadotropin
body mass index
blood urea nitrogen
Center for Biologics Evaluation and ResearchCenters for Disease Control and Prevention (United States)
Code of Federal Regulations
confidence interval
Council for International Organizations of Medical Sciences
Clinical Laboratory Improvement Amendments
Consolidated Standards of Reporting Trials
coronavirus disease 2019case report form
contract research organization
clinical study reportcomputed tomography
diastolic blood pressuredrug-induced liver injury
data monitoring committee
deoxyribonucleic aciddosing unit
ethics committee
extracorporeal membrane oxygenationelectrocardiogram
electronic case report form
electronic diary
exposure during pregnancy
European Medicines Agency
European Union
emergency use authorization
European Clinical Trials Database
Food and Drug Administration
fraction of inspired oxygenfollicle-stimulating hormone
Good Clinical Practice

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Abbreviation
GGT
GMC
GMFR
GMR
GMT
HBc Ab
HBe
HBeAg
HBsAg
HBV
HCV
HCV Ab
HIPAA
HIV
HR
HRT
IA
IB
ICD
ICH
ICU
ID
Ig
IgG
IgM
IMP
IND
INR
IP manual
IPAL
IRB
IRC
IRR
IRT
ISO
IV
IWR
LFT
LL
LLOQ
LNP
LPX

Term
gamma-glutamyl transferase
geometric mean concentrationgeometric mean fold risegeometric mean ratio
geometric mean titerhepatitis B core antibody
hepatitis B ehepatitis B e antigen
hepatitis B surface antigen
hepatitis B virus
hepatitis C virus
hepatitis C virus antibody
Health Insurance Portability and Accountability Act
human immunodeficiency virus
heart rate
hormone replacement therapy
interim analysis
investigator’s brochure
informed consent document
International Council for Harmonisation
intensive care unit
identification
immunoglobulin
immunoglobulin G
immunoglobulin M
investigational medicinal productinvestigational new druginternational normalized ratio
investigational product manual
Investigational Product Accountability Log
institutional review board
internal review committee
illness rate ratio
interactive response technology
International Organization for Standardization
intravenous(ly)interactive Web-based response
liver function test
lower limit
lower limit of quantitation
lipid nanoparticle
lipoplex

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Abbreviation
MAR
MCH
MCHC
MCV
MedDRA
MERS
MIS-C
modRNA
MRI
N
N/A
NAAT
non-S
P2 S
PaO2
PCR
PI
POS
PPE
PT
RBC
RBD
RCDC
RNA
RR
RSV
RT-PCR
S1
SAE
SAP
saRNA
SARS
SARS-CoV-2
SBP
SoA
SOP
SpO2
SRSD
SUSAR
TBD
TBili
ULN

Term
missing at randommean corpuscular hemoglobinmean corpuscular hemoglobin concentration
mean corpuscular volume
Medical Dictionary for Regulatory Activities
Middle East respiratory syndrome
multisystem inflammatory syndrome in children
nucleoside-modified messenger ribonucleic acidmagnetic resonance imaging
SARS-CoV-2 nucleoprotein
not applicable
nucleic acid amplification test
nonspike protein
SARS-CoV-2 full-length, P2 mutant, prefusion spike glycoprotein
partial pressure of oxygen, arterial
polymerase chain reaction
principal investigatorprobability of successpersonal protective equipment
prothrombin time
red blood cell
receptor-binding domain
reverse cumulative distribution curve
ribonucleic acidrespiratory rate
respiratory syncytial virus
reverse transcription–polymerase chain reaction
spike protein S1 subunit
serious adverse event
statistical analysis planself-amplifying messenger ribonucleic acidsevere acute respiratory syndrome
severe acute respiratory syndrome coronavirus 2
systolic blood pressureschedule of activities
standard operating procedureoxygen saturation as measured by pulse oximetry
single reference safety document
suspected unexpected serious adverse reaction
to be determinedtotal bilirubin
upper limit of normal

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Abbreviation
uRNA
US
vax
VE
WBC
WHO
WOCBP

Term
unmodified messenger ribonucleic acid
United States
vaccination
vaccine efficacy
white blood cell
World Health Organization
woman/women of childbearing potential

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10.7. Appendix 7: Stopping and Alert Rules for Enhanced COVID-19
In Phase 2/3, the unblinded team supporting the DMC (reporting team), including an
unblinded medical monitor, will review cases of severe COVID-19 as they are received, andwill review AEs at least weekly for additional potential cases of severe COVID-19 and willcontact the DMC in the event that the stopping rule or an alert is met. Specifically, theunblinded reporting team will contact the DMC chair, who will then convene the full DMC
as soon as possible. The DMC will review all available safety and/or efficacy data at thetime of the review. The DMC will make one of the following recommendations to Pfizer:
withhold final recommendation until further information/data are provided, continue thestudy as designed, modify the study and continue, or stop the study. The final decision toaccept or reject the committee’s recommendation resides with Pfizer management and will be
communicated to the committee chairperson in writing.

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At any point the unblinded team may discuss with the DMC chair whether the DMC should
review cases for an adverse imbalance of cases of COVID-19 and/or severe COVID-19
between the vaccine and placebo groups (see Section 9.6). In addition, at the time of the IAs
at 32, 62, 92, and 120 cases, the number of severe COVID-19 cases in the vaccine andplacebo groups will be assessed.
Stopping and alert rules will be applied as follows. The stopping rule will be triggered whenthe 1-sided probability of observing the same or a more extreme case split is 5% or less when
the true incidence of severe disease is the same for vaccine and placebo participants, and alert
criteria are triggered when this probability is less than 11%. In addition, when the total
number of severe cases is low (15 or less), the unblinded team supporting the DMC will
implement the alert rule when a reverse case split of 2:1 or worse is observed. For example,
at 3 cases 2:1, at 4 cases 3:1, etc. Below 15 cases, this rule is more rigorous than requiring
the probability of an observed adverse split or worse be <11%.
The stopping rule and alert rules are illustrated in Table 10 and Table 11, respectively, when
the total number of severe cases is 20 or less. For example, when there are 7 severe cases,
the adverse split has to be 7:0 to stop the study, but a split of 5:2 would trigger the alert rule.
Similarly, when there is a total of 9 severe cases, an adverse split of 9:0 triggers the stopping
rule, while a split of 6:3 or worse triggers the alert rule. The alert rule may be triggered withas few as 2 cases, with a split of 2:0.

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Table 10. Stopping Rule: Enrollment Is Stopped if the Number of Severe Cases inthe Vaccine Group Is Greater Than or Equal to the Prespecified Stopping
Rule Value (S)090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)

Total Severe Cases

Prespecified Stopping Rule Value(S): Number of Severe Cases in the
Vaccine Group to Stop

4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Abbreviation: N/A = not applicable.

4
5
6
7
7
8
9
9
10
10
11
12
12
13
13
14
15

If the True Ratio of Severe Cases
Between Vaccine and PlaceboGroups Is 1:1, Probability of S or
More Being Observed in the Vaccine
Group
N/A
3.13%
1.56%
0.78%
3.52%
1.95%
1.07%
3.27%
1.93%
4.61%
2.87%
1.76%
3.84%
2.45%
4.81%
3.18%
2.07%

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Table 11. Alert Rule: Further Action Is Taken if the Number of Severe Cases in the
Vaccine Group Is Greater Than or Equal to the Prespecified Alert Rule
Value (A)
Total
SevereCases

Prespecified AlertRule Value(A):
Number of
SevereCases in the
VaccineGroup toTrigger
Further
ActionIf the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
1:1,
Probabilityof A Being
Observed inthe Vaccine
Group

2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20

2
2
3
4
4
5
6
6
7
8
8
9
10
10
11
12
13
13
14

25.00%
37.50%
25.00%
15.63%
23.44%
16.41%
10.94%
16.41%
11.72%
8.06%
12.08%
8.73%
6.11%
9.16%
6.67%
4.72%
3.27%
5.18%
3.70%

If the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
1:1,
Probabilityof A or More
Being
Observed inthe Vaccine
Group
25.00%
50.00%
31.25%
18.75%
34.38%
22.66%
14.45%
25.39%
17.19%
11.33%
19.38%
13.34%
8.98%
15.09%
10.51%
7.17%
4.81%
8.35%
5.77%

If the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
2:1,
Probabilityof A or More
Being
Observed inthe Vaccine
Group44.49%
74.12%
59.32%
46.16%
68.10%
57.14%
46.90%
65.11%
56.02%
47.35%
63.25%
55.31%
47.66%
61.94%
54.81%
47.88%
41.34%
54.43%
48.06%

If the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
3:1,
Probabilityof A or More
Being
Observed inthe Vaccine
Group56.25%
84.38%
73.83%
63.28%
83.06%
75.64%
67.85%
83.43%
77.59%
71.33%
84.24%
79.40%
74.15%
85.16%
81.03%
76.53%
71.75%
82.51%
78.58%

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If the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
4:1,
Probabilityof A or More
Being
Observed inthe VaccineGroup64.00%
89.60%
81.92%
73.73%
90.11%
85.20%
79.69%
91.44%
87.91%
83.89%
92.74%
90.09%
87.02%
93.89%
91.83%
89.43%
86.71%
93.24%
91.33%

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10.8. Appendix 8: Criteria for Allowing Inclusion of Participants With Chronic Stable
HIV, HCV, or HBV Infection
Potential participants with chronic stable HIV, HCV, or HBV infection may be considered
for inclusion if they fulfill the following respective criteria.
Known HIV infection
Confirmed stable HIV disease defined as documented viral load <50 copies/mL andCD4 count >200 cells/mm3 within 6 months before enrollment, and on stable
antiretroviral therapy for at least 6 months.

Known HCV infection
History of chronic HCV with evidence of sustained virological response (defined asundetectable HCV RNA) for ≥12 weeks following HCV treatment or without
evidence of HCV RNA viremia (undetectable HCV viral load).

090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)

Known HBV infection
Confirmed inactive chronic HBV infection, defined as HBsAg present for ≥6 months and thefollowing:

HBeAg negative, anti-HBe positive

Serum HBV DNA <2000 IU/mLPersistently normal ALT and/or AST levels

In those who have had a liver biopsy performed, findings that confirm the absence ofsignificant necroinflammation.

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11. REFERENCES
1

World Health Organization. WHO Director-General's opening remarks at the media
briefing on COVID-19. Available from: https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19--11-march-2020. Published: 11 Mar 2020. Accessed: 01 Apr 2020.

2

World Health Organization. Coronavirus disease 2019 (COVID-19) situation report - 70.
In: Data as reported by national authorities by 10:00 CET 30 March 2020. Geneva,
Switzerland: World Health Organization; 2020.

3

Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19):
information for clinicians on investigational therapeutics for patients with COVID-19.
Available from: https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeuticoptions.html. Updated: 25 Apr 2020. Accessed: 26 Jun 2020.

4

Rauch S, Jasny E, Schmidt KE, et al. New vaccine technologies to combat outbreaksituations. Front Immunol 2018;9:1963.

5

Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics—developing a new class ofdrugs. Nat Rev Drug Discov 2014;13(10):759-80.

6

BioNTech RNA Pharmaceuticals GmbH. CorVAC/BNT162 Investigator’s Brochure.
Mainz, Germany: BioNTech RNA Pharmaceuticals GmbH; 25 Mar 2020.

7

Feldman RA, Fuhr R, Smolenov I, et al. mRNA vaccines against H10N8 and H7N9
influenza viruses of pandemic potential are immunogenic and well tolerated in healthy
adults in phase 1 randomized clinical trials. Vaccine 2019;37(25):3326-34.

8

US Food and Drug Administration. Guidance for industry: toxicity grading scale forhealthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials.
Rockville, MD: Center for Biologics Evaluation and Research; September 2007.

9

Agresti A. Introduction: distributions and inference for categorical data. In: Agresti A,
ed. Categorical data analysis. 2nd ed. Hoboken, NJ: John Wiley & Sons; 2002:1-35.

10

Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med
1985;4(2):213-26.

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Document Approval Record
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090177e195444379\Approved\Approved On: 16-Oct-2020 06:36 (GMT)23 2

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85"85Page 308

FDA-CBER-2021-5683-0014361

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Protocol Amendment 7, 06 October 2020090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)A PHASE 1/2/3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLIND,
DOSE-FINDING STUDY TO EVALUATE THE SAFETY, TOLERABILITY,IMMUNOGENICITY, AND EFFICACY OF SARS-COV-2 RNA VACCINECANDIDATES AGAINST COVID-19 IN HEALTHY INDIVIDUALS

Study Sponsor:

BioNTechStudy Conducted By:

PfizerStudy Intervention Number:

PF-07302048

Study Intervention Name:

RNA-Based COVID-19 Vaccines

US IND Number:

19736

EudraCT Number:2020-002641-42

Protocol Number:

C4591001

Phase:
1/2/3
Short Title: A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, andEfficacy of RNA Vaccine Candidates Against COVID-19 in Healthy IndividualsThis document and accompanying materials contain confidential information belonging to Pfizer. Except asotherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold thisinformation in confidence and not copy or disclose it to others (except where required by applicable law) or
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer
must be promptly notified.

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Protocol Amendment Summary of Changes Table
Document History
Document
Protocol amendment 7

Version Date
06 October 2020

Summary and Rationale for Changes








090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)













Reduced the lower age range to include
adolescents 12 to 15 years of age and added
corresponding objectives.
Removed reference to COVID-19 antibody
testing in Section 2.3.2.
Clarified with efficacy estimands and endpoints
that last dose refers to second dose.
Added an additional exploratory objective todescribe safety and immunogenicity inparticipants 16 to 55 years of age vaccinatedwith study intervention produced bymanufacturing “Process 1” or “Process 2.”
Clarified exclusion criterion 5.
Added Section 6.1.1 to describe manufacturing“Process 1” and “Process 2.”
Clarified the degree of unblinding on the
unblinded submissions team in Section 6.3.3.
Made provision for a second dose of BNT162b2
in participants who were affected by a
medication error at Visit 2 in Section 6.6.
Provided further clarification regarding
discontinuation of study intervention in
Section 7.1.
Modified the circumstances in which a local
NAAT result may be used in the COVID-19
case definition.
Added that 2 periods of potential COVID-19
symptoms within 4 days will be considered as asingle illness.
Provided guidance in Section 8.13 regarding
circumstances in which a SARS-CoV-2 test
might be required even if symptoms within 7days following each vaccination are consideredmore likely due to vaccine reactogenicity.
Made allowance in Section 8.13 for a second
SARS-CoV-2 test to be performed within thesame potential COVID-19 illness if it is inaccordance with routine practice.
Added Section 8.15 to describe the reporting of
SARS-CoV-2 test results and their implications
for participants receiving a second vaccine dose.
Added statistical hypothesis and power analysis
for evaluation of noninferiority of the immune
response to BNT162b2 in participants 12 to 15
years of age to the response in participants 16 to
25 years of age.

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Document History
Document

Version Date

Summary and Rationale for Changes
Protocol amendment 6(Germany-specific)

23 September 2020

Protocol amendment 6

08 September 2020






090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)















Amended scope of analyses of safety data in
Section 9.5.1.
Made various editorial changes.
According to regulatory request, inclusion
criterion 1 now specifies that participants lessthan 18 years of age will not be enrolled in theEU.
Reordered some procedures in the Phase 2/3
schedule of activities for consistency with themain body of the protocol.
Corrected the window for the 6-month follow-up
visit to be approximately 6 months after
Vaccination 2.
Reduced the volume of blood draws to ~20 mL.
Removed the need to have safety data reported
for participants to be included in the safety
objective assessment.
Added an exploratory objective to describe
safety, immunogenicity, and efficacy inparticipants with stable HIV disease.
Increased the sample size for Phase 2/3 to~43,998.
Clarified that inclusion criterion 4 (ie,participants at higher risk for acquiring COVID19) is applicable for Phase 2/3 only, andprovided some examples.
Removed exclusion criterion 2 (ie, known
infection with HIV, HCV, or HBV) for Phase 3
and added criteria for HIV-positive participants.
Decreased the lower age limit and removed theupper age limit for inclusion in Phase 2/3 inorder to evaluate BNT162b2 30 µg in older
adolescents and those over 85 years of age;
updated the title and other references to adults toalign with this change.
Renamed the immunological assays to alignwith other program-level documents.
Removed reference to the SARS-CoV-2 fulllength, P2 mutant, prefusion spike glycoprotein(P2 S) being “heads up.”Clarified that a positive SARS-CoV-2 NAAT
result without symptoms should not result in
discontinuation of study intervention.
Added clarification that potential COVID-19
illnesses that are consistent with the clinicalendpoint definition should not be recorded as
AEs.
Updated the analysis population descriptions toalign with the study SAP.

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Document History
Document

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)

Protocol amendment 5

Version Date
24 July 2020

Summary and Rationale for Changes
Following regulatory feedback: Renamed Stage 1 to Phase 1, removed Stage 2,
and renamed Stage 3 to Phase 2/3.
 Clarified that a single vaccine candidate,administered as 2 doses 21 days apart, will be
studied in Phase 2/3.
 Stated that the vaccine candidate selected forPhase 2/3 evaluation is BNT162b2 at a dose of
30 µg.
 Removed the potential to study BNT162b3.
 Immunogenicity data will be summarized for the
first 360 participants through 1 month after Dose2, rather than through 21 days after Dose 1.
 Provided further details of sponsor staff that will
be unblinded in Phase 2/3.
 Clarified which stopping rules apply to which
phase of the study.
In addition:
 Clarified the AE reporting requirements forpotential COVID-19 illnesses.
 Updated that Visit 1 may be conducted across 2
consecutive days in Phase 2/3.
 Moved the immunogenicity objectives inPhase 2/3 to become exploratory.
 Added an additional inclusion criterion to enroll
participants who, in the judgment of theinvestigator, are at risk for acquiring COVID-19.
 Modified exclusion criterion 5, so thatparticipants with a previous clinical or
microbiological diagnosis of COVID-19 are
excluded from all phases of the study.
 Clarified that there will be 2 all-available
efficacy populations.
 Clarified that immunogenicity samples will bedrawn for all participants; analyses will be based
upon results from subsets of samples, according
to the purpose.
 Updated that the 3-tier approach to summarizing
AEs will only be performed in Phase 2/3.
 Updated that at each interim analysis for
efficacy, only the first primary objective will be
evaluated.
 Changed to use the same posterior probability(99.5%) for all interim analyses, resulting incase split changes in Tables 5, 6, and 7.
 Updated the stopping and alert rule parameters
for enhanced COVID-19.

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Protocol amendment 4

Version Date
30 June 2020

Summary and Rationale for Changes
Given the rapidly evolving pandemic situation, andthe need to demonstrate VE as soon as possible, theprotocol has been amended to be powered to meet
new efficacy objectives. These new efficacy
objectives and corresponding endpoints have been
added to Section 3.
Further nonclinical data are available to support the
study of the BNT162b3 candidate in humans, and thecandidate has been added to the protocol.
The 6-month safety follow-up telephone contact has
been changed to an in-person visit for Stage 3
participants, to allow collection of an
immunogenicity blood sample.

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)The COVID-19 illness visit has now added
flexibility to permit a remote or in-person visit.
The COVID-19 illness symptoms have been updated
to align with the FDA-accepted definitions; thischange is also reflected in the criteria for temporary
delay of enrollment.
AEs that occur between consent and dosing will now
be reported on the AE (rather than Medical History)
CRF, to align with the latest Pfizer protocol
template.
Changes have been made to the headings to alignwith the latest Pfizer protocol template.
Clarified that only an unblinded site staff member
may obtain the participant’s randomization number
and study intervention allocation.
Additional interim analyses have been added toevaluate VE and futility during the study.

Protocol amendment 3

10 June 2020

As a result of regulatory feedback, an appendix has
been added to outline the stopping and alert rules tomonitor for potential enhanced COVID-19.
As data have become available from this study andthe BNT162-01 study in Germany, the following
decisions were made: Not to study the BNT162a1 and BNT162c2
vaccine candidates at this time. Therefore, thesecandidates have been removed from theprotocol.

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Document

Version Date

Summary and Rationale for ChangesTo study further lower dose levels of the
modRNA candidates. Therefore, a 20-µg doselevel is formally included for BNT162b1 and
BNT162b2.
To permit individual and group dosing
alterations for the second dose of study
intervention.

Following regulatory feedback, the BNT162b3
vaccine candidate has been removed from theprotocol until further nonclinical data are available tosupport study in humans.

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Given the rapidly evolving pandemic situation,
additional blood draws for exploratory COVID-19
research, intended to establish an immunologicalsurrogate of protection, will be taken from selectedparticipants who consent.
In order to increase flexibility enrolling participants,
an extended screening window (increased from 14 to
28 days) for sentinel participants in Stage 1 has been
added. This is considered acceptable since eligible
participants are expected to be either healthy or havestable medical conditions.
To increase the number of doses that can be obtained
from available vaccine vials, not all dose levels will
result in a dosing volume of 0.5 mL. Precise dosing
instructions will be provided in the IP manual.

Protocol amendment 2

27 May 2020

To facilitate the reporting of COVID-19 illness
diagnoses and potential symptoms to theinvestigator, participants may utilize a COVID-19
illness e-diary.
Given the urgent nature of the pandemic situation,
the following changes allow determination of theappropriate human dose level for both younger andolder adults to move speedily into the next phase ofclinical evaluation:
 Added a new vaccine candidate, BNT162b3,
modRNA encoding a membrane-anchored RBD
 Added a 50-µg dose level for vaccine candidates
based on the modRNA platform (ie, BNT162b1,
BNT162b2, and BNT162b3)
 Modified the criteria required for the IRC todetermine dose escalation in the 18- to 55-year
age cohort and advancement to groups ofparticipants 65 to 85 years of age

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Protocol amendment 1

Version Date

13 May 2020

Summary and Rationale for Changes
In addition:
 Removed hemoglobin change-from-baseline
abnormalities from the laboratory abnormality
grading scale as abnormalities should be gradedbased upon absolute values
 Following regulatory feedback: Modified exclusion criteria and prohibitedinhaled/nebulized corticosteroids for sentinel
participants in Stage 1
 Clarified that the rapid test for prior COVID-19
infection for sentinel participants in Stage 1 will
be used only for screening purposes Removed time frames for stopping rules
 Stated that data supporting the selection of
vaccine candidate(s)/dose level(s) andschedule(s) for Stages 2 and 3 will be submitted
to the FDA for review

Following preliminary experience in the
BioNTech study conducted in Germany(BNT162-01):
Decreased the dose levels for BNT162a1 and
BNT162c2

Additionally: Clarified the roles of BioNTech and Pfizer
 Amended text so that the IRC decision toprogress group(s) into Stages 2 and 3 can bebased upon safety and immunogenicity data
after Dose 1 or 2
 Clarified safety data requirements to permit dose
escalation
 Amended text so that the progression toparticipants 65 to 85 years of age can be based
upon data from the same RNA platform Incorporated a protocol administrative change tocorrect the variant designation and the encoded
antigen to BNT162c2
 Clarified that the SARS-CoV-2 neutralizing
assay does not employ wild-type virus
 Clarified that the SARS-CoV-2 spike protein–binding antibody assay is specific for the S1subunit Clarified that efficacy against COVID-19 isbased upon illness (not infection) rate ratio Incorporated a protocol administrative change tostate that the study placebo may be supplied in a
glass or plastic vial

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Document

Version Date

Summary and Rationale for Changes







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Original protocol

15 April 2020

Corrected a typographical error in Section 6.5.1
regarding the time frame for prior receipt ofblood/plasma products or immunoglobulins
Corrected a typographical error in Table 2
regarding the lower limit of diameter (cm) for
mild redness and swelling
Updated the °C fever scale in Table 4 to ensurethat all potential °F values are correctly assigned
Incorporated a protocol administrative change toclarify that a rapid test for prior COVID-19
infection will be performed for sentinel
participants in Stage 1, and a serum sample will
be drawn for potential future assessment
Clarified that, after screening, physicalexaminations in sentinel participants in Stage 1
will be directed
Clarified the descriptions of the populations foranalysis to align with the statistical analysis plan
Added a complete safety and immunogenicity
analysis approximately 6 months after Dose 2
for all participants in Stage 3
Amended text so that the stopping rules apply to
an RNA platform rather than a specific vaccine
candidate

N/A

This amendment incorporates all revisions to date, including amendments made at therequest of country health authorities and IRBs/ECs.

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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................14
1. PROTOCOL SUMMARY...................................................................................................16
1.1. Synopsis ..................................................................................................................16
1.2. Schema ....................................................................................................................23
1.3. Schedule of Activities .............................................................................................24
1.3.1. Phase 1 ........................................................................................................24
1.3.2. Phase 2/3.....................................................................................................29
2. INTRODUCTION ...............................................................................................................32
2.1. Study Rationale .......................................................................................................32
2.2. Background .............................................................................................................32
2.2.1. Clinical Overview.......................................................................................33

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2.3. Benefit/Risk Assessment.........................................................................................33
2.3.1. Risk Assessment .........................................................................................35
2.3.2. Benefit Assessment.....................................................................................37
2.3.3. Overall Benefit/Risk Conclusion................................................................37
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................37
3.1. For Phase 1 ..............................................................................................................37
3.2. For Phase 2/3 ...........................................................................................................39
4. STUDY DESIGN.................................................................................................................41
4.1. Overall Design.........................................................................................................41
4.1.1. Phase 1 ........................................................................................................42
4.1.2. Phase 2/3.....................................................................................................43
4.2. Scientific Rationale for Study Design .....................................................................44
4.3. Justification for Dose ..............................................................................................44
4.4. End of Study Definition ..........................................................................................45
5. STUDY POPULATION ......................................................................................................46
5.1. Inclusion Criteria.....................................................................................................46
5.2. Exclusion Criteria....................................................................................................47
5.3. Lifestyle Considerations..........................................................................................49
5.3.1. Contraception..............................................................................................49

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5.4. Screen Failures ........................................................................................................49
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study
Intervention Administration ......................................................................................50
6. STUDY INTERVENTION..................................................................................................50
6.1. Study Intervention(s) Administered ........................................................................51
6.1.1. Manufacturing Process ...............................................................................52
6.1.2. Administration ............................................................................................52
6.2. Preparation/Handling/Storage/Accountability ........................................................52
6.2.1. Preparation and Dispensing ........................................................................53
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................54
6.3.1. Allocation to Study Intervention ................................................................54
6.3.2. Blinding of Site Personnel ..........................................................................54
6.3.3. Blinding of the Sponsor ..............................................................................54
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6.3.4. Breaking the Blind......................................................................................55
6.4. Study Intervention Compliance...............................................................................55
6.5. Concomitant Therapy..............................................................................................56
6.5.1. Prohibited During the Study .......................................................................56
6.5.2. Permitted During the Study ........................................................................57
6.6. Dose Modification...................................................................................................57
6.7. Intervention After the End of the Study ..................................................................58
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANTDISCONTINUATION/WITHDRAWAL...........................................................................58
7.1. Discontinuation of Study Intervention ....................................................................58
7.2. Participant Discontinuation/Withdrawal From the Study .......................................58
7.2.1. Withdrawal of Consent ...............................................................................59
7.3. Lost to Follow-up ....................................................................................................59
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................60
8.1. Efficacy and/or Immunogenicity Assessments .......................................................61
8.1.1. Biological Samples .....................................................................................63
8.2. Safety Assessments .................................................................................................64
8.2.1. Clinical Safety Laboratory Assessments (Phase 1 Participants Only) .......64
8.2.2. Electronic Diary..........................................................................................65
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8.2.2.1. Grading Scales...........................................................................65
8.2.2.2. Local Reactions .........................................................................65
8.2.2.3. Systemic Events ........................................................................66
8.2.2.4. Fever..........................................................................................67
8.2.2.5. Antipyretic Medication .............................................................68
8.2.3. Phase 1 Stopping Rules ..............................................................................68
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19
and Phase 2/3 Stopping Rule ...........................................................................69
8.2.5. Randomization and Vaccination After a Stopping Rule Is Met .................70
8.2.6. Pregnancy Testing ......................................................................................70
8.3. Adverse Events and Serious Adverse Events..........................................................71
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......71
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................72
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8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................72
8.3.2. Method of Detecting AEs and SAEs ..........................................................72
8.3.3. Follow-up of AEs and SAEs.......................................................................72
8.3.4. Regulatory Reporting Requirements for SAEs...........................................73
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational
Exposure ..........................................................................................................73
8.3.5.1. Exposure During Pregnancy......................................................73
8.3.5.2. Exposure During Breastfeeding ................................................75
8.3.5.3. Occupational Exposure .............................................................75
8.3.6. Cardiovascular and Death Events...............................................................75
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not
Qualifying as AEs or SAEs..............................................................................76
8.3.8. Adverse Events of Special Interest .............................................................76
8.3.8.1. Lack of Efficacy ........................................................................76
8.3.9. Medical Device Deficiencies......................................................................76
8.3.10. Medication Errors .....................................................................................76
8.4. Treatment of Overdose............................................................................................77
8.5. Pharmacokinetics ....................................................................................................78
8.6. Pharmacodynamics..................................................................................................78
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8.7. Genetics ...................................................................................................................78
8.8. Biomarkers ..............................................................................................................78
8.9. Immunogenicity Assessments .................................................................................78
8.10. Health Economics .................................................................................................78
8.11. Study Procedures...................................................................................................78
8.11.1. Phase 1 ......................................................................................................78
8.11.1.1. Screening: (0 to 28 Days Before Visit 1) ................................78
8.11.1.2. Visit 1 – Vaccination 1: (Day 1) .............................................80
8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1to 3 Days After Visit 1) .....................................................................82
8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to
8 Days After Visit 1) .........................................................................83090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)

8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1) ...........84
8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to
8 Days After Visit 4) .........................................................................86
8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to
16 Days After Visit 4) .......................................................................88
8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After
Visit 4) ...............................................................................................89
8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (175 to 189 Days
After Visit 4)......................................................................................89
8.11.1.10. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 4)......................................................................................90
8.11.1.11. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 4)......................................................................................90
8.11.2. Phase 2/3...................................................................................................91
8.11.2.1. Visit 1 – Vaccination 1: (Day 1) .............................................91
8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days After Visit 1) ...........93
8.11.2.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2):(28 to 35 Days After Visit 2).............................................................95
8.11.2.4. Visit 4 – 6-Month Follow-up Visit: (175 to 189 Days
After Visit 2)......................................................................................96
8.11.2.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 2)......................................................................................97

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8.11.2.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 2)......................................................................................97
8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction ........................98
8.13. COVID-19 Surveillance (All Participants) ...........................................................99
8.13.1. Potential COVID-19 Illness Visit: (Optimally Within 3 Days After
Potential COVID-19 Illness Onset) ...............................................................100
8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After
Potential COVID-19 Illness Visit)................................................................101
8.14. Communication and Use of Technology.............................................................102
8.15. SARS-CoV-2 NAAT Results From Visits 1 and 2 and Potential COVID-19
Illness Visits ............................................................................................................103
9. STATISTICAL CONSIDERATIONS ..............................................................................103
9.1. Estimands and Statistical Hypotheses ...................................................................103
9.1.1. Estimands..................................................................................................103
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9.1.2. Statistical Hypotheses...............................................................................104
9.1.2.1. Statistical Hypothesis Evaluation for Efficacy........................104
9.1.2.2. Statistical Hypothesis Evaluation for Immunogenicity...........104
9.2. Sample Size Determination...................................................................................105
9.3. Analysis Sets .........................................................................................................107
9.4. Statistical Analyses ...............................................................................................107
9.4.1. Immunogenicity Analyses ........................................................................1089.4.2. Efficacy Analyses .....................................................................................113
9.4.3. Safety Analyses ........................................................................................114
9.4.4. Other Analyses..........................................................................................116
9.5. Interim Analyses ...................................................................................................116
9.5.1. Analysis Timing........................................................................................1199.6. Data Monitoring Committee or Other Independent Oversight Committee...........119
10. SUPPORTING DOCUMENTATION AND OPERATIONALCONSIDERATIONS ........................................................................................................121
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .............121
10.1.1. Regulatory and Ethical Considerations ..................................................121
10.1.1.1. Reporting of Safety Issues and Serious Breaches of theProtocol or ICH GCP.......................................................................121
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10.1.2. Informed Consent Process ......................................................................122
10.1.3. Data Protection .......................................................................................123
10.1.4. Dissemination of Clinical Study Data ....................................................123
10.1.5. Data Quality Assurance ..........................................................................124
10.1.6. Source Documents ..................................................................................126
10.1.7. Study and Site Start and Closure ............................................................126
10.1.8. Sponsor’s Qualified Medical Personnel .................................................127
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................128
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting ....................................................................130
10.3.1. Definition of AE .....................................................................................130
10.3.2. Definition of SAE ...................................................................................131
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.....................133
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10.3.4. Reporting of SAEs..................................................................................136
10.4. Appendix 4: Contraceptive Guidance .................................................................137
10.4.1. Male Participant Reproductive Inclusion Criteria ..................................137
10.4.2. Female Participant Reproductive Inclusion Criteria...............................137
10.4.3. Woman of Childbearing Potential ..........................................................138
10.4.4. Contraception Methods...........................................................................139
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ......141
10.6. Appendix 6: Abbreviations .................................................................................143
10.7. Appendix 7: Stopping and Alert Rules for Enhanced COVID-19 ......................147
10.8. Appendix 8: Criteria for Allowing Inclusion of Participants With Chronic
Stable HIV, HCV, or HBV Infection ......................................................................150
11. REFERENCES ................................................................................................................151
LIST OF TABLES
Table 1.

Local Reaction Grading Scale ..................................................................66

Table 2.

Systemic Event Grading Scale..................................................................67

Table 3.

Scale for Fever..........................................................................................68

Table 4.

Power Analysis for Noninferiority Assessment .....................................106

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Table 5.

Probability of Observing at Least 1 AE by Assumed True Event
Rates With Different Sample Sizes ........................................................106

Table 6.

Interim Analysis Plan and Boundaries for Efficacy and Futility............117

Table 7.

Statistical Design Operating Characteristics: Probability of Successor Failure for Interim Analyses...............................................................118

Table 8.

Statistical Design Operating Characteristics: Probability of Successfor Final Analysis and Overall................................................................118

Table 9.

Laboratory Abnormality Grading Scale .................................................128

Table 10.

Stopping Rule: Enrollment Is Stopped if the Number of Severe
Cases in the Vaccine Group Is Greater Than or Equal to the
Prespecified Stopping Rule Value (S) ....................................................148

Table 11.

Alert Rule: Further Action Is Taken if the Number of Severe Casesin the Vaccine Group Is Greater Than or Equal to the Prespecified
Alert Rule Value (A) ..............................................................................149

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1. PROTOCOL SUMMARY
1.1. Synopsis
Short Title: A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, andEfficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Individuals
Rationale

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A pneumonia of unknown cause detected in Wuhan, China, was first reported in
December 2019. On 08 January 2020, the pathogen causing this outbreak was identified as anovel coronavirus 2019. The outbreak was declared a Public Health Emergency ofInternational Concern on 30 January 2020. On 12 February 2020, the virus was officiallynamed as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the WHO
officially named the disease caused by SARS-CoV-2 as coronavirus disease 2019
(COVID-19). On 11 March 2020, the WHO upgraded the status of the COVID-19 outbreakfrom epidemic to pandemic, which is now spreading globally at high speed.
There are currently no licensed vaccines to prevent infection with SARS-CoV-2 or
COVID-19. Given the rapid transmission of COVID-19 and incidence of disease in the
United States and elsewhere, the rapid development of an effective vaccine is of utmost
importance.
BioNTech has developed RNA-based vaccine candidates using a platform approach thatenables the rapid development of vaccines against emerging viral diseases, including
SARS-CoV-2. Each vaccine candidate is based on a platform of nucleoside-modified
messenger RNA (modRNA, BNT162b). Each vaccine candidate expresses 1 of 2 antigens:the SARS-CoV-2 full-length, P2 mutant, prefusion spike glycoprotein (P2 S) (version 9) or atrimerized SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) (version 5).
The 2 SARS-CoV-2 vaccine candidates that will be tested in this study are therefore:
BNT162b1 (variant RBP020.3): a modRNA encoding the RBD;
BNT162b2 (variant RBP020.2): a modRNA encoding P2 S.
All candidates are formulated in the same lipid nanoparticle (LNP) composition. This study
is intended to investigate the safety, immunogenicity, and efficacy of these prophylactic
BNT162 vaccines against COVID-19.

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Objectives, Estimands, and Endpoints

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Objectives

Estimands

Endpoints

Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Primary:
In participants receiving at least 1 doseof study intervention, the percentage ofparticipants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each doseAdverse events (AEs) from
Dose 1 to 1 month after the lastdose
 Serious AEs (SAEs) from Dose 1
to 6 months after the last doseIn addition, the percentage ofparticipants with:
Abnormal hematology andchemistry laboratory values 1 and7 days after Dose 1; and 7 days
after Dose 2
Grading shifts in hematology andchemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2
Secondary:In participants complying with the key
protocol criteria (evaluableparticipants) at the following time
points after receipt of study
intervention:

Primary:
Local reactions (pain at the
injection site, redness, andswelling)

Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs

Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Hematology and chemistry laboratory
parameters detailed in Section 10.2

Secondary:

7 and 21 days after Dose 1; 7 and 14
days and 1, 6, 12, and 24 months after
Dose 2

Geometric mean titers (GMTs) at SARS-CoV-2 neutralizing titers
each time point
Geometric mean fold rise (GMFR)
from before vaccination to eachsubsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination

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Objectives

Estimands







Endpoints

S1-binding IgG levels and RBDGeometric mean concentrations
binding IgG levels(GMCs) at each time point
GMFR from before vaccination toeach subsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
Geometric mean ratio (GMR),
SARS-CoV-2 neutralizing titers
estimated by the ratio of theS1-binding IgG levels
geometric mean of SARS-CoV-2 
RBD-binding IgG levels
neutralizing titers to the geometricmean of binding IgG levels at eachtime point

For Phase 2/3

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Objectivesa

Estimands
Primary Efficacy

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 in participants
without evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 in participants
with and without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To define the safety profile ofprophylactic BNT162b2 in the first
360 participants randomized (Phase 2)

In participants receiving at least 1
dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 7 days after
the last dose
SAEs from Dose 1 to 7 days
after the last dose

Endpoints
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of thesecond dose) of past SARS-CoV-2
infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT

Primary Safety






Local reactions (pain at the
injection site, redness, andswelling)
Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened
muscle pain, and new orworsened joint pain)
AEs
SAEs

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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Protocol Amendment 7, 06 October 2020
Objectivesa

Estimands

To define the safety profile ofprophylactic BNT162b2 in allparticipants randomized in Phase 2/3

In participants receiving at least
1 dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the last dose
 SAEs from Dose 1 to 6 months
after the last dose

To define the safety profile ofprophylactic BNT162b2 inparticipants 12 to 15 years of age inPhase 3

In participants receiving at least
1 dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the last dose
 SAEs from Dose 1 to 6 months
after the last dose

Endpoints







AEs
SAEs
In a subset of at least 6000
participants:
o Local reactions (pain at the
injection site, redness, andswelling)o Systemic events (fever,fatigue, headache, chills,
vomiting, diarrhea, new orworsened muscle pain, andnew or worsened joint pain)
Local reactions (pain at the
injection site, redness, andswelling)
Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened
muscle pain, and new orworsened joint pain)
AEs
SAEs

Secondary Efficacy
To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed severe COVID-19 inparticipants without evidence of
infection before vaccination
To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed severe COVID-19 inparticipants with and without
evidence of infection before
vaccination
To describe the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms) inparticipants without evidence of
infection before vaccination
To describe the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms) inparticipants with and without
evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

Confirmed severe COVID-19
incidence per 1000 person-years offollow-up in participants with noserological or virological evidence of
past SARS-CoV-2 infection
Confirmed severe COVID-19
incidence per 1000 person-years offollow-up

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of thesecond dose) of past SARS-CoV-2
infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAATCONFIDENTIAL
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Objectivesa

Estimands
Secondary Immunogenicity

Endpoints

To demonstrate the noninferiority of
the immune response to prophylactic
BNT162b2 in participants 12 to 15
years of age compared to participants
16 to 25 years of age

GMR, estimated by the ratio of thegeometric mean of SARS-CoV-2
neutralizing titers in the 2 age groups(12-15 years of age to 16-25 years ofage) 1 month after completion of
vaccination

SARS-CoV-2 neutralizing titers inparticipants with no serological or
virological evidence (up to 1 monthafter receipt of the second dose) of
past SARS-CoV-2 infection

To evaluate the immune responseover time to prophylactic BNT162b2
and persistence of immune response
in participants with and without
serological or virological evidence of
SARS-CoV-2 infection before
vaccination
To evaluate the immune response(non-S) to SARS-CoV-2 inparticipants with and without
confirmed COVID-19 during thestudy
To describe the serological responses
to the BNT vaccine candidate in casesof:
Confirmed COVID-19

Confirmed severe COVID-19

SARS-CoV-2 infection without
confirmed COVID-19
To describe the safety,
immunogenicity, and efficacy ofprophylactic BNT162b2 in
individuals with confirmed stable HIV
diseaseTo describe the safety andimmunogenicity of prophylactic
BNT162b2 in individuals 16 to 55
years of age vaccinated with study
intervention produced bymanufacturing “Process 1” or“Process 2”b

GMC/GMT, GMFR, and percentageof participants with titers greater thandefined threshold(s), at baseline and1, 6, 12, and 24 months after
completion of vaccination

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)

Exploratory

a.
b.





S1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titersN-binding antibody

S1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titers
N-binding antibody
SARS-CoV-2 detection by
NAAT






All safety, immunogenicity, andefficacy endpoints described
above



All safety endpoints describedabove
SARS-CoV-2 neutralizing titersHIV-positive participants in Phase 3 will not be included in analyses of the objectives, with the
exception of the specific exploratory objective.
See Section 6.1.1 for a description of the manufacturing process.

Overall Design
This is a Phase 1/2/3, multicenter, multinational, randomized, placebo-controlled, observerblind, dose-finding, vaccine candidate–selection, and efficacy study in healthy individuals.
The study consists of 2 parts: Phase 1: to identify preferred vaccine candidate(s) and doselevel(s); Phase 2/3: an expanded cohort and efficacy part. These parts, and the progression
between them, are detailed in the schema (Section 1.2).

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The study will evaluate the safety, tolerability, and immunogenicity of 2 different
SARS-CoV-2 RNA vaccine candidates against COVID-19 and the efficacy of 1 candidate:

As a 2-dose (separated by 21 days) schedule;At various different dose levels in Phase 1;



In 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3: ≥12years of age [stratified as 12-15, 16-55, or >55 years of age]).

Dependent upon safety and/or immunogenicity data generated during the course of thisstudy, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
in Phase 1 may be started at the next highest dose, groups may not be started, groups may beterminated early, and/or groups may be added with dose levels below the lowest stated doseor intermediate between the lowest and highest stated doses.
The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)

Number of Participants
Each group in Phase 1 will comprise 15 participants (12 receiving active vaccine and3 receiving placebo). In this phase, 13 groups will be studied, corresponding to a total of
195 participants.
The vaccine candidate selected for Phase 2/3, BNT162b2 at a dose of 30 µg, will comprise
21,999 vaccine recipients. The 12- to 15-year stratum will comprise up to approximately
2000 participants (1000 vaccine recipients) enrolled at selected investigational sites. It is
intended that a minimum of 40% of participants will be in the >55-year stratum. An equal
number of participants will receive placebo, ie, randomized in a 1:1 ratio.
Intervention Groups and Duration
The study will evaluate a 2-dose (separated by 21 days) schedule of various different doselevels of 2 investigational RNA vaccine candidates for active immunization against
COVID-19 in 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3:
≥12 years of age [stratified as 12-15, 16-55, or >55 years of age]):

BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 20 µg, 30 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 20 µg, 30 µg

The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.

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Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Phase 1
dosing arms that are not evaluated in Phase 2/3.
Data Monitoring Committee or Other Independent Oversight Committee
The study will utilize an IRC, an internal Pfizer committee that will review data to allow
dose escalation or changes to continuation of specific groups.
An external data monitoring committee (DMC) will be formed and will review cumulative
unblinded data throughout the study.
Statistical Methods

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)The sample size for Phase 1 of the study is not based on any statistical hypothesis testing.
For Phase 2/3, the VE evaluation will be the primary objective. The VE is defined as
VE = 100 × (1 – IRR), where IRR is calculated as the ratio of the first confirmed COVID-19
illness rate in the vaccine group to the corresponding illness rate in the placebo group. Withassumptions of a true VE of 60% and 4 IAs planned, 164 COVID-19 cases will provide 90%
power to conclude true VE >30%. This would be achieved with a total 43,998 participants(21,999 vaccine recipients), based on the assumption of a 1.3% per year incidence in theplacebo group, accrual of 164 primary-endpoint cases within 6 months, and 20% of theparticipants being nonevaluable. If the attack rate is much higher, case accrual would be
expected to be more rapid, enabling the study’s primary endpoint to be evaluated muchsooner. The total number of participants enrolled in Phase 2/3 may vary depending on theincidence of COVID-19 at the time of the enrollment, the true underlying VE, and a potential
early stop for efficacy or futility.
VE will be evaluated using a beta-binomial model and the posterior probability of VE being>30% will be assessed.
In Phase 3, up to approximately 2000 participants are anticipated to be 12 to 15 years of age.
Noninferiority of immune response to prophylactic BNT162b2 in participants 12 to 15 yearsof age to response in participants 16 to 25 years of age will be assessed based on the GMR of
SARS-CoV-2 neutralizing titers using a 1.5-fold margin. A sample size of 200 evaluableparticipants (or 250 vaccine recipients) per age group will provide a power of 90.8% todeclare the noninferiority in terms of GMR (lower limit of 95% CI for GMR >0.67).
The primary safety objective will be evaluated by descriptive summary statistics for local
reactions, systemic events, AEs/SAEs, and abnormal hematology and chemistry laboratory
parameters (Phase 1 only), for each vaccine group. A 3-tier approach will be used tosummarize AEs in Phase 2/3.
Except for the objective to assess the noninferiority of immune response in participants 12 to
15 years of age compared to participants 16 to 25 years of age, the other immunogenicity
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objectives will be evaluated descriptively by GMT, GMC, GMFR, percentage of participants
with ≥4-fold rise, percentage of participants with ≥ specified threshold, and GMC ratio, andthe associated 95% confidence intervals (CIs), for SARS-CoV-2 neutralizing titers,
S1-binding IgG levels, and/or RBD-binding IgG levels at the various time points.
1.2. Schema
Phase 1For each vaccine candidate(4:1 randomization active:placebo)

Age: 18-55 yAge: 65-85 y

Low-dose-level 2-dose group (n=15)
IRC (safety)

IRC (safety

Low-dose-level 2-dose group (n=15)

after Dose 1)
Mid-dose-level 2-dose group (n=15)
IRC (safety)

IRC (safety

Mid-dose-level 2-dose group (n=15)

after Dose 1)
High-dose-level 2-dose group (n=15)
IRC (safety

High-dose-level 2-dose group (n=15)

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)

after Dose 1)
IRC choice of group(s) for Phase 2/3(safety & immunogenicity after Doses 1 and 2)

Phase 2/3
Single vaccine candidate
Safety and immunogenicity analysis of
Age: ≥12
Phase 2 data (first 360 participants)(Stratified 12-15, 16-55, or >55)
BNT162b2 30 µg or placebo 2 doses
by unblinded team (these participants(n~21,999 per group, total n~43.998)
will also be included in Phase 3
analyses)Abbreviation: IRC = internal review committee.

(1:1 randomization active:placebo)

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1.3. Schedule of Activities

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with theprotocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations orassessments required to protect the well-being of the participant.
1.3.1. Phase 1
An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 10 (24-month follow-up visit) that COVID-19 is suspected.
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

X

X

X

X

X

Obtain informed consent

X

Assign participant number

X

Obtain demography andmedical history data

X

Obtain details of medications
currently taken

X

Perform physical examination

X

2

3

4

5

6

7

8

10

Unplanned

Unplanned

12 to 16 28 to 35 175 to
350 to714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4COVID-19 Illness Visit
Illness
Onset

X

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Protocol Amendment 7, 06 October 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

Measure vital signs(including body temperature)

X

X

X

X

X

X

Collect blood sample forhematology and chemistrylaboratory testsb~10 mL~10 mL~10 mL~10 mL~10 mL

Collect screening blood
sample for HIV, HBsAg,
HBc Ab, and HCV Ab tests~10 mL

Serological test for prior
COVID-19 infection~20 mL

Perform urine pregnancy test
(if appropriate)X

Obtain nasal (midturbinate)swab(s)c

2

3

4

X

X

X

X

Collect nonstudy vaccine
information

X

X

Confirm eligibility

X

X

Collect prohibited medication
use

X

X

Review temporary delay
criteria

X

X

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 175 to
350 to714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4COVID-19 Illness Visit
Illness
Onset
X

X
X

X

X

X

X

X

X
X

Review hematology andchemistry results

X

5

X

X

X

X

X

X

X

X

X

X

X

X

X

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Protocol Amendment 7, 06 October 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

4

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

Confirm use of contraceptives(if appropriate)

X

X

X

X

X

X

~50 mL~50 mL

Obtain randomization number
and study intervention
allocation

X

Collect blood sample for
immunogenicity assessment~50 mL

Administer study intervention

X

X

Assess acute reactions for atleast 30 minutes after study
intervention administrationd

X

X

Explain participant
communication methods(including for e-diarycompletion), assist theparticipant with downloading
the app, or issue provisioned
device, if required

X

Provide thermometer andmeasuring device

X

5

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 175 to
350 to714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4COVID-19 Illness Visit
Illness
Onset
X

X~50 mL ~50 mL ~50 mL ~20 mL+++
optionale optionale optionale~170 mL ~170 mL ~170 mL~20 mL~20 mL~20 mL

X

Review reactogenicity e-diarydata (daily review is optimal
during the active diary period)

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Protocol Amendment 7, 06 October 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 46 to 8Days
After
Visit 1

Review ongoingreactogenicity e-diary
symptoms and obtain stopdatesCollect AEs and SAEs as
appropriate

4

5

X

X

X

X

X

X

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 175 to
350 to714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4COVID-19 Illness Visit
Illness
Onset
X

X

X

X

X

Collect e-diary or assist theparticipant to delete
application

X

X

X

X

X

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Protocol Amendment 7, 06 October 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 46 to 8Days
After
Visit 1

4

5

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 175 to
350 to714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4COVID-19 Illness Visit
Illness
Onset

Collection of COVID-19–
related clinical and laboratory
information (including local
diagnosis)

X

X

Abbreviations: e-diary = electronic diary; HBc Ab = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HCV Ab = hepatitis C virus antibody;
HIV = human immunodeficiency virus; NAAT = nucleic acid amplification test; vax = vaccination.

a.
b.
c.
d.
e.

The COVID-19 illness visit may be conducted as an in-person or telehealth visit.
Hematology: hemoglobin, complete blood count with differential, and platelets. Blood chemistry: alanine aminotransferase (ALT), aspartate
aminotransferase (AST), alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), and creatinine.
Two swabs will be taken at Visits 1 and 4. One will be tested (if possible at the site, otherwise at the central laboratory) within 24 hours and vaccination will
only proceed if it is NAAT-negative for SARS-CoV-2 genomes. The second will be sent to the central laboratory for potential later testing.
The first 5 participants in in each group will be observed at the site for at least 4 hours after study intervention administration. Further vaccination willcommence no sooner than 24 hours after the fifth participant received his or her vaccination.
An optional blood draw of ~170 mL will be taken at 1 of the visits (from selected participants who consent) for exploratory COVID-19 research.

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1.3.2. Phase 2/3

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An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 6 (24-month follow-up visit) that potential COVID-19 symptoms are reported, including
MIS-C.
Visit Number

1

Visit Description

Day 1bVisit Window (Days)

Obtain informed consent

X

Assign participant number

X

Obtain demography and medical history data
Perform clinical assessment

2

3

4

5

6

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
Potential
COVID-19
COVID-19
Illness Visita ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2

175 to 189
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

X

X

X

Vaccination 1 Vaccination 2

X

For participants who are HIV-positive, record latest
CD4 count and HIV viral load

X

Measure height and weightX

Measure temperature (body)

X

X

Perform urine pregnancy test (if appropriate)

X

X

Confirm use of contraceptives (if appropriate)

X

X

X

Collect nonstudy vaccine information

X

X

X

X

X

X

X

X

X

~20 mL/~10 mL~20 mL/~10 mL~20 mL/~10 mL~20 mL/~10 mL

Collect prohibited medication use

X

Confirm eligibility

X

X

Review temporary delay criteria

X

X

Obtain nasal (midturbinate) swab

Unplanned

XcCollect blood sample for immunogenicity
assessmentd

Unplanned~20 mL/~10 mL
X

X

X

X~20 mL/~10 mLX

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Visit Number

1

Visit Description

Day 1bVisit Window (Days)

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2

3

4

5

6

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
Potential
COVID-19
COVID-19
Illness Visita ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2

175 to 189
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

Xf

Xf

Xf

Vaccination 1 Vaccination 2

Obtain randomization number and study
intervention allocation

X

Administer study intervention

X

X

Assess acute reactions for at least 30 minutes after
study intervention administration

X

X

Explain participant communication methods(including for e-diary completion), assist theparticipant with downloading the app, or issue
provisioned device, if required

X

Provide/ensure the participant has a thermometer(all participants) and measuring device(reactogenicity subset participants only)

X

Unplanned

Unplanned

X

Review reactogenicity e-diary data (daily review is
optimal during the active diary period)e
Review ongoing reactogenicity e-diary symptoms
and obtain stop dateseCollect AEs and SAEs as appropriate

X

X

X

X

X

Collect e-diary or assist the participant to delete
application

X

Xf

X

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Visit Number

1

Visit Description

Day 1bVisit Window (Days)

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2

3

4

5

6

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
Potential
COVID-19
COVID-19
Illness Visita ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2

175 to 189
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

Vaccination 1 Vaccination 2

Collection of COVID-19–related clinical andlaboratory information (including local diagnosis)

Unplanned

X

UnplannedX

Abbreviations: HIV = human immunodeficiency virus; e-diary = electronic diary.

a.
b.
c.
d.
e.
f.

The COVID-19 illness visit may be conducted as an in-person or telehealth visit.
The visit may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and exclusion criteria onwards must be conducted on thesame day.
Including, if indicated, a physical examination.
20 mL is to be collected from participants ≥16 years of age; 10 mL is to be collected from participants 12 to 15 years of age.
Reactogenicity subset participants only.
Any AEs occurring up to 48 hours after the blood draw must be recorded (see Section 8.3.1).

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2. INTRODUCTION
The BNT162 RNA-based COVID-19 vaccines are currently being investigated forprevention of COVID-19 in healthy individuals.
2.1. Study Rationale
The purpose of the study is to rapidly describe the safety, tolerability, and immunogenicity of
2 BNT162 RNA-based COVID-19 vaccine candidates against COVID-19, and the efficacyof 1 candidate, in healthy individuals. There are currently no licensed vaccines to prevent
infection with SARS-CoV-2 or COVID-19. Given the global crisis of COVID-19 and fast
expansion of the disease in the United States and elsewhere, the rapid development of aneffective vaccine is of utmost importance.

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2.2. Background
In December 2019, a pneumonia outbreak of unknown cause occurred in Wuhan, China.
In January 2020, it became clear that a novel coronavirus (2019-nCoV) was the underlying
cause. Later in January, the genetic sequence of the 2019-nCoV became available to theWorld Health Organization (WHO) and public (MN908947.3), and the virus was categorized
in the Betacoronavirus subfamily. By sequence analysis, the phylogenetic tree revealed acloser relationship to severe acute respiratory syndrome (SARS) virus isolates than to anothercoronavirus infecting humans, the Middle East respiratory syndrome (MERS) virus.
SARS-CoV-2 infections and the resulting disease, COVID-19, have spread globally,affecting a growing number of countries.
On 11 March 2020, the WHO characterized the COVID-19 outbreak as a pandemic.1
The WHO Situation Update Report dated 30 March 2020 noted 693,224 confirmed caseswith 33,106 deaths globally, including 142,081 confirmed cases with 2457 deaths in theAmericas.2 The United States currently has the most reported cases globally. At the time ofthis communication, the number of confirmed cases continues to rise globally. There are
currently no vaccines or effective antiviral drugs to treat SARS-CoV-2 infections or the
disease it causes, COVID-19.3
A prophylactic, RNA-based SARS-CoV-2 vaccine provides one of the most flexible andfastest approaches available to immunize against the emerging virus.4,5The development of an RNA-based vaccine encoding a viral antigen, which is then expressedby the vaccine recipient as a protein capable of eliciting protective immune responses,
provides significant advantages over more traditional vaccine approaches. Unlike live
attenuated vaccines, RNA vaccines do not carry the risks associated with infection and may
be given to people who cannot be administered live virus (eg, pregnant women andimmunocompromised persons). RNA-based vaccines are manufactured via a cell-free invitro transcription process, which allows an easy and rapid production and the prospect of
producing high numbers of vaccination doses within a shorter time period than achieved with

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traditional vaccine approaches. This capability is pivotal to enable the most effective
response in outbreak scenarios.
Two SARS-CoV-2–RNA lipid nanoparticle (RNA-LNP) vaccines based on a platform of
nucleoside-modified messenger RNA (modRNA, BNT162b) will be evaluated in this study.
Each vaccine candidate expresses 1 of 2 antigens: the SARS-CoV-2 full-length, P2 mutant,prefusion spike glycoprotein (P2 S) (version 9) or a trimerized SARS-CoV-2 spikeglycoprotein-receptor binding domain (RBD) (version 5). The 2 SARS-CoV-2 vaccine
candidates that will be tested in this study are therefore:

BNT162b1 (variant RBP020.3): nucleoside-modified messenger RNA (modRNA)with blunted innate immune sensor–activating capacity and augmented expression
encoding the RBD.



BNT162b2 (variant RBP020.2): nucleoside-modified messenger RNA (modRNA) as
above, but encoding P2 S.

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2.
2.2.1. Clinical Overview
Prior to this study, given clinical data from other similarly formulated uRNA liposomal
vaccines from BioNTech in oncology trials6 and recent published results from clinical trials
using modRNA influenza vaccines by Moderna,7 the BNT162 vaccines were expected tohave a favorable safety profile with mild, localized, and transient effects. BNT162 vaccines
based on modRNA have now been administered to humans for the first time in this study andthe BNT162-01 study conducted in Germany by BioNTech, at doses between 1 µg and100 µg. The currently available safety and immunogenicity data are presented in the BNT162
IB.
2.3. Benefit/Risk Assessment
There is an ongoing global pandemic of COVID-19 with no preventative or therapeutic
options available. While there were no data available from clinical trials on the use of
BNT162 vaccines in humans at the outset of this study, available nonclinical data with thesevaccines, and data from nonclinical studies and clinical trials with the same or related RNAcomponents, or antigens, supported a favorable risk/benefit profile. Anticipated AEs after
vaccination were expected to be manageable using routine symptom-driven standard of careas determined by the investigators and, as a result, the profile of these vaccine candidates
supported initiation of this Phase 1/2/3 clinical study.
Updates as part of protocol amendment 6:
In order for the overall Phase 3 study population to be as representative anddiverse as possible, the inclusion of participants with known chronic stable HIV,
HCV, or HBV infection is permitted. Individuals with chronic viral diseases are atincreased risk for COVID-19 complications and severe disease. In addition, with
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the currently available therapies for their treatment, many individuals with chronic
stable HIV, HCV, and HBV infections are unlikely to be at higher safety risk as aparticipant in this vaccine study than individuals with other chronic stable medical
conditions.
All participants with chronic stable HIV disease will be included in thereactogenicity subset (see Section 8.2.2).

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Updates as part of protocol amendment 7:
The minimum age for inclusion in Phase 3 is lowered to 12 years, therefore
allowing the inclusion of participants 12 to 15 years of age.



For individuals 12 to 15 years of age, the immune responses in this age group may
be higher and reactogenicity is expected to be similar to younger adults 18 to 25
years of age. Inclusion of individuals 12 to 15 years of age was based upon asatisfactory blinded safety profile in participants 18 to 25 years of age.

All participants 12 to 15 years of age will be included in the reactogenicity subset(see Section 8.2.2).

More detailed information about the known and expected benefits and risks and reasonably
expected AEs of BNT162 RNA-based COVID-19 vaccines may be found in the IB, which is
the SRSD for this study.

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2.3.1. Risk Assessment
Potential Risk of ClinicalSignificance

Summary of Data/Rationale for Risk

Mitigation Strategy

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Study Intervention: BNT162 RNA-Based COVID-19 Vaccine
Potential for local reactions (injection These are common adverse reactions seensite redness, injection site swelling, with other vaccines, as noted in the FDA
and injection site pain) and systemic Center for Biologics Evaluation andResearch (CBER) guidelines on toxicity
events (fever, fatigue, headache,
grading scales for healthy adult volunteers
chills, vomiting, diarrhea, muscle
pain, and joint pain) following
enrolled in preventive vaccine clinicalvaccination.
trials.8

The Phase 1 study design includes the use of controlled vaccination anddose escalation to closely monitor and limit the rate of enrollment to ensure
participant safety. The study employs the use of a reactogenicity e-diary tomonitor local reactions and systemic events in real time. Stopping rules arealso in place. The first 5 participants in each group in Phase 1 will beobserved for 4 hours after vaccination to assess any immediate AEs. Allother participants will be observed for at least 30 minutes after vaccination.

Unknown AEs and laboratory
abnormalities with a novel vaccine.

The Phase 1 study design includes the use of controlled vaccination andThis study is one of the first 2 parallelrunning clinical studies with the BNT162 dose escalation to closely monitor and limit the rate of enrollment to ensure
vaccine candidates and as such there are no participant safety. An IRC (in Phase 1) and DMC (throughout the study)
will also review safety data. Stopping rules are also in place. The first 5
clinical data available for this vaccine.
participants in each group in Phase 1 will be observed for 4 hours after
vaccination to assess any immediate AEs. All other participants will beobserved for at least 30 minutes after vaccination.

Potential for COVID-19
enhancement.

Disease enhancement has been seen
following vaccination with respiratorysyncytial virus (RSV), feline coronavirus,
and Dengue virus vaccines.

Phase 1 excludes participants with likely previous or current COVID-19. In
Phase 2/3, temporary delay criteria defer vaccination of participants withsymptoms of potential COVID-19. All participants are followed for any
potential COVID-19 illness, including markers of severity, and have blood
samples taken for potential measurement of SARS-CoV-2 antigen-specificantibody and SARS-CoV-2 neutralizing titers.

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Potential Risk of ClinicalSignificance

Summary of Data/Rationale for Risk

Mitigation Strategy

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Study Procedures
Participants will be required to attend Without appropriate social distancing andhealthcare facilities during the global PPE, there is a potential for increased
exposure to SARS-CoV-2.
SARS-CoV-2 pandemic.
Venipuncture will be performed
during the study.

There is the risk of bleeding, bruising,hematoma formation, and infection at the
venipuncture site.

Pfizer will work with sites to ensure an appropriate COVID-19 prevention
strategy. Potential COVID-19 illness visits can be conducted via telehealth,without the need for an in-person visit, if required, with the participant
performing a self-swab.
Only appropriately qualified personnel would obtain the blood draw.

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2.3.2. Benefit Assessment
Benefits to individual participants may include:Receipt of a potentially efficacious COVID-19 vaccine during a global pandemicAccess to COVID-19 diagnostic testingContributing to research to help others in a time of global pandemic

2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in thisstudy, the potential risks identified in association with BNT162 RNA-based COVID-19
vaccine are justified by the anticipated benefits that may be afforded to healthy participants.
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS

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3.1. For Phase 1
Objectives

Estimands

Endpoints

Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Primary:
In participants receiving at least 1 doseof study intervention, the percentage ofparticipants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each doseAdverse events (AEs) from
Dose 1 to 1 month after the lastdose
 Serious AEs (SAEs) from Dose 1
to 6 months after the last dosePrimary:
Local reactions (pain at the
injection site, redness, andswelling)

Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs

In addition, the percentage ofHematology and chemistry laboratory
participants with:parameters detailed in Section 10.2
Abnormal hematology andchemistry laboratory values 1 and7 days after Dose 1; and 7 days
after Dose 2
Grading shifts in hematology andchemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2

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Objectives

Estimands

Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Secondary:In participants complying with the key
protocol criteria (evaluableparticipants) at the following time
points after receipt of study
intervention: 7 and 21 days after Dose
1; 7 and 14 days and 1, 6, 12, and 24
months after Dose 2







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Endpoints
Secondary:

Geometric mean titers (GMTs) at SARS-CoV-2 neutralizing titers
each time point
Geometric mean fold rise (GMFR)
from before vaccination to eachsubsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
S1-binding IgG levels and RBDGeometric mean concentrations
binding IgG levels(GMCs) at each time point
GMFR from prior to first dose of
study intervention to eachsubsequent time point
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
Geometric mean ratio (GMR),estimated by the ratio of thegeometric mean of SARS-CoV-2 neutralizing titers to the geometric mean of binding IgG levels at
each time point

SARS-CoV-2 neutralizing titers
S1-binding IgG levels
RBD-binding IgG levels

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3.2. For Phase 2/3
Objectivesa

Estimands
Primary Efficacy

Endpoints

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 in participants
without evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 in participants
with and without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To define the safety profile ofprophylactic BNT162b2 in the first
360 participants randomized (Phase 2)

In participants receiving at least 1
dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 7 days after
the last dose
SAEs from Dose 1 to 7 days
after the last dose

To define the safety profile ofprophylactic BNT162b2 in allparticipants randomized in Phase 2/3

In participants receiving at least
1 dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the last dose
SAEs from Dose 1 to 6 months
after the last dose





AEs
SAEs
In a subset of at least 6000
participants:
o Local reactions (pain at the
injection site, redness, andswelling)o Systemic events (fever,fatigue, headache, chills,
vomiting, diarrhea, new orworsened muscle pain, andnew or worsened joint pain)

To define the safety profile ofprophylactic BNT162b2 inparticipants 12 to 15 years of age inPhase 3

In participants receiving at least
1 dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the last dose

Local reactions (pain at the
injection site, redness, andswelling)
Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened
muscle pain, and new orworsened joint pain)
AEs
SAEs

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of thesecond dose) of past SARS-CoV-2
infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT

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Primary SafetySAEs from Dose 1 to 6
months after the last dose











Local reactions (pain at the
injection site, redness, andswelling)
Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened
muscle pain, and new orworsened joint pain)
AEs
SAEs

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Objectivesa
To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed severe COVID-19 inparticipants without evidence of
infection before vaccination

Endpoints

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

Confirmed severe COVID-19
incidence per 1000 person-years offollow-up in participants with noserological or virological evidence of
past SARS-CoV-2 infection

To describe the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms) inparticipants without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To describe the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms) inparticipants with and without
evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of thesecond dose) of past SARS-CoV-2
infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT

To demonstrate the noninferiority of
the immune response to prophylactic
BNT162b2 in participants 12 to 15
years of age compared to participants
16 to 25 years of age

GMR, estimated by the ratio of thegeometric mean of SARS-CoV-2
neutralizing titers in the 2 age groups(12-15 years of age to 16-25 years ofage) 1 month after completion of
vaccination

To evaluate the immune responseover time to prophylactic BNT162b2
and persistence of immune response
in participants with and without
serological or virological evidence of
SARS-CoV-2 infection before
vaccination

GMC/GMT, GMFR, and percentageof participants with titers greater thandefined threshold(s), at baseline and1, 6, 12, and 24 months after
completion of vaccination

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed severe COVID-19 inparticipants with and without
evidence of infection before
vaccination

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Estimands
Secondary Efficacy

Confirmed severe COVID-19
incidence per 1000 person-years offollow-up

Secondary Immunogenicity
SARS-CoV-2 neutralizing titers inparticipants with no serological or
virological evidence (up to 1 monthafter receipt of the second dose) of
past SARS-CoV-2 infection

ExploratoryS1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titers

To evaluate the immune response(non-S) to SARS-CoV-2 inparticipants with and without
confirmed COVID-19 during the
study



N-binding antibody

To describe the serological responses
to the BNT vaccine candidate in casesof:
Confirmed COVID-19

Confirmed severe COVID-19

SARS-CoV-2 infection without
confirmed COVID-19



S1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titers
N-binding antibody
SARS-CoV-2 detection by
NAAT





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Objectivesa

Estimands

To describe the safety,
immunogenicity, and efficacy ofprophylactic BNT162b2 in
individuals with confirmed stable
HIV disease
To describe the safety andimmunogenicity of prophylactic
BNT162b2 in individuals 16 to 55
years of age vaccinated with study
intervention produced bymanufacturing “Process 1” or“Process 2”ba.

EndpointsAll safety, immunogenicity, andefficacy endpoints described
above



All safety endpoints describedabove
SARS-CoV-2 neutralizing titersHIV-positive participants in Phase 3 will not be included in analyses of the objectives, with the
exception of the specific exploratory objective.
See Section 6.1.1 for description of the manufacturing process.

b.

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)This protocol will use a group of internal case reviewers to determine whether certain
investigator-reported events meet the definition of disease-related efficacy endpoints, using
predefined endpoint criteria.
For those AEs that are handled as disease-related efficacy endpoints (which may include
death), a DMC will conduct unblinded reviews on a regular basis throughout the trial(see Section 9.6).
Any AE that is determined by the internal case reviewers NOT to meet endpoint criteria isreported back to the investigator site of incidence. Refer to Section 8.3.1.1 for instructions
on how to report any such AE that meets the criteria for seriousness to Pfizer Safety.
4. STUDY DESIGN
4.1. Overall Design
This is a multicenter, multinational, Phase 1/2/3, randomized, placebo-controlled, observerblind, dose-finding, vaccine candidate–selection, and efficacy study in healthy individuals.
The study consists of 2 parts. Phase 1: to identify preferred vaccine candidate(s) and doselevel(s); Phase 2/3: an expanded cohort and efficacy part. These parts, and the progression
between them, are detailed in the schema (Section 1.2).
The study will evaluate the safety, tolerability, and immunogenicity of 2 different
SARS-CoV-2 RNA vaccine candidates against COVID-19 and the efficacy of 1 candidate:

As a 2-dose (separated by 21 days) schedule;At various different dose levels in Phase 1;



In 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3: ≥12years of age [stratified as 12-15, 16-55, or >55 years of age]).
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Dependent upon safety and/or immunogenicity data generated during the course of thisstudy, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
in Phase 1 may be started at the next highest dose, groups may not be started, groups may beterminated early, and/or groups may be added with dose levels below the lowest stated doseor intermediate between the lowest and highest stated doses.
The study is observer-blinded, as the physical appearance of the investigational vaccine
candidates and the placebo may differ. The participant, investigator, study coordinator, andother site staff will be blinded. At the study site, only the dispenser(s)/administrator(s) are
unblinded.
To facilitate rapid review of data in real time, sponsor staff will be unblinded to vaccine
allocation for the participants in Phase 1.
4.1.1. Phase 1
Each group (vaccine candidate/dose level/age group) will comprise 15 participants;
12 participants will be randomized to receive active vaccine and 3 to receive placebo.

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)For each vaccine candidate/dose level/age group, the following apply:Additional safety assessments (see Section 8.2)

Controlled enrollment (required only for the first candidate and/or dose level studied):No more than 5 participants (4 active, 1 placebo) can be vaccinated on the firstdayThe first 5 participants must be observed by blinded site staff for at least 4 hours
after vaccination for any acute reactions

Vaccination of the remaining participants will commence no sooner than 24 hours
after the fifth participant received his or her vaccination

Application of stopping rules

IRC review of safety data to determine escalation to the next dose level in the 18- to
55-year age cohort:Escalation between dose levels will be based on IRC review of at least 7-day
post–Dose 1 safety data in this study and/or the BioNTech study conducted inGermany (BNT162-01)

Note that, since both candidates are based upon the same RNA platform, dose
escalation for the second candidate studied may be based upon the safety profileof the first candidate studied being deemed acceptable at the same, or a higher,
dose level by the IRC
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Groups of participants 65 to 85 years of age will not be started until safety data for the RNA
platform have been deemed acceptable at the same, or a higher, dose level in the 18- to
55-year age cohort by the IRC.
In this phase, 13 groups will be studied, corresponding to a total of 195 participants.
The IRC will select 1 vaccine candidate that, in Phase 1, has an established dose level per age
group based on induction of a post–Dose 2 immune response, including neutralizing
antibodies, which is expected to be associated with protection against COVID-19, forprogression into Phase 2/3.

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4.1.2. Phase 2/3
On the basis of safety and/or immunogenicity data generated during the course of this study,
and/or the BioNTech study conducted in Germany (BNT162-01), 1 vaccine candidate wasselected to proceed into Phase 2/3. Participants in this phase will be ≥12 years of age,stratified as follows: 12 to 15 years, 16 to 55 years, or >55 years. The 12- to 15-year stratum
will comprise up to approximately 2000 participants enrolled at selected investigational sites.
It is intended that a minimum of 40% of participants will be in the >55-year stratum.
Commencement of each age stratum will be based upon satisfactory post–Dose 2 safety andimmunogenicity data from the 18- to 55-year and 65- to 85-year age groups in Phase 1,
respectively. The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a doseof 30 µg.
Phase 2/3 is event-driven. Under the assumption of a true VE rate of ≥60%, after the second
dose of investigational product, a target of 164 primary-endpoint cases of confirmed
COVID-19 due to SARS-CoV-2 occurring at least 7 days following the second dose of the
primary series of the candidate vaccine will be sufficient to provide 90% power to conclude
true VE >30% with high probability. The total number of participants enrolled in Phase 2/3
may vary depending on the incidence of COVID-19 at the time of the enrollment, the true
underlying VE, and a potential early stop for efficacy or futility.
Assuming a COVID-19 attack rate of 1.3% per year in the placebo group, accrual of 164
primary-endpoint cases within 6 months, an estimated 20% nonevaluable rate, and 1:1
randomization, the BNT162b2 vaccine candidate selected for Phase 2/3 is expected tocomprise approximately 21,999 vaccine recipients. This is the number of participants
initially targeted for Phase 2/3 and may be adjusted based on advice from DMC analyses ofcase accumulation and the percentage of participants who are seropositive at baseline.
Dependent upon the evolution of the pandemic, it is possible that the COVID-19 attack rate
may be much higher, in which case accrual would be expected to be more rapid, enabling thestudy’s primary endpoint to be evaluated much sooner.
The first 360 participants enrolled (180 to active vaccine and 180 to placebo, stratified
equally between 18 to 55 years and >55 to 85 years) will comprise the “Phase 2” portion.
Safety data through 7 days after Dose 2 and immunogenicity data through 1 month after
Dose 2 from these 360 participants will be analyzed by the unblinded statistical team,
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reviewed by the DMC, and submitted to appropriate regulatory authorities for review.
Enrollment may continue during this period and these participants would be included in theefficacy evaluation in the “Phase 3” portion of the study.

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)In Phase 3, up to approximately 2000 participants, enrolled at selected sites, are anticipatedto be 12 to 15 years of age. Noninferiority of immune response to prophylactic BNT162b2
in participants 12 to 15 years of age to response in participants 16 to 25 years of age will beassessed based on the GMR of SARS-CoV-2 neutralizing titers using a 1.5-fold margin. A
sample size of 200 evaluable participants (or 250 vaccine recipients) per age group will
provide a power of 90.8% to declare the noninferiority in terms of GMR (lower limit of 95%
CI for GMR >0.67). A random sample of 250 participants from each of the 2 age groups(12 to 15 years and 16 to 25 years) will be selected as an immunogenicity subset for thenoninferiority assessment.
The initial BNT162b2 was manufactured using “Process 1”; however, “Process 2” wasdeveloped to support an increased scale of manufacture. In the study, each lot of “Process
2,” manufactured BNT162b2 will be administered to approximately 250 participants 16 to 55
years of age. The safety and immunogenicity of prophylactic BNT162b2 in individuals 16 to
55 years of age vaccinated with “Process 1” and each lot of “Process 2” study intervention
will be described.
Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Phase 1
dosing arms that are not evaluated in Phase 2/3.
4.2. Scientific Rationale for Study Design
Additional surveillance for COVID-19 will be conducted as part of the study, given thepotential risk of disease enhancement. If a participant experiences symptoms, as detailed in
Section 8.13, a COVID-19 illness and subsequent convalescent visit will occur. As part ofthese visits, samples (nasal [midturbinate] swab and blood) will be taken for antigen andantibody assessment as well as recording of COVID-19–related clinical and laboratory
information (including local diagnosis).
Human reproductive safety data are not available for BNT162 RNA-based COVID-19
vaccines, but there is no suspicion of human teratogenicity based on the intended mechanismof action of the compound. Therefore, the use of a highly effective method of contraception
is required (see Appendix 4).
4.3. Justification for Dose
Because of the requirement for a rapid response to the newly emerged COVID-19 pandemic,
sufficient data were not available to experimentally validate the dose selection and initialstarting dose. Therefore, the original planned starting dose of 10 µg (for both BNT162b1 and
BNT162b2) in this study was based on nonclinical experience with the same RNAs encoding
other viral antigens (such as influenza and HIV antigens). The general safety andeffectiveness of uRNA and modRNA platforms have been demonstrated in oncological
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clinical trials with different administration routes (NCT02410733, NCT03871348). Doses of
up to 400 µg total uRNA have been administered IV as RNA lipoplex (RNA-LPX) and dosesof up to 1000 µg total naked modRNA have been administered intratumorally, both without
signs of unpredictable overstimulation of the immune system.
Based on nonclinical data of the RNA components, with other liposomes or in conjunction
with the lipid nanoparticles as will be tested clinically in this study, it was expected that
doses in the 1- to 5-µg range would be immunogenic and induce neutralizing antibodies;
however, it was anticipated that 3- to 10-fold higher doses would likely be required to elicit astronger antibody response. Based on previous clinical and nonclinical experience, it was
expected that doses of up to 100 µg would be well tolerated.

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Update as part of protocol amendment 2: preliminary experience in this study and the
BioNTech study conducted in Germany (BNT162-01) suggests that, for vaccine candidates
based on the modRNA platform, a dose level between 30 µg and 100 µg warrants
consideration. Therefore, a 50-µg dose level is formally included for BNT162b1 and
BNT162b2.
Update as part of protocol amendment 3: as data have become available from this study andthe BNT162-01 study in Germany, it was decided:

To not study the BNT162a1 and BNT162c2 vaccine candidates at this time, so thesecandidates have been removed from the protocol; andThat lower dose levels of BNT162b1 and BNT162b2 warrant consideration.
Therefore, a 20-µg dose level is formally included for both candidates.

Update as part of protocol amendment 4: the 50-µg dose level for BNT162b1 and BNT162b2
is removed and the 100-µg dose level for BNT162b2 is removed; similar dose levels of
BNT162b3 may be studied as for BNT162b1 and BNT162b2.
Update as part of protocol amendment 5: the vaccine candidate selected for Phase 2/3
evaluation is BNT162b2 at a dose of 30 µg. BNT162b3 will not be studied.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases ofthe study, including the last visit. Note that participants enrolled in Phase 1 in groups that do
not proceed to Phase 2/3 may be followed for fewer than 24 months (but no less than
6 months after the last vaccination).
The end of the study is defined as the date of last visit of the last participant in the study.

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5. STUDY POPULATIONThis study can fulfill its objectives only if appropriate participants are enrolled. The
following eligibility criteria are designed to select participants for whom participation in the
study is considered appropriate. All relevant medical and nonmedical conditions should betaken into consideration when deciding whether a particular participant is suitable for thisprotocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:

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1. Male or female participants between the ages of 18 and 55 years, inclusive, and 65 and85 years, inclusive (Phase 1), or ≥12 years (Phase 2/3), at randomization. Note thatparticipants <18 years of age cannot be enrolled in the EU.


Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female(Section 10.4.2) participants.

Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, vaccination
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Healthy participants who are determined by medical history, physical examination(if required), and clinical judgment of the investigator to be eligible for inclusion in the
study.
Note: Healthy participants with preexisting stable disease, defined as disease notrequiring significant change in therapy or hospitalization for worsening disease during
the 6 weeks before enrollment, can be included. Specific criteria for Phase 3 participants
with known stable infection with human immunodeficiency virus (HIV), hepatitis C virus(HCV), or hepatitis B virus (HBV) can be found in Section 10.8.
4. Phase 2/3 only: Participants who, in the judgment of the investigator, are at higher risk
for acquiring COVID-19 (including, but not limited to, use of mass transportation,
relevant demographics, and frontline essential workers).
Informed Consent:
5. Capable of giving personal signed informed consent/have parent(s)/legal guardiancapable of giving signed informed consent as described in Appendix 1, which includes
compliance with the requirements and restrictions listed in the ICD and in this protocol.
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5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Other medical or psychiatric condition including recent (within the past year) or active
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study
participation or, in the investigator’s judgment, make the participant inappropriate for the
study.
2. Phases 1 and 2 only: Known infection with human immunodeficiency virus (HIV),hepatitis C virus (HCV), or hepatitis B virus (HBV).
3. History of severe adverse reaction associated with a vaccine and/or severe allergic
reaction (eg, anaphylaxis) to any component of the study intervention(s).

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4. Receipt of medications intended to prevent COVID-19.
5. Previous clinical (based on COVID-19 symptoms/signs alone, if a SARS-CoV-2 NAAT
result was not available) or microbiological (based on COVID-19 symptoms/signs and apositive SARS-CoV-2 NAAT result) diagnosis of COVID-19.
6. Phase 1 only: Individuals at high risk for severe COVID-19, including those with any of
the following risk factors:Hypertension

Diabetes mellitus

Chronic pulmonary diseaseAsthma

Current vaping or smoking

History of chronic smoking within the prior year

Chronic liver diseaseStage 3 or worse chronic kidney disease (glomerular filtration rate
<60 mL/min/1.73 m2)



Resident in a long-term facility

BMI >30 kg/m2

Anticipating the need for immunosuppressive treatment within the next 6 months

7. Phase 1 only: Individuals currently working in occupations with high risk of exposure to
SARS-CoV-2 (eg, healthcare worker, emergency response personnel).

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8. Immunocompromised individuals with known or suspected immunodeficiency, as
determined by history and/or laboratory/physical examination.
9. Phase 1 only: Individuals with a history of autoimmune disease or an active autoimmune
disease requiring therapeutic intervention, including but not limited to: systemic or
cutaneous lupus erythematosus, autoimmune arthritis/rheumatoid arthritis, Guillain-Barré
syndrome, multiple sclerosis, Sjögren’s syndrome, idiopathic thrombocytopenia purpura,glomerulonephritis, autoimmune thyroiditis, giant cell arteritis (temporal arteritis),
psoriasis, and insulin-dependent diabetes mellitus (type 1).
10. Bleeding diathesis or condition associated with prolonged bleeding that would, in theopinion of the investigator, contraindicate intramuscular injection.
11. Women who are pregnant or breastfeeding.
Prior/Concomitant Therapy:

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12. Previous vaccination with any coronavirus vaccine.
13. Individuals who receive treatment with immunosuppressive therapy, including cytotoxic
agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned
receipt throughout the study. If systemic corticosteroids have been administered shortterm (<14 days) for treatment of an acute illness, participants should not be enrolled into
the study until corticosteroid therapy has been discontinued for at least 28 days before
study intervention administration. Inhaled/nebulized (except for participants in
Phase 1 – see exclusion criterion 14), intra-articular, intrabursal, or topical (skin or eyes)corticosteroids are permitted.
14. Phase 1 only: Regular receipt of inhaled/nebulized corticosteroids.
15. Receipt of blood/plasma products or immunoglobulin, from 60 days before study
intervention administration or planned receipt throughout the study.
Prior/Concurrent Clinical Study Experience:
16. Participation in other studies involving study intervention within 28 days prior to study
entry and/or during study participation.
17. Previous participation in other studies involving study intervention containing lipid
nanoparticles.
Diagnostic Assessments:
18. Phase 1 only: Positive serological test for SARS-CoV-2 IgM and/or IgG antibodies atthe screening visit.

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19. Phase 1 only: Any screening hematology and/or blood chemistry laboratory value thatmeets the definition of a ≥ Grade 1 abnormality.
Note: With the exception of bilirubin, participants with any stable Grade 1 abnormalities(according to the toxicity grading scale) may be considered eligible at the discretion of
the investigator. (Note: A “stable” Grade 1 laboratory abnormality is defined as a reportof Grade 1 on an initial blood sample that remains ≤ Grade 1 upon repeat testing on asecond sample from the same participant.)
20. Phase 1 only: Positive test for HIV, hepatitis B surface antigen (HBsAg), hepatitis B
core antibodies (HBc Abs), or hepatitis C virus antibodies (HCV Abs) at the screening
visit.
21. Phase 1 only: SARS-CoV-2 NAAT-positive nasal swab within 24 hours before receipt ofstudy intervention.

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Other Exclusions:
22. Investigator site staff or Pfizer/BioNTech employees directly involved in the conduct of
the study, site staff otherwise supervised by the investigator, and their respective family
members.
5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm thatthe participant has selected an appropriate method of contraception for the individual
participant and his or her partner(s) from the permitted list of contraception methods(see Appendix 4, Section 10.4.4) and will confirm that the participant has been instructed inits consistent and correct use. At time points indicated in the SoA, the investigator ordesignee will inform the participant of the need to use highly effective contraception
consistently and correctly and document the conversation and the participant’s affirmation in
the participant’s chart (participants need to affirm their consistent and correct use of at least 1of the selected methods of contraception). In addition, the investigator or designee will
instruct the participant to call immediately if the selected contraception method is
discontinued or if pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but
are not subsequently randomly assigned to study intervention. A minimal set of screen
failure information is required to ensure transparent reporting of screen failure participants tomeet the CONSORT publishing requirements and to respond to queries from regulatory
authorities. Minimal information includes demography, screen failure details, eligibility
criteria, and any SAE.

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Individuals who do not meet the criteria for participation in this study (screen failure) may berescreened under a different participant number.
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention
Administration
The following conditions are temporary or self-limiting and a participant may be vaccinatedonce the condition(s) has/have resolved and no other exclusion criteria are met.

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1. Current febrile illness (body temperature ≥100.4°F [≥38°C]) or other acute illness within
48 hours before study intervention administration. This includes current symptoms that
could represent a potential COVID-19 illness:

New or increased cough;

New or increased shortness of breath;Chills;

New or increased muscle pain;New loss of taste/smell;

Sore throat;

Diarrhea;Vomiting.

2. Receipt of any seasonal or pandemic influenza vaccine within 14 days, or any othernonstudy vaccine within 28 days, before study intervention administration.
3. Anticipated receipt of any seasonal or pandemic influenza vaccine within 14 days, or any
other nonstudy vaccine within 28 days, after study intervention administration.
4. Receipt of short-term (<14 days) systemic corticosteroids. Study intervention
administration should be delayed until systemic corticosteroid use has been discontinued
for at least 28 days. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin oreyes) corticosteroids are permitted.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s),placebo, medical device(s), or study procedure(s) intended to be administered to a study
participant according to the study protocol.

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The study will evaluate a 2-dose (separated by 21 days) schedule of various different doselevels of 2 investigational RNA vaccine candidates for active immunization against
COVID-19 in 3 age groups (18 to 55 years of age, 65 to 85 years of age, and ≥12 years ofage [stratified as 12-15, 16-55, or >55 years of age]).
These 2 investigational RNA vaccine candidates, with the addition of saline placebo, are the
3 potential study interventions that may be administered to a study participant:

BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 20 µg, 30 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 20 µg, 30 µgNormal saline (0.9% sodium chloride solution for injection)

The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.

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6.1. Study Intervention(s) Administered
Intervention NameType
Dose Formulation

BNT162b1(BNT162 RNA-LNP
vaccine utilizing
modRNA)
VaccinemodRNA

BNT162b2(BNT162 RNA-LNP
vaccine utilizing
modRNA)
VaccinemodRNA

Saline Placebo

Placebo
Normal saline (0.9%sodium chloride solution
for injection)
Unit Dose Strength(s)250 µg/0.5 mL
250 µg/0.5 mL
N/A
Dosage Level(s)a10-, 20-, 30-, 100-µg
10-, 20-, 30-µg
N/A
Route of Administration Intramuscular injection
Intramuscular injection
Intramuscular injection
Use
Experimental
Experimental
Placebo
IMP or NIMP
IMP
IMP
IMP
Sourcing
Provided centrally by the Provided centrally by the Provided centrally by thesponsorsponsorsponsorPackaging and Labeling Study intervention will be Study intervention will be Study intervention will be
provided in a glass vial as provided in a glass vial as provided in a glass or
open-label supply. Each
open-label supply. Each
plastic vial as open-labelvial will be labeled asvial will be labeled as
supply. Each vial will be
required per country
required per country
labeled as required per
requirement
requirement
country requirementa. Dependent upon safety and/or immunogenicity data generated during the course of this study, or the
BioNTech study conducted in Germany (BNT162-01), it is possible that groups may be started at the next
highest dose, groups may not be started, groups may be terminated early, and/or groups may be addedwith dose levels below the lowest stated dose or intermediate between the lowest and highest stated doses.

The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.

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6.1.1. Manufacturing Process
The scale of the BNT162b2 manufacturing has been increased to support future supply.
BNT162b2 generated using the manufacturing process supporting an increased supply(“Process 2”) will be administered to approximately 250 participants 16 to 55 years of age,per lot, in the study. The safety and immunogenicity of prophylactic BNT162b2 in
individuals 16 to 55 years of age vaccinated with material generated using the existing
manufacturing process “Process 1,” and with material from lots generated using the
manufacturing process supporting increased supply, “Process 2,” will be described.
In brief, the process changes relate to the method of production for the DNA template thatRNA drug substance is transcribed from, and the RNA drug substance purification method.
The BNT162b2 drug product is then produced using a scaled-up LNP manufacturing process.
6.1.2. Administration

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Participants will receive 1 dose of study intervention as randomized at each vaccination visit(Visits 1 and 4 for Phase 1 participants, Visits 1 and 2 for Phase 2/3 participants) inaccordance with the study’s SoA. The volume to be administered may vary by vaccine
candidate and dose level; full details are described in the IP manual.
Study intervention should be administered intramuscularly into the deltoid muscle, preferablyof the nondominant arm, by an unblinded administrator.
Standard vaccination practices must be observed and vaccine must not be injected into bloodvessels. Appropriate medication and other supportive measures for management of an acute
hypersensitivity reaction should be available in accordance with local guidelines for standard
immunization practices.
Administration of study interventions should be performed by an appropriately qualified,
GCP-trained, and vaccine-experienced member of the study staff (eg, physician, nurse,
physician’s assistant, nurse practitioner, pharmacist, or medical assistant) as allowed by
local, state, and institutional guidance.
Study intervention administration details will be recorded on the CRF.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study interventions received and any discrepancies arereported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only
authorized site staff may supply or administer study intervention. All study interventions
must be stored in a secure, environmentally controlled, and monitored (manual or
automated recording) area in accordance with the labeled storage conditions with accesslimited to the investigator and authorized site staff. At a minimum, daily minimum andmaximum temperatures for all site storage locations must be documented and available
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upon request. Data for nonworking days must indicate the minimum and maximum
temperatures since previously documented for all site storage locations upon return tobusiness.
3. Any excursions from the study intervention label storage conditions should be reported to
Pfizer upon discovery along with any actions taken. The site should actively pursue
options for returning the study intervention to the storage conditions described in thelabeling, as soon as possible. Once an excursion is identified, the study intervention must
be quarantined and not used until Pfizer provides permission to use the study
intervention. Specific details regarding the definition of an excursion and information thesite should report for each excursion will be provided to the site in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage conditions
stated on the label.
5. Study interventions should be stored in their original containers.

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6. See the IP manual for storage conditions of the study intervention.
7. The investigator, institution, or the head of the medical institution (where applicable) is
responsible for study intervention accountability, reconciliation, and record maintenance(ie, receipt, reconciliation, and final disposition records), such as the IPAL orsponsor-approved equivalent. All study interventions will be accounted for using a study
intervention accountability form/record.
8. Further guidance and information for the final disposition of unused study interventions
are provided in the IP manual. All destruction must be adequately documented. If
destruction is authorized to take place at the investigator site, the investigator must ensurethat the materials are destroyed in compliance with applicable environmental regulations,institutional policy, and any special instructions provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of
discovery as described in the IP manual.
6.2.1. Preparation and Dispensing
See the IP manual for instructions on how to prepare the study intervention foradministration. Study intervention should be prepared and dispensed by an appropriately
qualified and experienced member of the study staff (eg, physician, nurse, physician’s
assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as allowed by
local, state, and institutional guidance. A second staff member will verify the dispensing.
Study intervention and placebo will be prepared by qualified unblinded site personnel
according to the IP manual. The study intervention will be administered in such a way toensure the participants remain blinded.

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6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
Allocation (randomization) of participants to vaccine groups will proceed through the use of
an IRT system (IWR). The site personnel (study coordinator or specified designee) will be
required to enter or select information including but not limited to the user’s ID andpassword, the protocol number, and the participant number. The site personnel will then be
provided with a vaccine assignment and randomization number. The IRT system will
provide a confirmation report containing the participant number, randomization number, andstudy intervention allocation assigned. The confirmation report must be stored in the site’s
files.
The study-specific IRT reference manual and IP manual will provide the contact informationand further details on the use of the IRT system.

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6.3.2. Blinding of Site Personnel
In this observer blinded study, the study staff receiving, storing, dispensing, preparing, andadministering the study interventions will be unblinded. All other study and site personnel,
including the investigator, investigator staff, and participants, will be blinded to study
intervention assignments. In particular, the individuals who evaluate participant safety willbe blinded. Because the BNT162 RNA-based COVID-19 vaccine candidates and placebo
are different in physical appearance, the study intervention syringes will be administered in amanner that prevents the study participants from identifying the study intervention type basedon its appearance.
The responsibility of the unblinded dispenser and administrator must be assigned to anindividual or individuals who will not participate in the evaluation of any study participants.
Contact between the unblinded dispenser and study participants and unblinded administrator
and study participants should be kept to a minimum. The remaining site personnel must notknow study intervention assignments.
6.3.3. Blinding of the Sponsor
To facilitate rapid review of data in real time, sponsor staff will be unblinded to study
intervention allocation for the participants in Phase 1. The majority of sponsor staff will beblinded to study intervention allocation in Phase 2/3. All laboratory testing personnel
performing serology assays will remain blinded to study intervention assigned/received
throughout the study. The following sponsor staff, who will have no part in the blinded
conduct of the study, will be unblinded in Phase 2/3 (further details will be provided in a data
blinding plan):

Those study team members who are involved in ensuring that protocol requirements
for study intervention preparation, handling, allocation, and administration are
fulfilled at the site will be unblinded for the duration of the study (eg, unblinded study
manager, unblinded clinical research associate).
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Unblinded clinician(s), who are not direct members of the study team and will notparticipate in any other study-related activities, will review unblinded protocol
deviations.

An unblinded team supporting interactions with, and analyses for, the DMC(see Section 9.6). This will comprise a statistician, programmer(s), and a medical
monitor who will review cases of severe COVID-19 as they are received, and will
review AEs at least weekly for additional potential cases of severe COVID-19(see Section 8.2.3).

An unblinded submissions team will be responsible for preparing unblinded analyses
and documents to support regulatory activities that may be required while the study is
ongoing. This team will only be unblinded at the group level and not have access toindividual subject assignments. The programs that produce the summary tables will
be developed and validated by the blinded study team, and these programs will be runby the unblinded DMC team. The submissions team will not have access tounblinded COVID-19 cases unless efficacy is achieved in either an interim analysis or
the final analysis, as determined by the DMC.

6.3.4. Breaking the Blind
The IRT will be programmed with blind-breaking instructions. In case of an emergency, theinvestigator has the sole responsibility for determining if unblinding of a participant’s study
intervention assignment is warranted. Participant safety must always be the firstconsideration in making such a determination. If the investigator decides that unblinding iswarranted, the investigator should make every effort to contact the sponsor prior to
unblinding a participant’s vaccine assignment unless this could delay further management of
the participant. If a participant’s vaccine assignment is unblinded, the sponsor must be
notified within 24 hours after breaking the blind. The date and reason that the blind was
broken must be recorded in the source documentation and CRF.
The study-specific IRT reference manual and IP manual will provide the contact informationand further details on the use of the IRT system.
6.4. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from theinvestigator or designee, under medical supervision. The date and time of each dose
administered in the clinic will be recorded in the source documents and recorded in the CRF.
The dose of study intervention and study participant identification will be confirmed at thetime of dosing by a member of the study site staff other than the person administering thestudy intervention.

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6.5. Concomitant Therapy
The following concomitant medications and vaccinations will be recorded in the CRF:
All vaccinations received from 28 days prior to study enrollment until the 6-monthfollow-up visit (Visit 8 for Phase 1 participants, and Visit 4 for Phase 2/3
participants).

Prohibited medications listed in Section 6.5.1 will be recorded, to include start andstop dates, name of the medication, dose, unit, route, and frequency.

In addition, for participants enrolled in Phase 1, all current medication at baseline will
be recorded, to include start date, name of the medication, dose, unit, route, andfrequency.

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6.5.1. Prohibited During the Study
Receipt of the following vaccines and medications during the time periods listed below may
exclude a participant from the per-protocol analysis from that point onwards, and may
require vaccinations to be discontinued in that participant; however, it is anticipated that theparticipant would not be withdrawn from the study (see Section 7). Medications should not
be withheld if required for a participant’s medical care.
Unless considered medically necessary, no vaccines other than study intervention should be
administered within 28 days before and 28 days after each study vaccination. One exception
to this is that seasonal and pandemic influenza vaccine can be given at least 14 days after, orat least 14 days prior to, the administration of study intervention.
Receipt of chronic systemic treatment with known immunosuppressant medications, orradiotherapy, within 60 days before enrollment through conclusion of the study.
Receipt of systemic corticosteroids (≥20 mg/day of prednisone or equivalent) for ≥14 days is
prohibited from 28 days prior to enrollment to Visit 7 for Phase 1 participants, and Visit 3 forPhase 2/3 participants).
Receipt of inhaled/nebulized corticosteroids from 28 days prior to enrollment to Visit 7(1-month follow-up visit) for Phase 1 participants.
Receipt of blood/plasma products or immunoglobulins within 60 days before enrollment
through conclusion of the study.
Receipt of any other (nonstudy) coronavirus vaccine at any time prior to or during study
participation is prohibited.
Prophylactic antipyretics and other pain medication to prevent symptoms associated withstudy intervention administration are not permitted. However, if a participant is taking a

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medication for another condition, even if it may have antipyretic or pain-relieving properties,
it should not be withheld prior to study vaccination.
6.5.2. Permitted During the Study
The use of antipyretics and other pain medication to treat symptoms associated with study
intervention administration or ongoing conditions is permitted.
Medication other than that described as prohibited in Section 6.5.1 required for treatment ofpreexisting stable conditions is permitted.
Inhaled (except in Phase 1 participants – see Section 6.5.1), topical, or localized injections ofcorticosteroids (eg, intra-articular or intrabursal administration) are permitted.
6.6. Dose Modification

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)This protocol allows some alteration of vaccine dose for individual participants and/or dosegroups from the currently outlined dosing schedule. For reasons of reactogenicity,
tolerability, or safety, the IRC may recommend to reduce the second dose of study
intervention and/or increase the interval between doses.
If, due to a medication error, a participant receives 1 dose of BNT162b2 at Visit 1 and 1 doseof placebo at Visit 2 (or vice versa), the participant should be offered the possibility toreceive a second dose of BNT162b2 at an unscheduled visit. In this situation:
Obtain informed consent for administration of the additional dose.

Measure the participant’s body temperature.

Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention
into the deltoid muscle of the preferably nondominant arm. Please refer to the IP
manual for further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of
the CRF, and on an SAE form as applicable.



The participant should continue to adhere to the normal visit schedule but must be
followed for nonserious AEs for 1 month and SAEs for 6 months after the second
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dose of BNT162b2. This will require AEs to be elicited either by unscheduled
telephone contact(s) and/or in-person visit(s).
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANTDISCONTINUATION/WITHDRAWAL

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7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study
intervention (definitive discontinuation). Reasons for definitive discontinuation of study
intervention may include the following: AEs; participant request; investigator request;
pregnancy; protocol deviation (including no longer meeting all the inclusion criteria, or
meeting 1 or more exclusion criteria). In general, unless the investigator considers it unsafe
to administer the second dose, or the participant does not wish to receive it, it is preferredthat the second dose be administered. Note that a positive SARS-CoV-2 NAAT result
without symptoms does not meet exclusion criterion 5 and should not result in
discontinuation of study intervention, whereas a COVID-19 diagnosis does meet exclusion
criterion 5 and should result in discontinuation of study intervention (see Section 8.15).
Note that discontinuation of study intervention does not represent withdrawal from the study.
Per the study estimands, if study intervention is definitively discontinued, the participant willremain in the study to be evaluated for safety, immunogenicity, and efficacy. See the SoA
for data to be collected at the time of discontinuation of study intervention and follow-up for
any further evaluations that need to be completed.
In the event of discontinuation of study intervention, it must be documented on theappropriate CRF/in the medical records whether the participant is discontinuing further
receipt of study intervention or also from study procedures, posttreatment study follow-up,
and/or future collection of additional information.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request. Reasons fordiscontinuation from the study may include the following:

Refused further follow-up;

Lost to follow-up;



Death;



Study terminated by sponsor;



AEs;



Participant request;
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Investigator request;Protocol deviation.

If a participant does not return for a scheduled visit, every effort should be made to contact
the participant. All attempts to contact the participant and information received duringcontact attempts must be documented in the participant’s source document. In any
circumstance, every effort should be made to document participant outcome, if possible.
The investigator or his or her designee should capture the reason for withdrawal in the CRF
for all participants.
If a participant withdraws from the study, he/she may request destruction of any remaining
samples taken and not tested, and the investigator must document any such requests in thesite study records and notify the sponsor accordingly.

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If the participant withdraws from the study and also withdraws consent (see Section 7.2.1)
for disclosure of future information, no further evaluations should be performed and no
additional data should be collected. The sponsor may retain and continue to use any datacollected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not beviewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent
Participants who request to discontinue receipt of study intervention will remain in the study
and must continue to be followed for protocol-specified follow-up procedures. The only
exception to this is when a participant specifically withdraws consent for any further contact
with him or her or persons previously authorized by the participant to provide thisinformation. Participants should notify the investigator in writing of the decision towithdraw consent from future follow-up, whenever possible. The withdrawal of consent
should be explained in detail in the medical records by the investigator, as to whether thewithdrawal is only from further receipt of study intervention or also from study procedures
and/or posttreatment study follow-up, and entered on the appropriate CRF page. In the eventthat vital status (whether the participant is alive or dead) is being measured, publicly
available information should be used to determine vital status only as appropriately directedin accordance with local law.
7.3. Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return forscheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to attend a required study visit:The site must attempt to contact the participant and reschedule the missed visit assoon as possible and counsel the participant on the importance of maintaining the
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assigned visit schedule and ascertain whether or not the participant wishes to and/or
should continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must
make every effort to regain contact with the participant (where possible, 3 telephone
calls and, if necessary, a certified letter to the participant’s last known mailingaddress or local equivalent methods). These contact attempts should be documented
in the participant’s medical record;Should the participant continue to be unreachable, he/she will be considered to havewithdrawn from the study.

8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed anddated ICD before performing any study-specific procedures.

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)The full date of birth will be collected to critically evaluate the immune response and safety
profile by age.
Study procedures and their timing are summarized in the SoA. Protocol waivers or
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence orawareness to determine whether the participant should continue or discontinue study
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential
participants meet all eligibility criteria. The investigator will maintain a screening log torecord details of all participants screened and to confirm eligibility or record reasons forscreening failure, as applicable.
Every effort should be made to ensure that protocol-required tests and procedures arecompleted as described. However, it is anticipated that from time to time there may becircumstances outside the control of the investigator that may make it unfeasible to performthe test. In these cases, the investigator must take all steps necessary to ensure the safety andwell-being of the participant. When a protocol-required test cannot be performed, theinvestigator will document the reason for the missed test and any corrective and preventive
actions that he or she has taken to ensure that required processes are adhered to as soon as
possible. The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, andshipment instructions and contact information will be provided to the investigator site prior
to initiation of the study.
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The total blood sampling volume for individual participants in this study is approximately up
to: 515 mL for participants in Phase 1, 110 mL for Phase 2/3 participants ≥16 years of age,and 50 mL for participants in the 12- to 15-year age stratum. Additionally, 20 mL of bloodfor participants ≥16 years of age and 10 mL for participants in the 12- to 15-year age stratum
will be taken at an unplanned convalescent visit at any time a participant develops respiratory
symptoms indicating a potential COVID-19 infection. Select participants in Phase 1 will also
be asked to provide an additional blood sample of approximately 170 mL at either Visit 5, 6,
or 7. These participants would therefore have a total blood sampling volume of 700 mL
during the 24-month study period. Other additional blood samples may be taken for safetyassessments at times specified by Pfizer, provided the total volume taken during the study
does not exceed 550 mL during any period of 60 consecutive days.

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8.1. Efficacy and/or Immunogenicity Assessments
Efficacy will be assessed throughout a participant’s involvement in the study throughsurveillance for potential cases of COVID-19. If, at any time, a participant develops acuterespiratory illness (see Section 8.13), for the purposes of the study he or she will beconsidered to potentially have COVID-19 illness.9 In this circumstance, the participant
should contact the site, an in-person or telehealth visit should occur, and assessments should
be conducted as specified in the SoA. The assessments will include a nasal (midturbinate)swab, which will be tested at a central laboratory using a reverse transcription–polymerase
chain reaction (RT-PCR) test (Cepheid; FDA approved under EUA), or other equivalent
nucleic acid amplification–based test (ie, NAAT), to detect SARS-CoV-2. In addition,clinical information and results from local standard-of-care tests (as detailed in Section 8.13)
will be assessed. The central laboratory NAAT result will be used for the case definition,
unless no result is available from the central laboratory, in which case a local NAAT result
may be used if:
It was obtained using:An FDA-cleared assay; or an assay that is not FDA-cleared but was conducted in alaboratory that is currently CLIA-certified; or an assay performed by a laboratory
accredited according to the ISO 15189 standard by a national or regional accreditation
body;

AND


The assay is deemed acceptable by Pfizer.

Two definitions of SARS-CoV-2–related cases, and SARS-CoV-2–related severe cases, will
be considered (for both, the onset date of the case will be the date that symptoms were firstexperienced by the participant; if new symptoms are reported within 4 days after resolutionof all previous symptoms, they will be considered as part of a single illness):Confirmed COVID-19: presence of at least 1 of the following symptoms and
SARS-CoV-2 NAAT-positive during, or within 4 days before or after, the
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symptomatic period, either at the central laboratory or at a local testing facility (using
an acceptable test):Fever;

New or increased cough;

New or increased shortness of breath;Chills;

New or increased muscle pain;New loss of taste or smell;

Sore throat;

Diarrhea;Vomiting.

The second definition, which may be updated as more is learned about COVID-19, will
include the following additional symptoms defined by the CDC (listed athttps://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html):



Fatigue;Headache;

Nasal congestion or runny nose;Nausea.

Confirmed severe COVID-19: confirmed COVID-19 and presence of at least 1 of thefollowing:Clinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per
minute, HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or
PaO2/FiO2 <300 mm Hg);

Respiratory failure (defined as needing high-flow oxygen, noninvasive
ventilation, mechanical ventilation, or ECMO);

Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiringvasopressors);

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Significant acute renal, hepatic, or neurologic dysfunction*;Admission to an ICU;Death.

The DMC may recommend modification of the definition of severe disease according toemerging information.
* Three blinded case reviewers (medically qualified Pfizer staff members) will review all
potential COVID-19 illness events. If a NAAT-confirmed case in Phase 2/3 may beconsidered severe, or not, solely on the basis of this criterion, the blinded data will be
reviewed by the case reviewers to assess whether the criterion is met; the majority opinion
will prevail.
In addition, a serological definition will be used for participants without clinical presentationof COVID-19:

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Confirmed seroconversion to SARS-CoV-2 without confirmed COVID-19: positive
N-binding antibody result in a participant with a prior negative N-binding antibody
resultSerum samples will be obtained for immunogenicity testing at the visits specified in the SoA.
The following assays will be performed:

SARS-CoV-2 neutralization assay

S1-binding IgG level assay

RBD-binding IgG level assay

N-binding antibody assay

Note that all immunogenicity analyses will be based upon samples analyzed at the central
laboratory; the rapid test will only be performed at screening by all sites recruiting
participants in Phase 1 (see Section 8.11.1.1) to determine eligibility.
Serum obtained from the additional ~170-mL blood sample from select participants in Phase
1 at either Visit 5, 6, or 7 will be used for exploratory COVID-19 research, intended toestablish a surrogate endpoint that is reasonably likely to predict clinical benefit.
8.1.1. Biological Samples
Blood and nasal swab samples will be used only for scientific research. Each sample will belabeled with a code so that the laboratory personnel testing the samples will not know theparticipant’s identity. Samples that remain after performing assays outlined in the protocol
may be stored by Pfizer. Unless a time limitation is required by local regulations or ethical
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requirements, the samples will be stored for up to 15 years after the end of the study and thendestroyed. If allowed by the ICD, stored samples may be used for additional testing to better
understand the immune responses to the vaccine(s) under study in this protocol, to inform thedevelopment of other products, and/or for vaccine-related assay work supporting vaccine
programs. No testing of the participant’s DNA will be performed.
The participant may request that his or her samples, if still identifiable, be destroyed at any
time; however, any data already collected from those samples will still be used for thisresearch. The biological samples may be shared with other researchers as long asconfidentiality is maintained and no testing of the participant’s DNA is performed.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinicallaboratory measurements may be obtained at any time during the study to assess any
perceived safety issues.

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A clinical assessment, including medical history, will be performed on all participants at
his/her first visit to establish a baseline. Significant medical history and observations fromany physical examination, if performed, will be documented in the CRF.
AEs and SAEs are collected, recorded, and reported as defined in Section 8.3.
Acute reactions within the first 4 hours after administration of the study intervention (for the
first 5 participants vaccinated in each Phase 1 group), and within the first 30 minutes (for theremainder of participants), will be assessed and documented in the AE CRF.
The safety parameters also include reactogenicity e-diary reports of local reactions andsystemic events (including fever), and use of antipyretic medication that occur in the 7 days
after administration of the study intervention. These prospectively self-collected occurrencesof local reactions and systemic events are graded as described in Section 8.2.2.
8.2.1. Clinical Safety Laboratory Assessments (Phase 1 Participants Only)
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for
the timing and frequency. All protocol-required laboratory assessments, as defined inAppendix 2, must be conducted in accordance with the laboratory manual and the SoA.
Unscheduled clinical laboratory measurements may be obtained at any time during the study
to assess any perceived safety issues.
The investigator must review the laboratory report, document this review, and record any
clinically relevant changes occurring during the study in the AE section of the CRF. See
Appendix 2 for the grading scale for assessment of clinically significant abnormal laboratory
findings. Clinically significant abnormal laboratory findings are those which are notassociated with the underlying disease, unless judged by the investigator to be more severe
than expected for the participant's condition.

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All laboratory tests with values considered clinically significantly abnormal during
participation in the study or within 28 days after the last dose of study intervention should be
repeated until the values return to normal or baseline or are no longer considered clinicallysignificant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 5 for suggested actions and follow-up assessments in the event of potential
drug-induced liver injury (DILI).

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8.2.2. Electronic Diary
Participants will be required to complete a reactogenicity e-diary through an application(see Section 8.14) installed on a provisioned device or on the participant’s own personal
device. All participants in Phase 1, and a subset of at least the first 6000 randomized inPhase 2/3, will be asked to monitor and record local reactions, systemic events, andantipyretic medication usage for 7 days following administration of the study intervention.
All participants in Phase 3 who are HIV-positive or 12 to 15 years of age will be included inthis subset. The reactogenicity e-diary allows recording of these assessments only within afixed time window, thus providing the accurate representation of the participant’s experienceat that time. Data on local reactions and systemic events reported in the reactogenicity
e-diary will be transferred electronically to a third-party vendor, where they will be available
for review by investigators and the Pfizer clinicians at all times via an internet-based portal.
At intervals agreed to by the vendor and Pfizer, these data will be transferred electronicallyinto Pfizer's database for analysis and reporting. These data do not need to be reported by theinvestigator in the CRF as AEs.
Investigators (or designee) will be required to review the reactogenicity e-diary data online atfrequent intervals as part of the ongoing safety review.
The investigator or designee must obtain stop dates from the participant for any ongoing
local reactions, systemic events, or use of antipyretic medication on the last day that thereactogenicity e-diary was completed. The stop dates should be documented in the source
documents and the information entered in the CRF.
8.2.2.1. Grading Scales
The grading scales used in this study to assess local reactions and systemic events as
described below are derived from the FDA Center for Biologics Evaluation and Research(CBER) guidelines on toxicity grading scales for healthy adult volunteers enrolled inpreventive vaccine clinical trials.8
8.2.2.2. Local Reactions
During the reactogenicity e-diary reporting period, participants will be asked to assess
redness, swelling, and pain at the injection site and to record the symptoms in the
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reactogenicity e-diary. If a local reaction persists beyond the end of the reactogenicity
e-diary period following vaccination, the participant will be requested to report that
information. The investigator will enter this additional information in the CRF.
Redness and swelling will be measured and recorded in measuring device units(range: 1 to 21) and then categorized during analysis as absent, mild, moderate, or severe
based on the grading scale in Table 1. Measuring device units can be converted tocentimeters according to the following formula: 1 measuring device unit = 0.5 cm. Pain at
the injection site will be assessed by the participant as absent, mild, moderate, or severe
according the grading scale in Table 1.

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If a Grade 3 local reaction is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinicallyindicated. Only an investigator or medically qualified person is able to classify aparticipant’s local reaction as Grade 4. If a participant experiences a confirmed Grade 4 local
reaction, the investigator must immediately notify the sponsor and, if it is determined to berelated to the administration of the study intervention, further vaccinations will be
discontinued in that participant.
Table 1.

Local Reaction Grading Scale
Mild(Grade 1)

Moderate(Grade 2)

Pain at the
injection site

Does not interferewith activity

Interferes withactivity

Redness>2.0 cm to 5.0 cm(5 to 10 measuring
device units)>2.0 cm to 5.0 cm(5 to 10 measuring
device units)>5.0 cm to 10.0 cm(11 to 20 measuring
device units)>5.0 cm to 10.0 cm(11 to 20 measuring
device units)

Swelling

Severe(Grade 3)

Potentially Life
Threatening(Grade 4)
Prevents daily activity Emergency room visit
or hospitalization forsevere pain
>10 cmNecrosis or(≥21 measuringexfoliative dermatitis
device units)>10 cmNecrosis(≥21 measuring
device units)

8.2.2.3. Systemic Events
During the reactogenicity e-diary reporting period, participants will be asked to assess
vomiting, diarrhea, headache, fatigue, chills, new or worsened muscle pain, and new orworsened joint pain and to record the symptoms in the reactogenicity e-diary. The symptoms
will be assessed by the participant as absent, mild, moderate, or severe according to thegrading scale in Table 2.
If a Grade 3 systemic event is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinicallyindicated. Only an investigator or medically qualified person is able to classify aparticipant’s systemic event as Grade 4. If a participant experiences a confirmed Grade 4
systemic event, the investigator must immediately notify the sponsor and, if it is determined
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to be related to the administration of the study intervention, further vaccinations will be
discontinued in that participant.
Table 2.

Systemic Event Grading Scale

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Mild(Grade 1)

Moderate(Grade 2)>2 times in
24 hours

Severe(Grade 3)

Vomiting

1-2 times in
24 hours

Requires IV
hydration

Diarrhea

2 to 3 loose stools 4 to 5 loose stools
in 24 hours
in 24 hours

6 or more loosestools in 24 hours

Headache

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Fatigue/tiredness

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Chills

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

New orworsened
muscle pain

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Does not interfere Some interference
New orwith activity
with activity
worsened
joint pain
Abbreviation: IV = intravenous.

Prevents daily
routine activity

Potentially Life
Threatening(Grade 4)
Emergency room visit or
hospitalization for
hypotensive shock
Emergency room visit or
hospitalization for severe
diarrhea
Emergency room visit or
hospitalization for severe
headache
Emergency room visit or
hospitalization for severe
fatigue
Emergency room visit or
hospitalization for severe
chillsEmergency room visit or
hospitalization for severe
new or worsened muscle
painEmergency room visit or
hospitalization for severe
new or worsened joint pain

8.2.2.4. Fever
In order to record information on fever, a thermometer will be given to participants with
instructions on how to measure oral temperature at home. Temperature will be collected in
the reactogenicity e-diary in the evening daily during the reactogenicity e-diary reporting
period. It will also be collected at any time during the reactogenicity e-diary data collection
periods when fever is suspected. Fever is defined as an oral temperature of ≥38.0°C(100.4°F). The highest temperature for each day will be recorded in the reactogenicity
e-diary. Temperature will be measured and recorded to 1 decimal place and then categorized
during analysis according to the scale shown in Table 3.
If a fever of ≥39.0°C (102.1°F) is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinicallyindicated. Only an investigator or medically qualified person is able to confirm aparticipant’s fever as >40.0°C (>104.0°F). If a participant experiences a confirmed fever>40.0°C (>104.0°F), the investigator must immediately notify the sponsor and, if it is
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determined to be related to the administration of the study intervention, further vaccinations
will be discontinued in that participant.
Table 3.

Scale for Fever≥38.0-38.4°C (100.4-101.1°F)>38.4-38.9°C (101.2-102.0°F)>38.9-40.0°C (102.1-104.0°F)>40.0°C (>104.0°F)

8.2.2.5. Antipyretic Medication
The use of antipyretic medication to treat symptoms associated with study intervention
administration will be recorded in the reactogenicity e-diary daily during the reporting period(Day 1 to Day 7).

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8.2.3. Phase 1 Stopping Rules
The following stopping rules are in place for all Phase 1 participants, based on review of AE
data and e-diary reactogenicity data, until the start of Phase 2/3 or 30 days after the last doseof study intervention in Phase 1, whichever is later. These data will be monitored on an
ongoing basis by the investigator (or medically qualified designee) and sponsor in order topromptly identify and flag any event that potentially contributes to a stopping rule.
The sponsor study team will be unblinded during Phase 1, so will be able to assess whether
or not a stopping rule has been met on the basis of a participant’s individual study
intervention allocation.
In the event that sponsor personnel confirm that a stopping rule is met, the following actions
will commence:The IRC will review all appropriate data.

The stopping rule will PAUSE randomization and study intervention administration
for the impacted vaccine candidate all dose levels and age groups.



The DMC will review all appropriate data.

For all participants vaccinated, all other routine study conduct activities, including
ongoing data entry, reporting of AEs, participant reactogenicity e-diary completion,
blood sample collection, and participant follow-up, will continue during the pause.

A stopping rule is met if any of the following rules occur after administration of
investigational BNT162 vaccine; data from placebo recipients will not contribute to thestopping rules. Reactogenicity e-diary data confirmed by the investigator as being entered by
the participant in error will not contribute toward a stopping rule.
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The BNT162b RNA platform will be evaluated for contribution to stopping rules overall;
vaccine candidate dose levels within the platform and age groups will contribute to stopping
rules together. However, it is possible that the recommendations may include halting or
continuing randomization with any of the BNT162 vaccine candidates.
Stopping Rule Criteria for Each BNT162 Vaccine Candidate:
1. If any participant vaccinated with the BNT162 candidate (at any dose level) develops an
SAE that is assessed by the investigator as possibly related, or for which there is noalternative, plausible, attributable cause.

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2. If any participant vaccinated with the BNT162 candidate (at any dose level) develops a
Grade 4 local reaction or systemic event after vaccination (see Section 8.2.2) that is
assessed as possibly related by the investigator, or for which there is no alternative,plausible, attributable cause.
3. If any participant vaccinated with the BNT162 candidate (at any dose level) develops afever >40.0°C (>104.0°F) for at least 1 daily measurement after vaccination(see Section 8.2.2.4) that is assessed as possibly related by the investigator, or for which
there is no alternative, plausible, attributable cause.
4. If any 2 participants vaccinated with the BNT162 candidate (at any dose level) report thesame or similar severe (Grade 3) AE (including laboratory abnormalities) after
vaccination, assessed as possibly related by the investigator, or for which there is noalternative, plausible, attributable cause.
5. If any participant dies or requires ICU admission due to SARS-CoV-2 infection; if thisstopping rule is met, all available clinical and preclinical safety and immunogenicity data
should be reviewed to evaluate for enhanced COVID-19.
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19 and Phase 2/3
Stopping Rule
Participants in all phases of the study will be surveilled for potential COVID-19 illness from
Visit 1 onwards (see Section 8.13).
As this is a sponsor open-label study during Phase 1, the sponsor will conduct unblinded
reviews of the data during the course of the study, including for the purpose of safetyassessment. All NAAT-confirmed cases in Phase 1 will be reviewed contemporaneously by
the IRC and the DMC (see Section 9.6).
In Phase 2/3, the unblinded team supporting the DMC, including an unblinded medical
monitor, will review cases of severe COVID-19 as they are received and will review AEs atleast weekly for additional potential cases of severe COVID-19. At any point, the unblinded
team may discuss with the DMC chair whether the DMC should review cases for an adverse
imbalance of cases of COVID-19 and/or severe COVID-19 between the vaccine and placebogroups.
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The purpose of these reviews will be to identify whether any features of each case appear
unusual, in particular greater in severity, compared to available information at the time ofreview. Indicators of severity may include accelerated deterioration, need for hospitalization,need for ventilation, or death. Observed rates of these indicators will be compared with what
could be expected in a similar population to the study participants based upon available
information at the time of review.
Stopping and alert rules will be applied as follows. The stopping rule will be triggered whenthe 1-sided probability of observing the same or a more extreme case split is 5% or less when
the true incidence of severe disease is the same for vaccine and placebo participants, and alert
criteria are triggered when this probability is less than 11%. In addition, when the total
number of severe cases is low (15 or less), the unblinded team supporting the DMC will
implement the alert rule when a reverse case split of 2:1 or worse is observed. For example,
at 3 cases 2:1, at 4 cases 3:1, etc. Below 15 cases, this rule is more rigorous than requiring
the probability of an observed adverse split or worse be <11%. Further details can be foundin Section 10.7.

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8.2.5. Randomization and Vaccination After a Stopping Rule Is Met
Once the IRC (if in Phase 1) and DMC (all phases) have reviewed the safety data andprovided guidance, a notification will be sent from the sponsor to the sites with guidance on
how to proceed.
8.2.6. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA,
immediately before the administration of each vaccine dose. A negative pregnancy test result
will be required prior to the participant’s receiving the study intervention. Pregnancy tests
may also be repeated if requested by IRBs/ECs or if required by local regulations. In thecase of a positive confirmed pregnancy, the participant will be withdrawn fromadministration of study intervention but may remain in the study.

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8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or
the participant's parent(s)/legal guardian).
The investigator and any qualified designees are responsible for detecting, documenting, andrecording events that meet the definition of an AE or SAE and remain responsible to pursue
and obtain adequate information both to determine the outcome and to assess whether the
event meets the criteria for classification as an SAE or caused the participant to discontinue
the study intervention (see Section 7.1).
Each participant/parent(s)/legal guardian will be questioned about the occurrence of AEs in anonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up
information in an expedited fashion.

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8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection
period”) for each participant begins from the time the participant/parent(s)/legal guardian
provides informed consent, which is obtained before the participant’s participation in the
study (ie, before undergoing any study-related procedure and/or receiving study
intervention), through and including Visit 7 for Phase 1 participants, and Visit 3 for Phase
2/3 participants. In addition, any AEs occurring up to 48 hours after each subsequent blooddraw must be recorded on the CRF.
SAEs will be collected from the time the participant/parent(s)/legal guardian provides
informed consent to approximately 6 months after the last dose of study intervention (Visit 8
for Phase 1 participants, and Visit 4 for Phase 2/3 participants).
Follow-up by the investigator continues throughout and after the active collection period anduntil the AE or SAE or its sequelae resolve or stabilize at a level acceptable to theinvestigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervention
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE
reported using the Vaccines SAE Report Form.

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Investigators are not obligated to actively seek AEs or SAEs after the participant has
concluded study participation. However, if the investigator learns of any SAE, including adeath, at any time after a participant has completed the study, and he/she considers the event
to be reasonably related to the study intervention, the investigator must promptly report the
SAE to Pfizer using the Vaccines SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in
Section 8.3.1 are reported to Pfizer Safety on the Vaccines SAE Report Form immediately
upon awareness and under no circumstance should this exceed 24 hours, as indicated inAppendix 3. The investigator will submit any updated SAE data to the sponsor within
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF

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All nonserious AEs and SAEs occurring in a participant during the active collection period,
which begins after obtaining informed consent as described in Section 8.3.1, will be recordedon the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and theprocedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended andnonleading verbal questioning of the participant is the preferred method to inquire about
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow eachparticipant at subsequent visits/contacts. For each event, the investigator must pursue andobtain adequate information until resolution, stabilization, the event is otherwise explained,or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail toallow for a complete medical assessment of the case and independent determination of
possible causality. Any information relevant to the event, such as concomitant medications
and illnesses, must be provided. In the case of a participant death, a summary of available
autopsy findings must be submitted as soon as possible to Pfizer Safety.
Further information on follow-up procedures is given in Appendix 3.

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8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal
obligations and ethical responsibilities towards the safety of participants and the safety of astudy intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and otherregulatory agencies about the safety of a study intervention under clinical investigation. The
sponsor will comply with country-specific regulatory requirements relating to safety
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the
study and will notify the IRB/EC, if appropriate according to local requirements.

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8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding andoccupational exposure are reportable to Pfizer Safety within 24 hours of investigatorawareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if:A female participant is found to be pregnant while receiving or after discontinuing
study intervention.



A male participant who is receiving or has discontinued study intervention exposes afemale partner prior to or around the time of conception.



A female is found to be pregnant while being exposed or having been exposed to
study intervention due to environmental exposure. Below are examples ofenvironmental exposure during pregnancy:

A female family member or healthcare provider reports that she is pregnant after
having been exposed to the study intervention by inhalation or skin contact.

A male family member or healthcare provider who has been exposed to the study
intervention by inhalation or skin contact then exposes his female partner prior to
or around the time of conception.

The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s
awareness, irrespective of whether an SAE has occurred. The initial information submitted
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should include the anticipated date of delivery (see below for information related totermination of pregnancy).


If EDP occurs in a participant or a participant’s partner, the investigator must report
this information to Pfizer Safety on the Vaccines SAE Report Form and an EDP
Supplemental Form, regardless of whether an SAE has occurred. Details of thepregnancy will be collected after the start of study intervention and until 6 months
after the last dose of study intervention.



If EDP occurs in the setting of environmental exposure, the investigator must report
information to Pfizer Safety using the Vaccines SAE Report Form and EDP
Supplemental Form. Since the exposure information does not pertain to theparticipant enrolled in the study, the information is not recorded on a CRF; however,a copy of the completed Vaccines SAE Report Form is maintained in the investigatorsite file.

Follow-up is conducted to obtain general information on the pregnancy and its outcome for
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as afollow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural
integrity of the neonate can be assessed at the time of birth. In the event of a termination, thereason(s) for termination should be specified and, if clinically possible, the structural
integrity of the terminated fetus should be assessed by gross visual inspection (unlesspreprocedure test findings are conclusive for a congenital anomaly and the findings arereported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meetsthe criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal
demise, neonatal death, or congenital anomaly), the investigator should follow the procedures
for reporting SAEs. Additional information about pregnancy outcomes that are reported to
Pfizer Safety as SAEs follows:

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as
SAEs when the investigator assesses the infant death as related or possibly related to
exposure to the study intervention.

Additional information regarding the EDP may be requested by the sponsor. Further
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on
preterm infants to identify developmental delays). In the case of paternal exposure, theinvestigator will provide the participant with the Pregnant Partner Release of Information
Form to deliver to his partner. The investigator must document in the source documents thatthe participant was given the Pregnant Partner Release of Information Form to provide to his
partner.
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8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if:A female participant is found to be breastfeeding while receiving or after
discontinuing study intervention.



A female is found to be breastfeeding while being exposed or having been exposed to
study intervention (ie, environmental exposure). An example of environmental
exposure during breastfeeding is a female family member or healthcare provider who
reports that she is breastfeeding after having been exposed to the study intervention
by inhalation or skin contact.

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hoursof the investigator’s awareness, irrespective of whether an SAE has occurred. The
information must be reported using the Vaccines SAE Report Form. When exposure during
breastfeeding occurs in the setting of environmental exposure, the exposure information does
not pertain to the participant enrolled in the study, so the information is not recorded on a
CRF. However, a copy of the completed Vaccines SAE Report Form is maintained in theinvestigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specificallyapproved for use in breastfeeding women (eg, vitamins) is administered in accord withauthorized use. However, if the infant experiences an SAE associated with such a drug, theSAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with thestudy intervention, which may or may not lead to the occurrence of an AE. Such persons
may include healthcare providers, family members, and other roles that are involved in thetrial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of theinvestigator’s awareness, regardless of whether there is an associated SAE. The informationmust be reported using the Vaccines SAE Report Form. Since the information does not
pertain to a participant enrolled in the study, the information is not recorded on a CRF;
however, a copy of the completed Vaccines SAE Report Form is maintained in theinvestigator site file.
8.3.6. Cardiovascular and Death Events
Not applicable.

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8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs
or SAEs
Potential COVID-19 illnesses and their sequelae that are consistent with the clinical endpoint
definition should not be recorded as AEs. These data will be captured as efficacy assessment
data only on the relevant pages of the CRF, as these are expected endpoints.
Potential COVID-19 illnesses and their sequelae will not be reported according to thestandard process for expedited reporting of SAEs, even though the event may meet thedefinition of an SAE. These events will be recorded on the COVID-19 illness pages in theparticipant’s CRF within 1 day.
NOTE: However, if either of the following conditions applies, then the event must berecorded and reported as an SAE (instead of a disease-related event):
The event is, in the investigator’s opinion, of greater intensity, frequency, or duration than
expected for the individual participant.

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The investigator considers that there is a reasonable possibility that the event was related to
study intervention.
Potential COVID-19 illness events and their sequelae will be reviewed by a group of internal
blinded case reviewers. Any SAE that is determined by the internal case reviewers NOT tomeet endpoint criteria is reported back to the investigator site of incidence. The investigatormust report the SAE to Pfizer Safety within 24 hours of being made aware that the SAE did
not meet endpoint criteria. The investigator’s SAE awareness date is the date on which theinvestigator site of incidence receives the SAE back from the internal case reviewers.
8.3.8. Adverse Events of Special Interest
Not applicable.
8.3.8.1. Lack of Efficacy
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.
8.3.9. Medical Device Deficiencies
Not applicable.
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as
medication errors.
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Safety Event

Recorded on the CRF

Reported on the Vaccines SAE Report
Form to Pfizer Safety Within 24 Hours
of Awareness

Medication errors

All (regardless of whether
associated with an AE)

Only if associated with an SAE

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Medication errors include:Medication errors involving participant exposure to the study intervention;Potential medication errors or uses outside of what is foreseen in the protocol that do
or do not involve the study participant;The administration of expired study intervention;

The administration of an incorrect study intervention;

The administration of an incorrect dosage;The administration of study intervention that has undergone temperature excursion
from the specified storage range, unless it is determined by the sponsor that the study
intervention under question is acceptable for use.

Such medication errors occurring to a study participant are to be captured on the medication
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by theinvestigator, the medication error is recorded on the medication error page of the CRF and, if
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a Vaccines SAE
Report Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of study intervention greater than 1 dose of study intervention within
a 24-hour time period will be considered an overdose.
Pfizer does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
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1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs.
3. Document the quantity of the excess dose as well as the duration of the overdose in the
CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.

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8.7. Genetics
Genetics (specified analyses) are not evaluated in this study.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.9. Immunogenicity Assessments
Immunogenicity assessments are described in Section 8.1.
8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are notevaluated in this study.
8.11. Study Procedures
8.11.1. Phase 1
8.11.1.1. Screening: (0 to 28 Days Before Visit 1)
Before enrollment and before any study-related procedures are performed, voluntary, written
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.
It is anticipated that the procedures below will be conducted in a stepwise manner; however,the visit can occur over more than 1 day.
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Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance.

Obtain details of any medications currently taken.

Perform physical examination including vital signs (weight, height, body temperature,pulse rate, and seated blood pressure), evaluating any clinically significant
abnormalities within the following body systems: general appearance; skin; head,eyes, ears, nose, and throat; heart; lungs; abdomen; musculoskeletal; extremities;
neurological; and lymph nodes.

Collect a blood sample (approximately 20 mL) for potential future serologicalassessment and to perform a rapid test for prior COVID-19 infection.

Collect a blood sample (approximately 10 mL) for hematology and chemistrylaboratory tests as described in Section 10.2.

Collect a blood sample (approximately 10 mL) for HIV, HBsAg, HBc Ab, and HCV
Ab tests.



Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion
criteria are met.



Record AEs as described in Section 8.3. AEs that occur prior to dosing should be
noted on the Medical History CRF.



Ask the participant to contact the site staff or investigator immediately if any
significant illness or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.
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Complete the CRF.

8.11.1.2. Visit 1 – Vaccination 1: (Day 1)

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It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Review screening laboratory results (hematology and chemistry, and HIV, HBsAg,
HBc Ab, and HCV Ab tests).

Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested(if possible at the site, otherwise at the central laboratory) within 24 hours andvaccination will proceed only if it is NAAT-negative for SARS-CoV-2 genomes.
The second will be sent to the central laboratory for potential later testing.

Ensure and document that all of the inclusion criteria and none of the exclusion
criteria are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Obtain the participant’s randomization number and study intervention allocation
using the IRT system. Only an unblinded site staff member may obtain thisinformation.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention
into the deltoid muscle of the preferably nondominant arm. Please refer to the IP
manual for further instruction on this process.

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The first 5 participants vaccinated in each group must be observed by blinded site
staff for any acute reactions for at least 4 hours after vaccination. For participants
enrolled thereafter, blinded site staff must observe the participant for at least 30
minutes after study intervention administration for any acute reactions. Record any
acute reactions (including time of onset) in the participant’s source documents and on
the AE page of the CRF, and on an SAE form as applicable.

Issue a measuring device to measure local reactions at the injection site and athermometer for recording daily temperatures and provide instructions on their use.



Explain the e-diary technologies available for this study (see Section 8.14), and assist
the participant in downloading the study application onto the participant’s own device
or issue a provisioned device if required. Provide instructions on e-diary completion
and ask the participant to complete the reactogenicity e-diary from Day 1 to Day 7,
with Day 1 being the day of vaccination and, if utilized, the COVID-19 illness e-diary(to be completed if the participant is diagnosed with COVID-19 or has possible new
or increased symptoms, and when he/she receives a reminder, at least weekly).



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1
is the day of vaccination) to determine if an unscheduled reactogenicity visit isrequired:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.

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The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the reactogenicity ediary data online following vaccination to evaluate participant compliance and as partof the ongoing safety review. Daily review is optimal during the active diary period.

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8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1 to 3 Days After Visit 1)

Record AEs as described in Section 8.3.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistrylaboratory tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1
is the day of vaccination) to determine if an unscheduled reactogenicity visit isrequired:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.

Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.

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

Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the reactogenicity ediary data online following vaccination to evaluate participant compliance and as partof the ongoing safety review. Daily review is optimal during the active diary period.

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8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to 8 Days After Visit 1)

Record AEs as described in Section 8.3.



Review hematology and chemistry laboratory results and record any AEs inaccordance with Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistrylaboratory tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1
is the day of vaccination) to determine if an unscheduled reactogenicity visit isrequired:

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Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the reactogenicity ediary data online following vaccination to evaluate participant compliance and as partof the ongoing safety review. Daily review is optimal during the active diary period.

8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary
was completed and record stop dates in the CRF if required.



Review hematology and chemistry laboratory results and record any AEs inaccordance with Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within the
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following body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.


Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested (ifpossible at the site, otherwise at the central laboratory) within 24 hours andvaccination will only proceed if it is NAAT-negative for SARS-CoV-2 genomes.
The second will be sent to the central laboratory for potential later testing.

Ensure and document that all of the inclusion criteria and none of the exclusion
criteria are met. If not, the participant should not receive further study intervention
but will remain in the study to be evaluated for safety, immunogenicity, and efficacy(see Section 7.1).

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Collect a blood sample (approximately 10 mL) for hematology and chemistrylaboratory tests as described in Section 10.2.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention
into the deltoid muscle of the preferably nondominant arm. Please refer to the IP
manual for further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of
the CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the
injection site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and ask the participant to complete thereactogenicity e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination.
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Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1
is the day of vaccination) to determine if an unscheduled reactogenicity visit isrequired:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the reactogenicity ediary data online following vaccination to evaluate participant compliance and as partof the ongoing safety review. Daily review is optimal during the active diary period.

8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to 8 Days After Visit 4)

Record AEs as described in Section 8.3.



Review hematology and chemistry laboratory results and record any AEs inaccordance with Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.
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

Collect a blood sample (approximately 10 mL) for hematology and chemistrylaboratory tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



If the participant (select participants only, details will be provided by the sponsor)
consents, collect an additional 170 mL blood sample for exploratory COVID-19
research.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1
is the day of vaccination) to determine if an unscheduled reactogenicity visit isrequired:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to 16 Days After Visit 4)

Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary
was completed and record stop dates in the CRF if required.



Review hematology and chemistry laboratory results and record any AEs inaccordance with Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



If not collected at Visit 5, and the participant (select participants only, details will be
provided by the sponsor) consents, collect an additional 170-mL blood sample for
exploratory COVID-19 research.



Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately (this could be
via the COVID-19 illness e-diary) if he or she experiences any respiratory symptoms
as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.
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8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After Visit 4)

Record AEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



If not collected at Visit 5 or 6, and the participant (select participants only, details will
be provided by the sponsor) consents, collect an additional 170-mL blood sample for
exploratory COVID-19 research.



Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (175 to 189 Days After Visit 4)

Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Collect a blood sample (approximately 20 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended
event (eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.
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Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.1.10. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 4)Collect a blood sample (approximately 20 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.1.11. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 4)Collect a blood sample (approximately 20 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Collect the participant’s e-diary or assist the participant to remove the study
application from his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.2. Phase 2/3
8.11.2.1. Visit 1 – Vaccination 1: (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written,
study-specific informed consent will be obtained from the participant or his/herparent(s)/legal guardian, as appropriate. Each signature on the ICD must be personally dated
by the signatory. The investigator or his or her designee will also sign the ICD. A copy ofthe signed and dated ICD must be given to the participant/participant’s parent(s)/legal
guardian. The source data must reflect that the informed consent was obtained before
participation in the study.

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It is anticipated that the procedures below will be conducted in a stepwise manner. The visit
may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion andexclusion criteria onwards must be conducted on the same day.
Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance. For participants who are HIVpositive, record HIV viral load and CD4 count results from the most recent test
performed in the previous 6 months.



Perform a clinical assessment. If the clinical assessment indicates that a physicalexamination is necessary to comprehensively evaluate the participant, perform aphysical examination and record any findings in the source documents and, if
clinically significant, record on the medical history CRF.

Measure the participant’s height and weight.

Measure the participant’s body temperature.

Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion
criteria are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

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

Record AEs as described in Section 8.3.

Collect a blood sample (approximately 20 mL for participants ≥16 years of age andapproximately 10 mL for participants in the 12- to 15-year age stratum) for
immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Obtain the participant’s randomization number and study intervention allocation
number using the IRT system. Only an unblinded site staff member may obtain thisinformation.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention
into the deltoid muscle of the preferably nondominant arm. Please refer to the IP
manual for further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of
the CRF, and on an SAE form as applicable.

For participants in the reactogenicity subset, issue a measuring device to measure
local reactions at the injection site and a thermometer for recording daily
temperatures and provide instructions on their use.

For participants not in the reactogenicity subset, issue a thermometer to monitor for
fever (for COVID-19 surveillance) and provide instructions on its use.



Explain the e-diary technologies available for this study (see Section 8.14), and assist
the participant or his/her parent(s)/legal guardian, as appropriate, in downloading thestudy application onto the participant’s own device or issue a provisioned device if
required.

For participants in the reactogenicity subset, provide instructions onreactogenicity e-diary completion and ask the participant or his/her parent(s)/legal
guardian, as appropriate, to complete the reactogenicity e-diary from Day 1 to
Day 7, with Day 1 being the day of vaccination.

For all participants, provide instructions on COVID-19 illness e-diary completion
and ask the participant or his/her parent(s)/legal guardian, as appropriate, tocomplete the COVID-19 illness e-diary if the participant is diagnosed with
COVID-19 or has possible new or increased symptoms, and when he/she receivesa reminder, at least weekly. See Section 8.14 for further details.

If the participant is part of the reactogenicity subset, ask the participant or his/herparent(s)/legal guardian, as appropriate, to contact the site staff or investigator
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immediately if the participant experiences any of the following from Day 1 to Day 7
after vaccination (where Day 1 is the day of vaccination) to determine if anunscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator if a medically attended event (eg, doctor’s visit, emergency
room visit) or hospitalization occurs.



Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator (this could be via the COVID-19 illness e-diary) immediately
if he or she experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant or his/her parent(s)/legal guardian, as appropriate, to bring thee-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.

If the participant is part of the reactogenicity subset, the investigator or appropriately
qualified designee reviews the reactogenicity e-diary data online following vaccination toevaluate participant compliance and as part of the ongoing safety review. Daily review is
optimal during the active diary period.
8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days After Visit 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



If the participant is part of the reactogenicity subset, review the participant’s
reactogenicity e-diary data. Collect stop dates of any reactogenicity e-diary events
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ongoing on the last day that the reactogenicity e-diary was completed and record stop
dates in the CRF if required.


Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Ensure and document that all of the inclusion criteria and none of the exclusion
criteria are met. If not, the participant may not receive further study intervention but
will remain in the study to be evaluated for safety, immunogenicity, and efficacy(see Section 7.1).

Measure the participant’s body temperature.

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention
into the deltoid muscle of the preferably nondominant arm. Please refer to the IP
manual for further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of
the CRF, and on an SAE form as applicable.

Ensure the participant or his/her parent(s)/legal guardian, as appropriate, has ameasuring device to measure local reactions at the injection site and a thermometerfor recording daily temperatures.

Ensure the participant or his/her parent(s)/legal guardian, as appropriate, remains
comfortable with the chosen e-diary platform, confirm instructions on e-diarycompletion, and, if the participant is part of the reactogenicity subset, ask theparticipant or his/her parent(s)/legal guardian, as appropriate, to complete thereactogenicity e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination.



If the participant is part of the reactogenicity subset, ask the participant or his/herparent(s)/legal guardian, as appropriate, to contact the site staff or investigator
immediately if the participant experiences any of the following from Day 1 to Day 7
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after vaccination (where Day 1 is the day of vaccination) to determine if anunscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator if a medically attended event (eg, doctor’s visit, emergency
room visit) or hospitalization occurs.



Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator (this could be via the COVID-19 illness e-diary) immediately
if the participant experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant or his/her parent(s)/legal guardian, as appropriate, to bring thee-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.

If the participant is part of the reactogenicity subset, the investigator or appropriately
qualified designee reviews the reactogenicity e-diary data online following vaccination toevaluate participant compliance and as part of the ongoing safety review. Daily review is
optimal during the active diary period.
8.11.2.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2): (28 to 35 Days After
Visit 2)


Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. If the participant is part of thereactogenicity subset, review the participant’s reactogenicity e-diary data. Collectstop dates of any reactogenicity e-diary events ongoing on the last day that thereactogenicity e-diary was completed and record stop dates in the CRF if required.



Record nonstudy vaccinations as described in Section 6.5.
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

Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count resultsfrom the most recent test performed since Visit 1 (if any).

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 20 mL for participants ≥16 years of age, andapproximately 10 mL for participants in the 12- to 15-year age stratum) for
immunogenicity testing.



Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator if a medically attended event (eg, doctor’s visit, emergency
room visit) or hospitalization occurs.



Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator (this could be via the COVID-19 illness e-diary) immediately
if the participant experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.11.2.4. Visit 4 – 6-Month Follow-up Visit: (175 to 189 Days After Visit 2)

Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.

For participants who are HIV-positive, record HIV viral load and CD4 count resultsfrom the most recent test performed since Visit 3 (if any).

Collect a blood sample (approximately 20 mL for participants ≥16 years of age andapproximately 10 mL for participants in the 12- to 15-year age stratum) for
immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.



Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator (this could be via the COVID-19 illness e-diary) immediately
if the participant experiences any respiratory symptoms as detailed in Section 8.3.

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Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.2.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 2)Collect a blood sample (approximately 20 mL for participants ≥16 years of age andapproximately 10 mL for participants in the 12- to 15-year age stratum) for
immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count resultsfrom the most recent test performed since Visit 4 (if any).



Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact thesite staff or investigator (this could be via the COVID-19 illness e-diary) immediately
if the participant experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.2.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 2)Collect a blood sample (approximately 20 mL for participants ≥16 years of age andapproximately 10 mL for participants in the 12- to 15-year age stratum) for
immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count resultsfrom the most recent test performed since Visit 5 (if any).

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

Collect the participant’s e-diary or assist the participant to remove the study
application from his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction

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If a Grade 3 local reaction (Section 8.2.2.2), systemic event (Section 8.2.2.3), or fever(Section 8.2.2.4) is reported in the reactogenicity e-diary, a telephone contact should occur toascertain further details and determine whether a site visit is clinically indicated. If suspected
Grade 4 local reaction (Section 8.2.2.2), systemic event (Section 8.2.2.3), or fever(Section 8.2.2.4) is reported in the reactogenicity e-diary, a telephone contact or site visit
should occur to confirm whether the event meets the criteria for Grade 4.
A site visit must be scheduled as soon as possible to assess the participant unless any of thefollowing is true:The participant is unable to attend the unscheduled visit.

The local reaction/systemic event is no longer present at the time of the telephone
contact.



The participant or his/her parent(s)/legal guardian, as appropriate, recorded anincorrect value in the reactogenicity e-diary (confirmation of a reactogenicity e-diarydata entry error).



The PI or authorized designee determined it was not needed.

This telephone contact will be recorded in the participant’s source documentation and theCRF.
If the participant is unable to attend the unscheduled visit, or the PI or authorized designee
determined it was not needed, any ongoing local reactions/systemic events must be assessedat the next study visit.
During the unscheduled visit, the reactions should be assessed by the investigator or a
medically qualified member of the study staff such as a study physician or a study nurse, asapplicable to the investigator’s local practice, who will:Measure body temperature (°F/°C).

Measure minimum and maximum diameters of redness (if present).
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

Measure minimum and maximum diameters of swelling (if present).



Assess injection site pain (if present) in accordance with the grades provided in
Section 8.2.2.2.

Assess systemic events (if present) in accordance with the grades provided in
Section 8.2.2.3.

Assess for other findings associated with the reaction and record on the AE page of
the CRF, if appropriate.

The investigator or an authorized designee will complete the unscheduled visit assessment
page of the CRF.

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8.13. COVID-19 Surveillance (All Participants)
If a participant experiences any of the following (irrespective of perceived etiology or
clinical significance), he or she is instructed to contact the site immediately and, if
confirmed, participate in an in-person or telehealth visit as soon as possible, optimally within
3 days of symptom onset (and at the latest 4 days after symptom resolution). Note that if
new symptoms are reported within 4 days after resolution of all previous symptoms, they will
be considered as part of a single illness and a second illness visit is not required.
During the 7 days following each vaccination, potential COVID-19 symptoms that overlap
with solicited systemic events (ie, fever, chills, new or increased muscle pain, diarrhea,
vomiting) should not trigger a potential COVID-19 illness visit unless, in the investigator’sopinion, the clinical picture is more indicative of a possible COVID-19 illness than vaccine
reactogenicity. If, in the investigator’s opinion, the symptoms are considered more likely to
be vaccine reactogenicity, but a participant is required to demonstrate that they are SARSCoV-2–negative, a local SARS-CoV-2 test may be performed: if positive, the symptoms
should be recorded as a potential COVID-19 illness; if not, the symptoms should be recorded
as AEs (unless already captured in the reactogenicity e-diary).
Participants may utilize a COVID-19 illness e-diary through an application (see Section 8.14)
installed on a provisioned device or on the participant’s own personal device to prompt
him/her to report any symptoms. Note that this does not substitute for a participant’s routine
medical care. Therefore, participants should be encouraged to seek care, if appropriate, fromtheir usual provider.


A diagnosis of COVID-19;



Fever;

New or increased cough;

New or increased shortness of breath;
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Chills;

New or increased muscle pain;New loss of taste/smell;

Sore throat;

Diarrhea;Vomiting.

8.13.1. Potential COVID-19 Illness Visit: (Optimally Within 3 Days After Potential
COVID-19 Illness Onset)

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)This visit may be conducted as an in-person or telehealth visit; a telehealth visit involves thesharing of healthcare information and services via telecommunication technologies (eg,audio, video, video-conferencing software) remotely, thus allowing the participant andinvestigator to communicate on aspects of clinical care.
As a participant’s COVID-19 illness may evolve over time, several contacts may be required
to obtain the following information:


Record AEs, as appropriate as described in Section 8.3. Note: Potential COVID-19
illnesses that are consistent with the clinical endpoint definition should not berecorded as AEs. These data will be captured as efficacy assessment data only on therelevant pages of the CRF, as these are expected endpoints.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.



If the visit is conducted in person, obtain a nasal (midturbinate) swab (collected bysite staff). Alternatively, if conducted by telehealth, instruct the participant to selfcollect a nasal (midturbinate) swab and ship for assessment at the central laboratory.

Collect COVID-19–related standard-of-care clinical and laboratory information. This
includes, but is not limited to:Symptoms and signs, includingClinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per
minute, HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or
PaO2/FiO2 <300 mm Hg)



Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiringvasopressors)
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Significant acute renal, hepatic, or neurologic dysfunction

Respiratory failure (defined as needing high-flow oxygen, noninvasive
ventilation, mechanical ventilation, or ECMO)

Clinical diagnosis

Local laboratory SARS-CoV-2 test result(s). Note that if it is routine practice toperform a repeat local SARS-CoV-2 test for any reason, then a repeat nasal(midturbinate) swab should also be obtained and shipped for assessment at thecentral laboratory.



Full blood count

Blood chemistry, specifically creatinine, urea, liver function tests, and C-reactive
protein

Imaging results (eg, CT or MRI scan) to document neurologic dysfunction

Number and type of any healthcare contact; duration of hospitalization and ICU
stay



Death



Schedule an appointment for the participant to return for the potential COVID-19
convalescent visit once he or she has recovered.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After Potential
COVID-19 Illness Visit)

Record AEs, as appropriate as described in Section 8.3. Note: Potential COVID-19
illnesses that are consistent with the clinical endpoint definition should not berecorded as AEs. These data will be captured as efficacy assessment data only on therelevant pages of the CRF, as these are expected endpoints.



Record details of any of the prohibited medications specified in Section 6.5.1
received by the participant if required for his or her clinical care.

Collect a blood sample (approximately 20 mL for participants ≥16 years of age andapproximately 10 mL for participants in the 12- to 15-year age stratum) for
immunogenicity testing.

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

Collect/update COVID-19–related clinical and laboratory information (detailed in
Section 8.13.1).

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.14. Communication and Use of Technology
In a study of this nature that requires illness events to be reported outside of scheduled study
visits, it is vital that communication between the study site and the participant or his/herparent(s)/legal guardian, as appropriate, is maintained to ensure that endpoint events are notmissed. This study will employ various methods, tailored to the individual participant, toensure that communication is maintained and study information can be transmitted securely.
Using appropriate technology, such as a study application, a communication pathway
between the participant or his/her parent(s)/legal guardian, as appropriate, and the study site
staff will be established. The participant or his/her parent(s)/legal guardian, as appropriate,
may be able to utilize his or her own devices to access this technology, or use a device
provided by the sponsor. Traditional methods of telephone communication will also be
available. The technology solution may facilitate the following:Contact with the investigator, including the ability of the participant or his/herparent(s)/legal guardian, as appropriate, to report whether or not the participant has
experienced symptoms that could represent a potential COVID-19 illness (COVID-19
illness e-diary; see Section 8.13).

An alert in the event that the participant is hospitalized.



Visit reminders.



Messages of thanks and encouragement from the study team.



A platform for recording local reactions and systemic events (reactogenicity e-diary)– see Section 8.2.2.

If a participant or his/her parent(s)/legal guardian, as appropriate, is not actively completing
either the reactogenicity or COVID-19 illness e-diary, the investigator or designee is required
to contact the participant or his/her parent(s)/legal guardian, as appropriate, to ascertain why
and also to obtain details of any missed events.

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8.15. SARS-CoV-2 NAAT Results From Visits 1 and 2 and Potential COVID-19 Illness
VisitsNasal (midturbinate) swabs for SARS-CoV-2 NAAT are obtained at:Visits 1 and 2: To determine whether a participant will be included in efficacy analysesof those with no serological or virological evidence (up to 7 days after receipt of thesecond dose) of past SARS-CoV-2 infection.

Potential COVID-19 illness visits: To determine whether symptoms experienced by theparticipant fulfill the COVID-19 case definition.

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Research laboratory–generated positive results from the Visit 1 and Visit 2 swabs, and all
results from the illness visit swabs, will be provided to the site once available, but this will
not be in real time and cannot be relied upon to direct clinical care. Therefore, the participant
should be directed to seek additional testing through his/her primary healthcare providers at alicensed clinical laboratory when exhibiting potential COVID-19 symptoms or otherwise
receiving a positive result and counseled on whether to take any precautionary measurespending confirmatory testing.
Participants who have a positive SARS-CoV-2 NAAT result prior to Visit 2 should be
handled as follows:Positive SARS-CoV-2 test with no symptoms, either at Visit 1 or any time between Visit
1 and Visit 2: A positive test in an asymptomatic participant does not meet exclusion
criterion 5; therefore, Vaccination 2 should proceed as normal.

Confirmed COVID-19 (ie, symptoms and positive SARS-CoV-2 test): This meets
exclusion criterion 5; therefore, Vaccination 2 should not be given but the participant
should remain in the study.

9. STATISTICAL CONSIDERATIONS
Methodology for summary and statistical analyses of the data collected in this study is
described here and further detailed in a statistical analysis plan (SAP), which will bemaintained by the sponsor. The SAP may modify what is outlined in the protocol whereappropriate; however, any major modifications of the primary endpoint definitions or theiranalyses will also be reflected in a protocol amendment.
9.1. Estimands and Statistical Hypotheses
9.1.1. Estimands
The estimand corresponding to each primary, secondary, and tertiary/exploratory objective is
described in the table in Section 3.

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In the primary safety objective evaluations, missing reactogenicity e-diary data will not be
imputed. Missing AE dates will be imputed according to Pfizer safety rules. No othermissing information will be imputed in the safety analysis.
The estimands to evaluate the immunogenicity objectives are based on evaluable populations
for immunogenicity (Section 9.3). These estimands estimate the vaccine effect in the
hypothetical setting where participants follow the study schedules and protocol requirements
as directed. Missing antibody results will not be imputed. Immunogenicity results that are
below the LLOQ will be set to 0.5 × LLOQ in the analysis; this may be adjusted once
additional data on the assay characteristics become available.
The estimands to evaluate the efficacy objectives are based on evaluable populations for
efficacy (Section 9.3). These estimands estimate the vaccine effect in the hypotheticalsetting where participants follow the study schedules and protocol requirements as directed.
In addition, VE will be analyzed by all--available efficacy population. Missing laboratory
results will not be imputed for the primary analysis, but missing data imputation for theefficacy endpoint may be performed as a sensitivity analysis.

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9.1.2. Statistical Hypotheses
9.1.2.1. Statistical Hypothesis Evaluation for Efficacy
Phase 2/3 of the study has 2 primary efficacy endpoints evaluating VE, which is defined as
VE = 100 × (1 – IRR). IRR is calculated as the ratio of first confirmed COVID-19 illness ratein the vaccine group to the corresponding illness rate in the placebo group. In Phase 2/3, theassessment of VE will be based on posterior probabilities of VE1 > 30% and VE2 > 30%.
VE1 represents VE for prophylactic BNT162b2 against confirmed COVID-19 in participants
without evidence of infection before vaccination, and VE2 represents VE for prophylactic
BNT162b2 against confirmed COVID-19 in all participants after vaccination.
For participants with multiple confirmed cases, only the first case will contribute to the VE
calculation for each hypothesis. VE1 and VE2 will be evaluated sequentially to control theoverall type I error to the desired level of 2.5%. VE is demonstrated if there is sufficientevidence (posterior probability) that either VE1 >30% or both VE1 and VE2 are >30%. The
assessment for the primary analysis will be based on posterior probability using a Bayesianmodel.
9.1.2.2. Statistical Hypothesis Evaluation for Immunogenicity
One of the secondary objectives in the Phase 3 part of the study is to evaluate noninferiorityof the immune response to prophylactic BNT162b2 in participants 12 to 15 years of age
compared to the response in participants 16 to 25 years of age at 1 month after Dose 2. The(Dose 2) evaluable immunogenicity population will be used for the following hypothesis
testing:
H0: ln(µ2) – ln(µ1) ≤ ln(0.67)

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where ln (0.67) corresponds to a 1.5-fold margin for noninferiority, ln(µ2) and ln(µ1) are thenatural log of the geometric mean of SARS-CoV-2 neutralizing titers from BNT162b2
recipients 12 to 15 years of age and 16 to 25 years of age, respectively, measured 1 monthafter Dose 2. If the lower limit of the 95% CI for the GMR (12-15 years of age to 16-25
years of age) is >0.67, the noninferiority objective is met.
9.2. Sample Size Determination

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)The study sample size for Phase 1 of the study is not based on any statistical hypothesis
testing. Phase 1 comprises 15 participants (randomization ratio of 4:1 so that 12 receive
active vaccine and 3 receive placebo) per group; 13 vaccine groups are studied,corresponding to a total of 195 participants.
For Phase 2/3, with assumptions of a true VE of 60% after the second dose of investigational
product, a total of approximately 164 first confirmed COVID-19 illness cases will provide
90% power to conclude true VE >30% with high probability, allowing early stopping for
efficacy at the IA. This would be achieved with 17,600 evaluable participants per group or
21,999 vaccine recipients randomized in a 1:1 ratio with placebo, for a total sample size of
43,998, based on the assumption of a 1.3% illness rate per year in the placebo group, accrualof 164 primary-endpoint cases within 6 months, and 20% of the participants being
nonevaluable or having serological evidence of prior infection with SARS-CoV-2,
potentially making them immune to further infection. Dependent upon the evolution of thepandemic, it is possible that the COVID-19 attack rate may be much higher, in which caseaccrual would be expected to be more rapid, enabling the study’s primary endpoint to beevaluated much sooner. The total number of participants enrolled in Phase 2/3 may varydepending on the incidence of COVID-19 at the time of the enrollment, the true underlying
VE, and a potential early stop for efficacy or futility.
In Phase 3, approximately 2000 participants are anticipated to be 12 to 15 years of age. A
random sample of 250 participants will be selected for each of the 2 age groups (12 to 15
years and 16 to 25 years) as an immunogenicity subset for the noninferiority assessment.
With the standard deviation and observed GMT difference assumed in the power analysis
below, a sample size of 200 evaluable participants (or 250 vaccine recipients) per age groupwill provide a power of 90.8% to declare the noninferiority of adolescents to 16- to
25-year-olds in terms of neutralizing antibody GMR, 1 month after the second dose(see Table 4).

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Table 4.

Power Analysis for Noninferiority Assessment

Criteria

Standard
Deviation(Log Value)a

AssumedObserved GMT
Difference (Log
Scale)-0.2

Powerb

Number of
Evaluable
Participants per
Age Group
200

Lower limit of 95%
0.623
90.8%
CI for GMR(12-15/16-25)>0.67
Abbreviation: GMR = geometric mean ratio.
a. Reference: 1 month after Dose 2, BNT162b2 (30 µg), 18- to 55-year age group (C4591001 Phase 1,
N=12). Calculation may be updated if additional information becomes available to better estimate thestandard deviation.
b. At 0.05 alpha level (2-sided).

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For safety outcomes, Table 5 shows the probability of observing at least 1 AE for a given
true event rate of a particular AE, for various sample sizes. For example, if the true AE rate
is 10%, with 12 participants in a vaccine group, there is 72% probability of observing at least
1 AE.
Table 5.

Probability of Observing at Least 1 AE by Assumed True Event Rates
With Different Sample Sizes

N=12
N=45
Assumed
True Event
Rate of an
AE
0.01%
0.00
0.00
0.02%
0.00
0.01
0.04%
0.00
0.02
0.06%
0.01
0.03
0.08%
0.01
0.04
0.10%
0.01
0.04
0.15%
0.02
0.07
0.20%
0.02
0.09
0.25%
0.03
0.11
0.30%
0.04
0.13
0.35%
0.04
0.15
0.50%
0.06
0.20
1.00%
0.11
0.36
2.00%
0.22
0.60
3.00%
0.31
0.75
5.00%
0.46
0.90
7.00%
0.58
0.96
10.00%
0.72
0.99
Note: N = number in sample.

N=180

N=1000N=3000N=6000N=9000N=15000

0.02
0.04
0.07
0.10
0.13
0.16
0.24
0.30
0.36
0.42
0.47
0.59
0.84
0.97
>0.99
>0.99
>0.99
>0.99

0.10
0.18
0.33
0.45
0.55
0.63
0.78
0.86
0.92
0.95
0.97
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

0.26
0.45
0.70
0.83
0.91
0.95
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

0.45
0.70
0.91
0.97
0.99
0.99
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

0.59
0.83
0.97
0.99
0.99
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

0.78
0.95
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

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9.3. Analysis Sets
For purposes of analysis, the following populations are defined:
Population
Enrolled
Randomized
Dose 1 evaluable
immunogenicity

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Dose 2 evaluable
immunogenicity

Dose 1 all-available
immunogenicity
Dose 2 all-available
immunogenicity
Evaluable efficacy

All-available efficacy

SafetyDescription
All participants who have a signed ICD.
All participants who are assigned a randomization number in
the IWR system.
For Phase 1 only, all eligible randomized participants who
receive the vaccine to which they are randomly assigned at thefirst dose, have at least 1 valid and determinate
immunogenicity result after Dose 1, have blood collection
within an appropriate window after Dose 1, and have no otherimportant protocol deviations as determined by the clinician.
All eligible randomized participants who receive 2 doses ofthe vaccine to which they are randomly assigned, within thepredefined window, have at least 1 valid and determinate
immunogenicity result after Dose 2, have blood collection
within an appropriate window after Dose 2, and have no otherimportant protocol deviations as determined by the clinician.
For Phase 1 only: all randomized participants who receive atleast 1 dose of the study intervention with at least 1 valid anddeterminate immunogenicity result after Dose 1 but before
Dose 2.
All randomized participants who receive at least 1 dose of thestudy intervention with at least 1 valid and determinate
immunogenicity result after Dose 2.
All eligible randomized participants who receive all
vaccination(s) as randomized within the predefined windowand have no other important protocol deviations as determinedby the clinician.
1. All randomized participants who receive at least
1 vaccination.
2. All randomized participants who complete 2 vaccination
doses.
All randomized participants who receive at least 1 dose of thestudy intervention.

9.4. Statistical Analyses
The SAP will be developed and finalized before database lock for any of the planned
analyses in Section 9.5.1. It will describe the participant populations to be included in theanalyses and the procedures for accounting for missing, unused, and spurious data. Thissection provides a summary of the planned statistical analyses of the primary, secondary, andtertiary/exploratory endpoints.
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9.4.1. Immunogenicity Analyses
Immunogenicity samples will be drawn for all participants. Immunogenicity analyses will bebased upon results from appropriately sized subsets of samples, according to the purpose.
The statistical analysis of immunogenicity results will be primarily based on the evaluable
immunogenicity populations as defined in Section 9.3.
An additional analysis will be performed based on the all-available populations if there is alarge enough difference in sample size between the all-available immunogenicity populationand the evaluable immunogenicity population. Participants will be summarized according to
the vaccine group to which they were randomized.

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Endpoint
Secondaryimmunogenicity

Statistical Analysis Methods
Geometric mean titers/concentrations (GMTs/GMCs) of
SARS-CoV-2 neutralizing titers, S1-binding IgG level, andRBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, GMTs/GMCs and 2-sided 95% CIs will be
provided for each investigational product within each group before
vaccination and at each of the following time points:Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1, 6, 12
and 24 months after Dose 2

Geometric means will be calculated as the mean of the assay results
after making the logarithm transformation and then exponentiating themean to express results on the original scale. Two-sided 95% CIs will
be obtained by taking natural log transforms of concentrations/titers,
calculating the 95% CI with reference to the t-distribution, and thenexponentiating the confidence limits.
GMFRs of SARS-CoV-2 neutralizing titers, S1-binding IgG level,
and RBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, the GMFRs and 2-sided 95% CIs will be
provided for each investigational product within each group at each of
the following time points:Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1, 6, 12,
and 24 months after Dose 2

GMFRs will be limited to participants with nonmissing values prior to
the first dose and at the postvaccination time point. The GMFR will becalculated as the mean of the difference of logarithmically transformed
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assay results (later time point – earlier time point) and exponentiating
the mean. The associated 2-sided CIs will be obtained by calculating
CIs using Student’s t-distribution for the mean difference of thelogarithmically transformed assay results and exponentiating theconfidence limits.
Percentage of participants with ≥4-fold rise in SARS-CoV-2
neutralizing titers, S1-binding IgG level, and RBD-binding IgG
level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, percentages (and 2-sided 95% CIs) ofparticipants with ≥4-fold rise will be provided for each investigational
product within each group at each of the following time points:

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Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1, 6, 12,
and 24 months after Dose 2

The Clopper-Pearson method will be used to calculate the CIs.
GMR of SARS-CoV-2 neutralizing titer to S1-binding IgG level
and to RBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, the GMRs and 2-sided 95% CIs will be
provided for each investigational product within each group at each of
the following time points:Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1, 6, 12,
and 24 months after Dose 2

GMRs will be limited to participants with nonmissing values for both
SARS-CoV-2 neutralizing titers and S1-binding IgG level/RBDbinding IgG level at each time point. The GMR will be calculated as
the mean of the difference of logarithmically transformed assay results(eg, SARS-CoV-2 neutralizing titers minus S1-binding IgG level foreach participant) and exponentiating the mean. Two-sided CIs will beobtained by calculating CIs using Student’s t-distribution for the meandifference of the logarithmically transformed assay results andexponentiating the confidence limits.
For all the immunogenicity endpoints, the analysis will be based on the
Dose 1 and Dose 2 evaluable immunogenicity populations. An
additional analysis will be performed based on the all-available
immunogenicity populations if there is a large enough difference in
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Endpoint

Statistical Analysis Methods
sample size between the all-available immunogenicity populations andthe evaluable immunogenicity populations. Participants will besummarized according to the vaccine group to which they wererandomized. Missing serology data will not be imputed.

Secondaryimmunogenicity(noninferiority inthe 12- to 15-year
age groupcompared to the
16- to 25-year age
group)

GMR of SARS-CoV-2 neutralizing titers in participants 12 to 15
years of age to those 16 to 25 years of age
For participants with no serological or virological evidence (up to
1 month after receipt of the second dose) of past SARS-CoV-2
infection, the GMR of SARS-CoV-2 neutralizing titers in participants
12 to 15 years of age to those in participants 16 to 25 years of age and2-sided 95% CIs will be provided at 1 month after Dose 2 fornoninferiority assessment.
The GMR and its 2-sided 95% CI will be derived by calculating
differences in means and CIs on the natural log scale of the titers basedon the Student’s t-distribution and then exponentiating the results. The
difference in means on the natural log scale will be 12 to 15 years
minus 16 to 25 years. Noninferiority will be declared if the lower
bound of the 2-sided 95% CI for the GMR is greater than 0.67.
This analysis will be based on Dose 2 evaluable immunogenicity
populations. An additional analysis may be performed based on the
Dose 2 all-available immunogenicity population if needed.
Participants will be summarized according to the vaccine group towhich they were randomized. Missing serology data will not be
imputed.

Exploratory
immunogenicity

Geometric mean titers/concentrations (GMTs/GMCs) of
SARS-CoV-2 neutralizing titers, S1-binding IgG level, andRBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, GMTs/GMCs and 2-sided 95% CIs will be
provided for each investigational product within each group before
vaccination and at each of the following time points in Phase 2/3:


1, 6, 12, and 24 months after completion of vaccination inparticipants with and without serological or virologicalevidence of SARS-CoV-2 infection before vaccination

Geometric means will be calculated as the mean of the assay results
after making the logarithm transformation and then exponentiating themean to express results on the original scale. Two-sided 95% CIs will
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Statistical Analysis Methods
be obtained by taking natural log transforms of concentrations/titers,
calculating the 95% CI with reference to the t-distribution, and thenexponentiating the confidence limits.
GMFRs of SARS-CoV-2 neutralizing titers, S1-binding IgG level,
and RBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, the GMFRs and 2-sided 95% CIs will be
provided for each investigational product within each group at each of
the following time points in Phase 2/3:

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1, 6, 12, and 24 months after completion of vaccination inparticipants with and without serological or virologicalevidence of SARS-CoV-2 infection before vaccination

GMFRs will be limited to participants with nonmissing values prior to
the first dose and at the postvaccination time point. The GMFR will becalculated as the mean of the difference of logarithmically transformed
assay results (later time point – earlier time point) and exponentiating
the mean. The associated 2-sided CIs will be obtained by calculating
CIs using Student’s t-distribution for the mean difference of thelogarithmically transformed assay results and exponentiating theconfidence limits.
Percentage of participants with antibody levels ≥ predefined
threshold(s) for SARS-CoV-2 serological parameters
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels and/or
RBD-binding IgG levels, N-binding antibody, and SARS-CoV-2
detection by NAAT, percentages (and 2-sided 95% CIs) of participants
with antibody levels ≥ predefined threshold(s) will be provided foreach investigational product within each group at baseline and each of
the following time points in Phase 2/3:


1, 6, 12, and 24 months after completion of vaccination inparticipants with and without serological or virologicalevidence of SARS-CoV-2 infection before vaccination

The Clopper-Pearson method will be used to calculate the CIs.
Percentage of participants with the immune response (non-S) to
SARS-CoV-2 for N-binding antibody at the time points when data
are available
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Statistical Analysis Methods
The Clopper-Pearson method will be used to calculate the CIs.
For all of the immunogenicity endpoints, the analysis will be based on
the Dose 1 and Dose 2 evaluable immunogenicity populations. An
additional analysis will be performed based on the all-available
immunogenicity populations if there is a large enough difference insample size between the all-available immunogenicity populations andthe evaluable immunogenicity populations. Participants will besummarized according to the vaccine group to which they wererandomized. Missing serology data will not be imputed.
RCDCs for immunogenicity results

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Empirical RCDCs will be provided for SARS-CoV-2 neutralizing
titers, S1-binding IgG level, and RBD-binding IgG level after Dose 1
and after Dose 2.

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9.4.2. Efficacy Analyses
The statistical analysis of efficacy will be based on the evaluable efficacy population(primary analysis) and the all-available efficacy population as defined in Section 9.3.
Endpoint
Primary efficacy

Statistical Analysis Methods
Ratio of confirmed COVID-19 illness per 1000 person-years offollow-up in participants without evidence of infection before
vaccination for the active vaccine group to the placebo group
VE will be estimated by 100 × (1 – IRR), where IRR is the calculated
ratio of confirmed COVID-19 illness per 1000 person-years follow-up
in the active vaccine group to the corresponding illness rate in theplacebo group 7 days after the second dose. VE will be analyzed using
a beta-binomial model.

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After the above objective is met, the second primary endpoint will be
evaluated as below.
Ratio of confirmed COVID-19 illness per 1000 person-years offollow-up in participants with and without evidence of infection
before vaccination for the active vaccine group to the placebogroup
VE will be estimated by 100 × (1 – IRR), where IRR is the calculated
ratio of confirmed COVID-19 illness per 1000 person-years follow-up
in the active vaccine group to the corresponding illness rate in theplacebo group after 7 days after the second dose. VE will be analyzed
using a beta-binomial model.
The efficacy analysis for the first primary objective evaluation will bebased on the participants without evidence of infection before
vaccination and included in the evaluable efficacy population and in
the all-available efficacy population.
The efficacy analysis for the second primary objective evaluation will
be based on all participants included in the evaluable efficacy
population and in the all-available efficacy population.
For the primary endpoint analysis, missing efficacy data will not be
imputed. A sensitivity analysis will be performed by imputing missing
values with the assumption of MAR. A missing efficacy endpoint may
be imputed based on predicted probability using the fully conditional
specification method. Other imputation methods without the MAR
assumption may be explored. The details will be provided in the SAP.

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Endpoint
Secondary

Statistical Analysis Methods
Ratio of confirmed severe COVID-19 illness per 1000 person-years
of follow-up in participants without evidence of infection before
vaccination for the active vaccine group to the placebo group
Ratio of confirmed severe COVID-19 illness per 1000 person-years
of follow-up for the active vaccine group to the placebo group
These secondary efficacy objectives will be evaluated after the primaryobjectives are met. The analysis will be based on the evaluable efficacy
population and the all-available efficacy population. The analysis
methodology used for the primary efficacy endpoints will be applied
for the analysis of the above secondary efficacy endpoints.

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)The following secondary efficacy endpoints will be evaluateddescriptively with 95% CIs.
Ratio of confirmed COVID-19 illness (according to the
CDC-defined symptoms) per 1000 person-years of follow-up inparticipants without evidence of infection before vaccination for
the active vaccine group to the placebo group
Ratio of confirmed COVID-19 illness (according to the
CDC-defined symptoms) per 1000 person-years of follow-up inparticipants with and without evidence of infection before
vaccination for the active vaccine group to the placebo group
VE = 100 × (1 – IRR) will be estimated with confirmed COVID-19
illness according to the CDC-defined symptoms after 7 days after thesecond dose. The 2-sided 95% CI for VE will be derived using the
Clopper-Pearson method as described by Agresti.9
Missing efficacy data will not be imputed.

9.4.3. Safety Analyses
Endpoint
Primary

Statistical Analysis Methods
Descriptive statistics will be provided for each reactogenicity endpoint
for each dose and vaccine group. Local reactions and systemic eventsfrom Day 1 through Day 7 after each vaccination will be presented byseverity cumulatively across severity levels. Descriptive summary
statistics will include counts and percentages of participants with theindicated endpoint and the associated Clopper-Pearson 95% CIs.

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Endpoint

Statistical Analysis Methods
For Phase 1, descriptive statistics will be provided for abnormal
hematology and chemistry laboratory values at 1 and 7 days after
Dose 1 and 7 days after Dose 2, including grading shifts inhematology and chemistry laboratory assessments between baseline
and 1 and 7 days after Dose 1, and before Dose 2 and 7 days after
Dose 2. Descriptive summary statistics will include counts andpercentages of participants with the indicated endpoint and theassociated Clopper-Pearson 2-sided 95% CIs.
AEs will be categorized according to the Medical Dictionary forRegulatory Activities (MedDRA) terms. A 3-tier approach will be
used to summarize AEs in Phase 2/3. Under this approach AEs areclassified into 1 of 3 tiers: (1) Tier 1 events are prespecified events ofclinical importance and are identified in a list in the product’s safety
review plan; (2) Tier 2 events are those that are not Tier 1 but areconsidered “relatively common”; a MedDRA preferred term is defined
as a Tier 2 event if there are at least 1% of participants in at least 1
vaccine group reporting the event; and (3) Tier 3 events are those thatare neither Tier 1 nor Tier 2 events. For both Tier 1 and Tier 2 events,
2-sided 95% CIs for the difference between the vaccine and placebogroups in the percentage of participants reporting the events based on
the Miettinen and Nurminen method10 will be provided. In addition,
for Tier 1 events, the asymptotic p-values will also be presented forthe difference between groups in the percentage of participants
reporting the events, based on the same test statistic and under theassumption that the test statistic is asymptotically normally
distributed.
Descriptive summary statistics (counts, percentages, and associatedClopper-Pearson 95% CIs) will be provided for any AE events foreach vaccine group.
SAEs will be categorized according to MedDRA terms. Counts,
percentages, and the associated Clopper-Pearson 95% CIs of SAEs
from Dose 1 to 6 months after last dose will be provided for eachvaccine group.
The safety analyses are based on the safety population. Participants
will be summarized by vaccine group according to the investigational
products they actually received. Missing reactogenicity e-diary data
will not be imputed; missing AE dates will be handled according to
the Pfizer safety rules.

SecondaryNot applicable (N/A)
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Endpoint
Exploratory

Statistical Analysis Methods
N/A

9.4.4. Other Analyses
The ratios of (GMFR A to GMFR B) and (GMFR A to GMFR C) may be explored, where
GMFR A is the geometric mean of the ratio of the SARS-CoV-2 neutralizing titer at the
postvaccination time point to the corresponding titer at the prevaccination time point,
GFMR B is the geometric mean of the ratio of the S1-binding IgG level at the
postvaccination time point to the corresponding IgG level at the prevaccination time point,
and GMFR C is the geometric mean of the ratio of the RBD-binding IgG level at the
postvaccination time point to the corresponding antibody level at the prevaccination time
point.

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)The safety data and immunogenicity results for individuals with confirmed stable HIV
disease will be summarized descriptively. Furthermore, VE may be assessed if there is asufficient number of COVID-19 cases in this group of participants.
The safety and immunogenicity results for individuals 16 to 55 years of age vaccinated withstudy intervention produced by manufacturing “Process 1” or “Process 2” will besummarized descriptively.
9.5. Interim Analyses
As this is a sponsor open-label study during Phase 1, the sponsor may conduct unblinded
reviews of the data during the course of the study for the purpose of safety assessment,
facilitating dose escalation decisions, and/or supporting clinical development.
During Phase 2/3, 4 IAs are planned and will be performed by an unblinded statistical teamafter accrual of 32, 62, 92, and 120 cases. At each IA:

VE for the first primary objective will be evaluated . Overwhelming efficacy will bedeclared if the first primary study objective is met. The criteria for success at aninterim analysis are based on the posterior probability (ie, P[VE >30%|data]) at thecurrent number of cases. Overwhelming efficacy will be declared if the posterior
probability is higher than the success threshold. The success threshold for eachinterim analysis will be calibrated to protect overall type I error at 2.5%. Additional
details about the success threshold or boundary calculation at each interim analysis
will be provided in the SAP.

The study will stop for lack of benefit (futility) if the predicted probability of successat the final analysis or study success is <5%. The posterior predictive POS will becalculated using a beta-binomial model. The futility assessment will be performed
for the first primary endpoint and the futility boundary may be subject to change toreflect subsequent program-related decisions by the sponsor.
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Efficacy and futility boundaries will be applied in a nonbinding way.

Bayesian approaches require specification of a prior distribution for the possible values of theunknown vaccine effect, thereby accounting for uncertainty in its value. A minimally
informative beta prior, beta (0.700102, 1), is proposed for θ = (1-VE)/(2-VE). The prior iscentered at θ = 0.4118 (VE=30%) which can be considered pessimistic. The prior allows
considerable uncertainty; the 95% interval for θ is (0.005, 0.964) and the corresponding 95%
interval for VE is (-26.2, 0.995).
Table 6 illustrates the boundary for efficacy and futility if IAs are performed after accrual of
32 62, 92, and 120 cases in participants without evidence of infection before vaccination.
Table 6.

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AnalysisInterim Analysis Plan and Boundaries for Efficacy and Futility
Number of
Cases

Success Criteriaa

Futility Boundary

VE Point Estimate
VE Point Estimate(Case Split)(Case Split)
IA1
32
76.9% (6:26)
11.8% (15:17)
IA2
6268.1% (15:47)
27.8% (26:36)
IA3
92
62.7% (25:67)
38.6% (35:57)
IA4120
58.8% (35:85)
N/A
Final
164
52.3% (53:111)
Abbreviations: IA = interim analysis; N/A = not applicable; VE = vaccine efficacy.
Note: Case split = vaccine : placebo.
a. Interim efficacy claim: P(VE >30%|data) > 0.995; success at the final analysis: P(VE >30%|data)> 0.986.

Additional design operating characteristics (the boundary based on the number of cases
observed in the vaccine group; the probabilities for efficacy and futility given assumed
various VEs with a 1:1 randomization ratio) are listed in Table 7 and Table 8.

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Table 7.

Statistical Design Operating Characteristics: Probability of Success or
Failure for Interim Analyses

VaccineEfficacy(%)

Interim Analysis 1(Total Cases = 32)

30
50
60
70
80

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Table 8.

Probabilityof Success(Cases in
VaccineGroup ≤6)
0.006
0.054
0.150
0.368
0.722

Probabilityof Failure(Cases in
VaccineGroup ≥15)
0.315
0.078
0.021
0.003
<0.001

Interim Analysis 2(Total Cases = 62)
Probabilityof Success(Cases in
VaccineGroup ≤15)
0.003
0.051
0.160
0.310
0.238

Probabilityof Failure(Cases in
VaccineGroup ≥26)
0.231
0.056
0.010
<0.001<0.001

Interim Analysis 3(Total Cases = 92)
Probabilityof Success(Cases in
VaccineGroup ≤25)
0.002
0.063
0.175
0.195
0.037

Probabilityof Failure(Cases in
VaccineGroup ≥35)
0.239
0.103
0.019
0.001
<0.001

InterimAnalysis 4(Total Cases= 120)
Probability of
Success(CasesVaccineGroup ≤35)
0.002
0.075
0.160
0.085
0.003

Statistical Design Operating Characteristics: Probability of Success for
Final Analysis and Overall

Vaccine Efficacy (%)

30
50
60
70
80

Final Analysis(Total Cases = 164)
Probability of Success (Cases in Vaccine
Group ≤53)
0.007
0.196
0.220
0.036
<0.001

Overall Probability of Success

0.021
0.439
0.866
>0.999>0.999If neither success nor futility has been declared after all IAs, the final analysis will be
performed and the first primary objective will have been met if there are 53 or fewer cases
observed in the vaccine group out of a total of 164 first confirmed cases from 7 days after
receipt of the second dose of investigational product onwards.
After the primary objectives are met, the secondary VE endpoints (confirmed severe
COVID-19 in participants without evidence of infection before vaccination and confirmed
severe COVID-19 in all participants) will be evaluated sequentially, by the same method
used for the primary VE endpoint evaluation. Success thresholds for secondary VE will beappropriately chosen to control overall Type I error at 2.5%. Further details will be provided
in the SAP. The remaining secondary VE endpoints will be evaluated descriptively to
calculate the observed VE with 95% CIs.

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9.5.1. Analysis Timing

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Statistical analyses will be carried out when the following data are available:Complete safety and immunogenicity analysis approximately 1 month after Dose 2
for Phase 1.



Safety data through 7 days after Dose 2 and immunogenicity data through 1 monthafter Dose 2 from the first 360 participants enrolled (180 to active vaccine and 180 toplacebo, stratified equally between 18 to 55 years and >55 to 85 years) in Phase 2/3.



Safety data through 1 month after Dose 2 from at least 6000 participants enrolled(3000 to active vaccine and 3000 to placebo) in Phase 2/3. Additional analyses ofsafety data (with longer follow-up and/or additional participants) may be conducted if
required for regulatory purposes.



IAs for efficacy at 32, 62, 92, and 120 cases and futility at 32, 62, and 92 cases.

Safety data through 1 month after Dose 2 and noninferiority comparison of SARSCoV-2 neutralizing titers in participants 12 to 15 years of age compared to those inparticipants 16 to 25 years of age, 1 month after Dose 2Descriptive analysis of immunogenicity and safety of “Process 1” and “Process 2”
material, 1 month after Dose 2Complete safety and immunogenicity analysis approximately 6 months after Dose 2
for all participants in Phase 2/3.

Complete efficacy and persistence-of-immunogenicity analysis after complete data
are available or at the end of the study.

All analyses conducted on Phase 2/3 data while the study is ongoing will be performed by an
unblinded statistical team.
9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will use an IRC, a DMC, and a group of internal case reviewers. The IRC is
independent of the study team and includes only internal members. The DMC is independentof the study team and includes only external members. The IRC and DMC charters describe
the role of the IRC and DMC in more detail.
The responsibilities of the IRC are only in Phase 1 and will include:

Review of safety data to permit dose escalations in the 18- to 55-year age cohort



Review of safety data in the case of a stopping rule being met

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

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Review of safety and/or immunogenicity data to:Allow groups of participants of 65 to 85 years of age to proceed

Select vaccine candidate/dose level(s) to proceed into Phase 2/3. Data supporting
the selection, including results for both binding antibody levels and neutralizing
titers, and the ratio between them, will also be submitted to the FDA for review

Review of any available safety and/or immunogenicity data generated during thecourse of this study, or the BioNTech study conducted in Germany, to determine:Whether any groups may not be started



Whether any groups may be terminated earlyWhether any groups may be added with dose levels below the lowest stated doseor intermediate between the lowest and highest stated doses

Contemporaneous review of all NAAT-confirmed COVID-19 illnesses in Phase 1

The DMC will be responsible for ongoing monitoring of the safety of participants in the
study according to the charter. This may include, but is not limited to:Contemporaneous review of related AEs up to 1 month after completion of thevaccination scheduleContemporaneous review of all SAEs up to 6 months after completion of thevaccination scheduleContemporaneous review of all NAAT-confirmed COVID-19 illnesses in Phase 1

At the time of the planned IAs, and ad hoc if requested by the unblinded team, review
of cases of COVID-19 for an adverse imbalance of cases of COVID-19 and/or severe
COVID-19 between the vaccine and placebo groups

The recommendations made by the DMC to alter the conduct of the study will be forwarded
to the appropriate Pfizer personnel for final decision. Pfizer will forward such decisions,which may include summaries of aggregate analyses of safety data, to regulatory authorities,
as appropriate.
Three blinded case reviewers (medically qualified Pfizer staff members) will review all
potential COVID-19 illness events. If a NAAT-confirmed case in Phase 2/3 may beconsidered severe, or not, solely on the basis of “significant acute renal, hepatic, orneurologic dysfunction,” the blinded data will be reviewed by the case reviewers to assess
whether the criterion is met; the majority opinion will prevail.

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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:Consensus ethical principles derived from international guidelines including the
Declaration of Helsinki and CIOMS International Ethical Guidelines;Applicable ICH GCP guidelines;Applicable laws and regulations, including applicable privacy laws.

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents(eg, advertisements) must be reviewed and approved by the sponsor and submitted to an
IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study is
initiated.
Any amendments to the protocol will require IRB/EC approval before implementation ofchanges made to the study design, except for changes necessary to eliminate an immediate
hazard to study participants.
The investigator will be responsible for the following:Providing written summaries of the status of the study to the IRB/EC annually or
more frequently in accordance with the requirements, policies, and procedures
established by the IRB/EC;



Notifying the IRB/EC of SAEs or other significant safety findings as required by
IRB/EC procedures;Providing oversight of the conduct of the study at the site and adherence torequirements of 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014
for clinical studies (if applicable), and all other applicable local regulations.

10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicableregulatory authority in any area of the world, or if the investigator is aware of any new
information that might influence the evaluation of the benefits and risks of the study
intervention, Pfizer should be informed immediately.
In addition, the investigator will inform Pfizer immediately of any urgent safety measurestaken by the investigator to protect the study participants against any immediate hazard, andof any serious breaches of this protocol or of ICH GCP that the investigator becomes awareof.
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10.1.2. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to theparticipant or his or her parent(s)/legal guardian and answer all questions regarding the study.
The participant or his or her parent(s)/legal guardian should be given sufficient time andopportunity to ask questions and to decide whether or not to participate in the trial.
Participants must be informed that their participation is voluntary. Participants or theirparent(s)/legal guardian will be required to sign a statement of informed consent that meetsthe requirements of 21 CFR 50, local regulations, ICH guidelines, HIPAA requirements,
where applicable, and the IRB/EC or study center.
The investigator must ensure that each study participant or his or her parent(s)/legal guardianis fully informed about the nature and objectives of the study, the sharing of data related tothe study, and possible risks associated with participation, including the risks associated withthe processing of the participant’s personal data.

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)The participant must be informed that his/her personal study-related data will be used by thesponsor in accordance with local data protection law. The level of disclosure must also be
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical
Quality Assurance auditors or other authorized personnel appointed by the sponsor, byappropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant or his or her parent(s)/legal
guardian is fully informed about his or her right to access and correct his or her personal data
and to withdraw consent for the processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their
participation in the study.
A copy of the ICD(s) must be provided to the participant or his or her parent(s)/legal
guardian. Participants who are rescreened are required to sign a new ICD.
Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate
section that addresses the use of samples for optional additional research. The optional
additional research does not require the collection of any further samples. The investigator
or authorized designee will explain to each participant the objectives of the additional
research. Participants will be told that they are free to refuse to participate and may
withdraw their consent at any time and for any reason during the storage period.

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10.1.3. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementationof organizational and technical measures to ensure protection of participant data.

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Participants’ personal data will be stored at the study site in encrypted electronic and/or paper
form and will be password protected or secured in a locked room to ensure that only
authorized study staff have access. The study site will implement appropriate technical andorganizational measures to ensure that the personal data can be recovered in the event ofdisaster. In the event of a potential personal data breach, the study site will be responsiblefor determining whether a personal data breach has in fact occurred and, if so, providing
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personaldata, participants will be assigned a single, participant-specific numerical code. Any
participant records or data sets that are transferred to the sponsor will contain the numericalcode; participant names will not be transferred. All other identifiable data transferred to thesponsor will be identified by this single, participant-specific code. The study site will
maintain a confidential list of participants who participated in the study, linking eachparticipant’s numerical code to his or her actual identity and medical record identification. In
case of data transfer, the sponsor will protect the confidentiality of participants’ personal dataconsistent with the clinical study agreement and applicable privacy laws.
10.1.4. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting theresults of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or
www.pfizer.com, and other public registries in accordance with applicable local
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, andcomplete manner and are reported regardless of the outcome of the study or the country inwhich the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional
studies (conducted in patients) that evaluate the safety and/or efficacy of a product,
regardless of the geographical location in which the study is conducted. These results are
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies inaccordance with the format and timelines set forth by EU requirements.

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www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used
to identify individual participants have been removed) on www.pfizer.com for
Pfizer-sponsored interventional studies at the same time the corresponding study results areposted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinicaldata to the EMA website. Clinical data, under Phase 1 of this policy, includes clinicaloverviews, clinical summaries, CSRs, and appendices containing the protocol and protocol
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of thispolicy, includes the publishing of individual participant data. Policy 0070 applies to newmarketing authorization applications submitted via the centralized procedure since
01 January 2015 and applications for line extensions and for new indications submitted via
the centralized procedure since 01 July 2015.

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Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposesof “bona-fide scientific research” that contributes to the scientific understanding of thedisease, target, or compound class. Pfizer will make available data from these trials
24 months after study completion. Patient-level data will be anonymized in accordance withapplicable privacy laws and regulations. CSRs will have personally identifiable information
redacted.
Data requests are considered from qualified researchers with the appropriate competencies toperform the proposed analyses. Research teams must include a biostatistician. Data will not
be provided to applicants with significant conflicts of interest, including individuals
requesting access for commercial/competitive or legal purposes.
10.1.5. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unlesstransmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is
responsible for verifying that data entries are accurate and correct by physically orelectronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports theinformation entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted
electronic and/or paper form and are password protected or secured in a locked room toprevent access by unauthorized third parties.

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The investigator must permit study-related monitoring, audits, IRB/EC review, andregulatory agency inspections and provide direct access to source data documents. This
verification may also occur after study completion. It is important that the investigator(s)and their relevant personnel are available during the monitoring visits and possible audits orinspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality
such as risk management and mitigation strategies and analytical risk-based monitoring),
methods, responsibilities, and requirements, including handling of noncompliance issues andmonitoring techniques (central, remote, or on-site monitoring), are provided in themonitoring plan.

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)The sponsor or designee is responsible for the data management of this study, including
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data enteredinto the CRF by authorized site personnel are accurate, complete, and verifiable from source
documents; that the safety and rights of participants are being protected; and that the study is
being conducted in accordance with the currently approved protocol and any other study
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must
be retained by the investigator for 15 years after study completion unless local regulations or
institutional policies require a longer retention period. No records may be destroyed during
the retention period without the written approval of the sponsor. No records may betransferred to another location or party without written notification to the sponsor. The
investigator must ensure that the records continue to be stored securely for as long as they are
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of suchdata are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory
inspection notification in relation to the study. Furthermore, the investigator will cooperatewith the sponsor or its agents to prepare the investigator site for the inspection and will allow
the sponsor or its agent, whenever feasible, to be present during the inspection. The
investigator site and investigator will promptly resolve any discrepancies that are identified
between the study data and the participant's medical records. The investigator will promptly
provide copies of the inspection findings to the sponsor or its agent. Before response
submission to the regulatory authorities, the investigator will provide the sponsor or its
agents with an opportunity to review and comment on responses to any such findings.

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10.1.6. Source Documents
Source documents provide evidence for the existence of the participant and substantiate theintegrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be
consistent with the source documents or the discrepancies must be explained. The
investigator may need to request previous medical records or transfer records, depending on
the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the study monitoring plan.
Description of the use of computerized system is documented in the Data Management Plan.
10.1.7. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment ofparticipants.

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)The first act of recruitment is the date of the first participant’s first visit and will be the study
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any
time for any reason at the sole discretion of the sponsor. Study sites will be closed uponstudy completion. A study site is considered closed when all required documents and study
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor
or designee if requested to do so by the responsible IRB/EC or if such termination is required
to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limitedto:

Failure of the investigator to comply with the protocol, the requirements of the
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.

If the study is prematurely terminated or suspended, the sponsor shall promptly inform theinvestigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of
the reason for termination or suspension, as specified by the applicable regulatory
requirements. The investigator shall promptly inform the participant and should assure
appropriate participant therapy and/or follow-up.

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Study termination is also provided for in the clinical study agreement. If there is any conflict
between the contract and this protocol, the contract will control as to termination rights.
10.1.8. Sponsor’s Qualified Medical Personnel

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)The contact information for the sponsor's appropriately qualified medical personnel for the
study is documented in the study contact list located in the supporting study documentation.
To facilitate access to appropriately qualified medical personnel on study-related medical
questions or problems, participants are provided with a contact card at the time of informed
consent. The contact card contains, at a minimum, protocol and study intervention
identifiers, participant numbers, contact information for the investigator site, and contact
details for a contact center in the event that the investigator site staff cannot be reached toprovide advice on a medical question or problem originating from another healthcare
professional not involved in the participant’s participation in the study. The contact number
can also be used by investigator staff if they are seeking advice on medical questions or
problems; however, it should be used only in the event that the established communication
pathways between the investigator site and the study team are not available. It is therefore
intended to augment, but not replace, the established communication pathways between theinvestigator site and the study team for advice on medical questions or problems that may
arise during the study. The contact number is not intended for use by the participant directly,
and if a participant calls that number, he or she will be directed back to the investigator site.

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10.2. Appendix 2: Clinical Laboratory Tests

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)The following safety laboratory tests will be performed at times defined in the SoA section ofthis protocol. Additional laboratory results may be reported on these samples as a result of
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived
from calculated values. These additional tests would not require additional collection ofblood. Unscheduled clinical laboratory measurements may be obtained at any time during
the study to assess any perceived safety issues.
Hematology
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet countWBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)Basophils (Abs)
Lymphocytes (Abs)

Chemistry
BUN and creatinine
AST, ALT
Total bilirubin
Alkaline phosphatase

Other Urine pregnancy test (β-hCG)
At screening only: Hepatitis B core antibody
 Hepatitis B surface antigen
 Hepatitis C antibody
 Human immunodeficiency virus

Investigators must document their review of each laboratory safety report.
Clinically significant abnormal laboratory findings should be recorded in the AE CRF in
accordance with the following grading scale (Table 9).
Table 9.

Laboratory Abnormality Grading Scale

Hematology

Mild (Grade 1)

Hemoglobin
11.0 – 12.0
(Female) - g/dL
Hemoglobin
12.5 – 13.5
(Male) - g/dL
WBC increase 10,800 – 15,000
cells/mm3
WBC decrease 2,500 – 3,500
cells/mm3
Lymphocytes
750 – 1,000
decrease - cells/mm3
Neutrophils decrease 1,500 – 2,000- cells/mm3
Eosinophils 650 – 1500
cells/mm3
Platelets decreased - 125,000 – 140,000
cells/mm3

Moderate(Grade 2)

Severe (Grade 3)

9.5 – 10.9

8.0 – 9.4

Potentially Life
Threatening(Grade 4)<8.0

10.5 – 12.4

8.5 – 10.4

<8.5

15,001 – 20,000

20,001 – 25, 000>25,000

1,500 – 2,499

1,000 – 1,499<1,000500 – 749

250 – 499

<250

1,000 – 1,499

500 – 999

<500

1501 - 5000

>5000

Hypereosinophilic

100,000 – 124,000

25,000 – 99,000<25,000

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Table 9.

Laboratory Abnormality Grading Scale

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Chemistry

Mild (Grade 1)

Moderate(Grade 2)

Severe(Grade 3)

BUN - mg/dL
Creatinine – mg/dL

23 – 26
1.5 – 1.7

27 – 31
1.8 – 2.0> 31
2.1 – 2.5

Alkaline
phosphate –increase by factor
Liver function tests– ALT, AST
increase by factor
Bilirubin – whenaccompanied
by any increase inliver function test increase by factor
Bilirubin – whenliver function test is
normal - increase byfactor

1.1 – 2.0 x ULN

2.1 – 3.0 x ULN

3.1 – 10 x ULN

Potentially Life
Threatening(Grade 4)
Requires dialysis> 2.5 or requires
dialysis>10 x ULN

1.1 – 2.5 x ULN

2.6 – 5.0 x ULN

5.1 – 10 x ULN>10 x ULN

1.1 – 1.25 x ULN

1.26 – 1.5 x ULN

1.51 – 1.75 x ULN>1.75 x ULN

1.1 – 1.5 x ULN

1.6 – 2.0 x ULN

2.0 – 3.0 x ULN>3.0 x ULN

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen;
ULN = upper limit of normal; WBC = white blood cell.

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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition


An AE is any untoward medical occurrence in a patient or clinical study participant,temporally associated with the use of study intervention, whether or not consideredrelated to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including anabnormal laboratory finding), symptom, or disease (new or exacerbated) temporally
associated with the use of study intervention.

Events Meeting the AE Definition

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis)or other safety assessments (eg, ECG, radiological scans, vital sign measurements),
including those that worsen from baseline, considered clinically significant in the
medical and scientific judgment of the investigator Any abnormal laboratory test
results that meet any of the conditions below must be recorded as an AE:
Is associated with accompanying symptoms.



Requires additional diagnostic testing or medical/surgical intervention.



Leads to a change in study dosing (outside of any protocol-specified dose
adjustments) or discontinuation from the study, significant additional
concomitant drug treatment, or other therapy.



Exacerbation of a chronic or intermittent preexisting condition including either anincrease in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration eventhough it may have been present before the start of the study.



Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.



Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
intervention or a concomitant medication. Overdose per se will not be reported as
an AE/SAE unless it is an intentional overdose taken with possible
suicidal/self-harming intent. Such overdoses should be reported regardless ofsequelae.
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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safetyassessments which are associated with the underlying disease, unless judged by theinvestigator to be more severe than expected for the participant’s condition.



The disease/disorder being studied or expected progression, signs, or symptoms ofthe disease/disorder being studied, unless more severe than expected for theparticipant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).



Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present
or detected at the start of the study that do not worsen.

10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:a. Results in deathb. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which theparticipant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.
c. Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving
at least an overnight stay) at the hospital or emergency ward for observation and/or
treatment that would not have been appropriate in the physician’s office or outpatientsetting. Complications that occur during hospitalization are AEs. If a complication
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in
doubt as to whether “hospitalization” occurred or was necessary, the AE should beconsidered serious.
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Hospitalization for elective treatment of a preexisting condition that did not worsen frombaseline is not considered an AE.
d. Results in persistent disability/incapacity


The term disability means a substantial disruption of a person’s ability to conduct
normal life functions.

This definition is not intended to include experiences of relatively minor medicalsignificance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza,
and accidental trauma (eg, sprained ankle) which may interfere with or prevent
everyday life functions but do not constitute a substantial disruption.

e. Is a congenital anomaly/birth defect090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)

f. Other situations:Medical or scientific judgment should be exercised in deciding whether SAE
reporting is appropriate in other situations such as important medical events that
may not be immediately life-threatening or result in death or hospitalization but may
jeopardize the participant or may require medical or surgical intervention to prevent
one of the other outcomes listed in the above definition. These events should
usually be considered serious.



Examples of such events include invasive or malignant cancers, intensive treatment
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or
convulsions that do not result in hospitalization, or development of drug dependency
or drug abuse.

Suspected transmission via a Pfizer product of an infectious agent, pathogenic or
nonpathogenic, is considered serious. The event may be suspected from clinicalsymptoms or laboratory findings indicating an infection in a patient exposed to a
Pfizer product. The terms “suspected transmission” and “transmission” areconsidered synonymous. These cases are considered unexpected and handled asserious expedited cases by pharmacovigilance personnel. Such cases are also
considered for reporting as product defects, if appropriate.

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10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF andfor reporting serious adverse events on the Vaccines SAE Report Form to Pfizer Safety.
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious adverse
events (AEs); and (3) exposure to the study intervention under study during pregnancy orbreastfeeding, and occupational exposure.

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)It should be noted that the Vaccines SAE Report Form for reporting of SAE information is
not the same as the AE page of the CRF. When the same data are collected, the forms must
be completed in a consistent manner. AEs should be recorded using concise medical
terminology and the same AE term should be used on both the CRF and the Vaccines SAE
Report Form for reporting of SAE information.
Safety Event

Recorded on the CRF

SAE
Nonserious AE
Exposure to the study
intervention under study
during pregnancy orbreastfeeding, andoccupational exposure

All
All
All AEs/SAEs associatedwith exposure during
pregnancy or breastfeeding

Reported on the Vaccines
SAE Report Form to
Pfizer Safety Within 24
Hours of Awareness

All
None
All (and EDP supplemental
form for EDP)
Note: Include all SAEs
associated with exposure
Occupational exposure is not during pregnancy orbreastfeeding. Include allrecorded.
AEs/SAEs associated withoccupational exposure.

When an AE/SAE occurs, it is the responsibility of the investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostic
reports) related to the event.



The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s
medical records to Pfizer Safety in lieu of completion of the Vaccines SAE Report
Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases arerequested by Pfizer Safety. In this case, all participant identifiers, with the
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exception of the participant number, will be redacted on the copies of the medical
records before submission to Pfizer Safety.


The investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. Whenever possible, the diagnosis(not the individual signs/symptoms) will be documented as the AE/SAE.

Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during
the study and assign it to 1 of the following categories:

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)GRADE If required on the AE page of the CRF, the investigator will use theadjectives MILD, MODERATE, SEVERE, or LIFE-THREATENING todescribe the maximum intensity of the AE. For purposes of consistency,
these intensity grades are defined as follows:
1

MILD

Does not interfere with participant's usualfunction.

2

MODERATE

Interferes to some extent with participant's usualfunction.

3

SEVEREInterferes significantly with participant's usualfunction.

4

LIFE-THREATENING Life-threatening consequences; urgent
intervention indicated.

Assessment of Causality

The investigator is obligated to assess the relationship between study intervention
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence,
and/or arguments to suggest a causal relationship, rather than a relationship cannot
be ruled out.

The investigator will use clinical judgment to determine the relationship.



Alternative causes, such as underlying disease(s), concomitant therapy, and otherrisk factors, as well as the temporal relationship of the event to study intervention
administration, will be considered and investigated.

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The investigator will also consult the IB and/or product information, for marketed
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she
has reviewed the AE/SAE and has provided an assessment of causality.



There may be situations in which an SAE has occurred and the investigator has
minimal information to include in the initial report to the sponsor. However, it isvery important that the investigator always make an assessment of causality forevery event before the initial transmission of the SAE data to the sponsor.



The investigator may change his/her opinion of causality in light of follow-up
information and send an SAE follow-up report with the updated causality
assessment.



The causality assessment is one of the criteria used when determining regulatory
reporting requirements.



If the investigator does not know whether or not the study intervention caused theevent, then the event will be handled as “related to study intervention” for reporting
purposes, as defined by the sponsor. In addition, if the investigator determines thatan SAE is associated with study procedures, the investigator must record this causal
relationship in the source documents and CRF, and report such an assessment in the
dedicated section of the Vaccines SAE Report Form and in accordance with the
SAE reporting requirements.

Follow-up of AEs and SAEs


The investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by thesponsor to elucidate the nature and/or causality of the AE or SAE as fully as
possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other healthcare providers.



If a participant dies during participation in the study or during a recognizedfollow-up period, the investigator will provide Pfizer Safety with a copy of any
postmortem findings including histopathology.



New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours ofreceipt of the information.

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10.3.4. Reporting of SAEs

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SAE Reporting to Pfizer Safety via Vaccines SAE Report Form

Facsimile transmission of the Vaccines SAE Report Form is the preferred method totransmit this information to Pfizer Safety.



In circumstances when the facsimile is not working, notification by telephone isacceptable with a copy of the Vaccines SAE Report Form sent by overnight mail orcourier service.

Initial notification via telephone does not replace the need for the investigator tocomplete and sign the Vaccines SAE Report Form pages within the designatedreporting time frames.

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10.4. Appendix 4: Contraceptive Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during
the intervention period and for at least 28 days after the last dose of study intervention, whichcorresponds to the time needed to eliminate reproductive safety risk of the study
intervention(s):Refrain from donating sperm.

PLUS either:Be abstinent from heterosexual intercourse with a female of childbearing potential as
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) andagree to remain abstinent.

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)OR

Must agree to use a male condom when engaging in any activity that allows forpassage of ejaculate to another person.



In addition to male condom use, a highly effective method of contraception may beconsidered in WOCBP partners of male participants (refer to the list of highly
effective methods below in Section 10.4.4).

10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).

OR

Is a WOCBP and using an acceptable contraceptive method as described below
during the intervention period (for a minimum of 28 days after the last dose of study
intervention). The investigator should evaluate the effectiveness of the contraceptive
method in relationship to the first dose of study intervention.

The investigator is responsible for review of medical history, menstrual history, and recent
sexual activity to decrease the risk for inclusion of a woman with an early undetected
pregnancy.

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10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot
be confirmed before the first dose of study intervention, additional evaluation should beconsidered.
Women in the following categories are not considered WOCBP:

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)

1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.

For individuals with permanent infertility due to an alternate medical cause other than theabove, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should beapplied to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s
review of the participant’s medical records, medical examination, or medical history
interview. The method of documentation should be recorded in the participant’s medical
record for the study.
2. Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause. In addition, ahigh FSH level in the postmenopausal range must be used to confirm apostmenopausal state in women under 60 years of age and not using hormonal
contraception or HRT.



Female on HRT and whose menopausal status is in doubt will be required to use
one of the nonestrogen hormonal highly effective contraception methods if theywish to continue their HRT during the study. Otherwise, they must discontinue
HRT to allow confirmation of postmenopausal status before study enrollment.

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10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations
regarding the use of contraceptive methods for those participating in clinical trials.
1. Implantable progestogen-only hormone contraception associated with inhibition ofovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner:

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)

Vasectomized partner is a highly effective contraceptive method provided that thepartner is the sole sexual partner of the woman of childbearing potential and theabsence of sperm has been confirmed. If not, an additional highly effective methodof contraception should be used. The spermatogenesis cycle is approximately
90 days.

6. Combined (estrogen- and progestogen-containing) hormonal contraception associatedwith inhibition of ovulation:


Oral;



Intravaginal;Transdermal;



Injectable.

7. Progestogen-only hormone contraception associated with inhibition of ovulation:


Oral;



Injectable.

8. Sexual abstinence:Sexual abstinence is considered a highly effective method only if defined as
refraining from heterosexual intercourse during the entire period of risk associatedwith the study intervention. The reliability of sexual abstinence needs to be evaluatedin relation to the duration of the study and the preferred and usual lifestyle of theparticipant.

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9. Progestogen-only oral hormonal contraception where inhibition of ovulation is not the
primary mode of action.
10. Male or female condom with or without spermicide.
11. Cervical cap, diaphragm, or sponge with spermicide.

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12. A combination of male condom with either cervical cap, diaphragm, or sponge with
spermicide (double-barrier methods).

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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations intransaminases) are termed “tolerators,” while those who show transient liver injury, but adapt
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of amore serious potential outcome. These participants fail to adapt and therefore are"susceptible" to progressive and serious liver injury, commonly referred to as DILI.
Participants who experience a transaminase elevation above 3 × ULN should be monitored
more frequently to determine if they are an “adaptor” or are “susceptible.”

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LFTs are not required as a routine safety monitoring procedure for all participants in thisstudy. However, should an investigator deem it necessary to assess LFTs because aparticipant presents with clinical signs/symptoms, such LFT results should be managed andfollowed as described below.
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will beelevated within the same laboratory sample). In rare instances, by the time TBili elevations
are detected, AST/ALT values might have decreased. This occurrence is still regarded as apotential DILI. Therefore, abnormal elevations in either AST OR ALT in addition to TBili
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law
criteria) cases and should always be considered important medical events, even before allother possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on theparticipant’s individual baseline values and underlying conditions. Participants who present
with the following laboratory abnormalities should be evaluated further as potential DILI
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:Participants with AST/ALT and TBili baseline values within the normal range who
subsequently present with AST OR ALT values >3 × ULN AND a TBili value>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value<2 × ULN or not available.

For participants with baseline AST OR ALT OR TBili values above the ULN, thefollowing threshold values are used in the definition mentioned above, as needed,
depending on which values are above the ULN at baseline:Preexisting AST or ALT baseline values above the normal range: AST or ALT
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever issmaller).

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Rises in AST/ALT and TBili separated by more than a few weeks should be assessedindividually based on clinical judgment; any case where uncertainty remains as to whether it
represents a potential Hy’s law case should be reviewed with the sponsor.

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)The participant should return to the investigator site and be evaluated as soon as possible,
preferably within 48 hours from awareness of the abnormal results. This evaluation should
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili for suspected cases ofHy’s law, additional laboratory tests should include albumin, CK, direct and indirect
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should
also be given to drawing a separate tube of clotted blood and an anticoagulated tube of bloodfor further testing, as needed, for further contemporaneous analyses at the time of therecognized initial abnormalities to determine etiology. A detailed history, including relevant
information, such as review of ethanol, acetaminophen/paracetamol (either by itself or as a
coformulated product in prescription or over-the-counter medications), recreational drug,
supplement (herbal) use and consumption, family history, sexual history, travel history,
history of contact with a jaundiced person, surgery, blood transfusion, history of liver orallergic disease, and potential occupational exposure to chemicals, should be collected.
Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary
tract) and collection of serum samples for acetaminophen/paracetamol drug and/or protein
adduct levels may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if noother reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law)cases are to be reported as SAEs, irrespective of availability of all the results of theinvestigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results ofreasonable investigations have been received and have excluded an alternative etiology.

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10.6. Appendix 6: Abbreviations

090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)The following is a list of abbreviations that may be used in the protocol.
Abbreviation
2019-nCoV
Abs
AE
ALT
AST
-hCG
BMI
BUN
CBER
CDC
CFR
CI
CIOMS
CLIA
CONSORT
COVID-19
CRF
CRO
CSR
CT
DBP
DILI
DMC
DNA
DU
EC
ECMO
ECG
eCRF
e-diary
EDP
EMA
EU
EUA
EudraCT
FDA
FiO2
FSH
GCP

Term
novel coronavirus 2019absolute (in Appendix 2)
adverse event
alanine aminotransferase
aspartate aminotransferase
beta-human chorionic gonadotropin
body mass index
blood urea nitrogen
Center for Biologics Evaluation and ResearchCenters for Disease Control and Prevention (United States)
Code of Federal Regulations
confidence interval
Council for International Organizations of Medical Sciences
Clinical Laboratory Improvement Amendments
Consolidated Standards of Reporting Trials
coronavirus disease 2019case report form
contract research organization
clinical study reportcomputed tomography
diastolic blood pressuredrug-induced liver injury
data monitoring committee
deoxyribonucleic aciddosing unit
ethics committee
extracorporeal membrane oxygenationelectrocardiogram
electronic case report form
electronic diary
exposure during pregnancy
European Medicines Agency
European Union
emergency use authorization
European Clinical Trials Database
Food and Drug Administration
fraction of inspired oxygenfollicle-stimulating hormone
Good Clinical Practice

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Abbreviation
GGT
GMC
GMFR
GMR
GMT
HBc Ab
HBe
HBeAg
HBsAg
HBV
HCV
HCV Ab
HIPAA
HIV
HR
HRT
IA
IB
ICD
ICH
ICU
ID
Ig
IgG
IgM
IMP
IND
INR
IP manual
IPAL
IRB
IRC
IRR
IRT
ISO
IV
IWR
LFT
LL
LLOQ
LNP
LPX

Term
gamma-glutamyl transferase
geometric mean concentrationgeometric mean fold risegeometric mean ratio
geometric mean titerhepatitis B core antibody
hepatitis B ehepatitis B e antigen
hepatitis B surface antigen
hepatitis B virus
hepatitis C virus
hepatitis C virus antibody
Health Insurance Portability and Accountability Act
human immunodeficiency virus
heart rate
hormone replacement therapy
interim analysis
investigator’s brochure
informed consent document
International Council for Harmonisation
intensive care unit
identification
immunoglobulin
immunoglobulin G
immunoglobulin M
investigational medicinal productinvestigational new druginternational normalized ratio
investigational product manual
Investigational Product Accountability Log
institutional review board
internal review committee
illness rate ratio
interactive response technology
International Organization for Standardization
intravenous(ly)interactive Web-based response
liver function test
lower limit
lower limit of quantitation
lipid nanoparticle
lipoplex

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Abbreviation
MAR
MCH
MCHC
MCV
MedDRA
MERS
MIS-C
modRNA
MRI
N
N/A
NAAT
non-S
P2 S
PaO2
PCR
PI
POS
PPE
PT
RBC
RBD
RCDC
RNA
RR
RSV
RT-PCR
S1
SAE
SAP
saRNA
SARS
SARS-CoV-2
SBP
SoA
SOP
SpO2
SRSD
SUSAR
TBD
TBili
ULN

Term
missing at randommean corpuscular hemoglobinmean corpuscular hemoglobin concentration
mean corpuscular volume
Medical Dictionary for Regulatory Activities
Middle East respiratory syndrome
multisystem inflammatory syndrome in children
nucleoside-modified messenger ribonucleic acidmagnetic resonance imaging
SARS-CoV-2 nucleoprotein
not applicable
nucleic acid amplification test
nonspike protein
SARS-CoV-2 full-length, P2 mutant, prefusion spike glycoprotein
partial pressure of oxygen, arterial
polymerase chain reaction
principal investigatorprobability of successpersonal protective equipment
prothrombin time
red blood cell
receptor-binding domain
reverse cumulative distribution curve
ribonucleic acidrespiratory rate
respiratory syncytial virus
reverse transcription–polymerase chain reaction
spike protein S1 subunit
serious adverse event
statistical analysis planself-amplifying messenger ribonucleic acidsevere acute respiratory syndrome
severe acute respiratory syndrome coronavirus 2
systolic blood pressureschedule of activities
standard operating procedureoxygen saturation as measured by pulse oximetry
single reference safety document
suspected unexpected serious adverse reaction
to be determinedtotal bilirubin
upper limit of normal

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Abbreviation
uRNA
US
vax
VE
WBC
WHO
WOCBP

Term
unmodified messenger ribonucleic acid
United States
vaccination
vaccine efficacy
white blood cell
World Health Organization
woman/women of childbearing potential

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10.7. Appendix 7: Stopping and Alert Rules for Enhanced COVID-19
In Phase 2/3, the unblinded team supporting the DMC (reporting team), including an
unblinded medical monitor, will review cases of severe COVID-19 as they are received, andwill review AEs at least weekly for additional potential cases of severe COVID-19 and willcontact the DMC in the event that the stopping rule or an alert is met. Specifically, theunblinded reporting team will contact the DMC chair, who will then convene the full DMC
as soon as possible. The DMC will review all available safety and/or efficacy data at thetime of the review. The DMC will make one of the following recommendations to Pfizer:
withhold final recommendation until further information/data are provided, continue thestudy as designed, modify the study and continue, or stop the study. The final decision toaccept or reject the committee’s recommendation resides with Pfizer management and will be
communicated to the committee chairperson in writing.

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At any point the unblinded team may discuss with the DMC chair whether the DMC should
review cases for an adverse imbalance of cases of COVID-19 and/or severe COVID-19
between the vaccine and placebo groups (see Section 9.6). In addition, at the time of the IAs
at 32, 62, 92, and 120 cases, the number of severe COVID-19 cases in the vaccine andplacebo groups will be assessed.
Stopping and alert rules will be applied as follows. The stopping rule will be triggered whenthe 1-sided probability of observing the same or a more extreme case split is 5% or less when
the true incidence of severe disease is the same for vaccine and placebo participants, and alert
criteria are triggered when this probability is less than 11%. In addition, when the total
number of severe cases is low (15 or less), the unblinded team supporting the DMC will
implement the alert rule when a reverse case split of 2:1 or worse is observed. For example,
at 3 cases 2:1, at 4 cases 3:1, etc. Below 15 cases, this rule is more rigorous than requiring
the probability of an observed adverse split or worse be <11%.
The stopping rule and alert rules are illustrated in Table 10 and Table 11, respectively, when
the total number of severe cases is 20 or less. For example, when there are 7 severe cases,
the adverse split has to be 7:0 to stop the study, but a split of 5:2 would trigger the alert rule.
Similarly, when there is a total of 9 severe cases, an adverse split of 9:0 triggers the stopping
rule, while a split of 6:3 or worse triggers the alert rule. The alert rule may be triggered withas few as 2 cases, with a split of 2:0.

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Table 10. Stopping Rule: Enrollment Is Stopped if the Number of Severe Cases inthe Vaccine Group Is Greater Than or Equal to the Prespecified Stopping
Rule Value (S)090177e1951cd87d\Approved\Approved On: 07-Oct-2020 08:40 (GMT)

Total Severe Cases

Prespecified Stopping Rule Value(S): Number of Severe Cases in the
Vaccine Group to Stop

4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Abbreviation: N/A = not applicable.

4
5
6
7
7
8
9
9
10
10
11
12
12
13
13
14
15

If the True Ratio of Severe Cases
Between Vaccine and PlaceboGroups Is 1:1, Probability of S or
More Being Observed in the Vaccine
Group
N/A
3.13%
1.56%
0.78%
3.52%
1.95%
1.07%
3.27%
1.93%
4.61%
2.87%
1.76%
3.84%
2.45%
4.81%
3.18%
2.07%

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Table 11. Alert Rule: Further Action Is Taken if the Number of Severe Cases in the
Vaccine Group Is Greater Than or Equal to the Prespecified Alert Rule
Value (A)
Total
SevereCases

Prespecified AlertRule Value(A):
Number of
SevereCases in the
VaccineGroup toTrigger
Further
ActionIf the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
1:1,
Probabilityof A Being
Observed inthe Vaccine
Group

2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20

2
2
3
4
4
5
6
6
7
8
8
9
10
10
11
12
13
13
14

25.00%
37.50%
25.00%
15.63%
23.44%
16.41%
10.94%
16.41%
11.72%
8.06%
12.08%
8.73%
6.11%
9.16%
6.67%
4.72%
3.27%
5.18%
3.70%

If the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
1:1,
Probabilityof A or More
Being
Observed inthe Vaccine
Group
25.00%
50.00%
31.25%
18.75%
34.38%
22.66%
14.45%
25.39%
17.19%
11.33%
19.38%
13.34%
8.98%
15.09%
10.51%
7.17%
4.81%
8.35%
5.77%

If the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
2:1,
Probabilityof A or More
Being
Observed inthe Vaccine
Group44.49%
74.12%
59.32%
46.16%
68.10%
57.14%
46.90%
65.11%
56.02%
47.35%
63.25%
55.31%
47.66%
61.94%
54.81%
47.88%
41.34%
54.43%
48.06%

If the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
3:1,
Probabilityof A or More
Being
Observed inthe Vaccine
Group56.25%
84.38%
73.83%
63.28%
83.06%
75.64%
67.85%
83.43%
77.59%
71.33%
84.24%
79.40%
74.15%
85.16%
81.03%
76.53%
71.75%
82.51%
78.58%

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If the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
4:1,
Probabilityof A or More
Being
Observed inthe VaccineGroup64.00%
89.60%
81.92%
73.73%
90.11%
85.20%
79.69%
91.44%
87.91%
83.89%
92.74%
90.09%
87.02%
93.89%
91.83%
89.43%
86.71%
93.24%
91.33%

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10.8. Appendix 8: Criteria for Allowing Inclusion of Participants With Chronic Stable
HIV, HCV, or HBV Infection
Potential participants with chronic stable HIV, HCV, or HBV infection may be considered
for inclusion if they fulfill the following respective criteria.
Known HIV infection
Confirmed stable HIV disease defined as documented viral load <50 copies/mL andCD4 count >200 cells/mm3 within 6 months before enrollment, and on stable
antiretroviral therapy for at least 6 months.

Known HCV infection
History of chronic HCV with evidence of sustained virological response (defined asundetectable HCV RNA) for ≥12 weeks following HCV treatment or without
evidence of HCV RNA viremia (undetectable HCV viral load).

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Known HBV infection
Confirmed inactive chronic HBV infection, defined as HBsAg present for ≥6 months and thefollowing:

HBeAg negative, anti-HBe positive

Serum HBV DNA <2000 IU/mLPersistently normal ALT and/or AST levels

In those who have had a liver biopsy performed, findings that confirm the absence ofsignificant necroinflammation.

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11. REFERENCES
1

World Health Organization. WHO Director-General's opening remarks at the media
briefing on COVID-19. Available from: https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march2020. Published: 11 Mar 2020. Accessed: 01 Apr 2020.

2

World Health Organization. Coronavirus disease 2019 (COVID-19) situation report - 70.
In: Data as reported by national authorities by 10:00 CET 30 March 2020. Geneva,
Switzerland: World Health Organization; 2020.

3

Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19):
information for clinicians on investigational therapeutics for patients with COVID-19.
Available from: https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeuticoptions.html. Updated: 25 Apr 2020. Accessed: 26 Jun 2020.

4

Rauch S, Jasny E, Schmidt KE, et al. New vaccine technologies to combat outbreaksituations. Front Immunol 2018;9:1963.

5

Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics—developing a new class ofdrugs. Nat Rev Drug Discov 2014;13(10):759-80.

6

BioNTech RNA Pharmaceuticals GmbH. CorVAC/BNT162 Investigator’s Brochure.
Mainz, Germany: BioNTech RNA Pharmaceuticals GmbH; 25 Mar 2020.

7

Feldman RA, Fuhr R, Smolenov I, et al. mRNA vaccines against H10N8 and H7N9
influenza viruses of pandemic potential are immunogenic and well tolerated in healthy
adults in phase 1 randomized clinical trials. Vaccine 2019;37(25):3326-34.

8

US Food and Drug Administration. Guidance for industry: toxicity grading scale forhealthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials.
Rockville, MD: Center for Biologics Evaluation and Research; September 2007.

9

Agresti A. Introduction: distributions and inference for categorical data. In: Agresti A,
ed. Categorical data analysis. 2nd ed. Hoboken, NJ: John Wiley & Sons; 2002:1-35.

10

Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med
1985;4(2):213-26.

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Document Approval Record
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Page 460

FDA-CBER-2021-5683-0014513

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Protocol Amendment 6, 08 September 2020090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)A PHASE 1/2/3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLIND,
DOSE-FINDING STUDY TO EVALUATE THE SAFETY, TOLERABILITY,IMMUNOGENICITY, AND EFFICACY OF SARS-COV-2 RNA VACCINECANDIDATES AGAINST COVID-19 IN HEALTHY INDIVIDUALS

Study Sponsor:

BioNTechStudy Conducted By:

PfizerStudy Intervention Number:

PF-07302048

Study Intervention Name:

RNA-Based COVID-19 Vaccines

US IND Number:

19736

EudraCT Number:2020-002641-42

Protocol Number:

C4591001

Phase:
1/2/3
Short Title: A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, andEfficacy of RNA Vaccine Candidates Against COVID-19 in Healthy IndividualsThis document and accompanying materials contain confidential information belonging to Pfizer. Except asotherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold thisinformation in confidence and not copy or disclose it to others (except where required by applicable law) or
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer
must be promptly notified.

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Protocol Amendment Summary of Changes Table
Document History

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)

Document

Version Date

Protocol amendment 6

08 September 2020

Protocol amendment 5

24 July 2020

Summary and Rationale for Changes


Reordered some procedures in the Phase 2/3
schedule of activities for consistency with themain body of the protocol.
 Corrected the window for the 6-month follow-up
visit to be approximately 6 months after
Vaccination 2.
 Reduced the volume of blood draws to ~20 mL.
 Removed the need to have safety data reported
for participants to be included in the safety
objective assessment.
 Added an exploratory objective to describe
safety, immunogenicity, and efficacy inparticipants with stable HIV disease.
 Increased the sample size for Phase 2/3 to~43,998.
 Clarified that inclusion criterion 4 (ie,participants at higher risk for acquiring COVID19) is applicable for Phase 2/3 only, andprovided some examples.
 Removed exclusion criterion 2 (ie, known
infection with HIV, HCV, or HBV) for Phase 3
and added criteria for HIV-positive participants.
 Decreased the lower age limit and removed theupper age limit for inclusion in Phase 2/3 inorder to evaluate BNT162b2 30 µg in older
adolescents and those over 85 years of age;
updated the title and other references to adults toalign with this change.
 Renamed the immunological assays to alignwith other program-level documents.
 Removed reference to the SARS-CoV-2 fulllength, P2 mutant, prefusion spike glycoprotein(P2 S) being “heads up.” Clarified that a positive SARS-CoV-2 NAAT
result without symptoms should not result in
discontinuation of study intervention.
 Added clarification that potential COVID-19
illnesses that are consistent with the clinicalendpoint definition should not be recorded asAEs.
 Updated the analysis population descriptions toalign with the study SAP.
Following regulatory feedback: Renamed Stage 1 to Phase 1, removed Stage 2,
and renamed Stage 3 to Phase 2/3.

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Protocol amendment 4

30 June 2020

Clarified that a single vaccine candidate,administered as 2 doses 21 days apart, will be
studied in Phase 2/3.
Stated that the vaccine candidate selected forPhase 2/3 evaluation is BNT162b2 at a dose of
30 µg.
Removed the potential to study BNT162b3.
Immunogenicity data will be summarized for the
first 360 participants through 1 month after Dose2, rather than through 21 days after Dose 1.
Provided further details of sponsor staff that will
be unblinded in Phase 2/3.
Clarified which stopping rules apply to which
phase of the study.

In addition:
 Clarified the AE reporting requirements forpotential COVID-19 illnesses.
 Updated that Visit 1 may be conducted across 2
consecutive days in Phase 2/3.
 Moved the immunogenicity objectives inPhase 2/3 to become exploratory.
 Added an additional inclusion criterion to enroll
participants who, in the judgment of theinvestigator, are at risk for acquiring COVID-19.
 Modified exclusion criterion 5, so thatparticipants with a previous clinical or
microbiological diagnosis of COVID-19 are
excluded from all phases of the study.
 Clarified that there will be 2 all-available
efficacy populations.
 Clarified that immunogenicity samples will bedrawn for all participants; analyses will be based
upon results from subsets of samples, according
to the purpose.
 Updated that the 3-tier approach to summarizing
AEs will only be performed in Phase 2/3.
 Updated that at each interim analysis for
efficacy, only the first primary objective will be
evaluated.
 Changed to use the same posterior probability(99.5%) for all interim analyses, resulting incase split changes in Tables 5, 6, and 7.
 Updated the stopping and alert rule parameters
for enhanced COVID-19.
Given the rapidly evolving pandemic situation, andthe need to demonstrate VE as soon as possible, theprotocol has been amended to be powered to meet
new efficacy objectives. These new efficacy

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objectives and corresponding endpoints have been
added to Section 3.
Further nonclinical data are available to support the
study of the BNT162b3 candidate in humans, and thecandidate has been added to the protocol.
The 6-month safety follow-up telephone contact has
been changed to an in-person visit for Stage 3
participants, to allow collection of an
immunogenicity blood sample.
The COVID-19 illness visit has now added
flexibility to permit a remote or in-person visit.

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to align with the FDA-accepted definitions; thischange is also reflected in the criteria for temporary
delay of enrollment.
AEs that occur between consent and dosing will now
be reported on the AE (rather than Medical History)
CRF, to align with the latest Pfizer protocol
template.
Changes have been made to the headings to alignwith the latest Pfizer protocol template.
Clarified that only an unblinded site staff member
may obtain the participant’s randomization number
and study intervention allocation.
Additional interim analyses have been added toevaluate VE and futility during the study.

Protocol amendment 3

10 June 2020

As a result of regulatory feedback, an appendix has
been added to outline the stopping and alert rules tomonitor for potential enhanced COVID-19.
As data have become available from this study andthe BNT162-01 study in Germany, the following
decisions were made: Not to study the BNT162a1 and BNT162c2
vaccine candidates at this time. Therefore, thesecandidates have been removed from theprotocol.
 To study further lower dose levels of the
modRNA candidates. Therefore, a 20-µg doselevel is formally included for BNT162b1 and
BNT162b2.

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To permit individual and group dosing
alterations for the second dose of study
intervention.

Following regulatory feedback, the BNT162b3
vaccine candidate has been removed from theprotocol until further nonclinical data are available tosupport study in humans.

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Given the rapidly evolving pandemic situation,
additional blood draws for exploratory COVID-19
research, intended to establish an immunologicalsurrogate of protection, will be taken from selectedparticipants who consent.
In order to increase flexibility enrolling participants,
an extended screening window (increased from 14 to
28 days) for sentinel participants in Stage 1 has been
added. This is considered acceptable since eligible
participants are expected to be either healthy or havestable medical conditions.
To increase the number of doses that can be obtained
from available vaccine vials, not all dose levels will
result in a dosing volume of 0.5 mL. Precise dosing
instructions will be provided in the IP manual.

Protocol amendment 2

27 May 2020

To facilitate the reporting of COVID-19 illness
diagnoses and potential symptoms to theinvestigator, participants may utilize a COVID-19
illness e-diary.
Given the urgent nature of the pandemic situation,
the following changes allow determination of theappropriate human dose level for both younger andolder adults to move speedily into the next phase ofclinical evaluation:
 Added a new vaccine candidate, BNT162b3,
modRNA encoding a membrane-anchored RBD
 Added a 50-µg dose level for vaccine candidates
based on the modRNA platform (ie, BNT162b1,
BNT162b2, and BNT162b3)
 Modified the criteria required for the IRC todetermine dose escalation in the 18- to 55-year
age cohort and advancement to groups ofparticipants 65 to 85 years of age
In addition:
 Removed hemoglobin change-from-baseline
abnormalities from the laboratory abnormality

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13 May 2020

Summary and Rationale for Changes

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grading scale as abnormalities should be gradedbased upon absolute values
Following regulatory feedback:
Modified exclusion criteria and prohibitedinhaled/nebulized corticosteroids for sentinel
participants in Stage 1
Clarified that the rapid test for prior COVID-19
infection for sentinel participants in Stage 1 will
be used only for screening purposes
Removed time frames for stopping rules
Stated that data supporting the selection of
vaccine candidate(s)/dose level(s) andschedule(s) for Stages 2 and 3 will be submitted
to the FDA for review
Following preliminary experience in the
BioNTech study conducted in Germany(BNT162-01):
Decreased the dose levels for BNT162a1 and
BNT162c2

Additionally: Clarified the roles of BioNTech and Pfizer
 Amended text so that the IRC decision toprogress group(s) into Stages 2 and 3 can bebased upon safety and immunogenicity data
after Dose 1 or 2
 Clarified safety data requirements to permit dose
escalation
 Amended text so that the progression toparticipants 65 to 85 years of age can be based
upon data from the same RNA platform Incorporated a protocol administrative change tocorrect the variant designation and the encoded
antigen to BNT162c2
 Clarified that the SARS-CoV-2 neutralizing
assay does not employ wild-type virus
 Clarified that the SARS-CoV-2 spike protein–binding antibody assay is specific for the S1subunit Clarified that efficacy against COVID-19 isbased upon illness (not infection) rate ratio Incorporated a protocol administrative change tostate that the study placebo may be supplied in a
glass or plastic vial Corrected a typographical error in Section 6.5.1
regarding the time frame for prior receipt ofblood/plasma products or immunoglobulins

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Original protocol

15 April 2020

Corrected a typographical error in Table 2
regarding the lower limit of diameter (cm) for
mild redness and swelling
Updated the °C fever scale in Table 4 to ensurethat all potential °F values are correctly assigned
Incorporated a protocol administrative change toclarify that a rapid test for prior COVID-19
infection will be performed for sentinel
participants in Stage 1, and a serum sample will
be drawn for potential future assessment
Clarified that, after screening, physicalexaminations in sentinel participants in Stage 1
will be directed
Clarified the descriptions of the populations foranalysis to align with the statistical analysis plan
Added a complete safety and immunogenicity
analysis approximately 6 months after Dose 2
for all participants in Stage 3
Amended text so that the stopping rules apply to
an RNA platform rather than a specific vaccine
candidate

N/A

This amendment incorporates all revisions to date, including amendments made at therequest of country health authorities and IRBs/ECs.

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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................13
1. PROTOCOL SUMMARY...................................................................................................15
1.1. Synopsis ..................................................................................................................15
1.2. Schema ....................................................................................................................22
1.3. Schedule of Activities .............................................................................................23
1.3.1. Phase 1 ........................................................................................................23
1.3.2. Phase 2/3.....................................................................................................28
2. INTRODUCTION ...............................................................................................................30
2.1. Study Rationale .......................................................................................................30
2.2. Background .............................................................................................................30
2.2.1. Clinical Overview.......................................................................................31090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)

2.3. Benefit/Risk Assessment.........................................................................................312.3.1. Risk Assessment .........................................................................................33
2.3.2. Benefit Assessment.....................................................................................34
2.3.3. Overall Benefit/Risk Conclusion................................................................34
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................34
3.1. For Phase 1 ..............................................................................................................34
3.2. For Phase 2/3 ...........................................................................................................36
4. STUDY DESIGN.................................................................................................................38
4.1. Overall Design.........................................................................................................38
4.1.1. Phase 1 ........................................................................................................39
4.1.2. Phase 2/3.....................................................................................................40
4.2. Scientific Rationale for Study Design .....................................................................40
4.3. Justification for Dose ..............................................................................................41
4.4. End of Study Definition ..........................................................................................42
5. STUDY POPULATION ......................................................................................................425.1. Inclusion Criteria.....................................................................................................425.2. Exclusion Criteria....................................................................................................43
5.3. Lifestyle Considerations..........................................................................................45
5.3.1. Contraception..............................................................................................45

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5.4. Screen Failures ........................................................................................................46
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study
Intervention Administration ......................................................................................46
6. STUDY INTERVENTION..................................................................................................47
6.1. Study Intervention(s) Administered ........................................................................47
6.1.1. Administration ............................................................................................48
6.2. Preparation/Handling/Storage/Accountability ........................................................48
6.2.1. Preparation and Dispensing ........................................................................49
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................50
6.3.1. Allocation to Study Intervention ................................................................50
6.3.2. Blinding of Site Personnel ..........................................................................50
6.3.3. Blinding of the Sponsor ..............................................................................50
6.3.4. Breaking the Blind......................................................................................51
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6.4. Study Intervention Compliance...............................................................................51
6.5. Concomitant Therapy..............................................................................................51
6.5.1. Prohibited During the Study .......................................................................52
6.5.2. Permitted During the Study ........................................................................52
6.6. Dose Modification...................................................................................................53
6.7. Intervention After the End of the Study ..................................................................53
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANTDISCONTINUATION/WITHDRAWAL...........................................................................53
7.1. Discontinuation of Study Intervention ....................................................................53
7.2. Participant Discontinuation/Withdrawal From the Study .......................................53
7.2.1. Withdrawal of Consent ...............................................................................54
7.3. Lost to Follow-up ....................................................................................................54
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................55
8.1. Efficacy and/or Immunogenicity Assessments .......................................................56
8.1.1. Biological Samples .....................................................................................58
8.2. Safety Assessments .................................................................................................59
8.2.1. Clinical Safety Laboratory Assessments (Phase 1 Participants Only) .......59
8.2.2. Electronic Diary..........................................................................................60
8.2.2.1. Grading Scales...........................................................................60
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8.2.2.2. Local Reactions .........................................................................60
8.2.2.3. Systemic Events ........................................................................61
8.2.2.4. Fever..........................................................................................62
8.2.2.5. Antipyretic Medication .............................................................63
8.2.3. Phase 1 Stopping Rules ..............................................................................63
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19
and Phase 2/3 Stopping Rule ...........................................................................64
8.2.5. Randomization and Vaccination After a Stopping Rule Is Met .................65
8.2.6. Pregnancy Testing ......................................................................................65
8.3. Adverse Events and Serious Adverse Events..........................................................66
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......66
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................67
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................67
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8.3.2. Method of Detecting AEs and SAEs ..........................................................67
8.3.3. Follow-up of AEs and SAEs.......................................................................67
8.3.4. Regulatory Reporting Requirements for SAEs...........................................68
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational
Exposure ..........................................................................................................68
8.3.5.1. Exposure During Pregnancy......................................................68
8.3.5.2. Exposure During Breastfeeding ................................................70
8.3.5.3. Occupational Exposure .............................................................70
8.3.6. Cardiovascular and Death Events...............................................................70
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not
Qualifying as AEs or SAEs..............................................................................71
8.3.8. Adverse Events of Special Interest .............................................................71
8.3.8.1. Lack of Efficacy ........................................................................71
8.3.9. Medical Device Deficiencies......................................................................71
8.3.10. Medication Errors .....................................................................................71
8.4. Treatment of Overdose............................................................................................72
8.5. Pharmacokinetics ....................................................................................................73
8.6. Pharmacodynamics..................................................................................................73
8.7. Genetics ...................................................................................................................73
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8.8. Biomarkers ..............................................................................................................73
8.9. Immunogenicity Assessments .................................................................................73
8.10. Health Economics .................................................................................................73
8.11. Study Procedures...................................................................................................73
8.11.1. Phase 1 ......................................................................................................73
8.11.1.1. Screening: (0 to 28 Days Before Visit 1) ................................73
8.11.1.2. Visit 1 – Vaccination 1: (Day 1) .............................................74
8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1to 3 Days After Visit 1) .....................................................................77
8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to
8 Days After Visit 1) .........................................................................78
8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1) ...........79

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8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to
8 Days After Visit 4) .........................................................................81
8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to
16 Days After Visit 4) .......................................................................82
8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After
Visit 4) ...............................................................................................83
8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (175 to 189 Days
After Visit 4)......................................................................................84
8.11.1.10. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 4)......................................................................................85
8.11.1.11. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 4)......................................................................................85
8.11.2. Phase 2/3...................................................................................................86
8.11.2.1. Visit 1 – Vaccination 1: (Day 1) .............................................86
8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days After Visit 1) ...........88
8.11.2.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2):(28 to 35 Days After Visit 2).............................................................90
8.11.2.4. Visit 4 – 6-Month Follow-up Visit: (175 to 189 Days
After Visit 2)......................................................................................91
8.11.2.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 2)......................................................................................91
8.11.2.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 2)......................................................................................92
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8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction ........................92
8.13. COVID-19 Surveillance (All Participants) ...........................................................94
8.13.1. Potential COVID-19 Illness Visit: (Optimally Within 3 Days After
Potential COVID-19 Illness Onset) .................................................................94
8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After
Potential COVID-19 Illness Visit)..................................................................96
8.14. Communication and Use of Technology...............................................................97
9. STATISTICAL CONSIDERATIONS ................................................................................97
9.1. Estimands and Statistical Hypotheses .....................................................................97
9.1.1. Estimands....................................................................................................97
9.1.2. Statistical Hypotheses.................................................................................98
9.2. Sample Size Determination.....................................................................................98
9.3. Analysis Sets ...........................................................................................................99
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9.4. Statistical Analyses ...............................................................................................100
9.4.1. Immunogenicity Analyses ........................................................................100
9.4.2. Efficacy Analyses .....................................................................................105
9.4.3. Safety Analyses ........................................................................................106
9.4.4. Other Analyses..........................................................................................1089.5. Interim Analyses ...................................................................................................1089.5.1. Analysis Timing........................................................................................111
9.6. Data Monitoring Committee or Other Independent Oversight Committee...........111
10. SUPPORTING DOCUMENTATION AND OPERATIONALCONSIDERATIONS ........................................................................................................113
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .............113
10.1.1. Regulatory and Ethical Considerations ..................................................113
10.1.1.1. Reporting of Safety Issues and Serious Breaches of theProtocol or ICH GCP.......................................................................113
10.1.2. Informed Consent Process ......................................................................114
10.1.3. Data Protection .......................................................................................115
10.1.4. Dissemination of Clinical Study Data ....................................................115
10.1.5. Data Quality Assurance ..........................................................................116
10.1.6. Source Documents ..................................................................................118
10.1.7. Study and Site Start and Closure ............................................................118
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10.1.8. Sponsor’s Qualified Medical Personnel .................................................11910.2. Appendix 2: Clinical Laboratory Tests ...............................................................120
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting ....................................................................122
10.3.1. Definition of AE .....................................................................................122
10.3.2. Definition of SAE ...................................................................................123
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.....................125
10.3.4. Reporting of SAEs..................................................................................128
10.4. Appendix 4: Contraceptive Guidance .................................................................129
10.4.1. Male Participant Reproductive Inclusion Criteria ..................................129
10.4.2. Female Participant Reproductive Inclusion Criteria...............................129
10.4.3. Woman of Childbearing Potential ..........................................................130
10.4.4. Contraception Methods...........................................................................131
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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ......133
10.6. Appendix 6: Abbreviations .................................................................................135
10.7. Appendix 7: Stopping and Alert Rules for Enhanced COVID-19 ......................139
10.8. Appendix 8: Criteria for Allowing Inclusion of Participants With Chronic
Stable HIV, HCV, or HBV Infection ......................................................................142
11. REFERENCES ................................................................................................................143
LIST OF TABLES
Table 1.

Local Reaction Grading Scale ..................................................................61

Table 2.

Systemic Event Grading Scale..................................................................62

Table 3.

Scale for Fever..........................................................................................63

Table 4.

Probability of Observing at Least 1 AE by Assumed True Event
Rates With Different Sample Sizes ..........................................................99

Table 5.

Interim Analysis Plan and Boundaries for Efficacy and Futility............109

Table 6.

Statistical Design Operating Characteristics: Probability of Successor Failure for Interim Analyses...............................................................110

Table 7.

Statistical Design Operating Characteristics: Probability of Successfor Final Analysis and Overall................................................................110

Table 8.

Laboratory Abnormality Grading Scale .................................................120

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Table 9.

Stopping Rule: Enrollment Is Stopped if the Number of Severe
Cases in the Vaccine Group Is Greater Than or Equal to the
Prespecified Stopping Rule Value (S) ....................................................140

Table 10.

Alert Rule: Further Action Is Taken if the Number of Severe Casesin the Vaccine Group Is Greater Than or Equal to the Prespecified
Alert Rule Value (A) ..............................................................................141

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1. PROTOCOL SUMMARY
1.1. Synopsis
Short Title: A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, andEfficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Individuals
Rationale

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A pneumonia of unknown cause detected in Wuhan, China, was first reported in
December 2019. On 08 January 2020, the pathogen causing this outbreak was identified as anovel coronavirus 2019. The outbreak was declared a Public Health Emergency ofInternational Concern on 30 January 2020. On 12 February 2020, the virus was officiallynamed as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the WHO
officially named the disease caused by SARS-CoV-2 as coronavirus disease 2019
(COVID-19). On 11 March 2020, the WHO upgraded the status of the COVID-19 outbreakfrom epidemic to pandemic, which is now spreading globally at high speed.
There are currently no licensed vaccines to prevent infection with SARS-CoV-2 or
COVID-19. Given the rapid transmission of COVID-19 and incidence of disease in the
United States and elsewhere, the rapid development of an effective vaccine is of utmost
importance.
BioNTech has developed RNA-based vaccine candidates using a platform approach thatenables the rapid development of vaccines against emerging viral diseases, including
SARS-CoV-2. Each vaccine candidate is based on a platform of nucleoside-modified
messenger RNA (modRNA, BNT162b). Each vaccine candidate expresses 1 of 2 antigens:the SARS-CoV-2 full-length, P2 mutant, prefusion spike glycoprotein (P2 S) (version 9) or atrimerized SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) (version 5).
The 2 SARS-CoV-2 vaccine candidates that will be tested in this study are therefore:
BNT162b1 (variant RBP020.3): a modRNA encoding the RBD;
BNT162b2 (variant RBP020.2): a modRNA encoding P2 S.
All candidates are formulated in the same lipid nanoparticle (LNP) composition. This study
is intended to investigate the safety, immunogenicity, and efficacy of these prophylactic
BNT162 vaccines against COVID-19.

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Objectives, Estimands, and Endpoints

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)For Phase 1
Objectives

Estimands

Endpoints

Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Primary:
In participants receiving at least 1 doseof study intervention, the percentage ofparticipants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each doseAdverse events (AEs) from
Dose 1 to 1 month after the lastdose
 Serious AEs (SAEs) from Dose 1
to 6 months after the last doseIn addition, the percentage ofparticipants with:
Abnormal hematology andchemistry laboratory values 1 and7 days after Dose 1; and 7 days
after Dose 2
Grading shifts in hematology andchemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2
Secondary:In participants complying with the key
protocol criteria (evaluableparticipants) at the following time
points after receipt of study
intervention:

Primary:
Local reactions (pain at the
injection site, redness, andswelling)

Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs

Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Hematology and chemistry laboratory
parameters detailed in Section 10.2

Secondary:

7 and 21 days after Dose 1; 7 and 14
days and 1, 6, 12, and 24 months after
Dose 2

Geometric mean titers (GMTs) at SARS-CoV-2 neutralizing titers
each time point
Geometric mean fold rise (GMFR)
from before vaccination to eachsubsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination

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Objectives

Estimands







Endpoints

S1-binding IgG levels and RBDGeometric mean concentrations
binding IgG levels(GMCs) at each time point
GMFR from before vaccination toeach subsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
Geometric mean ratio (GMR),
SARS-CoV-2 neutralizing titers
estimated by the ratio of theS1-binding IgG levels
geometric mean of SARS-CoV-2 
RBD-binding IgG levels
neutralizing titers to the geometricmean of binding IgG levels at eachtime point

For Phase 2/3

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)

Objectivesa

Estimands
Primary Efficacy

Endpoints

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 in participants
without evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of the last
dose) of past SARS-CoV-2 infection

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 in participants
with and without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAATCONFIDENTIAL
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Objectivesa

Estimands
Primary Safety

To define the safety profile ofprophylactic BNT162b2 in the first
360 participants randomized (Phase 2)

In participants receiving at least 1
dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 7 days after
the last dose
SAEs from Dose 1 to 7 days
after the last dose
In participants receiving at least
1 dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the last dose
 SAEs from Dose 1 to 6 months
after the last dose

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)

To define the safety profile ofprophylactic BNT162b2 in allparticipants randomized in Phase 2/3

Endpoints









Local reactions (pain at the
injection site, redness, andswelling)
Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened
muscle pain, and new orworsened joint pain)
AEs
SAEs
AEs
SAEs
In a subset of at least 6000
participants:
o Local reactions (pain at the
injection site, redness, andswelling)o Systemic events (fever,fatigue, headache, chills,
vomiting, diarrhea, new orworsened muscle pain, andnew or worsened joint pain)

Secondary Efficacy
To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed severe COVID-19 inparticipants without evidence of
infection before vaccination
To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed severe COVID-19 inparticipants with and without
evidence of infection before
vaccination
To describe the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms) inparticipants without evidence of
infection before vaccination
To describe the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms) inparticipants with and without
evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

Confirmed severe COVID-19
incidence per 1000 person-years offollow-up in participants with noserological or virological evidence of
past SARS-CoV-2 infection
Confirmed severe COVID-19
incidence per 1000 person-years offollow-up

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of the last
dose) of past SARS-CoV-2 infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAATCONFIDENTIAL
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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
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Protocol Amendment 6, 08 September 2020
Objectivesa

Estimands
Exploratory

To evaluate the immune responseover time to prophylactic BNT162b2
and persistence of immune response
in participants with and without
serological or virological evidence of
SARS-CoV-2 infection before
vaccination
To evaluate the immune response(non-S) to SARS-CoV-2 inparticipants with and without
confirmed COVID-19 during thestudy
To describe the serological responses
to the BNT vaccine candidate in casesof:
Confirmed COVID-19

Confirmed severe COVID-19

SARS-CoV-2 infection without
confirmed COVID-19
To describe the safety,
immunogenicity, and efficacy ofprophylactic BNT162b2 in
individuals with confirmed stable HIV
disease

GMC/GMT, GMFR, and percentageof participants with titers greater thandefined threshold(s), at baseline and1, 6, 12, and 24 months after
completion of vaccination

EndpointsS1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titersN-binding antibody

S1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titers
N-binding antibody
SARS-CoV-2 detection by
NAAT






All safety, immunogenicity, andefficacy endpoints describedabove

a. HIV-positive participants in Phase 3 will not be included in analyses of the objectives, with the
exception of the specific exploratory objective.

Overall Design
This is a Phase 1/2/3, multicenter, multinational, randomized, placebo-controlled, observerblind, dose-finding, vaccine candidate–selection, and efficacy study in healthy individuals.
The study consists of 2 parts: Phase 1: to identify preferred vaccine candidate(s) and doselevel(s); Phase 2/3: an expanded cohort and efficacy part. These parts, and the progression
between them, are detailed in the schema (Section 1.2).
The study will evaluate the safety, tolerability, and immunogenicity of 2 different
SARS-CoV-2 RNA vaccine candidates against COVID-19 and the efficacy of 1 candidate:

As a 2-dose (separated by 21 days) schedule;At various different dose levels in Phase 1;



In 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3: ≥16years of age [stratified as ≤55 or >55 years of age]).

Dependent upon safety and/or immunogenicity data generated during the course of thisstudy, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
in Phase 1 may be started at the next highest dose, groups may not be started, groups may be
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terminated early, and/or groups may be added with dose levels below the lowest stated doseor intermediate between the lowest and highest stated doses.
The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.
Number of Participants
Each group in Phase 1 will comprise 15 participants (12 receiving active vaccine and3 receiving placebo). In this phase, 13 groups will be studied, corresponding to a total of
195 participants.
The vaccine candidate selected for Phase 2/3, BNT162b2 at a dose of 30 µg, will comprise
21,999 vaccine recipients. It is intended that a minimum of 40% of participants will be in the>55-year stratum. An equal number of participants will receive placebo, ie, randomized in a
1:1 ratio.

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)Intervention Groups and Duration
The study will evaluate a 2-dose (separated by 21 days) schedule of various different doselevels of 2 investigational RNA vaccine candidates for active immunization against
COVID-19 in 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3:
≥16 years of age [stratified as ≤55 or >55 years of age]):

BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 20 µg, 30 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 20 µg, 30 µg

The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.
Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Phase 1
dosing arms that are not evaluated in Phase 2/3.
Data Monitoring Committee or Other Independent Oversight Committee
The study will utilize an IRC, an internal Pfizer committee that will review data to allow
dose escalation or changes to continuation of specific groups.
An external data monitoring committee (DMC) will be formed and will review cumulative
unblinded data throughout the study.
Statistical Methods
The sample size for Phase 1 of the study is not based on any statistical hypothesis testing.
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For Phase 2/3, the VE evaluation will be the primary objective. The VE is defined as
VE = 100 × (1 – IRR), where IRR is calculated as the ratio of the first confirmed COVID-19
illness rate in the vaccine group to the corresponding illness rate in the placebo group. Withassumptions of a true VE of 60% and 4 IAs planned, 164 COVID-19 cases will provide 90%
power to conclude true VE >30%. This would be achieved with a total 43,998 participants(21,999 vaccine recipients), based on the assumption of a 1.3% per year incidence in theplacebo group, accrual of 164 primary-endpoint cases within 6 months, and 20% of theparticipants being nonevaluable. If the attack rate is much higher, case accrual would be
expected to be more rapid, enabling the study’s primary endpoint to be evaluated muchsooner. The total number of participants enrolled in Phase 2/3 may vary depending on theincidence of COVID-19 at the time of the enrollment, the true underlying VE, and a potential
early stop for efficacy or futility.

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)

VE will be evaluated using a beta-binomial model and the posterior probability of VE being>30% will be assessed.
The primary safety objective will be evaluated by descriptive summary statistics for local
reactions, systemic events, AEs/SAEs, and abnormal hematology and chemistry laboratory
parameters (Phase 1 only), for each vaccine group. A 3-tier approach will be used tosummarize AEs in Phase 2/3.
The immunogenicity objectives will be evaluated descriptively by GMT, GMC, GMFR,
percentage of participants with ≥4-fold rise, percentage of participants with ≥ specified
threshold, and GMC ratio, and the associated 95% confidence intervals (CIs), for
SARS-CoV-2 neutralizing titers, S1-binding IgG levels, and RBD-binding IgG levels at thevarious time points.

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1.2. Schema
Phase 1For each vaccine candidate(4:1 randomization active:placebo)

Age: 18-55 yAge: 65-85 y

Low-dose-level 2-dose group (n=15)
IRC (safety)

IRC (safety

Low-dose-level 2-dose group (n=15)

after Dose 1)
Mid-dose-level 2-dose group (n=15)
IRC (safety)

IRC (safety

Mid-dose-level 2-dose group (n=15)

after Dose 1)
High-dose-level 2-dose group (n=15)
IRC (safety

High-dose-level 2-dose group (n=15)

after Dose 1)

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)

IRC choice of group(s) for Phase 2/3(safety & immunogenicity after Doses 1 and 2)

Phase 2/3
Single vaccine candidate
Safety and immunogenicity analysis of
Age: ≥16
Phase 2 data (first 360 participants)(Stratified 16-55 or >55)
by unblinded team (these participants
BNT162b2 30 µg or placebo 2 doses
will also be included in Phase 3(n~21,999 per group, total n~43.998)
analyses)Abbreviation: IRC = internal review committee.

(1:1 randomization active:placebo)

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1.3. Schedule of Activities

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with theprotocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations orassessments required to protect the well-being of the participant.
1.3.1. Phase 1
An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 10 (24-month follow-up visit) that COVID-19 is suspected.
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

X

X

X

X

X

Obtain informed consent

X

Assign participant number

X

Obtain demography andmedical history data

X

Obtain details of medications
currently taken

X

Perform physical examination

X

2

3

4

5

6

7

8

10

Unplanned

Unplanned

12 to 16 28 to 35 175 to
350 to714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4COVID-19 Illness Visit
Illness
Onset

X

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Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

Measure vital signs(including body temperature)

X

X

X

X

X

X

Collect blood sample forhematology and chemistrylaboratory testsb~10 mL~10 mL~10 mL~10 mL~10 mL

Collect screening blood
sample for HIV, HBsAg,
HBc Ab, and HCV Ab tests~10 mL

Serological test for prior
COVID-19 infection~20 mL

Perform urine pregnancy test
(if appropriate)X

Obtain nasal (midturbinate)swab(s)c

2

3

4

X

X

X

X

Collect nonstudy vaccine
information

X

X

Confirm eligibility

X

X

Collect prohibited medication
use

X

X

Review temporary delay
criteria

X

X

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 175 to
350 to714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4COVID-19 Illness Visit
Illness
Onset
X

X
X

X

X

X

X

X

X
X

Review hematology andchemistry results

X

5

X

X

X

X

X

X

X

X

X

X

X

X

X

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Protocol Amendment 6, 08 September 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

4

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

Confirm use of contraceptives(if appropriate)

X

X

X

X

X

X

~50 mL~50 mL

Obtain randomization number
and study intervention
allocation

X

Collect blood sample for
immunogenicity assessment~50 mL

Administer study intervention

X

X

Assess acute reactions for atleast 30 minutes after study
intervention administrationd

X

X

Explain participant
communication methods(including for e-diarycompletion), assist theparticipant with downloading
the app, or issue provisioned
device, if required

X

Provide thermometer andmeasuring device

X

5

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 175 to
350 to714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4COVID-19 Illness Visit
Illness
Onset
X

X~50 mL ~50 mL ~50 mL ~20 mL+++
optionale optionale optionale~170 mL ~170 mL ~170 mL~20 mL~20 mL~20 mL

X

Review reactogenicity e-diarydata (daily review is optimal
during the active diary period)

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Protocol Amendment 6, 08 September 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 46 to 8Days
After
Visit 1

Review ongoingreactogenicity e-diary
symptoms and obtain stopdatesCollect AEs and SAEs as
appropriate

4

5

X

X

X

X

X

X

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 175 to
350 to714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4COVID-19 Illness Visit
Illness
Onset
X

X

X

X

X

Collect e-diary or assist theparticipant to delete
application

X

X

X

X

X

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Protocol Amendment 6, 08 September 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 46 to 8Days
After
Visit 1

4

5

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 175 to
350 to714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4COVID-19 Illness Visit
Illness
Onset

Collection of COVID-19–
related clinical and laboratory
information (including local
diagnosis)

X

X

Abbreviations: e-diary = electronic diary; HBc Ab = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HCV Ab = hepatitis C virus antibody;
HIV = human immunodeficiency virus; NAAT = nucleic acid amplification test; vax = vaccination.

a.
b.
c.
d.
e.

The COVID-19 illness visit may be conducted as an in-person or telehealth visit.
Hematology: hemoglobin, complete blood count with differential, and platelets. Blood chemistry: alanine aminotransferase (ALT), aspartate
aminotransferase (AST), alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), and creatinine.
Two swabs will be taken at Visits 1 and 4. One will be tested (if possible at the site, otherwise at the central laboratory) within 24 hours and vaccination will
only proceed if it is NAAT-negative for SARS-CoV-2 genomes. The second will be sent to the central laboratory for potential later testing.
The first 5 participants in in each group will be observed at the site for at least 4 hours after study intervention administration. Further vaccination willcommence no sooner than 24 hours after the fifth participant received his or her vaccination.
An optional blood draw of ~170 mL will be taken at 1 of the visits (from selected participants who consent) for exploratory COVID-19 research.

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1.3.2. Phase 2/3
An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 6 (24-month follow-up visit) that COVID-19 is suspected.

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Visit Number

1

Visit Description

3

4

5

6

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
Potential
COVID-19
COVID-19
Illness Visita ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2

175 to 189
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

X

X

X

Vaccination 1 Vaccination 2

Day 1bVisit Window (Days)

Obtain informed consent

X

Assign participant number

X

Obtain demography and medical history data
Perform clinical assessment

2

Unplanned

Xc

X

For participants who are HIV positive, record latest
CD4 count and HIV viral load

X

Measure height and weightX

Measure temperature (body)

X

X

Perform urine pregnancy test (if appropriate)

X

X

Confirm use of contraceptives (if appropriate)

X

X

X

Collect nonstudy vaccine information

X

X

X

X

X

X

X

X

X

~20 mL~20 mL~20 mL~20 mL

Collect prohibited medication use

X

Confirm eligibility

X

X

Review temporary delay criteria

X

X

Collect blood sample for immunogenicity
assessmentd

Unplanned~20 mL

Obtain nasal (midturbinate) swab

X

Obtain randomization number and study
intervention allocation

X

X

X

X

~20 mLX

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Visit Number

1

Visit Description

Day 1bVisit Window (Days)

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2

3

4

5

6

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
Potential
COVID-19
COVID-19
Illness Visita ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2

175 to 189
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

Xe

Xe

Xe

Vaccination 1 Vaccination 2

Administer study intervention

X

X

Assess acute reactions for at least 30 minutes after
study intervention administration

X

X

Explain participant communication methods(including for e-diary completion), assist theparticipant with downloading the app, or issue
provisioned device, if required

X

Provide/ensure the participant has a thermometer(all participants) and measuring device(reactogenicity subset participants only)

X

Unplanned

Unplanned

X

Review reactogenicity e-diary data (daily review is
optimal during the active diary period)dReview ongoing reactogenicity e-diary symptoms
and obtain stop datesd
Collect AEs and SAEs as appropriate

X

X

X

X

X

Collect e-diary or assist the participant to delete
application

X

Xe

X

X

X

Collection of COVID-19–related clinical andlaboratory information (including local diagnosis)
Abbreviations: HIV = human immunodeficiency virus; e-diary = electronic diary.

a. The COVID-19 illness visit may be conducted as an in-person or telehealth visit.
b. The visit may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and exclusion criteria onwards must be conducted on thesame day.
c. Including, if indicated, a physical examination.
d. Reactogenicity subset participants only.
e. Any AEs occurring up to 48 hours after the blood draw must be recorded (see Section 8.3.1).
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2. INTRODUCTION
The BNT162 RNA-based COVID-19 vaccines are currently being investigated forprevention of COVID-19 in healthy individuals.
2.1. Study Rationale
The purpose of the study is to rapidly describe the safety, tolerability, and immunogenicity of
2 BNT162 RNA-based COVID-19 vaccine candidates against COVID-19, and the efficacyof 1 candidate, in healthy individuals. There are currently no licensed vaccines to prevent
infection with SARS-CoV-2 or COVID-19. Given the global crisis of COVID-19 and fast
expansion of the disease in the United States and elsewhere, the rapid development of aneffective vaccine is of utmost importance.

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2.2. Background
In December 2019, a pneumonia outbreak of unknown cause occurred in Wuhan, China.
In January 2020, it became clear that a novel coronavirus (2019-nCoV) was the underlying
cause. Later in January, the genetic sequence of the 2019-nCoV became available to theWorld Health Organization (WHO) and public (MN908947.3), and the virus was categorized
in the Betacoronavirus subfamily. By sequence analysis, the phylogenetic tree revealed acloser relationship to severe acute respiratory syndrome (SARS) virus isolates than to anothercoronavirus infecting humans, the Middle East respiratory syndrome (MERS) virus.
SARS-CoV-2 infections and the resulting disease, COVID-19, have spread globally,affecting a growing number of countries.
On 11 March 2020, the WHO characterized the COVID-19 outbreak as a pandemic.1
The WHO Situation Update Report dated 30 March 2020 noted 693,224 confirmed caseswith 33,106 deaths globally, including 142,081 confirmed cases with 2457 deaths in theAmericas.2 The United States currently has the most reported cases globally. At the time ofthis communication, the number of confirmed cases continues to rise globally. There are
currently no vaccines or effective antiviral drugs to treat SARS-CoV-2 infections or the
disease it causes, COVID-19.3
A prophylactic, RNA-based SARS-CoV-2 vaccine provides one of the most flexible andfastest approaches available to immunize against the emerging virus.4,5The development of an RNA-based vaccine encoding a viral antigen, which is then expressedby the vaccine recipient as a protein capable of eliciting protective immune responses,
provides significant advantages over more traditional vaccine approaches. Unlike live
attenuated vaccines, RNA vaccines do not carry the risks associated with infection and may
be given to people who cannot be administered live virus (eg, pregnant women andimmunocompromised persons). RNA-based vaccines are manufactured via a cell-free invitro transcription process, which allows an easy and rapid production and the prospect of
producing high numbers of vaccination doses within a shorter time period than achieved with

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traditional vaccine approaches. This capability is pivotal to enable the most effective
response in outbreak scenarios.
Two SARS-CoV-2–RNA lipid nanoparticle (RNA-LNP) vaccines based on a platform of
nucleoside-modified messenger RNA (modRNA, BNT162b) will be evaluated in this study.
Each vaccine candidate expresses 1 of 2 antigens: the SARS-CoV-2 full-length, P2 mutant,prefusion spike glycoprotein (P2 S) (version 9) or a trimerized SARS-CoV-2 spikeglycoprotein-receptor binding domain (RBD) (version 5). The 2 SARS-CoV-2 vaccine
candidates that will be tested in this study are therefore:

BNT162b1 (variant RBP020.3): nucleoside-modified messenger RNA (modRNA) withblunted innate immune sensor–activating capacity and augmented expression encoding
the RBD.



BNT162b2 (variant RBP020.2): nucleoside-modified messenger RNA (modRNA) as
above, but encoding P2 S.

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2.
2.2.1. Clinical Overview
Prior to this study, given clinical data from other similarly formulated uRNA liposomal
vaccines from BioNTech in oncology trials6 and recent published results from clinical trials
using modRNA influenza vaccines by Moderna,7 the BNT162 vaccines were expected tohave a favorable safety profile with mild, localized, and transient effects. BNT162 vaccines
based on modRNA have now been administered to humans for the first time in this study andthe BNT162-01 study conducted in Germany by BioNTech, at doses between 1 µg and100 µg. The currently available safety and immunogenicity data are presented in the BNT162
IB.
2.3. Benefit/Risk Assessment
There is an ongoing global pandemic of COVID-19 with no preventative or therapeutic
options available. While there were no data available from clinical trials on the use of
BNT162 vaccines in humans at the outset of this study, available nonclinical data with thesevaccines, and data from nonclinical studies and clinical trials with the same or related RNAcomponents, or antigens, supported a favorable risk/benefit profile. Anticipated AEs after
vaccination were expected to be manageable using routine symptom-driven standard of careas determined by the investigators and, as a result, the profile of these vaccine candidates
supported initiation of this Phase 1/2/3 clinical study.
Updates as part of protocol amendment 6:
In order for the overall Phase 3 study population to be as representative and diverse as
possible, the inclusion of participants with known chronic stable HIV, HCV, or HBV
infection is permitted. Individuals with chronic viral diseases are at increased risk for
COVID-19 complications and severe disease. In addition, with the currently available
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therapies for their treatment, many individuals with chronic stable HIV, HCV, and HBV
infections are unlikely to be at higher safety risk as a participant in this vaccine study
than individuals with other chronic stable medical conditions.
All participants with chronic stable HIV disease will be included in the reactogenicity
subset (see Section 8.2.2).

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More detailed information about the known and expected benefits and risks and reasonably
expected AEs of BNT162 RNA-based COVID-19 vaccines may be found in the IB, which is
the SRSD for this study.

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2.3.1. Risk Assessment
Potential Risk of ClinicalSignificance

Summary of Data/Rationale for Risk

Mitigation Strategy

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Study Intervention: BNT162 RNA-Based COVID-19 Vaccine
Potential for local reactions (injection These are common adverse reactions seensite redness, injection site swelling, with other vaccines, as noted in the FDA
and injection site pain) and systemic Center for Biologics Evaluation andResearch (CBER) guidelines on toxicity
events (fever, fatigue, headache,
grading scales for healthy adult volunteers
chills, vomiting, diarrhea, muscle
pain, and joint pain) following
enrolled in preventive vaccine clinicalvaccination.
trials.8

The Phase 1 study design includes the use of controlled vaccination anddose escalation to closely monitor and limit the rate of enrollment to ensure
participant safety. The study employs the use of a reactogenicity e-diary tomonitor local reactions and systemic events in real time. Stopping rules arealso in place. The first 5 participants in each group in Phase 1 will beobserved for 4 hours after vaccination to assess any immediate AEs. Allother participants will be observed for at least 30 minutes after vaccination.

Unknown AEs and laboratory
abnormalities with a novel vaccine.

The Phase 1 study design includes the use of controlled vaccination andThis study is one of the first 2 parallelrunning clinical studies with the BNT162 dose escalation to closely monitor and limit the rate of enrollment to ensure
vaccine candidates and as such there are no participant safety. An IRC (in Phase 1) and DMC (throughout the study)
will also review safety data. Stopping rules are also in place. The first 5
clinical data available for this vaccine.
participants in each group in Phase 1 will be observed for 4 hours after
vaccination to assess any immediate AEs. All other participants will beobserved for at least 30 minutes after vaccination.

Potential for COVID-19
enhancement.

Disease enhancement has been seen
following vaccination with respiratorysyncytial virus (RSV), feline coronavirus,
and Dengue virus vaccines.

Phase 1 excludes participants with likely previous or current COVID-19. In
Phase 2/3, temporary delay criteria defer vaccination of participants withpossible current clinical COVID-19. All participants are followed for
SARS-CoV-2 antigen-specific antibody and SARS-CoV-2 neutralizing
titers, and COVID-19 illness, including markers of severity.

Study Procedures
Participants will be required to attend Without appropriate social distancing andhealthcare facilities during the global PPE, there is a potential for increased
exposure to SARS-CoV-2.
SARS-CoV-2 pandemic.
Venipuncture will be performed
during the study.

There is the risk of bleeding, bruising,hematoma formation, and infection at the
venipuncture site.

Pfizer will work with sites to ensure an appropriate COVID-19 prevention
strategy. Potential COVID-19 illness visits can be conducted via telehealth,without the need for an in-person visit, if required, with the participant
performing a self-swab.
Only appropriately qualified personnel would obtain the blood draw.

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2.3.2. Benefit Assessment
Benefits to individual participants may include:Receipt of a potentially efficacious COVID-19 vaccine during a global pandemicAccess to COVID-19 diagnostic and antibody testingContributing to research to help others in a time of global pandemic

2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in thisstudy, the potential risks identified in association with BNT162 RNA-based COVID-19
vaccine are justified by the anticipated benefits that may be afforded to healthy participants.
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS

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3.1. For Phase 1
Objectives

Estimands

Endpoints

Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Primary:
In participants receiving at least 1 doseof study intervention, the percentage ofparticipants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each doseAdverse events (AEs) from
Dose 1 to 1 month after the lastdose
 Serious AEs (SAEs) from Dose 1
to 6 months after the last dosePrimary:
Local reactions (pain at the
injection site, redness, andswelling)

Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs

In addition, the percentage ofHematology and chemistry laboratory
participants with:parameters detailed in Section 10.2
Abnormal hematology andchemistry laboratory values 1 and7 days after Dose 1; and 7 days
after Dose 2
Grading shifts in hematology andchemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2

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Objectives

Estimands

Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Secondary:In participants complying with the key
protocol criteria (evaluableparticipants) at the following time
points after receipt of study
intervention: 7 and 21 days after Dose
1; 7 and 14 days and 1, 6, 12, and 24
months after Dose 2







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Endpoints
Secondary:

Geometric mean titers (GMTs) at SARS-CoV-2 neutralizing titers
each time point
Geometric mean fold rise (GMFR)
from before vaccination to eachsubsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
S1-binding IgG levels and RBDGeometric mean concentrations
binding IgG levels(GMCs) at each time point
GMFR from prior to first dose of
study intervention to eachsubsequent time point
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
Geometric mean ratio (GMR),estimated by the ratio of thegeometric mean of SARS-CoV-2 neutralizing titers to the geometric mean of binding IgG levels at
each time point

SARS-CoV-2 neutralizing titers
S1-binding IgG levels
RBD-binding IgG levels

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3.2. For Phase 2/3
Objectivesa
To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 in participants
without evidence of infection before
vaccination

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 in participants
with and without evidence of
infection before vaccination

Estimands
Primary Efficacy
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

Endpoints
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of the last
dose) of past SARS-CoV-2 infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT

Primary Safety
In participants receiving at least 1
dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 7 days after
the last dose
SAEs from Dose 1 to 7 days
after the last dose

To define the safety profile ofprophylactic BNT162b2 in allparticipants randomized in Phase 2/3

In participants receiving at least
1 dose of study intervention, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the last dose
SAEs from Dose 1 to 6 months
after the last dose

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed severe COVID-19 inparticipants without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

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To define the safety profile ofprophylactic BNT162b2 in the first
360 participants randomized (Phase 2)



Local reactions (pain at the
injection site, redness, andswelling)
Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened
muscle pain, and new orworsened joint pain)
AEs
SAEs

AEs
SAEs
In a subset of at least 6000
participants:
o Local reactions (pain at the
injection site, redness, andswelling)o Systemic events (fever,fatigue, headache, chills,
vomiting, diarrhea, new orworsened muscle pain, andnew or worsened joint pain)

Secondary Efficacy
Confirmed severe COVID-19
incidence per 1000 person-years offollow-up in participants with noserological or virological evidence of
past SARS-CoV-2 infection

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Objectivesa

Estimands

Endpoints

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed severe COVID-19 inparticipants with and without
evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

Confirmed severe COVID-19
incidence per 1000 person-years offollow-up

To describe the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms) inparticipants without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of the last
dose) of past SARS-CoV-2 infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT

To describe the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms) inparticipants with and without
evidence of infection before
vaccination

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Exploratory
To evaluate the immune responseover time to prophylactic BNT162b2
and persistence of immune response
in participants with and without
serological or virological evidence of
SARS-CoV-2 infection before
vaccination

GMC/GMT, GMFR, and percentageof participants with titers greater thandefined threshold(s), at baseline and1, 6, 12, and 24 months after
completion of vaccination

S1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titers

To evaluate the immune response(non-S) to SARS-CoV-2 inparticipants with and without
confirmed COVID-19 during the
study



N-binding antibody

To describe the serological responses
to the BNT vaccine candidate in casesof:
Confirmed COVID-19

Confirmed severe COVID-19

SARS-CoV-2 infection without
confirmed COVID-19
To describe the safety,
immunogenicity, and efficacy ofprophylactic BNT162b2 in
individuals with confirmed stable
HIV diseaseS1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titers
N-binding antibody
SARS-CoV-2 detection by
NAAT






All safety, immunogenicity, andefficacy endpoints describedabove

a. HIV-positive participants in Phase 3 will not be included in analyses of the objectives, with the
exception of the specific exploratory objective.

This protocol will use a group of internal case reviewers to determine whether certain
investigator-reported events meet the definition of disease-related efficacy endpoints, using
predefined endpoint criteria.

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For those AEs that are handled as disease-related efficacy endpoints (which may include
death), a DMC will conduct unblinded reviews on a regular basis throughout the trial(see Section 9.6).
Any AE that is determined by the internal case reviewers NOT to meet endpoint criteria isreported back to the investigator site of incidence. Refer to Section 8.3.1.1 for instructions
on how to report any such AE that meets the criteria for seriousness to Pfizer Safety.
4. STUDY DESIGN
4.1. Overall Design
This is a multicenter, multinational, Phase 1/2/3, randomized, placebo-controlled, observerblind, dose-finding, vaccine candidate–selection, and efficacy study in healthy individuals.
The study consists of 2 parts. Phase 1: to identify preferred vaccine candidate(s) and doselevel(s); Phase 2/3: an expanded cohort and efficacy part. These parts, and the progression
between them, are detailed in the schema (Section 1.2).

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)The study will evaluate the safety, tolerability, and immunogenicity of 2 different
SARS-CoV-2 RNA vaccine candidates against COVID-19 and the efficacy of 1 candidate:

As a 2-dose (separated by 21 days) schedule;At various different dose levels in Phase 1;



In 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3: ≥16years of age [stratified as ≤55 or >55 years of age]).

Dependent upon safety and/or immunogenicity data generated during the course of thisstudy, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
in Phase 1 may be started at the next highest dose, groups may not be started, groups may beterminated early, and/or groups may be added with dose levels below the lowest stated doseor intermediate between the lowest and highest stated doses.
The study is observer-blinded, as the physical appearance of the investigational vaccine
candidates and the placebo may differ. The participant, investigator, study coordinator, andother site staff will be blinded. At the study site, only the dispenser(s)/administrator(s) are
unblinded.
To facilitate rapid review of data in real time, sponsor staff will be unblinded to vaccine
allocation for the participants in Phase 1.

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4.1.1. Phase 1
Each group (vaccine candidate/dose level/age group) will comprise 15 participants;
12 participants will be randomized to receive active vaccine and 3 to receive placebo.

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)For each vaccine candidate/dose level/age group, the following apply:Additional safety assessments (see Section 8.2)

Controlled enrollment (required only for the first candidate and/or dose level studied):No more than 5 participants (4 active, 1 placebo) can be vaccinated on the first day

The first 5 participants must be observed by blinded site staff for at least 4 hours after
vaccination for any acute reactions

Vaccination of the remaining participants will commence no sooner than 24 hours
after the fifth participant received his or her vaccination

Application of stopping rules

IRC review of safety data to determine escalation to the next dose level in the 18- to
55-year age cohort:Escalation between dose levels will be based on IRC review of at least 7-day
post–Dose 1 safety data in this study and/or the BioNTech study conducted inGermany (BNT162-01)

Note that, since both candidates are based upon the same RNA platform, dose
escalation for the second candidate studied may be based upon the safety profile ofthe first candidate studied being deemed acceptable at the same, or a higher, doselevel by the IRC

Groups of participants 65 to 85 years of age will not be started until safety data for the RNA
platform have been deemed acceptable at the same, or a higher, dose level in the 18- to
55-year age cohort by the IRC.
In this phase, 13 groups will be studied, corresponding to a total of 195 participants.
The IRC will select 1 vaccine candidate that, in Phase 1, has an established dose level per age
group based on induction of a post–Dose 2 immune response, including neutralizing
antibodies, which is expected to be associated with protection against COVID-19, forprogression into Phase 2/3.

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4.1.2. Phase 2/3
On the basis of safety and/or immunogenicity data generated during the course of this study,
and/or the BioNTech study conducted in Germany (BNT162-01), 1 vaccine candidate wasselected to proceed into Phase 2/3. Participants in this phase will be ≥16 years of age,stratified as follows: 16 to 55 years or >55 years. It is intended that a minimum of 40% ofparticipants will be in the >55-year stratum. Commencement of each age stratum will bebased upon satisfactory post–Dose 2 safety and immunogenicity data from the 18- to 55-year
and 65- to 85-year age groups in Phase 1, respectively. The vaccine candidate selected forPhase 2/3 evaluation is BNT162b2 at a dose of 30 µg.

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Phase 2/3 is event-driven. Under the assumption of a true VE rate of ≥60%, after the lastdose of investigational product, a target of 164 primary-endpoint cases of confirmed
COVID-19 due to SARS-CoV-2 occurring at least 7 days following the last dose of the
primary series of the candidate vaccine will be sufficient to provide 90% power to conclude
true VE >30% with high probability. The total number of participants enrolled in Phase 2/3
may vary depending on the incidence of COVID-19 at the time of the enrollment, the true
underlying VE, and a potential early stop for efficacy or futility.
Assuming a COVID-19 attack rate of 1.3% per year in the placebo group, accrual of 164
primary-endpoint cases within 6 months, an estimated 20% nonevaluable rate, and 1:1
randomization, the BNT162b2 vaccine candidate selected for Phase 2/3 is expected tocomprise approximately 21,999 vaccine recipients. This is the number of participants
initially targeted for Phase 2/3 and may be adjusted based on advice from DMC analyses ofcase accumulation and the percentage of participants who are seropositive at baseline.
Dependent upon the evolution of the pandemic, it is possible that the COVID-19 attack rate
may be much higher, in which case accrual would be expected to be more rapid, enabling thestudy’s primary endpoint to be evaluated much sooner.
The first 360 participants enrolled (180 to active vaccine and 180 to placebo, stratified
equally between 18 to 55 years and >55 to 85 years) will comprise the “Phase 2” portion.
Safety data through 7 days after Dose 2 and immunogenicity data through 1 month after
Dose 2 from these 360 participants will be analyzed by the unblinded statistical team,reviewed by the DMC, and submitted to appropriate regulatory authorities for review.
Enrollment may continue during this period and these participants would be included in theefficacy evaluation in the “Phase 3” portion of the study.
Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Phase 1
dosing arms that are not evaluated in Phase 2/3.
4.2. Scientific Rationale for Study Design
Additional surveillance for COVID-19 will be conducted as part of the study, given thepotential risk of disease enhancement. If a participant experiences symptoms, as detailed in
Section 8.13, a COVID-19 illness and subsequent convalescent visit will occur. As part ofthese visits, samples (nasal [midturbinate] swab and blood) will be taken for antigen and
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antibody assessment as well as recording of COVID-19–related clinical and laboratory
information (including local diagnosis).
Human reproductive safety data are not available for BNT162 RNA-based COVID-19
vaccines, but there is no suspicion of human teratogenicity based on the intended mechanismof action of the compound. Therefore, the use of a highly effective method of contraception
is required (see Appendix 4).
4.3. Justification for Dose

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Because of the requirement for a rapid response to the newly emerged COVID-19 pandemic,
sufficient data were not available to experimentally validate the dose selection and initialstarting dose. Therefore, the original planned starting dose of 10 µg (for both BNT162b1 and
BNT162b2) in this study was based on nonclinical experience with the same RNAs encoding
other viral antigens (such as influenza and HIV antigens). The general safety andeffectiveness of uRNA and modRNA platforms have been demonstrated in oncologicalclinical trials with different administration routes (NCT02410733, NCT03871348). Doses of
up to 400 µg total uRNA have been administered IV as RNA lipoplex (RNA-LPX) and dosesof up to 1000 µg total naked modRNA have been administered intratumorally, both without
signs of unpredictable overstimulation of the immune system.
Based on nonclinical data of the RNA components, with other liposomes or in conjunction
with the lipid nanoparticles as will be tested clinically in this study, it was expected that
doses in the 1- to 5-µg range would be immunogenic and induce neutralizing antibodies;
however, it was anticipated that 3- to 10-fold higher doses would likely be required to elicit astronger antibody response. Based on previous clinical and nonclinical experience, it was
expected that doses of up to 100 µg would be well tolerated.
Update as part of protocol amendment 2: preliminary experience in this study and the
BioNTech study conducted in Germany (BNT162-01) suggests that, for vaccine candidates
based on the modRNA platform, a dose level between 30 µg and 100 µg warrants
consideration. Therefore, a 50-µg dose level is formally included for BNT162b1 and
BNT162b2.
Update as part of protocol amendment 3: as data have become available from this study andthe BNT162-01 study in Germany, it was decided:

To not study the BNT162a1 and BNT162c2 vaccine candidates at this time, so thesecandidates have been removed from the protocol; andThat lower dose levels of BNT162b1 and BNT162b2 warrant consideration. Therefore, a
20-µg dose level is formally included for both candidates.

Update as part of protocol amendment 4: the 50-µg dose level for BNT162b1 and BNT162b2
is removed and the 100-µg dose level for BNT162b2 is removed; similar dose levels of
BNT162b3 may be studied as for BNT162b1 and BNT162b2.
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Update as part of protocol amendment 5: the vaccine candidate selected for Phase 2/3
evaluation is BNT162b2 at a dose of 30 µg. BNT162b3 will not be studied.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases ofthe study, including the last visit. Note that participants enrolled in Phase 1 in groups that do
not proceed to Phase 2/3 may be followed for fewer than 24 months (but no less than
6 months after the last vaccination).
The end of the study is defined as the date of last visit of the last participant in the study.
5. STUDY POPULATION

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)This study can fulfill its objectives only if appropriate participants are enrolled. The
following eligibility criteria are designed to select participants for whom participation in the
study is considered appropriate. All relevant medical and nonmedical conditions should betaken into consideration when deciding whether a particular participant is suitable for thisprotocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male or female participants between the ages of 18 and 55 years, inclusive, and 65 and85 years, inclusive (Phase 1), or ≥16 years (Phase 2/3), at randomization.


Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female(Section 10.4.2) participants.

Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, vaccination
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Healthy participants who are determined by medical history, physical examination(if required), and clinical judgment of the investigator to be eligible for inclusion in the
study.
Note: Healthy participants with preexisting stable disease, defined as disease notrequiring significant change in therapy or hospitalization for worsening disease during
the 6 weeks before enrollment, can be included. Specific criteria for Phase 3 participants

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with known stable infection with human immunodeficiency virus (HIV), hepatitis C virus(HCV), or hepatitis B virus (HBV) can be found in Section 10.8.
4. Phase 2/3 only: Participants who, in the judgment of the investigator, are at higher risk
for acquiring COVID-19 (including, but not limited to, use of mass transportation,
relevant demographics, and frontline essential workers).
Informed Consent:
5. Capable of giving personal signed informed consent as described in Appendix 1, which
includes compliance with the requirements and restrictions listed in the ICD and in thisprotocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:

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Medical Conditions:
1. Other medical or psychiatric condition including recent (within the past year) or active
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study
participation or, in the investigator’s judgment, make the participant inappropriate for the
study.
2. Phases 1 and 2 only: Known infection with human immunodeficiency virus (HIV),hepatitis C virus (HCV), or hepatitis B virus (HBV).
3. History of severe adverse reaction associated with a vaccine and/or severe allergic
reaction (eg, anaphylaxis) to any component of the study intervention(s).
4. Receipt of medications intended to prevent COVID-19.
5. Previous clinical or microbiological diagnosis of COVID-19.
6. Phase 1 only: Individuals at high risk for severe COVID-19, including those with any of
the following risk factors:Hypertension

Diabetes mellitus

Chronic pulmonary diseaseAsthma

Current vaping or smoking

History of chronic smoking within the prior year

Chronic liver disease
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<60 mL/min/1.73 m2)



Resident in a long-term facility

BMI >30 kg/m2

Anticipating the need for immunosuppressive treatment within the next 6 months

7. Phase 1 only: Individuals currently working in occupations with high risk of exposure to
SARS-CoV-2 (eg, healthcare worker, emergency response personnel).
8. Immunocompromised individuals with known or suspected immunodeficiency, as
determined by history and/or laboratory/physical examination.

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9. Phase 1 only: Individuals with a history of autoimmune disease or an active autoimmune
disease requiring therapeutic intervention, including but not limited to: systemic or
cutaneous lupus erythematosus, autoimmune arthritis/rheumatoid arthritis, Guillain-Barré
syndrome, multiple sclerosis, Sjögren’s syndrome, idiopathic thrombocytopenia purpura,glomerulonephritis, autoimmune thyroiditis, giant cell arteritis (temporal arteritis),
psoriasis, and insulin-dependent diabetes mellitus (type 1).
10. Bleeding diathesis or condition associated with prolonged bleeding that would, in theopinion of the investigator, contraindicate intramuscular injection.
11. Women who are pregnant or breastfeeding.
Prior/Concomitant Therapy:
12. Previous vaccination with any coronavirus vaccine.
13. Individuals who receive treatment with immunosuppressive therapy, including cytotoxic
agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned
receipt throughout the study. If systemic corticosteroids have been administered shortterm (<14 days) for treatment of an acute illness, participants should not be enrolled into
the study until corticosteroid therapy has been discontinued for at least 28 days before
study intervention administration. Inhaled/nebulized (except for participants in
Phase 1 – see exclusion criterion 14), intra-articular, intrabursal, or topical (skin or eyes)corticosteroids are permitted.
14. Phase 1 only: Regular receipt of inhaled/nebulized corticosteroids.
15. Receipt of blood/plasma products or immunoglobulin, from 60 days before study
intervention administration or planned receipt throughout the study.

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Prior/Concurrent Clinical Study Experience:
16. Participation in other studies involving study intervention within 28 days prior to study
entry and/or during study participation.
17. Previous participation in other studies involving study intervention containing lipid
nanoparticles.
Diagnostic Assessments:
18. Phase 1 only: Positive serological test for SARS-CoV-2 IgM and/or IgG antibodies atthe screening visit.

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19. Phase 1 only: Any screening hematology and/or blood chemistry laboratory value thatmeets the definition of a ≥ Grade 1 abnormality.
Note: With the exception of bilirubin, participants with any stable Grade 1 abnormalities(according to the toxicity grading scale) may be considered eligible at the discretion of
the investigator. (Note: A “stable” Grade 1 laboratory abnormality is defined as a reportof Grade 1 on an initial blood sample that remains ≤ Grade 1 upon repeat testing on asecond sample from the same participant.)
20. Phase 1 only: Positive test for HIV, hepatitis B surface antigen (HBsAg), hepatitis B
core antibodies (HBc Abs), or hepatitis C virus antibodies (HCV Abs) at the screening
visit.
21. Phase 1 only: SARS-CoV-2 NAAT-positive nasal swab within 24 hours before receipt ofstudy intervention.
Other Exclusions:
22. Investigator site staff or Pfizer/BioNTech employees directly involved in the conduct of
the study, site staff otherwise supervised by the investigator, and their respective family
members.
5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm thatthe participant has selected an appropriate method of contraception for the individual
participant and his or her partner(s) from the permitted list of contraception methods(see Appendix 4, Section 10.4.4) and will confirm that the participant has been instructed inits consistent and correct use. At time points indicated in the SoA, the investigator ordesignee will inform the participant of the need to use highly effective contraception
consistently and correctly and document the conversation and the participant’s affirmation in
the participant’s chart (participants need to affirm their consistent and correct use of at least 1
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instruct the participant to call immediately if the selected contraception method is
discontinued or if pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but
are not subsequently randomly assigned to study intervention. A minimal set of screen
failure information is required to ensure transparent reporting of screen failure participants tomeet the CONSORT publishing requirements and to respond to queries from regulatory
authorities. Minimal information includes demography, screen failure details, eligibility
criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may berescreened under a different participant number.

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5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention
Administration
The following conditions are temporary or self-limiting and a participant may be vaccinatedonce the condition(s) has/have resolved and no other exclusion criteria are met.
1. Current febrile illness (body temperature ≥100.4°F [≥38°C]) or other acute illness within
48 hours before study intervention administration. This includes current symptoms that
could represent a potential COVID-19 illness:

New or increased cough;

New or increased shortness of breath;Chills;

New or increased muscle pain;New loss of taste/smell;

Sore throat;

Diarrhea;Vomiting.

2. Receipt of any seasonal or pandemic influenza vaccine within 14 days, or any othernonstudy vaccine within 28 days, before study intervention administration.
3. Anticipated receipt of any seasonal or pandemic influenza vaccine within 14 days, or any
other nonstudy vaccine within 28 days, after study intervention administration.
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4. Receipt of short-term (<14 days) systemic corticosteroids. Study intervention
administration should be delayed until systemic corticosteroid use has been discontinued
for at least 28 days. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin oreyes) corticosteroids are permitted.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s),placebo, medical device(s), or study procedure(s) intended to be administered to a study
participant according to the study protocol.
The study will evaluate a 2-dose (separated by 21 days) schedule of various different doselevels of 2 investigational RNA vaccine candidates for active immunization against
COVID-19 in 3 age groups (18 to 55 years of age, 65 to 85 years of age, and ≥16 years ofage [stratified as ≤55 or >55 years of age]).

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These 2 investigational RNA vaccine candidates, with the addition of saline placebo, are the
3 potential study interventions that may be administered to a study participant:

BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 20 µg, 30 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 20 µg, 30 µgNormal saline (0.9% sodium chloride solution for injection)

The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.
6.1. Study Intervention(s) Administered
Intervention NameType
Dose Formulation

BNT162b1(BNT162 RNA-LNP
vaccine utilizing
modRNA)
VaccinemodRNA

BNT162b2(BNT162 RNA-LNP
vaccine utilizing
modRNA)
VaccinemodRNA

Saline Placebo

Placebo
Normal saline (0.9%sodium chloride solution
for injection)
Unit Dose Strength(s)250 µg/0.5 mL
250 µg/0.5 mL
N/Aa
Dosage Level(s)10-, 20-, 30-, 100-µg
10-, 20-, 30-µg
N/A
Route of Administration Intramuscular injection
Intramuscular injection
Intramuscular injection
Use
Experimental
Experimental
Placebo
IMP or NIMP
IMP
IMP
IMP
Sourcing
Provided centrally by the Provided centrally by the Provided centrally by thesponsorsponsorsponsorPackaging and Labeling Study intervention will be Study intervention will be Study intervention will be
provided in a glass vial as provided in a glass vial as provided in a glass or
open-label supply. Each
open-label supply. Each
plastic vial as open-labelvial will be labeled asvial will be labeled as
supply. Each vial will be
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BNT162b2
Saline Placebo
BNT162b1(BNT162 RNA-LNP(BNT162 RNA-LNP
vaccine utilizing
vaccine utilizing
modRNA)
modRNA)required per country
required per country
labeled as required per
requirement
requirement
country requirement
Dependent upon safety and/or immunogenicity data generated during the course of this study, or the
BioNTech study conducted in Germany (BNT162-01), it is possible that groups may be started at the next
highest dose, groups may not be started, groups may be terminated early, and/or groups may be addedwith dose levels below the lowest stated dose or intermediate between the lowest and highest stated doses.

Intervention Namea.

The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.
6.1.1. Administration

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Participants will receive 1 dose of study intervention as randomized at each vaccination visit(Visits 1 and 4 for Phase 1 participants, Visits 1 and 2 for Phase 2/3 participants) inaccordance with the study’s SoA. The volume to be administered may vary by vaccine
candidate and dose level; full details are described in the IP manual.
Study intervention should be administered intramuscularly into the deltoid muscle, preferablyof the nondominant arm, by an unblinded administrator.
Standard vaccination practices must be observed and vaccine must not be injected into bloodvessels. Appropriate medication and other supportive measures for management of an acute
hypersensitivity reaction should be available in accordance with local guidelines for standard
immunization practices.
Administration of study interventions should be performed by an appropriately qualified,
GCP-trained, and vaccine-experienced member of the study staff (eg, physician, nurse,
physician’s assistant, nurse practitioner, pharmacist, or medical assistant) as allowed by
local, state, and institutional guidance.
Study intervention administration details will be recorded on the CRF.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study interventions received and any discrepancies arereported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only
authorized site staff may supply or administer study intervention. All study interventions
must be stored in a secure, environmentally controlled, and monitored (manual or
automated recording) area in accordance with the labeled storage conditions with accesslimited to the investigator and authorized site staff. At a minimum, daily minimum andmaximum temperatures for all site storage locations must be documented and available
upon request. Data for nonworking days must indicate the minimum and maximum
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temperatures since previously documented for all site storage locations upon return tobusiness.
3. Any excursions from the study intervention label storage conditions should be reported to
Pfizer upon discovery along with any actions taken. The site should actively pursue
options for returning the study intervention to the storage conditions described in thelabeling, as soon as possible. Once an excursion is identified, the study intervention must
be quarantined and not used until Pfizer provides permission to use the study
intervention. Specific details regarding the definition of an excursion and information thesite should report for each excursion will be provided to the site in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage conditions
stated on the label.
5. Study interventions should be stored in their original containers.

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6. See the IP manual for storage conditions of the study intervention.
7. The investigator, institution, or the head of the medical institution (where applicable) is
responsible for study intervention accountability, reconciliation, and record maintenance(ie, receipt, reconciliation, and final disposition records), such as the IPAL orsponsor-approved equivalent. All study interventions will be accounted for using a study
intervention accountability form/record.
8. Further guidance and information for the final disposition of unused study interventions
are provided in the IP manual. All destruction must be adequately documented. If
destruction is authorized to take place at the investigator site, the investigator must ensurethat the materials are destroyed in compliance with applicable environmental regulations,institutional policy, and any special instructions provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of
discovery as described in the IP manual.
6.2.1. Preparation and Dispensing
See the IP manual for instructions on how to prepare the study intervention foradministration. Study intervention should be prepared and dispensed by an appropriately
qualified and experienced member of the study staff (eg, physician, nurse, physician’s
assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as allowed by
local, state, and institutional guidance. A second staff member will verify the dispensing.
Study intervention and placebo will be prepared by qualified unblinded site personnel
according to the IP manual. The study intervention will be administered in such a way toensure the participants remain blinded.

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6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
Allocation (randomization) of participants to vaccine groups will proceed through the use of
an IRT system (IWR). The site personnel (study coordinator or specified designee) will be
required to enter or select information including but not limited to the user’s ID andpassword, the protocol number, and the participant number. The site personnel will then be
provided with a vaccine assignment and randomization number. The IRT system will
provide a confirmation report containing the participant number, randomization number, andstudy intervention allocation assigned. The confirmation report must be stored in the site’s
files.
The study-specific IRT reference manual and IP manual will provide the contact informationand further details on the use of the IRT system.

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6.3.2. Blinding of Site Personnel
In this observer blinded study, the study staff receiving, storing, dispensing, preparing, andadministering the study interventions will be unblinded. All other study and site personnel,
including the investigator, investigator staff, and participants, will be blinded to study
intervention assignments. In particular, the individuals who evaluate participant safety willbe blinded. Because the BNT162 RNA-based COVID-19 vaccine candidates and placebo
are different in physical appearance, the study intervention syringes will be administered in amanner that prevents the study participants from identifying the study intervention type basedon its appearance.
The responsibility of the unblinded dispenser and administrator must be assigned to anindividual or individuals who will not participate in the evaluation of any study participants.
Contact between the unblinded dispenser and study participants and unblinded administrator
and study participants should be kept to a minimum. The remaining site personnel must notknow study intervention assignments.
6.3.3. Blinding of the Sponsor
To facilitate rapid review of data in real time, sponsor staff will be unblinded to study
intervention allocation for the participants in Phase 1. The majority of sponsor staff will beblinded to study intervention allocation in Phase 2/3. All laboratory testing personnel
performing serology assays will remain blinded to study intervention assigned/received
throughout the study. The following sponsor staff, who will have no part in the blinded
conduct of the study, will be unblinded in Phase 2/3 (further details will be provided in a data
blinding plan):

Those study team members who are involved in ensuring that protocol requirements forstudy intervention preparation, handling, allocation, and administration are fulfilled at thesite will be unblinded for the duration of the study (eg, unblinded study manager,
unblinded clinical research associate).
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Unblinded clinician(s), who are not direct members of the study team and will notparticipate in any other study-related activities, will review unblinded protocol
deviations.

An unblinded team supporting interactions with, and analyses for, the DMC(see Section 9.6). This will comprise a statistician, programmer(s), and a medical
monitor who will review cases of severe COVID-19 as they are received, and will review
AEs at least weekly for additional potential cases of severe COVID-19(see Section 8.2.3).

An unblinded submissions team will be responsible for preparing unblinded analyses anddocuments to support regulatory activities that may be required while the study is
ongoing. All statistical analyses conducted on Phase 2/3 data while the study is ongoing,that are not in support of the DMC, will be performed by this team. This team will nothave access to unblinded COVID-19 cases unless efficacy is achieved in either an interim
analysis or the final analysis, as determined by the DMC.

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6.3.4. Breaking the Blind
The IRT will be programmed with blind-breaking instructions. In case of an emergency, theinvestigator has the sole responsibility for determining if unblinding of a participant’s study
intervention assignment is warranted. Participant safety must always be the firstconsideration in making such a determination. If the investigator decides that unblinding iswarranted, the investigator should make every effort to contact the sponsor prior to
unblinding a participant’s vaccine assignment unless this could delay further management of
the participant. If a participant’s vaccine assignment is unblinded, the sponsor must be
notified within 24 hours after breaking the blind. The date and reason that the blind was
broken must be recorded in the source documentation and CRF.
The study-specific IRT reference manual and IP manual will provide the contact informationand further details on the use of the IRT system.
6.4. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from theinvestigator or designee, under medical supervision. The date and time of each dose
administered in the clinic will be recorded in the source documents and recorded in the CRF.
The dose of study intervention and study participant identification will be confirmed at thetime of dosing by a member of the study site staff other than the person administering thestudy intervention.
6.5. Concomitant Therapy
The following concomitant medications and vaccinations will be recorded in the CRF:
All vaccinations received from 28 days prior to study enrollment until the 6-monthfollow-up visit (Visit 8 for Phase 1 participants, and Visit 4 for Phase 2/3 participants).
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Prohibited medications listed in Section 6.5.1 will be recorded, to include start and stop
dates, name of the medication, dose, unit, route, and frequency.

In addition, for participants enrolled in Phase 1, all current medication at baseline will berecorded, to include start date, name of the medication, dose, unit, route, and frequency.

6.5.1. Prohibited During the Study
Receipt of the following vaccines and medications during the time periods listed below may
exclude a participant from the per-protocol analysis from that point onwards, and may
require vaccinations to be discontinued in that participant; however, it is anticipated that theparticipant would not be withdrawn from the study (see Section 7). Medications should not
be withheld if required for a participant’s medical care.

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Unless considered medically necessary, no vaccines other than study intervention should be
administered within 28 days before and 28 days after each study vaccination. One exception
to this is that seasonal and pandemic influenza vaccine can be given at least 14 days after, orat least 14 days prior to, the administration of study intervention.
Receipt of chronic systemic treatment with known immunosuppressant medications, orradiotherapy, within 60 days before enrollment through conclusion of the study.
Receipt of systemic corticosteroids (≥20 mg/day of prednisone or equivalent) for ≥14 days is
prohibited from 28 days prior to enrollment to Visit 7 for Phase 1 participants, and Visit 3 forPhase 2/3 participants).
Receipt of inhaled/nebulized corticosteroids from 28 days prior to enrollment to Visit 7(1-month follow-up visit) for Phase 1 participants.
Receipt of blood/plasma products or immunoglobulins within 60 days before enrollment
through conclusion of the study.
Receipt of any other (nonstudy) coronavirus vaccine at any time prior to or during study
participation is prohibited.
Prophylactic antipyretics and other pain medication to prevent symptoms associated withstudy intervention administration are not permitted. However, if a participant is taking a
medication for another condition, even if it may have antipyretic or pain-relieving properties,
it should not be withheld prior to study vaccination.
6.5.2. Permitted During the Study
The use of antipyretics and other pain medication to treat symptoms associated with study
intervention administration or ongoing conditions is permitted.
Medication other than that described as prohibited in Section 6.5.1 required for treatment ofpreexisting stable conditions is permitted.
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Inhaled (except in Phase 1 participants – see Section 6.5.1), topical, or localized injections ofcorticosteroids (eg, intra-articular or intrabursal administration) are permitted.
6.6. Dose Modification
This protocol allows some alteration of vaccine dose for individual participants and/or dosegroups from the currently outlined dosing schedule. For reasons of reactogenicity,
tolerability, or safety, the IRC may recommend to reduce the second dose of study
intervention and/or increase the interval between doses.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANTDISCONTINUATION/WITHDRAWAL

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7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study
intervention (definitive discontinuation). Reasons for definitive discontinuation of study
intervention may include the following: AEs; participant request; investigator request;
pregnancy; protocol deviation (including no longer meeting all the inclusion criteria, or
meeting 1 or more exclusion criteria). Note that a positive SARS-CoV-2 NAAT result
without symptoms should not result in discontinuation of study intervention.
Note that discontinuation of study intervention does not represent withdrawal from the study.
Per the study estimands, if study intervention is definitively discontinued, the participant willremain in the study to be evaluated for safety, immunogenicity, and efficacy. See the SoA
for data to be collected at the time of discontinuation of study intervention and follow-up for
any further evaluations that need to be completed.
In the event of discontinuation of study intervention, it must be documented on theappropriate CRF/in the medical records whether the participant is discontinuing further
receipt of study intervention or also from study procedures, posttreatment study follow-up,
and/or future collection of additional information.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request. Reasons fordiscontinuation from the study may include the following:

Refused further follow-up;

Lost to follow-up;



Death;



Study terminated by sponsor;



AEs;
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Investigator request;Protocol deviation.

If a participant does not return for a scheduled visit, every effort should be made to contact
the participant. All attempts to contact the participant and information received duringcontact attempts must be documented in the participant’s source document. In any
circumstance, every effort should be made to document participant outcome, if possible.
The investigator or his or her designee should capture the reason for withdrawal in the CRF
for all participants.

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If a participant withdraws from the study, he/she may request destruction of any remaining
samples taken and not tested, and the investigator must document any such requests in thesite study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1)
for disclosure of future information, no further evaluations should be performed and no
additional data should be collected. The sponsor may retain and continue to use any datacollected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not beviewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent
Participants who request to discontinue receipt of study intervention will remain in the study
and must continue to be followed for protocol-specified follow-up procedures. The only
exception to this is when a participant specifically withdraws consent for any further contact
with him or her or persons previously authorized by the participant to provide thisinformation. Participants should notify the investigator in writing of the decision towithdraw consent from future follow-up, whenever possible. The withdrawal of consent
should be explained in detail in the medical records by the investigator, as to whether thewithdrawal is only from further receipt of study intervention or also from study procedures
and/or posttreatment study follow-up, and entered on the appropriate CRF page. In the eventthat vital status (whether the participant is alive or dead) is being measured, publicly
available information should be used to determine vital status only as appropriately directedin accordance with local law.
7.3. Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return forscheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to attend a required study visit:

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The site must attempt to contact the participant and reschedule the missed visit as soon as
possible and counsel the participant on the importance of maintaining the assigned visit
schedule and ascertain whether or not the participant wishes to and/or should continue inthe study;

Before a participant is deemed lost to follow-up, the investigator or designee must makeevery effort to regain contact with the participant (where possible, 3 telephone calls and,if necessary, a certified letter to the participant’s last known mailing address or local
equivalent methods). These contact attempts should be documented in the participant’s
medical record;Should the participant continue to be unreachable, he/she will be considered to havewithdrawn from the study.

8. STUDY ASSESSMENTS AND PROCEDURES

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The full date of birth will be collected to critically evaluate the immune response and safety
profile by age.
Study procedures and their timing are summarized in the SoA. Protocol waivers or
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence orawareness to determine whether the participant should continue or discontinue study
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential
participants meet all eligibility criteria. The investigator will maintain a screening log torecord details of all participants screened and to confirm eligibility or record reasons forscreening failure, as applicable.
Every effort should be made to ensure that protocol-required tests and procedures arecompleted as described. However, it is anticipated that from time to time there may becircumstances outside the control of the investigator that may make it unfeasible to performthe test. In these cases, the investigator must take all steps necessary to ensure the safety andwell-being of the participant. When a protocol-required test cannot be performed, theinvestigator will document the reason for the missed test and any corrective and preventive
actions that he or she has taken to ensure that required processes are adhered to as soon as
possible. The study team must be informed of these incidents in a timely manner.

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For samples being collected and shipped, detailed collection, processing, storage, andshipment instructions and contact information will be provided to the investigator site prior
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately up
to 515 mL for participants in Phase 1, and approximately up to 110 mL for Phase 2/3
participants. Additionally, 20 mL of blood will be taken at an unplanned convalescent visit
at any time a participant develops respiratory symptoms indicating a potential COVID-19
infection. Select participants in Phase 1 will also be asked to provide an additional blood
sample of approximately 170 mL at either Visit 5, 6, or 7. These participants would
therefore have a total blood sampling volume of 700 mL during the 24-month study period.
Other additional blood samples may be taken for safety assessments at times specified by
Pfizer, provided the total volume taken during the study does not exceed 550 mL during any
period of 60 consecutive days.

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8.1. Efficacy and/or Immunogenicity Assessments
Efficacy will be assessed throughout a participant’s involvement in the study throughsurveillance for potential cases of COVID-19. If, at any time, a participant develops acuterespiratory illness (see Section 8.13), for the purposes of the study he or she will beconsidered to potentially have COVID-19 illness.9 In this circumstance, the participant
should contact the site, an in-person or telehealth visit should occur, and assessments should
be conducted as specified in the SoA. The assessments will include a nasal (midturbinate)swab, which will be tested at a central laboratory using a reverse transcription–polymerase
chain reaction (RT-PCR) test (Cepheid; FDA approved under EUA), or other equivalent
nucleic acid amplification–based test (ie, NAAT), to detect SARS-CoV-2. In addition,clinical information and results from local standard-of-care tests (as detailed in Section 8.13)
will be assessed. A local NAAT result will be considered acceptable if it was obtained using:An FDA-cleared (including Emergency Use Authorization) assay; orAn assay that is not FDA-cleared but was conducted in a laboratory that is currently
CLIA-certified; orAn assay performed by a laboratory accredited according to the ISO 15189 standard by anational or regional accreditation body.

Two definitions of SARS-CoV-2–related cases, and SARS-CoV-2–related severe cases, will
be considered (for both, the onset date of the case will be the date that symptoms were firstexperienced by the participant):Confirmed COVID-19: presence of at least 1 of the following symptoms and
SARS-CoV-2 NAAT positive during, or within 4 days before or after, the symptomatic
period, either at the central laboratory or at a local testing facility (using an acceptabletest):

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Fever;

New or increased cough;

New or increased shortness of breath;Chills;

New or increased muscle pain;New loss of taste or smell;

Sore throat;

Diarrhea;Vomiting.

The second definition, which may be updated as more is learned about COVID-19, will
include the following additional symptoms defined by the CDC (listed athttps://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html):



Fatigue;Headache;

Nasal congestion or runny nose;Nausea.

Confirmed severe COVID-19: confirmed COVID-19 and presence of at least 1 of thefollowing:Clinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per minute,HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or PaO2/FiO2<300 mm Hg);

Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation,mechanical ventilation, or ECMO);

Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiring vasopressors);

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Death.

The DMC may recommend modification of the definition of severe disease according toemerging information.
* Three blinded case reviewers (medically qualified Pfizer staff members) will review all
potential COVID-19 illness events. If a NAAT-confirmed case in Phase 2/3 may beconsidered severe, or not, solely on the basis of this criterion, the blinded data will be
reviewed by the case reviewers to assess whether the criterion is met; the majority opinion
will prevail.
In addition, a serological definition will be used for participants without clinical presentationof COVID-19:


Confirmed seroconversion to SARS-CoV-2 without confirmed COVID-19: positive
N-binding antibody result in a participant with a prior negative N-binding antibody result

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Serum samples will be obtained for immunogenicity testing at the visits specified in the SoA.
The following assays will be performed:

SARS-CoV-2 neutralization assay

S1-binding IgG level assay

RBD-binding IgG level assay

N-binding antibody assay

Note that all immunogenicity analyses will be based upon samples analyzed at the central
laboratory; the rapid test will only be performed at screening by all sites recruiting
participants in Phase 1 (see Section 8.11.1.1) to determine eligibility.
Serum obtained from the additional ~170-mL blood sample from select participants in Phase
1 at either Visit 5, 6, or 7 will be used for exploratory COVID-19 research, intended toestablish a surrogate endpoint that is reasonably likely to predict clinical benefit.
8.1.1. Biological Samples
Blood and nasal swab samples will be used only for scientific research. Each sample will belabeled with a code so that the laboratory personnel testing the samples will not know theparticipant’s identity. Samples that remain after performing assays outlined in the protocol
may be stored by Pfizer. Unless a time limitation is required by local regulations or ethicalrequirements, the samples will be stored for up to 15 years after the end of the study and thendestroyed. If allowed by the ICD, stored samples may be used for additional testing to better
understand the immune responses to the vaccine(s) under study in this protocol, to inform thedevelopment of other products, and/or for vaccine-related assay work supporting vaccine
programs. No testing of the participant’s DNA will be performed.
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The participant may request that his or her samples, if still identifiable, be destroyed at any
time; however, any data already collected from those samples will still be used for thisresearch. The biological samples may be shared with other researchers as long asconfidentiality is maintained and no testing of the participant’s DNA is performed.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinicallaboratory measurements may be obtained at any time during the study to assess any
perceived safety issues.
A clinical assessment, including medical history, will be performed on all participants at
his/her first visit to establish a baseline. Significant medical history and observations fromany physical examination, if performed, will be documented in the CRF.
AEs and SAEs are collected, recorded, and reported as defined in Section 8.3.

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Acute reactions within the first 4 hours after administration of the study intervention (for the
first 5 participants vaccinated in each Phase 1 group), and within the first 30 minutes (for theremainder of participants), will be assessed and documented in the AE CRF.
The safety parameters also include reactogenicity e-diary reports of local reactions andsystemic events (including fever), and use of antipyretic medication that occur in the 7 days
after administration of the study intervention. These prospectively self-collected occurrencesof local reactions and systemic events are graded as described in Section 8.2.2.
8.2.1. Clinical Safety Laboratory Assessments (Phase 1 Participants Only)
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for
the timing and frequency. All protocol-required laboratory assessments, as defined inAppendix 2, must be conducted in accordance with the laboratory manual and the SoA.
Unscheduled clinical laboratory measurements may be obtained at any time during the study
to assess any perceived safety issues.
The investigator must review the laboratory report, document this review, and record any
clinically relevant changes occurring during the study in the AE section of the CRF. See
Appendix 2 for the grading scale for assessment of clinically significant abnormal laboratory
findings. Clinically significant abnormal laboratory findings are those which are notassociated with the underlying disease, unless judged by the investigator to be more severe
than expected for the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during
participation in the study or within 28 days after the last dose of study intervention should be
repeated until the values return to normal or baseline or are no longer considered clinicallysignificant by the investigator or medical monitor.

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If such values do not return to normal/baseline within a period of time judged reasonable by
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 5 for suggested actions and follow-up assessments in the event of potential
drug-induced liver injury (DILI).
8.2.2. Electronic Diary

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Participants will be required to complete a reactogenicity e-diary through an application(see Section 8.14) installed on a provisioned device or on the participant’s own personal
device. All participants in Phase 1, and a subset of at least the first 6000 randomized inPhase 2/3, will be asked to monitor and record local reactions, systemic events, andantipyretic medication usage for 7 days following administration of the study intervention.
All participants in Phase 3 who are HIV positive will be included in this subset. The
reactogenicity e-diary allows recording of these assessments only within a fixed time
window, thus providing the accurate representation of the participant’s experience at thattime. Data on local reactions and systemic events reported in the reactogenicity e-diary willbe transferred electronically to a third-party vendor, where they will be available for review
by investigators and the Pfizer clinicians at all times via an internet-based portal.
At intervals agreed to by the vendor and Pfizer, these data will be transferred electronicallyinto Pfizer's database for analysis and reporting. These data do not need to be reported by theinvestigator in the CRF as AEs.
Investigators (or designee) will be required to review the reactogenicity e-diary data online atfrequent intervals as part of the ongoing safety review.
The investigator or designee must obtain stop dates from the participant for any ongoing
local reactions, systemic events, or use of antipyretic medication on the last day that thereactogenicity e-diary was completed. The stop dates should be documented in the source
documents and the information entered in the CRF.
8.2.2.1. Grading Scales
The grading scales used in this study to assess local reactions and systemic events as
described below are derived from the FDA Center for Biologics Evaluation and Research(CBER) guidelines on toxicity grading scales for healthy adult volunteers enrolled inpreventive vaccine clinical trials.8
8.2.2.2. Local Reactions
During the reactogenicity e-diary reporting period, participants will be asked to assess
redness, swelling, and pain at the injection site and to record the symptoms in thereactogenicity e-diary. If a local reaction persists beyond the end of the reactogenicity
e-diary period following vaccination, the participant will be requested to report that
information. The investigator will enter this additional information in the CRF.

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Redness and swelling will be measured and recorded in measuring device units(range: 1 to 21) and then categorized during analysis as absent, mild, moderate, or severe
based on the grading scale in Table 1. Measuring device units can be converted tocentimeters according to the following formula: 1 measuring device unit = 0.5 cm. Pain at
the injection site will be assessed by the participant as absent, mild, moderate, or severe
according the grading scale in Table 1.
If a Grade 3 local reaction is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinicallyindicated. Only an investigator or medically qualified person is able to classify aparticipant’s local reaction as Grade 4. If a participant experiences a confirmed Grade 4 local
reaction, the investigator must immediately notify the sponsor and, if it is determined to berelated to the administration of the study intervention, further vaccinations will be
discontinued in that participant.
Table 1.

Local Reaction Grading Scale

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Mild(Grade 1)

Moderate(Grade 2)

Pain at the
injection site

Does not interferewith activity

Interferes withactivity

Redness>2.0 cm to 5.0 cm(5 to 10 measuring
device units)>2.0 cm to 5.0 cm(5 to 10 measuring
device units)>5.0 cm to 10.0 cm(11 to 20 measuring
device units)>5.0 cm to 10.0 cm(11 to 20 measuring
device units)

Swelling

Severe(Grade 3)

Potentially Life
Threatening(Grade 4)
Prevents daily activity Emergency room visit
or hospitalization forsevere pain
>10 cmNecrosis or(≥21 measuringexfoliative dermatitis
device units)>10 cmNecrosis(≥21 measuring
device units)

8.2.2.3. Systemic Events
During the reactogenicity e-diary reporting period, participants will be asked to assess
vomiting, diarrhea, headache, fatigue, chills, new or worsened muscle pain, and new orworsened joint pain and to record the symptoms in the reactogenicity e-diary. The symptoms
will be assessed by the participant as absent, mild, moderate, or severe according to thegrading scale in Table 2.
If a Grade 3 systemic event is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinicallyindicated. Only an investigator or medically qualified person is able to classify aparticipant’s systemic event as Grade 4. If a participant experiences a confirmed Grade 4
systemic event, the investigator must immediately notify the sponsor and, if it is determined
to be related to the administration of the study intervention, further vaccinations will be
discontinued in that participant.

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Table 2.

Systemic Event Grading Scale

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Mild(Grade 1)

Moderate(Grade 2)>2 times in
24 hours

Severe(Grade 3)

Vomiting

1-2 times in
24 hours

Requires IV
hydration

Diarrhea

2 to 3 loose stools 4 to 5 loose stools
in 24 hours
in 24 hours

6 or more loosestools in 24 hours

Headache

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Fatigue/tiredness

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Chills

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

New orworsened
muscle pain

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Does not interfere Some interference
New orwith activity
with activity
worsened
joint pain
Abbreviation: IV = intravenous.

Prevents daily
routine activity

Potentially Life
Threatening(Grade 4)
Emergency room visit or
hospitalization for
hypotensive shock
Emergency room visit or
hospitalization for severe
diarrhea
Emergency room visit or
hospitalization for severe
headache
Emergency room visit or
hospitalization for severe
fatigue
Emergency room visit or
hospitalization for severe
chillsEmergency room visit or
hospitalization for severe
new or worsened muscle
painEmergency room visit or
hospitalization for severe
new or worsened joint pain

8.2.2.4. Fever
In order to record information on fever, a thermometer will be given to participants with
instructions on how to measure oral temperature at home. Temperature will be collected in
the reactogenicity e-diary in the evening daily during the reactogenicity e-diary reporting
period. It will also be collected at any time during the reactogenicity e-diary data collection
periods when fever is suspected. Fever is defined as an oral temperature of ≥38.0°C(100.4°F). The highest temperature for each day will be recorded in the reactogenicity
e-diary. Temperature will be measured and recorded to 1 decimal place and then categorized
during analysis according to the scale shown in Table 3.
If a fever of ≥39.0°C (102.1°F) is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinicallyindicated. Only an investigator or medically qualified person is able to confirm aparticipant’s fever as >40.0°C (>104.0°F). If a participant experiences a confirmed fever>40.0°C (>104.0°F), the investigator must immediately notify the sponsor and, if it isdetermined to be related to the administration of the study intervention, further vaccinations
will be discontinued in that participant.

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Table 3.

Scale for Fever≥38.0-38.4°C (100.4-101.1°F)>38.4-38.9°C (101.2-102.0°F)>38.9-40.0°C (102.1-104.0°F)>40.0°C (>104.0°F)

8.2.2.5. Antipyretic Medication
The use of antipyretic medication to treat symptoms associated with study intervention
administration will be recorded in the reactogenicity e-diary daily during the reporting period(Day 1 to Day 7).

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8.2.3. Phase 1 Stopping Rules
The following stopping rules are in place for all Phase 1 participants, based on review of AE
data and e-diary reactogenicity data, until the start of Phase 2/3 or 30 days after the last doseof study intervention in Phase 1, whichever is later. These data will be monitored on an
ongoing basis by the investigator (or medically qualified designee) and sponsor in order topromptly identify and flag any event that potentially contributes to a stopping rule.
The sponsor study team will be unblinded during Phase 1, so will be able to assess whether
or not a stopping rule has been met on the basis of a participant’s individual study
intervention allocation.
In the event that sponsor personnel confirm that a stopping rule is met, the following actions
will commence:The IRC will review all appropriate data.

The stopping rule will PAUSE randomization and study intervention administration for
the impacted vaccine candidate all dose levels and age groups.



The DMC will review all appropriate data.

For all participants vaccinated, all other routine study conduct activities, including
ongoing data entry, reporting of AEs, participant reactogenicity e-diary completion,
blood sample collection, and participant follow-up, will continue during the pause.

A stopping rule is met if any of the following rules occur after administration of
investigational BNT162 vaccine; data from placebo recipients will not contribute to thestopping rules. Reactogenicity e-diary data confirmed by the investigator as being entered by
the participant in error will not contribute toward a stopping rule.
The BNT162b RNA platform will be evaluated for contribution to stopping rules overall;
vaccine candidate dose levels within the platform and age groups will contribute to stopping
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rules together. However, it is possible that the recommendations may include halting or
continuing randomization with any of the BNT162 vaccine candidates.
Stopping Rule Criteria for Each BNT162 Vaccine Candidate:
1. If any participant vaccinated with the BNT162 candidate (at any dose level) develops an
SAE that is assessed by the investigator as possibly related, or for which there is noalternative, plausible, attributable cause.
2. If any participant vaccinated with the BNT162 candidate (at any dose level) develops a
Grade 4 local reaction or systemic event after vaccination (see Section 8.2.2) that is
assessed as possibly related by the investigator, or for which there is no alternative,plausible, attributable cause.

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3. If any participant vaccinated with the BNT162 candidate (at any dose level) develops afever >40.0°C (>104.0°F) for at least 1 daily measurement after vaccination(see Section 8.2.2.4) that is assessed as possibly related by the investigator, or for which
there is no alternative, plausible, attributable cause.
4. If any 2 participants vaccinated with the BNT162 candidate (at any dose level) report thesame or similar severe (Grade 3) AE (including laboratory abnormalities) after
vaccination, assessed as possibly related by the investigator, or for which there is noalternative, plausible, attributable cause.
5. If any participant dies or requires ICU admission due to SARS-CoV-2 infection; if thisstopping rule is met, all available clinical and preclinical safety and immunogenicity data
should be reviewed to evaluate for enhanced COVID-19.
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19 and Phase 2/3
Stopping Rule
Participants in all phases of the study will be surveilled for potential COVID-19 illness from
Visit 1 onwards (see Section 8.13).
As this is a sponsor open-label study during Phase 1, the sponsor will conduct unblinded
reviews of the data during the course of the study, including for the purpose of safetyassessment. All NAAT-confirmed cases in Phase 1 will be reviewed contemporaneously by
the IRC and the DMC (see Section 9.6).
In Phase 2/3, the unblinded team supporting the DMC, including an unblinded medical
monitor, will review cases of severe COVID-19 as they are received and will review AEs atleast weekly for additional potential cases of severe COVID-19. At any point, the unblinded
team may discuss with the DMC chair whether the DMC should review cases for an adverse
imbalance of cases of COVID-19 and/or severe COVID-19 between the vaccine and placebogroups.

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The purpose of these reviews will be to identify whether any features of each case appear
unusual, in particular greater in severity, compared to available information at the time ofreview. Indicators of severity may include accelerated deterioration, need for hospitalization,need for ventilation, or death. Observed rates of these indicators will be compared with what
could be expected in a similar population to the study participants based upon available
information at the time of review.
Stopping and alert rules will be applied as follows. The stopping rule will be triggered whenthe 1-sided probability of observing the same or a more extreme case split is 5% or less when
the true incidence of severe disease is the same for vaccine and placebo participants, and alert
criteria are triggered when this probability is less than 11%. In addition, when the total
number of severe cases is low (15 or less), the unblinded team supporting the DMC will
implement the alert rule when a reverse case split of 2:1 or worse is observed. For example,
at 3 cases 2:1, at 4 cases 3:1, etc. Below 15 cases, this rule is more rigorous than requiring
the probability of an observed adverse split or worse be <11%. Further details can be foundin Section 10.7.

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8.2.5. Randomization and Vaccination After a Stopping Rule Is Met
Once the IRC (if in Phase 1) and DMC (all phases) have reviewed the safety data andprovided guidance, a notification will be sent from the sponsor to the sites with guidance on
how to proceed.
8.2.6. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA,
immediately before the administration of each vaccine dose. A negative pregnancy test result
will be required prior to the participant’s receiving the study intervention. Pregnancy tests
may also be repeated if requested by IRBs/ECs or if required by local regulations. In thecase of a positive confirmed pregnancy, the participant will be withdrawn fromadministration of study intervention but may remain in the study.

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8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or
the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, andrecording events that meet the definition of an AE or SAE and remain responsible to pursue
and obtain adequate information both to determine the outcome and to assess whether the
event meets the criteria for classification as an SAE or caused the participant to discontinue
the study intervention (see Section 7.1).
Each participant will be questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up
information in an expedited fashion.

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8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection
period”) for each participant begins from the time the participant provides informed consent,
which is obtained before the participant’s participation in the study (ie, before undergoing
any study-related procedure and/or receiving study intervention), through and including
Visit 7 for Phase 1 participants, and Visit 3 for Phase 2/3 participants. In addition, any AEs
occurring up to 48 hours after each subsequent blood draw must be recorded on the CRF.
SAEs will be collected from the time the participant provides informed consent toapproximately 6 months after the last dose of study intervention (Visit 8 for Phase 1
participants, and Visit 4 for Phase 2/3 participants).
Follow-up by the investigator continues throughout and after the active collection period anduntil the AE or SAE or its sequelae resolve or stabilize at a level acceptable to theinvestigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervention
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE
reported using the Vaccines SAE Report Form.
Investigators are not obligated to actively seek AEs or SAEs after the participant has
concluded study participation. However, if the investigator learns of any SAE, including a
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death, at any time after a participant has completed the study, and he/she considers the event
to be reasonably related to the study intervention, the investigator must promptly report the
SAE to Pfizer using the Vaccines SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in
Section 8.3.1 are reported to Pfizer Safety on the Vaccines SAE Report Form immediately
upon awareness and under no circumstance should this exceed 24 hours, as indicated inAppendix 3. The investigator will submit any updated SAE data to the sponsor within
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period,
which begins after obtaining informed consent as described in Section 8.3.1, will be recordedon the AE section of the CRF.

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)The investigator is to record on the CRF all directly observed and all spontaneously reported
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and theprocedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended andnonleading verbal questioning of the participant is the preferred method to inquire about
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow eachparticipant at subsequent visits/contacts. For each event, the investigator must pursue andobtain adequate information until resolution, stabilization, the event is otherwise explained,or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail toallow for a complete medical assessment of the case and independent determination of
possible causality. Any information relevant to the event, such as concomitant medications
and illnesses, must be provided. In the case of a participant death, a summary of available
autopsy findings must be submitted as soon as possible to Pfizer Safety.
Further information on follow-up procedures is given in Appendix 3.

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8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal
obligations and ethical responsibilities towards the safety of participants and the safety of astudy intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and otherregulatory agencies about the safety of a study intervention under clinical investigation. The
sponsor will comply with country-specific regulatory requirements relating to safety
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the
study and will notify the IRB/EC, if appropriate according to local requirements.

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8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding andoccupational exposure are reportable to Pfizer Safety within 24 hours of investigatorawareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if:A female participant is found to be pregnant while receiving or after discontinuing study
intervention.



A male participant who is receiving or has discontinued study intervention exposes afemale partner prior to or around the time of conception.



A female is found to be pregnant while being exposed or having been exposed to study
intervention due to environmental exposure. Below are examples of environmental
exposure during pregnancy:

A female family member or healthcare provider reports that she is pregnant after
having been exposed to the study intervention by inhalation or skin contact.

A male family member or healthcare provider who has been exposed to the study
intervention by inhalation or skin contact then exposes his female partner prior to or
around the time of conception.

The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s
awareness, irrespective of whether an SAE has occurred. The initial information submitted
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should include the anticipated date of delivery (see below for information related totermination of pregnancy).


If EDP occurs in a participant or a participant’s partner, the investigator must report thisinformation to Pfizer Safety on the Vaccines SAE Report Form and an EDP
Supplemental Form, regardless of whether an SAE has occurred. Details of thepregnancy will be collected after the start of study intervention and until 6 months after
the last dose of study intervention.



If EDP occurs in the setting of environmental exposure, the investigator must report
information to Pfizer Safety using the Vaccines SAE Report Form and EDP
Supplemental Form. Since the exposure information does not pertain to the participant
enrolled in the study, the information is not recorded on a CRF; however, a copy of thecompleted Vaccines SAE Report Form is maintained in the investigator site file.

Follow-up is conducted to obtain general information on the pregnancy and its outcome for
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as afollow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural
integrity of the neonate can be assessed at the time of birth. In the event of a termination, thereason(s) for termination should be specified and, if clinically possible, the structural
integrity of the terminated fetus should be assessed by gross visual inspection (unlesspreprocedure test findings are conclusive for a congenital anomaly and the findings arereported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meetsthe criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal
demise, neonatal death, or congenital anomaly), the investigator should follow the procedures
for reporting SAEs. Additional information about pregnancy outcomes that are reported to
Pfizer Safety as SAEs follows:

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard tocausality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs
when the investigator assesses the infant death as related or possibly related to exposure
to the study intervention.

Additional information regarding the EDP may be requested by the sponsor. Further
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on
preterm infants to identify developmental delays). In the case of paternal exposure, theinvestigator will provide the participant with the Pregnant Partner Release of Information
Form to deliver to his partner. The investigator must document in the source documents thatthe participant was given the Pregnant Partner Release of Information Form to provide to his
partner.
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8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if:A female participant is found to be breastfeeding while receiving or after discontinuing
study intervention.



A female is found to be breastfeeding while being exposed or having been exposed to
study intervention (ie, environmental exposure). An example of environmental exposure
during breastfeeding is a female family member or healthcare provider who reports that
she is breastfeeding after having been exposed to the study intervention by inhalation orskin contact.

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hoursof the investigator’s awareness, irrespective of whether an SAE has occurred. The
information must be reported using the Vaccines SAE Report Form. When exposure during
breastfeeding occurs in the setting of environmental exposure, the exposure information does
not pertain to the participant enrolled in the study, so the information is not recorded on a
CRF. However, a copy of the completed Vaccines SAE Report Form is maintained in theinvestigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specificallyapproved for use in breastfeeding women (eg, vitamins) is administered in accord withauthorized use. However, if the infant experiences an SAE associated with such a drug, theSAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with thestudy intervention, which may or may not lead to the occurrence of an AE. Such persons
may include healthcare providers, family members, and other roles that are involved in thetrial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of theinvestigator’s awareness, regardless of whether there is an associated SAE. The informationmust be reported using the Vaccines SAE Report Form. Since the information does not
pertain to a participant enrolled in the study, the information is not recorded on a CRF;
however, a copy of the completed Vaccines SAE Report Form is maintained in theinvestigator site file.
8.3.6. Cardiovascular and Death Events
Not applicable.

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8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs
or SAEs
Potential COVID-19 illnesses and their sequelae that are consistent with the clinical endpoint
definition should not be recorded as AEs. These data will be captured as efficacy assessment
data only on the relevant pages of the CRF, as these are expected endpoints.
Potential COVID-19 illnesses and their sequelae will not be reported according to thestandard process for expedited reporting of SAEs, even though the event may meet thedefinition of an SAE. These events will be recorded on the COVID-19 illness pages in theparticipant’s CRF within 1 day.
Potential COVID-19 illness events and their sequelae will be reviewed by a group of internal
blinded case reviewers. Any SAE that is determined by the internal case reviewers NOT tomeet endpoint criteria is reported back to the investigator site of incidence. The investigatormust report the SAE to Pfizer Safety within 24 hours of being made aware that the SAE did
not meet endpoint criteria. The investigator’s SAE awareness date is the date on which theinvestigator site of incidence receives the SAE back from the internal case reviewers.

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8.3.8. Adverse Events of Special Interest
Not applicable.
8.3.8.1. Lack of Efficacy
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.
8.3.9. Medical Device Deficiencies
Not applicable.
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as
medication errors.
Safety Event

Recorded on the CRF

Reported on the Vaccines SAE Report
Form to Pfizer Safety Within 24 Hours
of Awareness

Medication errors

All (regardless of whether
associated with an AE)

Only if associated with an SAE

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Medication errors include:Medication errors involving participant exposure to the study intervention;Potential medication errors or uses outside of what is foreseen in the protocol that do or
do not involve the study participant;The administration of expired study intervention;

The administration of an incorrect study intervention;

The administration of an incorrect dosage;The administration of study intervention that has undergone temperature excursion fromthe specified storage range, unless it is determined by the sponsor that the study
intervention under question is acceptable for use.

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Such medication errors occurring to a study participant are to be captured on the medication
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by theinvestigator, the medication error is recorded on the medication error page of the CRF and, if
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a Vaccines SAE
Report Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of study intervention greater than 1 dose of study intervention within
a 24-hour time period will be considered an overdose.
Pfizer does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs.
3. Document the quantity of the excess dose as well as the duration of the overdose in the
CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
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Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7. Genetics
Genetics (specified analyses) are not evaluated in this study.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.9. Immunogenicity Assessments

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Immunogenicity assessments are described in Section 8.1.
8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are notevaluated in this study.
8.11. Study Procedures
8.11.1. Phase 1
8.11.1.1. Screening: (0 to 28 Days Before Visit 1)
Before enrollment and before any study-related procedures are performed, voluntary, written
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.
It is anticipated that the procedures below will be conducted in a stepwise manner; however,the visit can occur over more than 1 day.
Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance.
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Obtain details of any medications currently taken.

Perform physical examination including vital signs (weight, height, body temperature,pulse rate, and seated blood pressure), evaluating any clinically significant abnormalities
within the following body systems: general appearance; skin; head, eyes, ears, nose, andthroat; heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph
nodes.



Collect a blood sample (approximately 20 mL) for potential future serological assessment
and to perform a rapid test for prior COVID-19 infection.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.

Collect a blood sample (approximately 10 mL) for HIV, HBsAg, HBc Ab, and HCV Ab
tests.



Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Record AEs as described in Section 8.3. AEs that occur prior to dosing should be notedon the Medical History CRF.



Ask the participant to contact the site staff or investigator immediately if any significant
illness or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

Complete the CRF.

8.11.1.2. Visit 1 – Vaccination 1: (Day 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.
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

Record AEs as described in Section 8.3.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Review screening laboratory results (hematology and chemistry, and HIV, HBsAg,
HBc Ab, and HCV Ab tests).

Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested(if possible at the site, otherwise at the central laboratory) within 24 hours andvaccination will proceed only if it is NAAT-negative for SARS-CoV-2 genomes.
The second will be sent to the central laboratory for potential later testing.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Obtain the participant’s randomization number and study intervention allocation using
the IRT system. Only an unblinded site staff member may obtain this information.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.



The first 5 participants vaccinated in each group must be observed by blinded site staff
for any acute reactions for at least 4 hours after vaccination. For participants enrolled
thereafter, blinded site staff must observe the participant for at least 30 minutes after
study intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Issue a measuring device to measure local reactions at the injection site and athermometer for recording daily temperatures and provide instructions on their use.
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Explain the e-diary technologies available for this study (see Section 8.14), and assist theparticipant in downloading the study application onto the participant’s own device orissue a provisioned device if required. Provide instructions on e-diary completion andask the participant to complete the reactogenicity e-diary from Day 1 to Day 7, with
Day 1 being the day of vaccination and, if utilized, the COVID-19 illness e-diary (to becompleted if the participant is diagnosed with COVID-19 or has possible new orincreased symptoms, and when he/she receives a reminder, at least weekly).



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

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8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1 to 3 Days After Visit 1)

Record AEs as described in Section 8.3.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.

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The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

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8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to 8 Days After Visit 1)

Record AEs as described in Section 8.3.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.

Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.
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

Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

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8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary wascompleted and record stop dates in the CRF if required.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

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Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested (ifpossible at the site, otherwise at the central laboratory) within 24 hours and vaccination
will only proceed if it is NAAT-negative for SARS-CoV-2 genomes. The second will besent to the central laboratory for potential later testing.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met. If not, the participant should not receive further study intervention but willremain in the study to be evaluated for safety, immunogenicity, and efficacy(see Section 7.1).

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection
site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and ask the participant to complete thereactogenicity e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.
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

Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to 8 Days After Visit 4)

Record AEs as described in Section 8.3.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

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If the participant (select participants only, details will be provided by the sponsor)
consents, collect an additional 170 mL blood sample for exploratory COVID-19 research.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to 16 Days After Visit 4)

Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary wascompleted and record stop dates in the CRF if required.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

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

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



If not collected at Visit 5, and the participant (select participants only, details will be
provided by the sponsor) consents, collect an additional 170-mL blood sample for
exploratory COVID-19 research.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately (this could be via
the COVID-19 illness e-diary) if he or she experiences any respiratory symptoms as
detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After Visit 4)

Record AEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

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If not collected at Visit 5 or 6, and the participant (select participants only, details will be
provided by the sponsor) consents, collect an additional 170-mL blood sample for
exploratory COVID-19 research.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (175 to 189 Days After Visit 4)

Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect a blood sample (approximately 20 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.1.10. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 4)Collect a blood sample (approximately 20 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.1.11. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 4)Collect a blood sample (approximately 20 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect the participant’s e-diary or assist the participant to remove the study applicationfrom his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.2. Phase 2/3
8.11.2.1. Visit 1 – Vaccination 1: (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written,
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.

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It is anticipated that the procedures below will be conducted in a stepwise manner. The visit
may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion andexclusion criteria onwards must be conducted on the same day.
Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance. For participants who are HIV
positive, record HIV viral load and CD4 count results from the most recent test
performed in the previous 6 months.



Perform a clinical assessment. If the clinical assessment indicates that a physicalexamination is necessary to comprehensively evaluate the participant, perform a physicalexamination and record any findings in the source documents and, if clinicallysignificant, record on the medical history CRF.

Measure the participant’s height and weight.

Measure the participant’s body temperature.

Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.



Record AEs as described in Section 8.3.
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

Collect a blood sample (approximately 20 mL) for immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Obtain the participant’s randomization number and study intervention allocation number
using the IRT system. Only an unblinded site staff member may obtain this information.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

For participants in the reactogenicity subset, issue a measuring device to measure local
reactions at the injection site and a thermometer for recording daily temperatures andprovide instructions on their use.

For participants not in the reactogenicity subset, issue a thermometer to monitor for fever(for COVID-19 surveillance) and provide instructions on its use.



Explain the e-diary technologies available for this study (see Section 8.14), and assist theparticipant in downloading the study application onto the participant’s own device orissue a provisioned device if required.



For participants in the reactogenicity subset, provide instructions on reactogenicity
e-diary completion and ask the participant to complete the reactogenicity e-diary fromDay 1 to Day 7, with Day 1 being the day of vaccination.

For all participants, provide instructions on COVID-19 illness e-diary completion andask the participant to complete the COVID-19 illness e-diary if he/she is diagnosed
with COVID-19 or has possible new or increased symptoms, and when he/she
receives a reminder, at least weekly. See Section 8.14 for further details.

If the participant is part of the reactogenicity subset, ask the participant to contact the site
staff or investigator immediately if he or she experiences any of the following from Day
1 to Day 7 after vaccination (where Day 1 is the day of vaccination) to determine if anunscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).
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

Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.

If the participant is part of the reactogenicity subset, the investigator or appropriately
qualified designee reviews the reactogenicity e-diary data online following vaccination toevaluate participant compliance and as part of the ongoing safety review. Daily review is
optimal during the active diary period.
8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days After Visit 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



If the participant is part of the reactogenicity subset, review the participant’s
reactogenicity e-diary data. Collect stop dates of any reactogenicity e-diary events
ongoing on the last day that the reactogenicity e-diary was completed and record stop
dates in the CRF if required.



Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.
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Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met. If not, the participant may not receive further study intervention but will remainin the study to be evaluated for safety, immunogenicity, and efficacy(see Section 7.1).

Measure the participant’s body temperature.

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection
site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and, if the participant is part of thereactogenicity subset, ask the participant to complete the reactogenicity e-diary fromDay 1 to Day 7, with Day 1 being the day of vaccination.



If the participant is part of the reactogenicity subset, ask the participant to contact the site
staff or investigator immediately if he or she experiences any of the following fromDay 1 to Day 7 after vaccination (where Day 1 is the day of vaccination) to determine if
an unscheduled reactogenicity visit is required:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.

Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.
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

Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.

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If the participant is part of the reactogenicity subset, the investigator or appropriately
qualified designee reviews the reactogenicity e-diary data online following vaccination toevaluate participant compliance and as part of the ongoing safety review. Daily review is
optimal during the active diary period.
8.11.2.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2): (28 to 35 Days After
Visit 2)


Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. If the participant is part of thereactogenicity subset, review the participant’s reactogenicity e-diary data. Collect stop
dates of any reactogenicity e-diary events ongoing on the last day that the reactogenicity
e-diary was completed and record stop dates in the CRF if required.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

For participants who are HIV positive, record HIV viral load and CD4 count results fromthe most recent test performed since Visit 1 (if any).

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 20 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.
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Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.2.4. Visit 4 – 6-Month Follow-up Visit: (175 to 189 Days After Visit 2)

Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.

For participants who are HIV positive, record HIV viral load and CD4 count results fromthe most recent test performed since Visit 3 (if any).

Collect a blood sample (approximately 20 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.3.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.2.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 2)Collect a blood sample (approximately 20 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

For participants who are HIV positive, record HIV viral load and CD4 count results fromthe most recent test performed since Visit 4 (if any).



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

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Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.2.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 2)Collect a blood sample (approximately 20 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

For participants who are HIV positive, record HIV viral load and CD4 count results fromthe most recent test performed since Visit 5 (if any).

Collect the participant’s e-diary or assist the participant to remove the study applicationfrom his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction
If a Grade 3 local reaction (Section 8.2.2.2), systemic event (Section 8.2.2.3), or fever(Section 8.2.2.4) is reported in the reactogenicity e-diary, a telephone contact should occur toascertain further details and determine whether a site visit is clinically indicated. If suspected
Grade 4 local reaction (Section 8.2.2.2), systemic event (Section 8.2.2.3), or fever(Section 8.2.2.4) is reported in the reactogenicity e-diary, a telephone contact or site visit
should occur to confirm whether the event meets the criteria for Grade 4.
A site visit must be scheduled as soon as possible to assess the participant unless any of thefollowing is true:The participant is unable to attend the unscheduled visit.

The local reaction/systemic event is no longer present at the time of the telephone
contact.

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The participant recorded an incorrect value in the reactogenicity e-diary (confirmation ofa reactogenicity e-diary data entry error).



The PI or authorized designee determined it was not needed.

This telephone contact will be recorded in the participant’s source documentation and theCRF.
If the participant is unable to attend the unscheduled visit, or the PI or authorized designee
determined it was not needed, any ongoing local reactions/systemic events must be assessedat the next study visit.

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During the unscheduled visit, the reactions should be assessed by the investigator or a
medically qualified member of the study staff such as a study physician or a study nurse, asapplicable to the investigator’s local practice, who will:Measure body temperature (°F/°C).

Measure minimum and maximum diameters of redness (if present).

Measure minimum and maximum diameters of swelling (if present).



Assess injection site pain (if present) in accordance with the grades provided in
Section 8.2.2.2.

Assess systemic events (if present) in accordance with the grades provided in
Section 8.2.2.3.

Assess for other findings associated with the reaction and record on the AE page of the
CRF, if appropriate.

The investigator or an authorized designee will complete the unscheduled visit assessment
page of the CRF.

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8.13. COVID-19 Surveillance (All Participants)

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If a participant experiences any of the following (irrespective of perceived etiology or
clinical significance), he or she is instructed to contact the site immediately and, if
confirmed, participate in an in-person or telehealth visit as soon as possible, optimally within
3 days of symptom onset (and at the latest 4 days after symptom resolution). During the
7 days following each vaccination, potential COVID-19 symptoms that overlap with solicitedsystemic events (ie, fever, chills, new or increased muscle pain, diarrhea, vomiting) should
not trigger a potential COVID-19 illness visit unless, in the investigator’s opinion, theclinical picture is more indicative of a possible COVID-19 illness than vaccine
reactogenicity. Participants may utilize a COVID-19 illness e-diary through an application(see Section 8.14) installed on a provisioned device or on the participant’s own personal
device to prompt him/her to report any symptoms. Note that this does not substitute for aparticipant’s routine medical care. Therefore, participants should be encouraged to seek care,
if appropriate, from their usual provider.


A diagnosis of COVID-19;



Fever;

New or increased cough;

New or increased shortness of breath;Chills;

New or increased muscle pain;New loss of taste/smell;

Sore throat;

Diarrhea;Vomiting.

8.13.1. Potential COVID-19 Illness Visit: (Optimally Within 3 Days After Potential
COVID-19 Illness Onset)
This visit may be conducted as an in-person or telehealth visit; a telehealth visit involves thesharing of healthcare information and services via telecommunication technologies (eg,audio, video, video-conferencing software) remotely, thus allowing the participant andinvestigator to communicate on aspects of clinical care.
As a participant’s COVID-19 illness may evolve over time, several contacts may be required
to obtain the following information:

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

Record AEs, as appropriate as described in Section 8.3. Note: Potential COVID-19
illnesses that are consistent with the clinical endpoint definition should not be recorded asAEs. These data will be captured as efficacy assessment data only on the relevant pagesof the CRF, as these are expected endpoints.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



If the visit is conducted in person, obtain a nasal (midturbinate) swab (collected by site
staff). Alternatively, if conducted by telehealth, instruct the participant to self-collect a
nasal (midturbinate) swab and ship for assessment at the central laboratory. The result
from this swab will be provided to the site once it is available, but this will not be in realtime, and cannot be relied upon to direct clinical care. Therefore, the participant should
be encouraged to seek care, if appropriate, from his or her usual provider.

Collect COVID-19–related standard-of-care clinical and laboratory information. This
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Symptoms and signs, includingClinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per
minute, HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or
PaO2/FiO2 <300 mm Hg)



Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiringvasopressors)Significant acute renal, hepatic, or neurologic dysfunction

Respiratory failure (defined as needing high-flow oxygen, noninvasive
ventilation, mechanical ventilation, or ECMO)

Clinical diagnosis

Local laboratory COVID-19 test resultFull blood count

Blood chemistry, specifically creatinine, urea, liver function tests, and C-reactive
protein

Imaging results (eg, CT or MRI scan) to document neurologic dysfunction

Number and type of any healthcare contact; duration of hospitalization and ICU stay



Death
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Schedule an appointment for the participant to return for the potential COVID-19
convalescent visit once he or she has recovered.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After Potential
COVID-19 Illness Visit)

Record AEs, as appropriate as described in Section 8.3. Note: Potential COVID-19
illnesses that are consistent with the clinical endpoint definition should not be recorded asAEs. These data will be captured as efficacy assessment data only on the relevant pagesof the CRF, as these are expected endpoints.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect a blood sample (approximately 20 mL) for immunogenicity testing.

Collect/update COVID-19–related clinical and laboratory information (detailed in
Section 8.13.1).

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.14. Communication and Use of Technology

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In a study of this nature that requires illness events to be reported outside of scheduled study
visits, it is vital that communication between the study site and the participant is maintained
to ensure that endpoint events are not missed. This study will employ various methods,
tailored to the individual participant, to ensure that communication is maintained and study
information can be transmitted securely. Using appropriate technology, such as a study
application, a communication pathway between the participant and the study site staff will beestablished. The participant may be able to utilize his or her own devices to access thistechnology, or use a device provided by the sponsor. Traditional methods of telephone
communication will also be available. The technology solution may facilitate the following:Contact with the investigator, including the ability of the participant to report whether or
not he or she has experienced symptoms that could represent a potential COVID-19
illness (COVID-19 illness e-diary; see Section 8.13).

An alert in the event that the participant is hospitalized.



Visit reminders.



Messages of thanks and encouragement from the study team.



A platform for recording local reactions and systemic events (reactogenicity e-diary) –see Section 8.2.2.

If a participant is not actively completing either the reactogenicity or COVID-19 illness
e-diary, the investigator or designee is required to contact the participant to ascertain why
and also to obtain details of any missed events.
9. STATISTICAL CONSIDERATIONS
Methodology for summary and statistical analyses of the data collected in this study is
described here and further detailed in a statistical analysis plan (SAP), which will bemaintained by the sponsor. The SAP may modify what is outlined in the protocol whereappropriate; however, any major modifications of the primary endpoint definitions or theiranalyses will also be reflected in a protocol amendment.
9.1. Estimands and Statistical Hypotheses
9.1.1. Estimands
The estimand corresponding to each primary, secondary, and tertiary/exploratory objective is
described in the table in Section 3.
In the primary safety objective evaluations, missing reactogenicity e-diary data will not be
imputed. Missing AE dates will be imputed according to Pfizer safety rules. No othermissing information will be imputed in the safety analysis.

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The estimands to evaluate the immunogenicity objectives are based on evaluable populations
for immunogenicity (Section 9.3). These estimands estimate the vaccine effect in the
hypothetical setting where participants follow the study schedules and protocol requirements
as directed. Missing antibody results will not be imputed. Immunogenicity results that are
below the LLOQ will be set to 0.5 × LLOQ in the analysis; this may be adjusted once
additional data on the assay characteristics become available.
The estimands to evaluate the efficacy objectives are based on evaluable populations for
efficacy (Section 9.3). These estimands estimate the vaccine effect in the hypotheticalsetting where participants follow the study schedules and protocol requirements as directed.
In addition, VE will be analyzed by all--available efficacy population. Missing laboratory
results will not be imputed for the primary analysis, but missing data imputation for theefficacy endpoint may be performed as a sensitivity analysis.

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9.1.2. Statistical Hypotheses
Phase 2/3 of the study has 2 primary efficacy endpoints evaluating VE, which is defined as
VE = 100 × (1 – IRR). IRR is calculated as the ratio of first confirmed COVID-19 illness ratein the vaccine group to the corresponding illness rate in the placebo group. In Phase 2/3, theassessment of VE will be based on posterior probabilities of VE1 > 30% and VE2 > 30%.
VE1 represents VE for prophylactic BNT162b2 against confirmed COVID-19 in participants
without evidence of infection before vaccination, and VE2 represents VE for prophylactic
BNT162b2 against confirmed COVID-19 in all participants after vaccination.
For participants with multiple confirmed cases, only the first case will contribute to the VE
calculation for each hypothesis. VE1 and VE2 will be evaluated sequentially to control theoverall type I error to the desired level of 2.5%. VE is demonstrated if there is sufficientevidence (posterior probability) that either VE1 >30% or both VE1 and VE2 are >30%. The
assessment for the primary analysis will be based on posterior probability using a Bayesianmodel.
9.2. Sample Size Determination
The study sample size for Phase 1 of the study is not based on any statistical hypothesis
testing. Phase 1 comprises 15 participants (randomization ratio of 4:1 so that 12 receive
active vaccine and 3 receive placebo) per group; 13 vaccine groups are studied,corresponding to a total of 195 participants.
For Phase 2/3, with assumptions of a true VE of 60% after the last dose of investigational
product, a total of approximately 164 first confirmed COVID-19 illness cases will provide
90% power to conclude true VE >30% with high probability, allowing early stopping for
efficacy at the IA. This would be achieved with 17,600 evaluable participants per group or
21,999 vaccine recipients randomized in a 1:1 ratio with placebo, for a total sample size of
43,998, based on the assumption of a 1.3% illness rate per year in the placebo group, accrualof 164 primary-endpoint cases within 6 months, and 20% of the participants being
nonevaluable or having serological evidence of prior infection with SARS-CoV-2,
potentially making them immune to further infection. Dependent upon the evolution of the
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pandemic, it is possible that the COVID-19 attack rate may be much higher, in which caseaccrual would be expected to be more rapid, enabling the study’s primary endpoint to beevaluated much sooner. The total number of participants enrolled in Phase 2/3 may varydepending on the incidence of COVID-19 at the time of the enrollment, the true underlying
VE, and a potential early stop for efficacy or futility.
For safety outcomes, Table 4 shows the probability of observing at least 1 AE for a given
true event rate of a particular AE, for various sample sizes. For example, if the true AE rate
is 10%, with 12 participants in a vaccine group, there is 72% probability of observing at least
1 AE.

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Table 4.

Probability of Observing at Least 1 AE by Assumed True Event Rates
With Different Sample Sizes

Assumed
N=12
True Event
Rate of an
AE
0.01%
0.00
0.02%
0.00
0.04%
0.00
0.06%
0.01
0.08%
0.01
0.10%
0.01
0.15%
0.02
0.20%
0.02
0.25%
0.03
0.30%
0.04
0.35%
0.04
0.50%
0.06
1.00%
0.11
2.00%
0.22
3.00%
0.31
5.00%
0.46
7.00%
0.58
10.00%
0.72
Note: N = number in sample.

N=45

N=180

N=3000N=6000N=9000N=15000

0.00
0.01
0.02
0.03
0.04
0.04
0.07
0.09
0.11
0.13
0.15
0.20
0.36
0.60
0.75
0.90
0.96
0.99

0.02
0.04
0.07
0.10
0.13
0.16
0.24
0.30
0.36
0.42
0.47
0.59
0.84
0.97
>0.99
>0.99
>0.99
>0.99

0.26
0.45
0.70
0.83
0.91
0.95
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

0.45
0.70
0.91
0.97
0.99
0.99
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

0.59
0.83
0.97
0.99
0.99
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

0.78
0.95
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

9.3. Analysis Sets
For purposes of analysis, the following populations are defined:
Population
Enrolled
Randomized
Dose 1 evaluable
immunogenicity

Description
All participants who have a signed ICD.
All participants who are assigned a randomization number in
the IWR system.
For Phase 1 only, all eligible randomized participants who
receive the vaccine to which they are randomly assigned at the

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Population

Dose 2 evaluable
immunogenicity

Dose 1 all-available
immunogenicity
Dose 2 all-available
immunogenicity

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Evaluable efficacy

All-available efficacy

Description
first dose, have at least 1 valid and determinate
immunogenicity result after Dose 1, have blood collection
within an appropriate window after Dose 1, and have no othermajor protocol deviations as determined by the clinician.
All eligible randomized participants who receive 2 doses ofthe vaccine to which they are randomly assigned, within thepredefined window, have at least 1 valid and determinate
immunogenicity result after Dose 2, have blood collection
within an appropriate window after Dose 2, and have no othermajor protocol deviations as determined by the clinician.
For Phase 1 only: all participants who receive at least 1 doseof the study intervention with at least 1 valid and determinate
immunogenicity result after Dose 1 but before Dose 2.
All participants who receive at least 1 dose of the study
intervention with at least 1 valid and determinate
immunogenicity result after Dose 2.
All eligible randomized participants who receive all
vaccination(s) as randomized within the predefined windowand have no other major protocol deviations as determined by
the clinician.
1. All eligible randomized participants who receive at least
1 vaccination.
2. All eligible randomized participants who complete
2 vaccination doses.

SafetyAll randomized participants who receive at least 1 dose of thestudy intervention.

9.4. Statistical Analyses
The SAP will be developed and finalized before database lock for any of the planned
analyses in Section 9.5.1. It will describe the participant populations to be included in theanalyses and the procedures for accounting for missing, unused, and spurious data. Thissection provides a summary of the planned statistical analyses of the primary, secondary, andtertiary/exploratory endpoints.
9.4.1. Immunogenicity Analyses
Immunogenicity samples will be drawn for all participants. Immunogenicity analyses will bebased upon results from appropriately sized subsets of samples, according to the purpose.
The statistical analysis of immunogenicity results will be primarily based on the evaluable
immunogenicity populations as defined in Section 9.3.
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An additional analysis will be performed based on the all-available populations if there is alarge enough difference in sample size between the all-available immunogenicity populationand the evaluable immunogenicity population. Participants will be summarized according to
the vaccine group to which they were randomized.
Endpoint
Secondaryimmunogenicity

Statistical Analysis Methods
Geometric mean titers/concentrations (GMTs/GMCs) of
SARS-CoV-2 neutralizing titers, S1-binding IgG level, andRBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, GMTs/GMCs and 2-sided 95% CIs will be
provided for each investigational product within each group before
vaccination and at each of the following time points:

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Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1, 6, 12
and 24 months after Dose 2

Geometric means will be calculated as the mean of the assay results
after making the logarithm transformation and then exponentiating themean to express results on the original scale. Two-sided 95% CIs will
be obtained by taking natural log transforms of concentrations/titers,
calculating the 95% CI with reference to the t-distribution, and thenexponentiating the confidence limits.
GMFRs of SARS-CoV-2 neutralizing titers, S1-binding IgG level,
and RBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, the GMFRs and 2-sided 95% CIs will be
provided for each investigational product within each group at each of
the following time points:Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1, 6, 12,
and 24 months after Dose 2

GMFRs will be limited to participants with nonmissing values prior to
the first dose and at the postvaccination time point. The GMFR will becalculated as the mean of the difference of logarithmically transformed
assay results (later time point – earlier time point) and exponentiating
the mean. The associated 2-sided CIs will be obtained by calculating
CIs using Student’s t-distribution for the mean difference of thelogarithmically transformed assay results and exponentiating theconfidence limits.

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Endpoint

Statistical Analysis Methods
Percentage of participants with ≥4-fold rise in SARS-CoV-2
neutralizing titers, S1-binding IgG level, and RBD-binding IgG
level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, percentages (and 2-sided 95% CIs) ofparticipants with ≥4-fold rise will be provided for each investigational
product within each group at each of the following time points:Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1, 6, 12,
and 24 months after Dose 2

The Clopper-Pearson method will be used to calculate the CIs.

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)GMR of SARS-CoV-2 neutralizing titer to S1-binding IgG level
and to RBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, the GMRs and 2-sided 95% CIs will be
provided for each investigational product within each group at each of
the following time points:Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1, 6, 12,
and 24 months after Dose 2

GMRs will be limited to participants with nonmissing values for both
SARS-CoV-2 neutralizing titers and S1-binding IgG level/RBDbinding IgG level at each time point. The GMR will be calculated as
the mean of the difference of logarithmically transformed assay results(eg, SARS-CoV-2 neutralizing titers minus S1-binding IgG level foreach participant) and exponentiating the mean. Two-sided CIs will beobtained by calculating CIs using Student’s t-distribution for the meandifference of the logarithmically transformed assay results andexponentiating the confidence limits.
For all the immunogenicity endpoints, the analysis will be based on the
Dose 1 and Dose 2 evaluable immunogenicity populations. An
additional analysis will be performed based on the all-available
immunogenicity populations if there is a large enough difference insample size between the all-available immunogenicity populations andthe evaluable immunogenicity populations. Participants will besummarized according to the vaccine group to which they wererandomized. Missing serology data will not be imputed.

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Endpoint
Exploratory
immunogenicity

Statistical Analysis Methods
Geometric mean titers/concentrations (GMTs/GMCs) of
SARS-CoV-2 neutralizing titers, S1-binding IgG level, andRBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, GMTs/GMCs and 2-sided 95% CIs will be
provided for each investigational product within each group before
vaccination and at each of the following time points in Phase 2/3:

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1, 6, 12, and 24 months after completion of vaccination inparticipants with and without serological or virological evidence of
SARS-CoV-2 infection before vaccination

Geometric means will be calculated as the mean of the assay results
after making the logarithm transformation and then exponentiating themean to express results on the original scale. Two-sided 95% CIs will
be obtained by taking natural log transforms of concentrations/titers,
calculating the 95% CI with reference to the t-distribution, and thenexponentiating the confidence limits.
GMFRs of SARS-CoV-2 neutralizing titers, S1-binding IgG level,
and RBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, andRBD-binding IgG levels, the GMFRs and 2-sided 95% CIs will be
provided for each investigational product within each group at each of
the following time points in Phase 2/3:


1, 6, 12, and 24 months after completion of vaccination inparticipants with and without serological or virologicalevidence of SARS-CoV-2 infection before vaccination

GMFRs will be limited to participants with nonmissing values prior to
the first dose and at the postvaccination time point. The GMFR will becalculated as the mean of the difference of logarithmically transformed
assay results (later time point – earlier time point) and exponentiating
the mean. The associated 2-sided CIs will be obtained by calculating
CIs using Student’s t-distribution for the mean difference of thelogarithmically transformed assay results and exponentiating theconfidence limits.
Percentage of participants with antibody levels ≥ predefined
threshold(s) for SARS-CoV-2 serological parameters

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Endpoint

Statistical Analysis Methods
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels and/or
RBD-binding IgG levels, N-binding antibody, and SARS-CoV-2
detection by NAAT, percentages (and 2-sided 95% CIs) of participants
with antibody levels ≥ predefined threshold(s) will be provided foreach investigational product within each group at baseline and each of
the following time points in Phase 2/3:


1, 6, 12, and 24 months after completion of vaccination inparticipants with and without serological or virological evidence of
SARS-CoV-2 infection before vaccination

The Clopper-Pearson method will be used to calculate the CIs.
Percentage of participants with the immune response (non-S) to
SARS-CoV-2 for N-binding antibody at the time points when data
are available

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)The Clopper-Pearson method will be used to calculate the CIs.
For all of the immunogenicity endpoints, the analysis will be based on
the Dose 1 and Dose 2 evaluable immunogenicity populations. An
additional analysis will be performed based on the all-available
immunogenicity populations if there is a large enough difference insample size between the all-available immunogenicity populations andthe evaluable immunogenicity populations. Participants will besummarized according to the vaccine group to which they wererandomized. Missing serology data will not be imputed.
RCDCs for immunogenicity results
Empirical RCDCs will be provided for SARS-CoV-2 neutralizing
titers, S1-binding IgG level, and RBD-binding IgG level after Dose 1
and after Dose 2.

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9.4.2. Efficacy Analyses
The statistical analysis of efficacy will be based on the evaluable efficacy population(primary analysis) and the all-available efficacy population as defined in Section 9.3.
Endpoint
Primary efficacy

Statistical Analysis Methods
Ratio of confirmed COVID-19 illness per 1000 person-years offollow-up in participants without evidence of infection before
vaccination for the active vaccine group to the placebo group
VE will be estimated by 100 × (1 – IRR), where IRR is the calculated
ratio of confirmed COVID-19 illness per 1000 person-years follow-up
in the active vaccine group to the corresponding illness rate in theplacebo group 7 days after the last dose. VE will be analyzed using abeta-binomial model.

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After the above objective is met, the second primary endpoint will be
evaluated as below.
Ratio of confirmed COVID-19 illness per 1000 person-years offollow-up in participants with and without evidence of infection
before vaccination for the active vaccine group to the placebogroup
VE will be estimated by 100 × (1 – IRR), where IRR is the calculated
ratio of confirmed COVID-19 illness per 1000 person-years follow-up
in the active vaccine group to the corresponding illness rate in theplacebo group after 7 days after the last dose. VE will be analyzed
using a beta-binomial model.
The efficacy analysis for the first primary objective evaluation will bebased on the participants without evidence of infection before
vaccination and included in the evaluable efficacy population and in
the all-available efficacy population.
The efficacy analysis for the second primary objective evaluation will
be based on all participants included in the evaluable efficacy
population and in the all-available efficacy population.
For the primary endpoint analysis, missing efficacy data will not be
imputed. A sensitivity analysis will be performed by imputing missing
values with the assumption of MAR. A missing efficacy endpoint may
be imputed based on predicted probability using the fully conditional
specification method. Other imputation methods without the MAR
assumption may be explored. The details will be provided in the SAP.

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Endpoint
Secondary

Statistical Analysis Methods
Ratio of confirmed severe COVID-19 illness per 1000 person-years
of follow-up in participants without evidence of infection before
vaccination for the active vaccine group to the placebo group
Ratio of confirmed severe COVID-19 illness per 1000 person-years
of follow-up for the active vaccine group to the placebo group
These secondary efficacy objectives will be evaluated after the primaryobjectives are met. The analysis will be based on the evaluable efficacy
population and the all-available efficacy population. The analysis
methodology used for the primary efficacy endpoints will be applied
for the analysis of the above secondary efficacy endpoints.

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)The following secondary efficacy endpoints will be evaluateddescriptively with 95% CIs.
Ratio of confirmed COVID-19 illness (according to the
CDC-defined symptoms) per 1000 person-years of follow-up inparticipants without evidence of infection before vaccination for
the active vaccine group to the placebo group
Ratio of confirmed COVID-19 illness (according to the
CDC-defined symptoms) per 1000 person-years of follow-up inparticipants with and without evidence of infection before
vaccination for the active vaccine group to the placebo group
VE = 100 × (1 – IRR) will be estimated with confirmed COVID-19
illness according to the CDC-defined symptoms after 7 days after thelast dose. The 2-sided 95% CI for VE will be derived using the
Clopper-Pearson method as described by Agresti.9
Missing efficacy data will not be imputed.

9.4.3. Safety Analyses
Endpoint
Primary

Statistical Analysis Methods
Descriptive statistics will be provided for each reactogenicity endpoint
for each dose and vaccine group. Local reactions and systemic eventsfrom Day 1 through Day 7 after each vaccination will be presented byseverity cumulatively across severity levels. Descriptive summary
statistics will include counts and percentages of participants with theindicated endpoint and the associated Clopper-Pearson 95% CIs.

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Endpoint

Statistical Analysis Methods
For Phase 1, descriptive statistics will be provided for abnormal
hematology and chemistry laboratory values at 1 and 7 days after
Dose 1 and 7 days after Dose 2, including grading shifts inhematology and chemistry laboratory assessments between baseline
and 1 and 7 days after Dose 1, and before Dose 2 and 7 days after
Dose 2. Descriptive summary statistics will include counts andpercentages of participants with the indicated endpoint and theassociated Clopper-Pearson 2-sided 95% CIs.
AEs will be categorized according to the Medical Dictionary forRegulatory Activities (MedDRA) terms. A 3-tier approach will be
used to summarize AEs in Phase 2/3. Under this approach AEs areclassified into 1 of 3 tiers: (1) Tier 1 events are prespecified events ofclinical importance and are identified in a list in the product’s safety
review plan; (2) Tier 2 events are those that are not Tier 1 but areconsidered “relatively common”; a MedDRA preferred term is defined
as a Tier 2 event if there are at least 1% of participants in at least 1
vaccine group reporting the event; and (3) Tier 3 events are those thatare neither Tier 1 nor Tier 2 events. For both Tier 1 and Tier 2 events,
2-sided 95% CIs for the difference between the vaccine and placebogroups in the percentage of participants reporting the events based on
the Miettinen and Nurminen method10 will be provided. In addition,
for Tier 1 events, the asymptotic p-values will also be presented forthe difference between groups in the percentage of participants
reporting the events, based on the same test statistic and under theassumption that the test statistic is asymptotically normally
distributed.
Descriptive summary statistics (counts, percentages, and associatedClopper-Pearson 95% CIs) will be provided for any AE events foreach vaccine group.
SAEs will be categorized according to MedDRA terms. Counts,
percentages, and the associated Clopper-Pearson 95% CIs of SAEs
from Dose 1 to 6 months after last dose will be provided for eachvaccine group.
The safety analyses are based on the safety population. Participants
will be summarized by vaccine group according to the investigational
products they actually received. Missing reactogenicity e-diary data
will not be imputed; missing AE dates will be handled according to
the Pfizer safety rules.

SecondaryNot applicable (N/A)
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Endpoint
Exploratory

Statistical Analysis Methods
N/A

9.4.4. Other Analyses
The ratios of (GMFR A to GMFR B) and (GMFR A to GMFR C) may be explored, where
GMFR A is the geometric mean of the ratio of the SARS-CoV-2 neutralizing titer at the
postvaccination time point to the corresponding titer at the prevaccination time point,
GFMR B is the geometric mean of the ratio of the S1-binding IgG level at the
postvaccination time point to the corresponding IgG level at the prevaccination time point,
and GMFR C is the geometric mean of the ratio of the RBD-binding IgG level at the
postvaccination time point to the corresponding antibody level at the prevaccination time
point.

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)The safety data and immunogenicity results for individuals with confirmed stable HIV
disease will be summarized descriptively. Furthermore, VE may be assessed if there is asufficient number of COVID-19 cases in this group of participants.
9.5. Interim Analyses
As this is a sponsor open-label study during Phase 1, the sponsor may conduct unblinded
reviews of the data during the course of the study for the purpose of safety assessment,
facilitating dose escalation decisions, and/or supporting clinical development.
During Phase 2/3, 4 IAs are planned and will be performed by an unblinded statistical teamafter accrual of 32, 62, 92, and 120 cases. At each IA:

VE for the first primary objective will be evaluated . Overwhelming efficacy will bedeclared if the first primary study objective is met. The criteria for success at an interim
analysis are based on the posterior probability (ie, P[VE >30%|data]) at the current
number of cases. Overwhelming efficacy will be declared if the posterior probability ishigher than the success threshold. The success threshold for each interim analysis will becalibrated to protect overall type I error at 2.5%. Additional details about the successthreshold or boundary calculation at each interim analysis will be provided in the SAP.

The study will stop for lack of benefit (futility) if the predicted probability of success at
the final analysis or study success is <5%. The posterior predictive POS will becalculated using a beta-binomial model. The futility assessment will be performed for the
first primary endpoint and the futility boundary may be subject to change to reflectsubsequent program-related decisions by the sponsor.

Efficacy and futility boundaries will be applied in a nonbinding way.

Bayesian approaches require specification of a prior distribution for the possible values of theunknown vaccine effect, thereby accounting for uncertainty in its value. A minimally
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informative beta prior, beta (0.700102, 1), is proposed for θ = (1-VE)/(2-VE). The prior iscentered at θ = 0.4118 (VE=30%) which can be considered pessimistic. The prior allows
considerable uncertainty; the 95% interval for θ is (0.005, 0.964) and the corresponding 95%
interval for VE is (-26.2, 0.995).
Table 5 illustrates the boundary for efficacy and futility if IAs are performed after accrual of
32 62, 92, and 120 cases in participants without evidence of infection before vaccination.
Table 5.

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AnalysisInterim Analysis Plan and Boundaries for Efficacy and Futility
Number of
Cases

Success Criteriaa

Futility Boundary

VE Point Estimate
VE Point Estimate(Case Split)(Case Split)
IA1
32
76.9% (6:26)
11.8% (15:17)
IA2
6268.1% (15:47)
27.8% (26:36)
IA3
92
62.7% (25:67)
38.6% (35:57)
IA4120
58.8% (35:85)
N/A
Final
164
52.3% (53:111)
Abbreviations: IA = interim analysis; N/A = not applicable; VE = vaccine efficacy.
Note: Case split = vaccine : placebo.
a. Interim efficacy claim: P(VE >30%|data) > 0.995; success at the final analysis: P(VE >30%|data)> 0.986.

Additional design operating characteristics (the boundary based on the number of cases
observed in the vaccine group; the probabilities for efficacy and futility given assumed
various VEs with a 1:1 randomization ratio) are listed in Table 6 and Table 7.

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Table 6.

Statistical Design Operating Characteristics: Probability of Success or
Failure for Interim Analyses

VaccineEfficacy(%)

Interim Analysis 1(Total Cases = 32)

30
50
60
70
80

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Table 7.

Probabilityof Success(Cases in
VaccineGroup ≤6)
0.006
0.054
0.150
0.368
0.722

Probabilityof Failure(Cases in
VaccineGroup ≥15)
0.315
0.078
0.021
0.003
<0.001

Interim Analysis 2(Total Cases = 62)
Probabilityof Success(Cases in
VaccineGroup ≤15)
0.003
0.051
0.160
0.310
0.238

Probabilityof Failure(Cases in
VaccineGroup ≥26)
0.231
0.056
0.010
<0.001<0.001

Interim Analysis 3(Total Cases = 92)
Probabilityof Success(Cases in
VaccineGroup ≤25)
0.002
0.063
0.175
0.195
0.037

Probabilityof Failure(Cases in
VaccineGroup ≥35)
0.239
0.103
0.019
0.001
<0.001

InterimAnalysis 4(Total Cases= 120)
Probability of
Success(CasesVaccineGroup ≤35)
0.002
0.075
0.160
0.085
0.003

Statistical Design Operating Characteristics: Probability of Success for
Final Analysis and Overall

Vaccine Efficacy (%)

30
50
60
70
80

Final Analysis(Total Cases = 164)
Probability of Success (Cases in Vaccine
Group ≤53)
0.007
0.196
0.220
0.036
<0.001

Overall Probability of Success

0.021
0.439
0.866
>0.999>0.999If neither success nor futility has been declared after all IAs, the final analysis will be
performed and the first primary objective will have been met if there are 53 or fewer cases
observed in the vaccine group out of a total of 164 first confirmed cases from 7 days after
receipt of the last dose of investigational product onwards.
After the primary objectives are met, the secondary VE endpoints (confirmed severe
COVID-19 in participants without evidence of infection before vaccination and confirmed
severe COVID-19 in all participants) will be evaluated sequentially, by the same method
used for the primary VE endpoint evaluation. Success thresholds for secondary VE will beappropriately chosen to control overall Type I error at 2.5%. Further details will be provided
in the SAP. The remaining secondary VE endpoints will be evaluated descriptively to
calculate the observed VE with 95% CIs.

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9.5.1. Analysis Timing

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Statistical analyses will be carried out when the following data are available:Complete safety and immunogenicity analysis approximately 1 month after Dose 2 forPhase 1.



Safety data through 7 days after Dose 2 and immunogenicity data through 1 month after
Dose 2 from the first 360 participants enrolled (180 to active vaccine and 180 to placebo,
stratified equally between 18 to 55 years and >55 to 85 years) in Phase 2/3.



Safety data through 1 month after Dose 2 from the first 6000 participants enrolled (3000to active vaccine and 3000 to placebo) in Phase 2/3.



IAs for efficacy at 32, 62, 92, and 120 cases and futility at 32, 62, and 92 cases.

Complete safety and immunogenicity analysis approximately 6 months after Dose 2 for
all participants in Phase 2/3.

Complete efficacy and persistence-of-immunogenicity analysis after complete data are
available at the end of the study.

All analyses conducted on Phase 2/3 data while the study is ongoing will be performed by an
unblinded statistical team.
9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will use an IRC, a DMC, and a group of internal case reviewers. The IRC is
independent of the study team and includes only internal members. The DMC is independentof the study team and includes only external members. The IRC and DMC charters describe
the role of the IRC and DMC in more detail.
The responsibilities of the IRC are only in Phase 1 and will include:

Review of safety data to permit dose escalations in the 18- to 55-year age cohort



Review of safety data in the case of a stopping rule being met

Review of safety and/or immunogenicity data to:Allow groups of participants of 65 to 85 years of age to proceed

Select vaccine candidate/dose level(s) to proceed into Phase 2/3. Data supporting theselection, including results for both binding antibody levels and neutralizing titers,
and the ratio between them, will also be submitted to the FDA for review

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

Review of any available safety and/or immunogenicity data generated during the courseof this study, or the BioNTech study conducted in Germany, to determine:Whether any groups may not be started



Whether any groups may be terminated earlyWhether any groups may be added with dose levels below the lowest stated dose orintermediate between the lowest and highest stated doses

Contemporaneous review of all NAAT-confirmed COVID-19 illnesses in Phase 1090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)The DMC will be responsible for ongoing monitoring of the safety of participants in the
study according to the charter. This may include, but is not limited to:Contemporaneous review of related AEs up to 1 month after completion of thevaccination scheduleContemporaneous review of all SAEs up to 6 months after completion of the vaccination
schedule

Contemporaneous review of all NAAT-confirmed COVID-19 illnesses in Phase 1

At the time of the planned IAs, and ad hoc if requested by the unblinded team, review ofcases of COVID-19 for an adverse imbalance of cases of COVID-19 and/or severe
COVID-19 between the vaccine and placebo groups

The recommendations made by the DMC to alter the conduct of the study will be forwarded
to the appropriate Pfizer personnel for final decision. Pfizer will forward such decisions,which may include summaries of aggregate analyses of safety data, to regulatory authorities,
as appropriate.
Three blinded case reviewers (medically qualified Pfizer staff members) will review all
potential COVID-19 illness events. If a NAAT-confirmed case in Phase 2/3 may beconsidered severe, or not, solely on the basis of “significant acute renal, hepatic, orneurologic dysfunction,” the blinded data will be reviewed by the case reviewers to assess
whether the criterion is met; the majority opinion will prevail.

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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:Consensus ethical principles derived from international guidelines including the
Declaration of Helsinki and CIOMS International Ethical Guidelines;Applicable ICH GCP guidelines;Applicable laws and regulations, including applicable privacy laws.

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents(eg, advertisements) must be reviewed and approved by the sponsor and submitted to an
IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study is
initiated.
Any amendments to the protocol will require IRB/EC approval before implementation ofchanges made to the study design, except for changes necessary to eliminate an immediate
hazard to study participants.
The investigator will be responsible for the following:Providing written summaries of the status of the study to the IRB/EC annually or more
frequently in accordance with the requirements, policies, and procedures established by
the IRB/EC;



Notifying the IRB/EC of SAEs or other significant safety findings as required by IRB/EC
procedures;Providing oversight of the conduct of the study at the site and adherence to requirementsof 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014 for clinicalstudies (if applicable), and all other applicable local regulations.

10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicableregulatory authority in any area of the world, or if the investigator is aware of any new
information that might influence the evaluation of the benefits and risks of the study
intervention, Pfizer should be informed immediately.
In addition, the investigator will inform Pfizer immediately of any urgent safety measurestaken by the investigator to protect the study participants against any immediate hazard, andof any serious breaches of this protocol or of ICH GCP that the investigator becomes awareof.
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10.1.2. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to theparticipant and answer all questions regarding the study. The participant should be given
sufficient time and opportunity to ask questions and to decide whether or not to participate in
the trial.
Participants must be informed that their participation is voluntary. Participants will be
required to sign a statement of informed consent that meets the requirements of 21 CFR 50,
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/EC
or study center.
The investigator must ensure that each study participant is fully informed about the natureand objectives of the study, the sharing of data related to the study, and possible risks
associated with participation, including the risks associated with the processing of theparticipant’s personal data.

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)The participant must be informed that his/her personal study-related data will be used by thesponsor in accordance with local data protection law. The level of disclosure must also be
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical
Quality Assurance auditors or other authorized personnel appointed by the sponsor, byappropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or
her right to access and correct his or her personal data and to withdraw consent for theprocessing of his or her personal data.
The medical record must include a statement that written informed consent was obtained
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their
participation in the study.
A copy of the ICD(s) must be provided to the participant. Participants who are rescreened are
required to sign a new ICD.
Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate
section that addresses the use of samples for optional additional research. The optional
additional research does not require the collection of any further samples. The investigator
or authorized designee will explain to each participant the objectives of the additional
research. Participants will be told that they are free to refuse to participate and may
withdraw their consent at any time and for any reason during the storage period.

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10.1.3. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementationof organizational and technical measures to ensure protection of participant data.

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Participants’ personal data will be stored at the study site in encrypted electronic and/or paper
form and will be password protected or secured in a locked room to ensure that only
authorized study staff have access. The study site will implement appropriate technical andorganizational measures to ensure that the personal data can be recovered in the event ofdisaster. In the event of a potential personal data breach, the study site will be responsiblefor determining whether a personal data breach has in fact occurred and, if so, providing
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personaldata, participants will be assigned a single, participant-specific numerical code. Any
participant records or data sets that are transferred to the sponsor will contain the numericalcode; participant names will not be transferred. All other identifiable data transferred to thesponsor will be identified by this single, participant-specific code. The study site will
maintain a confidential list of participants who participated in the study, linking eachparticipant’s numerical code to his or her actual identity and medical record identification. In
case of data transfer, the sponsor will protect the confidentiality of participants’ personal dataconsistent with the clinical study agreement and applicable privacy laws.
10.1.4. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting theresults of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or
www.pfizer.com, and other public registries in accordance with applicable local
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, andcomplete manner and are reported regardless of the outcome of the study or the country inwhich the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional
studies (conducted in patients) that evaluate the safety and/or efficacy of a product,
regardless of the geographical location in which the study is conducted. These results are
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies inaccordance with the format and timelines set forth by EU requirements.

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www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used
to identify individual participants have been removed) on www.pfizer.com for
Pfizer-sponsored interventional studies at the same time the corresponding study results areposted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinicaldata to the EMA website. Clinical data, under Phase 1 of this policy, includes clinicaloverviews, clinical summaries, CSRs, and appendices containing the protocol and protocol
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of thispolicy, includes the publishing of individual participant data. Policy 0070 applies to newmarketing authorization applications submitted via the centralized procedure since
01 January 2015 and applications for line extensions and for new indications submitted via
the centralized procedure since 01 July 2015.

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Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposesof “bona-fide scientific research” that contributes to the scientific understanding of thedisease, target, or compound class. Pfizer will make available data from these trials
24 months after study completion. Patient-level data will be anonymized in accordance withapplicable privacy laws and regulations. CSRs will have personally identifiable information
redacted.
Data requests are considered from qualified researchers with the appropriate competencies toperform the proposed analyses. Research teams must include a biostatistician. Data will not
be provided to applicants with significant conflicts of interest, including individuals
requesting access for commercial/competitive or legal purposes.
10.1.5. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unlesstransmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is
responsible for verifying that data entries are accurate and correct by physically orelectronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports theinformation entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted
electronic and/or paper form and are password protected or secured in a locked room toprevent access by unauthorized third parties.

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The investigator must permit study-related monitoring, audits, IRB/EC review, andregulatory agency inspections and provide direct access to source data documents. This
verification may also occur after study completion. It is important that the investigator(s)and their relevant personnel are available during the monitoring visits and possible audits orinspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality
such as risk management and mitigation strategies and analytical risk-based monitoring),
methods, responsibilities, and requirements, including handling of noncompliance issues andmonitoring techniques (central, remote, or on-site monitoring), are provided in themonitoring plan.

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)The sponsor or designee is responsible for the data management of this study, including
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data enteredinto the CRF by authorized site personnel are accurate, complete, and verifiable from source
documents; that the safety and rights of participants are being protected; and that the study is
being conducted in accordance with the currently approved protocol and any other study
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must
be retained by the investigator for 15 years after study completion unless local regulations or
institutional policies require a longer retention period. No records may be destroyed during
the retention period without the written approval of the sponsor. No records may betransferred to another location or party without written notification to the sponsor. The
investigator must ensure that the records continue to be stored securely for as long as they are
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of suchdata are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory
inspection notification in relation to the study. Furthermore, the investigator will cooperatewith the sponsor or its agents to prepare the investigator site for the inspection and will allow
the sponsor or its agent, whenever feasible, to be present during the inspection. The
investigator site and investigator will promptly resolve any discrepancies that are identified
between the study data and the participant's medical records. The investigator will promptly
provide copies of the inspection findings to the sponsor or its agent. Before response
submission to the regulatory authorities, the investigator will provide the sponsor or its
agents with an opportunity to review and comment on responses to any such findings.

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10.1.6. Source Documents
Source documents provide evidence for the existence of the participant and substantiate theintegrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be
consistent with the source documents or the discrepancies must be explained. The
investigator may need to request previous medical records or transfer records, depending on
the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the study monitoring plan.
Description of the use of computerized system is documented in the Data Management Plan.
10.1.7. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment ofparticipants.

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)The first act of recruitment is the date of the first participant’s first visit and will be the study
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any
time for any reason at the sole discretion of the sponsor. Study sites will be closed uponstudy completion. A study site is considered closed when all required documents and study
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor
or designee if requested to do so by the responsible IRB/EC or if such termination is required
to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limitedto:

Failure of the investigator to comply with the protocol, the requirements of the IRB/EC
or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.

If the study is prematurely terminated or suspended, the sponsor shall promptly inform theinvestigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of
the reason for termination or suspension, as specified by the applicable regulatory
requirements. The investigator shall promptly inform the participant and should assure
appropriate participant therapy and/or follow-up.

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Study termination is also provided for in the clinical study agreement. If there is any conflict
between the contract and this protocol, the contract will control as to termination rights.
10.1.8. Sponsor’s Qualified Medical Personnel

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)The contact information for the sponsor's appropriately qualified medical personnel for the
study is documented in the study contact list located in the supporting study documentation.
To facilitate access to appropriately qualified medical personnel on study-related medical
questions or problems, participants are provided with a contact card at the time of informed
consent. The contact card contains, at a minimum, protocol and study intervention
identifiers, participant numbers, contact information for the investigator site, and contact
details for a contact center in the event that the investigator site staff cannot be reached toprovide advice on a medical question or problem originating from another healthcare
professional not involved in the participant’s participation in the study. The contact number
can also be used by investigator staff if they are seeking advice on medical questions or
problems; however, it should be used only in the event that the established communication
pathways between the investigator site and the study team are not available. It is therefore
intended to augment, but not replace, the established communication pathways between theinvestigator site and the study team for advice on medical questions or problems that may
arise during the study. The contact number is not intended for use by the participant directly,
and if a participant calls that number, he or she will be directed back to the investigator site.

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10.2. Appendix 2: Clinical Laboratory Tests

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)The following safety laboratory tests will be performed at times defined in the SoA section ofthis protocol. Additional laboratory results may be reported on these samples as a result of
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived
from calculated values. These additional tests would not require additional collection ofblood. Unscheduled clinical laboratory measurements may be obtained at any time during
the study to assess any perceived safety issues.
Hematology
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet countWBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)Basophils (Abs)
Lymphocytes (Abs)

Chemistry
BUN and creatinine
AST, ALT
Total bilirubin
Alkaline phosphatase

Other Urine pregnancy test (β-hCG)
At screening only: Hepatitis B core antibody
 Hepatitis B surface antigen
 Hepatitis C antibody
 Human immunodeficiency virus

Investigators must document their review of each laboratory safety report.
Clinically significant abnormal laboratory findings should be recorded in the AE CRF in
accordance with the following grading scale (Table 8).
Table 8.

Laboratory Abnormality Grading Scale

Hematology

Mild (Grade 1)

Hemoglobin
11.0 – 12.0
(Female) - g/dL
Hemoglobin
12.5 – 13.5
(Male) - g/dL
WBC increase 10,800 – 15,000
cells/mm3
WBC decrease 2,500 – 3,500
cells/mm3
Lymphocytes
750 – 1,000
decrease - cells/mm3
Neutrophils decrease 1,500 – 2,000- cells/mm3
Eosinophils 650 – 1500
cells/mm3
Platelets decreased - 125,000 – 140,000
cells/mm3

Moderate(Grade 2)

Severe (Grade 3)

9.5 – 10.9

8.0 – 9.4

Potentially Life
Threatening(Grade 4)<8.0

10.5 – 12.4

8.5 – 10.4

<8.5

15,001 – 20,000

20,001 – 25, 000>25,000

1,500 – 2,499

1,000 – 1,499<1,000500 – 749

250 – 499

<250

1,000 – 1,499

500 – 999

<500

1501 - 5000

>5000

Hypereosinophilic

100,000 – 124,000

25,000 – 99,000<25,000

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Table 8.

Laboratory Abnormality Grading Scale

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Chemistry

Mild (Grade 1)

Moderate(Grade 2)

Severe(Grade 3)

BUN - mg/dL
Creatinine – mg/dL

23 – 26
1.5 – 1.7

27 – 31
1.8 – 2.0> 31
2.1 – 2.5

Alkaline
phosphate –increase by factor
Liver function tests– ALT, AST
increase by factor
Bilirubin – whenaccompanied
by any increase inliver function test increase by factor
Bilirubin – whenliver function test is
normal - increase byfactor

1.1 – 2.0 x ULN

2.1 – 3.0 x ULN

3.1 – 10 x ULN

Potentially Life
Threatening(Grade 4)
Requires dialysis> 2.5 or requires
dialysis>10 x ULN

1.1 – 2.5 x ULN

2.6 – 5.0 x ULN

5.1 – 10 x ULN>10 x ULN

1.1 – 1.25 x ULN

1.26 – 1.5 x ULN

1.51 – 1.75 x ULN>1.75 x ULN

1.1 – 1.5 x ULN

1.6 – 2.0 x ULN

2.0 – 3.0 x ULN>3.0 x ULN

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen;
ULN = upper limit of normal; WBC = white blood cell.

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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition


An AE is any untoward medical occurrence in a patient or clinical study participant,temporally associated with the use of study intervention, whether or not consideredrelated to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including anabnormal laboratory finding), symptom, or disease (new or exacerbated) temporally
associated with the use of study intervention.

Events Meeting the AE Definition

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis)or other safety assessments (eg, ECG, radiological scans, vital sign measurements),
including those that worsen from baseline, considered clinically significant in the
medical and scientific judgment of the investigator Any abnormal laboratory test
results that meet any of the conditions below must be recorded as an AE:
Is associated with accompanying symptoms.



Requires additional diagnostic testing or medical/surgical intervention.



Leads to a change in study dosing (outside of any protocol-specified dose
adjustments) or discontinuation from the study, significant additional
concomitant drug treatment, or other therapy.



Exacerbation of a chronic or intermittent preexisting condition including either anincrease in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration eventhough it may have been present before the start of the study.



Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.



Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
intervention or a concomitant medication. Overdose per se will not be reported as
an AE/SAE unless it is an intentional overdose taken with possible suicidal/selfharming intent. Such overdoses should be reported regardless of sequelae.

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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safetyassessments which are associated with the underlying disease, unless judged by theinvestigator to be more severe than expected for the participant’s condition.



The disease/disorder being studied or expected progression, signs, or symptoms ofthe disease/disorder being studied, unless more severe than expected for theparticipant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).



Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present
or detected at the start of the study that do not worsen.

10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:a. Results in deathb. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which theparticipant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.
c. Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving
at least an overnight stay) at the hospital or emergency ward for observation and/or
treatment that would not have been appropriate in the physician’s office or outpatientsetting. Complications that occur during hospitalization are AEs. If a complication
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in
doubt as to whether “hospitalization” occurred or was necessary, the AE should beconsidered serious.
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Hospitalization for elective treatment of a preexisting condition that did not worsen frombaseline is not considered an AE.
d. Results in persistent disability/incapacity


The term disability means a substantial disruption of a person’s ability to conduct
normal life functions.

This definition is not intended to include experiences of relatively minor medicalsignificance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza,
and accidental trauma (eg, sprained ankle) which may interfere with or prevent
everyday life functions but do not constitute a substantial disruption.

e. Is a congenital anomaly/birth defect090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)

f. Other situations:Medical or scientific judgment should be exercised in deciding whether SAE
reporting is appropriate in other situations such as important medical events that
may not be immediately life-threatening or result in death or hospitalization but may
jeopardize the participant or may require medical or surgical intervention to prevent
one of the other outcomes listed in the above definition. These events should
usually be considered serious.



Examples of such events include invasive or malignant cancers, intensive treatment
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or
convulsions that do not result in hospitalization, or development of drug dependency
or drug abuse.

Suspected transmission via a Pfizer product of an infectious agent, pathogenic or
nonpathogenic, is considered serious. The event may be suspected from clinicalsymptoms or laboratory findings indicating an infection in a patient exposed to a
Pfizer product. The terms “suspected transmission” and “transmission” areconsidered synonymous. These cases are considered unexpected and handled asserious expedited cases by pharmacovigilance personnel. Such cases are also
considered for reporting as product defects, if appropriate.

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10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF andfor reporting serious adverse events on the Vaccines SAE Report Form to Pfizer Safety.
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious adverse
events (AEs); and (3) exposure to the study intervention under study during pregnancy orbreastfeeding, and occupational exposure.

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)It should be noted that the Vaccines SAE Report Form for reporting of SAE information is
not the same as the AE page of the CRF. When the same data are collected, the forms must
be completed in a consistent manner. AEs should be recorded using concise medical
terminology and the same AE term should be used on both the CRF and the Vaccines SAE
Report Form for reporting of SAE information.
Safety Event

Recorded on the CRF

SAE
Nonserious AE
Exposure to the study
intervention under study
during pregnancy orbreastfeeding, andoccupational exposure

All
All
All AEs/SAEs associatedwith exposure during
pregnancy or breastfeeding

Reported on the Vaccines
SAE Report Form to
Pfizer Safety Within 24
Hours of Awareness

All
None
All (and EDP supplemental
form for EDP)
Note: Include all SAEs
associated with exposure
Occupational exposure is not during pregnancy orbreastfeeding. Include allrecorded.
AEs/SAEs associated withoccupational exposure.

When an AE/SAE occurs, it is the responsibility of the investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostic
reports) related to the event.



The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s
medical records to Pfizer Safety in lieu of completion of the Vaccines SAE Report
Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases arerequested by Pfizer Safety. In this case, all participant identifiers, with the
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exception of the participant number, will be redacted on the copies of the medical
records before submission to Pfizer Safety.


The investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. Whenever possible, the diagnosis(not the individual signs/symptoms) will be documented as the AE/SAE.

Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during
the study and assign it to 1 of the following categories:

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)GRADE If required on the AE page of the CRF, the investigator will use theadjectives MILD, MODERATE, SEVERE, or LIFE-THREATENING todescribe the maximum intensity of the AE. For purposes of consistency,
these intensity grades are defined as follows:
1

MILD

Does not interfere with participant's usualfunction.

2

MODERATE

Interferes to some extent with participant's usualfunction.

3

SEVEREInterferes significantly with participant's usualfunction.

4

LIFE-THREATENING Life-threatening consequences; urgent
intervention indicated.

Assessment of Causality

The investigator is obligated to assess the relationship between study intervention
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence,
and/or arguments to suggest a causal relationship, rather than a relationship cannot
be ruled out.

The investigator will use clinical judgment to determine the relationship.



Alternative causes, such as underlying disease(s), concomitant therapy, and otherrisk factors, as well as the temporal relationship of the event to study intervention
administration, will be considered and investigated.

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The investigator will also consult the IB and/or product information, for marketed
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she
has reviewed the AE/SAE and has provided an assessment of causality.



There may be situations in which an SAE has occurred and the investigator has
minimal information to include in the initial report to the sponsor. However, it isvery important that the investigator always make an assessment of causality forevery event before the initial transmission of the SAE data to the sponsor.



The investigator may change his/her opinion of causality in light of follow-up
information and send an SAE follow-up report with the updated causality
assessment.



The causality assessment is one of the criteria used when determining regulatory
reporting requirements.



If the investigator does not know whether or not the study intervention caused theevent, then the event will be handled as “related to study intervention” for reporting
purposes, as defined by the sponsor. In addition, if the investigator determines thatan SAE is associated with study procedures, the investigator must record this causal
relationship in the source documents and CRF, and report such an assessment in the
dedicated section of the Vaccines SAE Report Form and in accordance with the
SAE reporting requirements.

Follow-up of AEs and SAEs


The investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by thesponsor to elucidate the nature and/or causality of the AE or SAE as fully as
possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other healthcare providers.



If a participant dies during participation in the study or during a recognizedfollow-up period, the investigator will provide Pfizer Safety with a copy of any
postmortem findings including histopathology.



New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours ofreceipt of the information.

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10.3.4. Reporting of SAEs

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SAE Reporting to Pfizer Safety via Vaccines SAE Report Form

Facsimile transmission of the Vaccines SAE Report Form is the preferred method totransmit this information to Pfizer Safety.



In circumstances when the facsimile is not working, notification by telephone isacceptable with a copy of the Vaccines SAE Report Form sent by overnight mail orcourier service.

Initial notification via telephone does not replace the need for the investigator tocomplete and sign the Vaccines SAE Report Form pages within the designatedreporting time frames.

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10.4. Appendix 4: Contraceptive Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during
the intervention period and for at least 28 days after the last dose of study intervention, whichcorresponds to the time needed to eliminate reproductive safety risk of the study
intervention(s):Refrain from donating sperm.

PLUS either:Be abstinent from heterosexual intercourse with a female of childbearing potential as
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) andagree to remain abstinent.

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)OR

Must agree to use a male condom when engaging in any activity that allows for passageof ejaculate to another person.



In addition to male condom use, a highly effective method of contraception may beconsidered in WOCBP partners of male participants (refer to the list of highly effective
methods below in Section 10.4.4).

10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using an acceptable contraceptive method as described below during
the intervention period (for a minimum of 28 days after the last dose of study
intervention). The investigator should evaluate the effectiveness of the contraceptive
method in relationship to the first dose of study intervention.

The investigator is responsible for review of medical history, menstrual history, and recent
sexual activity to decrease the risk for inclusion of a woman with an early undetected
pregnancy.

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10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot
be confirmed before the first dose of study intervention, additional evaluation should beconsidered.
Women in the following categories are not considered WOCBP:

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)

1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.

For individuals with permanent infertility due to an alternate medical cause other than theabove, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should beapplied to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s
review of the participant’s medical records, medical examination, or medical history
interview. The method of documentation should be recorded in the participant’s medical
record for the study.
2. Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause. In addition, ahigh FSH level in the postmenopausal range must be used to confirm apostmenopausal state in women under 60 years of age and not using hormonal
contraception or HRT.



Female on HRT and whose menopausal status is in doubt will be required to use
one of the nonestrogen hormonal highly effective contraception methods if theywish to continue their HRT during the study. Otherwise, they must discontinue
HRT to allow confirmation of postmenopausal status before study enrollment.

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10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations
regarding the use of contraceptive methods for those participating in clinical trials.
1. Implantable progestogen-only hormone contraception associated with inhibition ofovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner:

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)

Vasectomized partner is a highly effective contraceptive method provided that thepartner is the sole sexual partner of the woman of childbearing potential and theabsence of sperm has been confirmed. If not, an additional highly effective methodof contraception should be used. The spermatogenesis cycle is approximately
90 days.

6. Combined (estrogen- and progestogen-containing) hormonal contraception associatedwith inhibition of ovulation:


Oral;



Intravaginal;Transdermal;



Injectable.

7. Progestogen-only hormone contraception associated with inhibition of ovulation:


Oral;



Injectable.

8. Sexual abstinence:Sexual abstinence is considered a highly effective method only if defined as
refraining from heterosexual intercourse during the entire period of risk associatedwith the study intervention. The reliability of sexual abstinence needs to be evaluatedin relation to the duration of the study and the preferred and usual lifestyle of theparticipant.

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9. Progestogen-only oral hormonal contraception where inhibition of ovulation is not the
primary mode of action.
10. Male or female condom with or without spermicide.
11. Cervical cap, diaphragm, or sponge with spermicide.

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12. A combination of male condom with either cervical cap, diaphragm, or sponge with
spermicide (double-barrier methods).

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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations intransaminases) are termed “tolerators,” while those who show transient liver injury, but adapt
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of amore serious potential outcome. These participants fail to adapt and therefore are"susceptible" to progressive and serious liver injury, commonly referred to as DILI.
Participants who experience a transaminase elevation above 3 × ULN should be monitored
more frequently to determine if they are an “adaptor” or are “susceptible.”

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LFTs are not required as a routine safety monitoring procedure for all participants in thisstudy. However, should an investigator deem it necessary to assess LFTs because aparticipant presents with clinical signs/symptoms, such LFT results should be managed andfollowed as described below.
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will beelevated within the same laboratory sample). In rare instances, by the time TBili elevations
are detected, AST/ALT values might have decreased. This occurrence is still regarded as apotential DILI. Therefore, abnormal elevations in either AST OR ALT in addition to TBili
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law
criteria) cases and should always be considered important medical events, even before allother possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on theparticipant’s individual baseline values and underlying conditions. Participants who present
with the following laboratory abnormalities should be evaluated further as potential DILI
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:Participants with AST/ALT and TBili baseline values within the normal range who
subsequently present with AST OR ALT values >3 × ULN AND a TBili value >2 × ULN
with no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or notavailable.

For participants with baseline AST OR ALT OR TBili values above the ULN, thefollowing threshold values are used in the definition mentioned above, as needed,
depending on which values are above the ULN at baseline:Preexisting AST or ALT baseline values above the normal range: AST or ALT values>2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is smaller).

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Rises in AST/ALT and TBili separated by more than a few weeks should be assessedindividually based on clinical judgment; any case where uncertainty remains as to whether it
represents a potential Hy’s law case should be reviewed with the sponsor.

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)The participant should return to the investigator site and be evaluated as soon as possible,
preferably within 48 hours from awareness of the abnormal results. This evaluation should
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili for suspected cases ofHy’s law, additional laboratory tests should include albumin, CK, direct and indirect
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should
also be given to drawing a separate tube of clotted blood and an anticoagulated tube of bloodfor further testing, as needed, for further contemporaneous analyses at the time of therecognized initial abnormalities to determine etiology. A detailed history, including relevant
information, such as review of ethanol, acetaminophen/paracetamol (either by itself or as a
coformulated product in prescription or over-the-counter medications), recreational drug,
supplement (herbal) use and consumption, family history, sexual history, travel history,
history of contact with a jaundiced person, surgery, blood transfusion, history of liver orallergic disease, and potential occupational exposure to chemicals, should be collected.
Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary
tract) and collection of serum samples for acetaminophen/paracetamol drug and/or protein
adduct levels may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if noother reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law)cases are to be reported as SAEs, irrespective of availability of all the results of theinvestigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results ofreasonable investigations have been received and have excluded an alternative etiology.

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10.6. Appendix 6: Abbreviations

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)The following is a list of abbreviations that may be used in the protocol.
Abbreviation
2019-nCoV
Abs
AE
ALT
AST
-hCG
BMI
BUN
CBER
CDC
CFR
CI
CIOMS
CLIA
CONSORT
COVID-19
CRF
CRO
CSR
CT
DBP
DILI
DMC
DNA
DU
EC
ECMO
ECG
eCRF
e-diary
EDP
EMA
EU
EUA
EudraCT
FDA
FiO2
FSH
GCP

Term
novel coronavirus 2019absolute (in Appendix 2)
adverse event
alanine aminotransferase
aspartate aminotransferase
beta-human chorionic gonadotropin
body mass index
blood urea nitrogen
Center for Biologics Evaluation and ResearchCenters for Disease Control and Prevention (United States)
Code of Federal Regulations
confidence interval
Council for International Organizations of Medical Sciences
Clinical Laboratory Improvement Amendments
Consolidated Standards of Reporting Trials
coronavirus disease 2019case report form
contract research organization
clinical study reportcomputed tomography
diastolic blood pressuredrug-induced liver injury
data monitoring committee
deoxyribonucleic aciddosing unit
ethics committee
extracorporeal membrane oxygenationelectrocardiogram
electronic case report form
electronic diary
exposure during pregnancy
European Medicines Agency
European Union
emergency use application
European Clinical Trials Database
Food and Drug Administration
fraction of inspired oxygenfollicle-stimulating hormone
Good Clinical Practice

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Abbreviation
GGT
GMC
GMFR
GMR
GMT
HBc Ab
HBe
HBeAg
HBsAg
HBV
HCV
HCV Ab
HIPAA
HIV
HR
HRT
IA
IB
ICD
ICH
ICU
ID
Ig
IgG
IgM
IMP
IND
INR
IP manual
IPAL
IRB
IRC
IRR
IRT
ISO
IV
IWR
LFT
LL
LLOQ
LNP
LPX

Term
gamma-glutamyl transferase
geometric mean concentrationgeometric mean fold risegeometric mean ratio
geometric mean titerhepatitis B core antibody
hepatitis B ehepatitis B e antigen
hepatitis B surface antigen
hepatitis B virus
hepatitis C virus
hepatitis C virus antibody
Health Insurance Portability and Accountability Act
human immunodeficiency virus
heart rate
hormone replacement therapy
interim analysis
investigator’s brochure
informed consent document
International Council for Harmonisation
intensive care unit
identification
immunoglobulin
immunoglobulin G
immunoglobulin M
investigational medicinal productinvestigational new druginternational normalized ratio
investigational product manual
Investigational Product Accountability Log
institutional review board
internal review committee
illness rate ratio
interactive response technology
International Organization for Standardization
intravenous(ly)interactive Web-based response
liver function test
lower limit
lower limit of quantitation
lipid nanoparticle
lipoplex

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Abbreviation
MAR
MCH
MCHC
MCV
MedDRAMERS
modRNA
MRI
N
N/A
NAAT
non-S
P2 S
PaO2
PCR
PI
POS
PPE
PT
RBC
RBD
RCDC
RNA
RR
RSV
RT-PCR
S1
SAE
SAP
saRNA
SARS
SARS-CoV-2
SBP
SoA
SOP
SpO2
SRSD
SUSAR
TBD
TBili
ULN
uRNA

Term
missing at randommean corpuscular hemoglobinmean corpuscular hemoglobin concentration
mean corpuscular volume
Medical Dictionary for Regulatory Activities
Middle East respiratory syndrome
nucleoside-modified messenger ribonucleic acidmagnetic resonance imaging
SARS-CoV-2 nucleoprotein
not applicable
nucleic acid amplification test
nonspike protein
SARS-CoV-2 full-length, P2 mutant, prefusion spike glycoprotein
partial pressure of oxygen, arterial
polymerase chain reaction
principal investigatorprobability of successpersonal protective equipment
prothrombin time
red blood cell
receptor-binding domain
reverse cumulative distribution curve
ribonucleic acidrespiratory rate
respiratory syncytial virus
reverse transcription–polymerase chain reaction
spike protein S1 subunit
serious adverse event
statistical analysis planself-amplifying messenger ribonucleic acidsevere acute respiratory syndrome
severe acute respiratory syndrome coronavirus 2
systolic blood pressureschedule of activities
standard operating procedureoxygen saturation as measured by pulse oximetry
single reference safety document
suspected unexpected serious adverse reaction
to be determinedtotal bilirubin
upper limit of normal
unmodified messenger ribonucleic acid

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Abbreviation
US
vax
VE
WBC
WHO
WOCBP

Term
United States
vaccination
vaccine efficacy
white blood cell
World Health Organization
woman/women of childbearing potential

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10.7. Appendix 7: Stopping and Alert Rules for Enhanced COVID-19
In Phase 2/3, the unblinded team supporting the DMC (reporting team), including an
unblinded medical monitor, will review cases of severe COVID-19 as they are received, andwill review AEs at least weekly for additional potential cases of severe COVID-19 and willcontact the DMC in the event that the stopping rule or an alert is met. Specifically, theunblinded reporting team will contact the DMC chair, who will then convene the full DMC
as soon as possible. The DMC will review all available safety and/or efficacy data at thetime of the review. The DMC will make one of the following recommendations to Pfizer:
withhold final recommendation until further information/data are provided, continue thestudy as designed, modify the study and continue, or stop the study. The final decision toaccept or reject the committee’s recommendation resides with Pfizer management and will be
communicated to the committee chairperson in writing.

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At any point the unblinded team may discuss with the DMC chair whether the DMC should
review cases for an adverse imbalance of cases of COVID-19 and/or severe COVID-19
between the vaccine and placebo groups (see Section 9.6). In addition, at the time of the IAs
at 32, 62, 92, and 120 cases, the number of severe COVID-19 cases in the vaccine andplacebo groups will be assessed.
Stopping and alert rules will be applied as follows. The stopping rule will be triggered whenthe 1-sided probability of observing the same or a more extreme case split is 5% or less when
the true incidence of severe disease is the same for vaccine and placebo participants, and alert
criteria are triggered when this probability is less than 11%. In addition, when the total
number of severe cases is low (15 or less), the unblinded team supporting the DMC will
implement the alert rule when a reverse case split of 2:1 or worse is observed. For example,
at 3 cases 2:1, at 4 cases 3:1, etc. Below 15 cases, this rule is more rigorous than requiring
the probability of an observed adverse split or worse be <11%.
The stopping rule and alert rules are illustrated in Table 9 and Table 10, respectively, when
the total number of severe cases is 20 or less. For example, when there are 7 severe cases,
the adverse split has to be 7:0 to stop the study, but a split of 5:2 would trigger the alert rule.
Similarly, when there is a total of 9 severe cases, an adverse split of 9:0 triggers the stopping
rule, while a split of 6:3 or worse triggers the alert rule. The alert rule may be triggered withas few as 2 cases, with a split of 2:0.

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Table 9.

Stopping Rule: Enrollment Is Stopped if the Number of Severe Cases inthe Vaccine Group Is Greater Than or Equal to the Prespecified Stopping
Rule Value (S)090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)

Total Severe Cases

Prespecified Stopping Rule Value(S): Number of Severe Cases in the
Vaccine Group to Stop

4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Abbreviation: N/A = not applicable.

4
5
6
7
7
8
9
9
10
10
11
12
12
13
13
14
15

If the True Ratio of Severe Cases
Between Vaccine and PlaceboGroups Is 1:1, Probability of S or
More Being Observed in the Vaccine
Group
N/A
3.13%
1.56%
0.78%
3.52%
1.95%
1.07%
3.27%
1.93%
4.61%
2.87%
1.76%
3.84%
2.45%
4.81%
3.18%
2.07%

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Table 10. Alert Rule: Further Action Is Taken if the Number of Severe Cases in the
Vaccine Group Is Greater Than or Equal to the Prespecified Alert Rule
Value (A)
Total
SevereCases

Prespecified AlertRule Value(A):
Number of
SevereCases in the
VaccineGroup toTrigger
Further
ActionIf the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
1:1,
Probabilityof A Being
Observed inthe Vaccine
Group

2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20

2
2
3
4
4
5
6
6
7
8
8
9
10
10
11
12
13
13
14

25.00%
37.50%
25.00%
15.63%
23.44%
16.41%
10.94%
16.41%
11.72%
8.06%
12.08%
8.73%
6.11%
9.16%
6.67%
4.72%
3.27%
5.18%
3.70%

If the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
1:1,
Probabilityof A or More
Being
Observed inthe Vaccine
Group
25.00%
50.00%
31.25%
18.75%
34.38%
22.66%
14.45%
25.39%
17.19%
11.33%
19.38%
13.34%
8.98%
15.09%
10.51%
7.17%
4.81%
8.35%
5.77%

If the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
2:1,
Probabilityof A or More
Being
Observed inthe Vaccine
Group44.49%
74.12%
59.32%
46.16%
68.10%
57.14%
46.90%
65.11%
56.02%
47.35%
63.25%
55.31%
47.66%
61.94%
54.81%
47.88%
41.34%
54.43%
48.06%

If the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
3:1,
Probabilityof A or More
Being
Observed inthe Vaccine
Group56.25%
84.38%
73.83%
63.28%
83.06%
75.64%
67.85%
83.43%
77.59%
71.33%
84.24%
79.40%
74.15%
85.16%
81.03%
76.53%
71.75%
82.51%
78.58%

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If the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
4:1,
Probabilityof A or More
Being
Observed inthe VaccineGroup64.00%
89.60%
81.92%
73.73%
90.11%
85.20%
79.69%
91.44%
87.91%
83.89%
92.74%
90.09%
87.02%
93.89%
91.83%
89.43%
86.71%
93.24%
91.33%

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Protocol Amendment 6, 08 September 2020

10.8. Appendix 8: Criteria for Allowing Inclusion of Participants With Chronic Stable
HIV, HCV, or HBV Infection
Potential participants with chronic stable HIV, HCV, or HBV infection may be considered
for inclusion if they fulfill the following respective criteria.
Known HIV infection
Confirmed stable HIV disease defined as documented viral load <50 copies/mL and CD4
count >200 cells/mm3 within 6 months before enrollment, and on stable antiretroviraltherapy for at least 6 months.

Known HCV infection
History of chronic HCV with evidence of sustained virological response (defined asundetectable HCV RNA) for ≥12 weeks following HCV treatment or without evidenceof HCV RNA viremia (undetectable HCV viral load).

090177e194dca764\Approved\Approved On: 08-Sep-2020 23:40 (GMT)

Known HBV infection
Confirmed inactive chronic HBV infection, defined as HBsAg present for ≥6 months andthe following:

HBeAg negative, anti-HBe positive

Serum HBV DNA <2000 IU/mLPersistently normal ALT and/or AST levels

In those who have had a liver biopsy performed, findings that confirm the absence ofsignificant necroinflammation.

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11. REFERENCES
1

World Health Organization. WHO Director-General's opening remarks at the media
briefing on COVID-19. Available from: https://www.who.int/dg/speeches/detail/whodirector-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march2020. Published: 11 Mar 2020. Accessed: 01 Apr 2020.

2

World Health Organization. Coronavirus disease 2019 (COVID-19) situation report - 70.
In: Data as reported by national authorities by 10:00 CET 30 March 2020. Geneva,
Switzerland: World Health Organization; 2020.

3

Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19):
information for clinicians on investigational therapeutics for patients with COVID-19.
Available from: https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeuticoptions.html. Updated: 25 Apr 2020. Accessed: 26 Jun 2020.

4

Rauch S, Jasny E, Schmidt KE, et al. New vaccine technologies to combat outbreaksituations. Front Immunol 2018;9:1963.

5

Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics—developing a new class ofdrugs. Nat Rev Drug Discov 2014;13(10):759-80.

6

BioNTech RNA Pharmaceuticals GmbH. CorVAC/BNT162 Investigator’s Brochure.
Mainz, Germany: BioNTech RNA Pharmaceuticals GmbH; 25 Mar 2020.

7

Feldman RA, Fuhr R, Smolenov I, et al. mRNA vaccines against H10N8 and H7N9
influenza viruses of pandemic potential are immunogenic and well tolerated in healthy
adults in phase 1 randomized clinical trials. Vaccine 2019;37(25):3326-34.

8

US Food and Drug Administration. Guidance for industry: toxicity grading scale forhealthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials.
Rockville, MD: Center for Biologics Evaluation and Research; September 2007.

9

Agresti A. Introduction: distributions and inference for categorical data. In: Agresti A,
ed. Categorical data analysis. 2nd ed. Hoboken, NJ: John Wiley & Sons; 2002:1-35.

10

Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med
1985;4(2):213-26.

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Document Approval Record
Document Name:

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Signed By:

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FDA-CBER-2021-5683-0014657

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Protocol Amendment 5, 24 July 2020090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)A PHASE 1/2/3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLIND,
DOSE-FINDING STUDY TO EVALUATE THE SAFETY, TOLERABILITY,IMMUNOGENICITY, AND EFFICACY OF SARS-COV-2 RNA VACCINECANDIDATES AGAINST COVID-19 IN HEALTHY ADULTS

Study Sponsor:

BioNTechStudy Conducted By:

PfizerStudy Intervention Number:

PF-07302048

Study Intervention Name:

RNA-Based COVID-19 Vaccines

US IND Number:

19736

EudraCT Number:2020-002641-42

Protocol Number:

C4591001

Phase:
1/2/3
Short Title: A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, andEfficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Adults

This document and accompanying materials contain confidential information belonging to Pfizer. Except asotherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold thisinformation in confidence and not copy or disclose it to others (except where required by applicable law) or
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer
must be promptly notified.

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Protocol Amendment 5, 24 July 2020

Protocol Amendment Summary of Changes Table
Document History
Document

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)

Protocol amendment 5

Version Date
24 July 2020

Summary and Rationale for Changes
Following regulatory feedback: Renamed Stage 1 to Phase 1, removed Stage 2,
and renamed Stage 3 to Phase 2/3.
 Clarified that a single vaccine candidate,administered as 2 doses 21 days apart, will be
studied in Phase 2/3.
 Stated that the vaccine candidate selected forPhase 2/3 evaluation is BNT162b2 at a dose of
30 µg.
 Removed the potential to study BNT162b3.
 Immunogenicity data will be summarized for the
first 360 participants through 1 month after Dose2, rather than through 21 days after Dose 1.
 Provided further details of sponsor staff that will
be unblinded in Phase 2/3.
 Clarified which stopping rules apply to which
phase of the study.
In addition:
 Clarified the AE reporting requirements forpotential COVID-19 illnesses.
 Updated that Visit 1 may be conducted across 2
consecutive days in Phase 2/3.
 Moved the immunogenicity objectives inPhase 2/3 to become exploratory.
 Added an additional inclusion criterion to enroll
participants who, in the judgment of theinvestigator, are at risk for acquiring COVID-19.
 Modified exclusion criterion 5, so thatparticipants with a previous clinical or
microbiological diagnosis of COVID-19 are
excluded from all phases of the study.
 Clarified that there will be 2 all-available
efficacy populations.
 Clarified that immunogenicity samples will bedrawn for all participants; analyses will be based
upon results from subsets of samples, according
to the purpose.
 Updated that the 3-tier approach to summarizing
AEs will only be performed in Phase 2/3.
 Updated that at each interim analysis for
efficacy, only the first primary objective will be
evaluated.
 Changed to use the same posterior probability(99.5%) for all interim analyses, resulting incase split changes in Tables 5, 6, and 7.

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Document History
Document

Version Date

Summary and Rationale for Changes
Protocol amendment 4

30 June 2020

Updated the stopping and alert rule parameters
for enhanced COVID-19.
Given the rapidly evolving pandemic situation, andthe need to demonstrate VE as soon as possible, theprotocol has been amended to be powered to meet
new efficacy objectives. These new efficacy
objectives and corresponding endpoints have been
added to Section 3.
Further nonclinical data are available to support the
study of the BNT162b3 candidate in humans, and thecandidate has been added to the protocol.

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)The 6-month safety follow-up telephone contact has
been changed to an in-person visit for Stage 3
participants, to allow collection of an
immunogenicity blood sample.
The COVID-19 illness visit has now added
flexibility to permit a remote or in-person visit.
The COVID-19 illness symptoms have been updated
to align with the FDA-accepted definitions; thischange is also reflected in the criteria for temporary
delay of enrollment.
AEs that occur between consent and dosing will now
be reported on the AE (rather than Medical History)
CRF, to align with the latest Pfizer protocol
template.
Changes have been made to the headings to alignwith the latest Pfizer protocol template.
Clarified that only an unblinded site staff member
may obtain the participant’s randomization number
and study intervention allocation.
Additional interim analyses have been added toevaluate VE and futility during the study.

Protocol amendment 3

10 June 2020

As a result of regulatory feedback, an appendix has
been added to outline the stopping and alert rules tomonitor for potential enhanced COVID-19.
As data have become available from this study andthe BNT162-01 study in Germany, the following
decisions were made: Not to study the BNT162a1 and BNT162c2
vaccine candidates at this time. Therefore, these

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Version Date

Summary and Rationale for Changes



candidates have been removed from theprotocol.
To study further lower dose levels of the
modRNA candidates. Therefore, a 20-µg doselevel is formally included for BNT162b1 and
BNT162b2.
To permit individual and group dosing
alterations for the second dose of study
intervention.

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Following regulatory feedback, the BNT162b3
vaccine candidate has been removed from theprotocol until further nonclinical data are available tosupport study in humans.
Given the rapidly evolving pandemic situation,
additional blood draws for exploratory COVID-19
research, intended to establish an immunologicalsurrogate of protection, will be taken from selectedparticipants who consent.
In order to increase flexibility enrolling participants,
an extended screening window (increased from 14 to
28 days) for sentinel participants in Stage 1 has been
added. This is considered acceptable since eligible
participants are expected to be either healthy or havestable medical conditions.
To increase the number of doses that can be obtained
from available vaccine vials, not all dose levels will
result in a dosing volume of 0.5 mL. Precise dosing
instructions will be provided in the IP manual.

Protocol amendment 2

27 May 2020

To facilitate the reporting of COVID-19 illness
diagnoses and potential symptoms to theinvestigator, participants may utilize a COVID-19
illness e-diary.
Given the urgent nature of the pandemic situation,
the following changes allow determination of theappropriate human dose level for both younger andolder adults to move speedily into the next phase ofclinical evaluation:
 Added a new vaccine candidate, BNT162b3,
modRNA encoding a membrane-anchored RBD
 Added a 50-µg dose level for vaccine candidates
based on the modRNA platform (ie, BNT162b1,
BNT162b2, and BNT162b3)
 Modified the criteria required for the IRC todetermine dose escalation in the 18- to 55-year

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Protocol amendment 1

Version Date

13 May 2020

Summary and Rationale for Changes
age cohort and advancement to groups ofparticipants 65 to 85 years of age
In addition:
 Removed hemoglobin change-from-baseline
abnormalities from the laboratory abnormality
grading scale as abnormalities should be gradedbased upon absolute values
 Following regulatory feedback: Modified exclusion criteria and prohibitedinhaled/nebulized corticosteroids for sentinel
participants in Stage 1
 Clarified that the rapid test for prior COVID-19
infection for sentinel participants in Stage 1 will
be used only for screening purposes Removed time frames for stopping rules
 Stated that data supporting the selection of
vaccine candidate(s)/dose level(s) andschedule(s) for Stages 2 and 3 will be submitted
to the FDA for review

Following preliminary experience in the
BioNTech study conducted in Germany(BNT162-01):
Decreased the dose levels for BNT162a1 and
BNT162c2

Additionally: Clarified the roles of BioNTech and Pfizer
 Amended text so that the IRC decision toprogress group(s) into Stages 2 and 3 can bebased upon safety and immunogenicity data
after Dose 1 or 2
 Clarified safety data requirements to permit dose
escalation
 Amended text so that the progression toparticipants 65 to 85 years of age can be based
upon data from the same RNA platform Incorporated a protocol administrative change tocorrect the variant designation and the encoded
antigen to BNT162c2
 Clarified that the SARS-CoV-2 neutralizing
assay does not employ wild-type virus
 Clarified that the SARS-CoV-2 spike protein–binding antibody assay is specific for the S1subunit Clarified that efficacy against COVID-19 isbased upon illness (not infection) rate ratio

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Document

Version Date

Summary and Rationale for Changes






090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)
Original protocol

15 April 2020

Incorporated a protocol administrative change tostate that the study placebo may be supplied in a
glass or plastic vial
Corrected a typographical error in Section 6.5.1
regarding the time frame for prior receipt ofblood/plasma products or immunoglobulins
Corrected a typographical error in Table 2
regarding the lower limit of diameter (cm) for
mild redness and swelling
Updated the °C fever scale in Table 4 to ensurethat all potential °F values are correctly assigned
Incorporated a protocol administrative change toclarify that a rapid test for prior COVID-19
infection will be performed for sentinel
participants in Stage 1, and a serum sample will
be drawn for potential future assessment
Clarified that, after screening, physicalexaminations in sentinel participants in Stage 1
will be directed
Clarified the descriptions of the populations foranalysis to align with the statistical analysis plan
Added a complete safety and immunogenicity
analysis approximately 6 months after Dose 2
for all participants in Stage 3
Amended text so that the stopping rules apply to
an RNA platform rather than a specific vaccine
candidate

N/A

This amendment incorporates all revisions to date, including amendments made at therequest of country health authorities and IRBs/ECs.

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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................12
1. PROTOCOL SUMMARY...................................................................................................141.1. Synopsis ..................................................................................................................14
1.2. Schema ....................................................................................................................21
1.3. Schedule of Activities .............................................................................................22
1.3.1. Phase 1 ........................................................................................................22
1.3.2. Phase 2/3.....................................................................................................27
2. INTRODUCTION ...............................................................................................................29
2.1. Study Rationale .......................................................................................................29
2.2. Background .............................................................................................................29
2.2.1. Clinical Overview.......................................................................................30

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2.3. Benefit/Risk Assessment.........................................................................................30
2.3.1. Risk Assessment .........................................................................................312.3.2. Benefit Assessment.....................................................................................32
2.3.3. Overall Benefit/Risk Conclusion................................................................32
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................32
3.1. For Phase 1 ..............................................................................................................32
3.2. For Phase 2/3 ...........................................................................................................34
4. STUDY DESIGN.................................................................................................................36
4.1. Overall Design.........................................................................................................36
4.1.1. Phase 1 ........................................................................................................36
4.1.2. Phase 2/3.....................................................................................................37
4.2. Scientific Rationale for Study Design .....................................................................38
4.3. Justification for Dose ..............................................................................................38
4.4. End of Study Definition ..........................................................................................39
5. STUDY POPULATION ......................................................................................................40
5.1. Inclusion Criteria.....................................................................................................40
5.2. Exclusion Criteria....................................................................................................41
5.3. Lifestyle Considerations..........................................................................................43
5.3.1. Contraception..............................................................................................43

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5.4. Screen Failures ........................................................................................................43
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study
Intervention Administration ......................................................................................44
6. STUDY INTERVENTION..................................................................................................44
6.1. Study Intervention(s) Administered ........................................................................45
6.1.1. Administration ............................................................................................45
6.2. Preparation/Handling/Storage/Accountability ........................................................46
6.2.1. Preparation and Dispensing ........................................................................47
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................47
6.3.1. Allocation to Study Intervention ................................................................47
6.3.2. Blinding of Site Personnel ..........................................................................48
6.3.3. Blinding of the Sponsor ..............................................................................48
6.3.4. Breaking the Blind......................................................................................49
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6.4. Study Intervention Compliance...............................................................................49
6.5. Concomitant Therapy..............................................................................................49
6.5.1. Prohibited During the Study .......................................................................49
6.5.2. Permitted During the Study ........................................................................50
6.6. Dose Modification...................................................................................................50
6.7. Intervention After the End of the Study ..................................................................50
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANTDISCONTINUATION/WITHDRAWAL...........................................................................51
7.1. Discontinuation of Study Intervention ....................................................................51
7.2. Participant Discontinuation/Withdrawal From the Study .......................................51
7.2.1. Withdrawal of Consent ...............................................................................52
7.3. Lost to Follow-up ....................................................................................................52
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................53
8.1. Efficacy and/or Immunogenicity Assessments .......................................................54
8.1.1. Biological Samples .....................................................................................56
8.2. Safety Assessments .................................................................................................57
8.2.1. Clinical Safety Laboratory Assessments (Phase 1 Participants Only) .......57
8.2.2. Electronic Diary..........................................................................................58
8.2.2.1. Grading Scales...........................................................................58
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8.2.2.2. Local Reactions .........................................................................58
8.2.2.3. Systemic Events ........................................................................59
8.2.2.4. Fever..........................................................................................60
8.2.2.5. Antipyretic Medication .............................................................61
8.2.3. Phase 1 Stopping Rules ..............................................................................61
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19
and Phase 2/3 Stopping Rule ...........................................................................62
8.2.5. Randomization and Vaccination After a Stopping Rule Is Met .................63
8.2.6. Pregnancy Testing ......................................................................................63
8.3. Adverse Events and Serious Adverse Events..........................................................64
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......64
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................65
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................65
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8.3.2. Method of Detecting AEs and SAEs ..........................................................65
8.3.3. Follow-up of AEs and SAEs.......................................................................65
8.3.4. Regulatory Reporting Requirements for SAEs...........................................66
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational
Exposure ..........................................................................................................66
8.3.5.1. Exposure During Pregnancy......................................................66
8.3.5.2. Exposure During Breastfeeding ................................................68
8.3.5.3. Occupational Exposure .............................................................68
8.3.6. Cardiovascular and Death Events...............................................................68
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not
Qualifying as AEs or SAEs..............................................................................69
8.3.8. Adverse Events of Special Interest .............................................................69
8.3.8.1. Lack of Efficacy ........................................................................69
8.3.9. Medical Device Deficiencies......................................................................69
8.3.10. Medication Errors .....................................................................................69
8.4. Treatment of Overdose............................................................................................70
8.5. Pharmacokinetics ....................................................................................................71
8.6. Pharmacodynamics..................................................................................................71
8.7. Genetics ...................................................................................................................71
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8.8. Biomarkers ..............................................................................................................71
8.9. Immunogenicity Assessments .................................................................................71
8.10. Health Economics .................................................................................................71
8.11. Study Procedures...................................................................................................71
8.11.1. Phase 1 ......................................................................................................71
8.11.1.1. Screening: (0 to 28 Days Before Visit 1) ................................71
8.11.1.2. Visit 1 – Vaccination 1: (Day 1) .............................................72
8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1to 3 Days After Visit 1) .....................................................................75
8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to
8 Days After Visit 1) .........................................................................76
8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1) ...........77090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)

8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to
8 Days After Visit 4) .........................................................................79
8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to
16 Days After Visit 4) .......................................................................80
8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After
Visit 4) ...............................................................................................81
8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (154 to 168 Days
After Visit 4)......................................................................................82
8.11.1.10. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 4)......................................................................................83
8.11.1.11. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 4)......................................................................................83
8.11.2. Phase 2/3...................................................................................................84
8.11.2.1. Visit 1 – Vaccination 1: (Day 1) .............................................84
8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days After Visit 1) ...........86
8.11.2.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2):(28 to 35 Days After Visit 2).............................................................88
8.11.2.4. Visit 4 – 6-Month Follow-up Visit: (154 to 168 Days
After Visit 2)......................................................................................89
8.11.2.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 2)......................................................................................89
8.11.2.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 2)......................................................................................90
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8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction ........................90
8.13. COVID-19 Surveillance (All Participants) ...........................................................91
8.13.1. Potential COVID-19 Illness Visit: (Optimally Within 3 Days After
Potential COVID-19 Illness Onset) .................................................................92
8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After
Potential COVID-19 Illness Visit)..................................................................93
8.14. Communication and Use of Technology...............................................................94
9. STATISTICAL CONSIDERATIONS ................................................................................94
9.1. Estimands and Statistical Hypotheses .....................................................................94
9.1.1. Estimands....................................................................................................94
9.1.2. Statistical Hypotheses.................................................................................95
9.2. Sample Size Determination.....................................................................................95
9.3. Analysis Sets ...........................................................................................................96090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)

9.4. Statistical Analyses .................................................................................................97
9.4.1. Immunogenicity Analyses ..........................................................................98
9.4.2. Efficacy Analyses .....................................................................................102
9.4.3. Safety Analyses ........................................................................................104
9.4.4. Other Analyses..........................................................................................105
9.5. Interim Analyses ...................................................................................................105
9.5.1. Analysis Timing........................................................................................1089.6. Data Monitoring Committee or Other Independent Oversight Committee...........108
10. SUPPORTING DOCUMENTATION AND OPERATIONALCONSIDERATIONS ........................................................................................................110
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .............110
10.1.1. Regulatory and Ethical Considerations ..................................................110
10.1.1.1. Reporting of Safety Issues and Serious Breaches of theProtocol or ICH GCP.......................................................................110
10.1.2. Informed Consent Process ......................................................................111
10.1.3. Data Protection .......................................................................................112
10.1.4. Dissemination of Clinical Study Data ....................................................112
10.1.5. Data Quality Assurance ..........................................................................113
10.1.6. Source Documents ..................................................................................115
10.1.7. Study and Site Start and Closure ............................................................115
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10.1.8. Sponsor’s Qualified Medical Personnel .................................................116
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................117
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting ....................................................................119
10.3.1. Definition of AE .....................................................................................119
10.3.2. Definition of SAE ...................................................................................120
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.....................122
10.3.4. Reporting of SAEs..................................................................................125
10.4. Appendix 4: Contraceptive Guidance .................................................................126
10.4.1. Male Participant Reproductive Inclusion Criteria ..................................126
10.4.2. Female Participant Reproductive Inclusion Criteria...............................126
10.4.3. Woman of Childbearing Potential ..........................................................127
10.4.4. Contraception Methods...........................................................................128
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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ......130
10.6. Appendix 6: Abbreviations .................................................................................132
10.7. Appendix 7: Stopping and Alert Rules for Enhanced COVID-19 ......................136
11. REFERENCES ................................................................................................................139
LIST OF TABLES
Table 1.

Local Reaction Grading Scale ..................................................................59

Table 2.

Systemic Event Grading Scale..................................................................60

Table 3.

Scale for Fever..........................................................................................61

Table 4.

Probability of Observing at Least 1 AE by Assumed True Event
Rates With Different Sample Sizes ..........................................................96

Table 5.

Interim Analysis Plan and Boundaries for Efficacy and Futility............106

Table 6.

Statistical Design Operating Characteristics: Probability of Successor Failure for Interim Analyses...............................................................107

Table 7.

Statistical Design Operating Characteristics: Probability of Successfor Final Analysis and Overall................................................................107

Table 8.

Laboratory Abnormality Grading Scale .................................................117

Table 9.

Stopping Rule: Enrollment Is Stopped if the Number of Severe
Cases in the Vaccine Group Is Greater Than or Equal to the
Prespecified Stopping Rule Value (S) ....................................................137
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Table 10.

Alert Rule: Further Action Is Taken if the Number of Severe Casesin the Vaccine Group Is Greater Than or Equal to the Prespecified
Alert Rule Value (A) ..............................................................................138

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1. PROTOCOL SUMMARY
1.1. Synopsis
Short Title: A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, andEfficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Adults
Rationale

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A pneumonia of unknown cause detected in Wuhan, China, was first reported in
December 2019. On 08 January 2020, the pathogen causing this outbreak was identified as anovel coronavirus 2019. The outbreak was declared a Public Health Emergency ofInternational Concern on 30 January 2020. On 12 February 2020, the virus was officiallynamed as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the WHO
officially named the disease caused by SARS-CoV-2 as coronavirus disease 2019
(COVID-19). On 11 March 2020, the WHO upgraded the status of the COVID-19 outbreakfrom epidemic to pandemic, which is now spreading globally at high speed.
There are currently no licensed vaccines to prevent infection with SARS-CoV-2 or
COVID-19. Given the rapid transmission of COVID-19 and incidence of disease in the
United States and elsewhere, the rapid development of an effective vaccine is of utmost
importance.
BioNTech has developed RNA-based vaccine candidates using a platform approach thatenables the rapid development of vaccines against emerging viral diseases, including
SARS-CoV-2. Each vaccine candidate is based on a platform of nucleoside-modified
messenger RNA (modRNA, BNT162b). Each vaccine candidate expresses 1 of 2 antigens:the SARS-CoV-2 full-length, P2 mutant, “heads up,” prefusion spike glycoprotein (P2 S)(version 9) or a trimerized SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD)(version 5). The 2 SARS-CoV-2 vaccine candidates that will be tested in this study are
therefore:
BNT162b1 (variant RBP020.3): a modRNA encoding the RBD;
BNT162b2 (variant RBP020.2): a modRNA encoding P2 S.
All candidates are formulated in the same lipid nanoparticle (LNP) composition. This study
is intended to investigate the safety, immunogenicity, and efficacy of these prophylactic
BNT162 vaccines against COVID-19.

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Objectives, Estimands, and Endpoints

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)For Phase 1
Objectives

Estimands

Endpoints

Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Primary:
In participants receiving at least 1 doseof study intervention and having safety
data reported after any vaccination, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each doseAdverse events (AEs) from
Dose 1 to 1 month after the lastdose
 Serious AEs (SAEs) from Dose 1
to 6 months after the last doseIn addition, the percentage ofparticipants with:
Abnormal hematology andchemistry laboratory values 1 and7 days after Dose 1; and 7 days
after Dose 2
Grading shifts in hematology andchemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2
Secondary:In participants complying with the key
protocol criteria (evaluableparticipants) at the following time
points after receipt of study
intervention:

Primary:
Local reactions (pain at the
injection site, redness, andswelling)

Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs

Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Hematology and chemistry laboratory
parameters detailed in Section 10.2

Secondary:

7 and 21 days after Dose 1; 7 and 14
days and 1, 6, 12, and 24 months after
Dose 2

Geometric mean titers (GMTs) at SARS-CoV-2 serum neutralizing titers
each time point
Geometric mean fold rise (GMFR)
from before vaccination to eachsubsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination

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Objectives

Estimands







Geometric mean concentrations(GMCs) at each time point
GMFR from before vaccination toeach subsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
Geometric mean ratio (GMR),
estimated by the ratio of thegeometric mean of SARS-CoV-2
serum neutralizing titers to thegeometric mean of SARS-CoV-2–
binding antibody levels at eachtime point

Endpoints
SARS-CoV-2 anti-S1 binding antibody
levels and anti-RBD binding antibody
levels

SARS-CoV-2 serum neutralizing
titers
SARS-CoV-2 anti-S1 binding
antibody levels
SARS-CoV-2 anti-RBD binding
antibody levels

For Phase 2/3

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Objectives

Estimands
Primary Efficacy

Endpoints

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 in participants
without evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of the last
dose) of past SARS-CoV-2 infection

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 in participants
with and without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

COVID-19 incidence per 1000
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Objectives

Estimands
Primary Safety

To define the safety profile ofprophylactic BNT162b2 in the first
360 participants randomized (Phase 2)

In participants receiving at least 1
dose of study intervention and havingsafety data reported after any
vaccination, the percentage ofparticipants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the last dose
SAEs from Dose 1 to 6 months
after the last dose
In participants receiving at least
1 dose of study intervention andhaving safety data reported after any
vaccination, the percentage ofparticipants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the last dose
 SAEs from Dose 1 to 6 months
after the last dose

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To define the safety profile ofprophylactic BNT162b2 in allparticipants randomized in Phase 2/3

Endpoints










Local reactions (pain at the
injection site, redness, andswelling)
Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened
muscle pain, and new orworsened joint pain)
AEs
SAEs

AEs
SAEs
In a subset of at least 6000
participants:
o Local reactions (pain at the
injection site, redness, andswelling)o Systemic events (fever,fatigue, headache, chills,
vomiting, diarrhea, new orworsened muscle pain, andnew or worsened joint pain)

Secondary Efficacy
To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed severe COVID-19 inparticipants without evidence of
infection before vaccination
To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed severe COVID-19 inparticipants with and without
evidence of infection before
vaccination
To describe the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms) inparticipants without evidence of
infection before vaccination
To describe the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms) inparticipants with and without
evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

Confirmed severe COVID-19
incidence per 1000 person-years offollow-up in participants with noserological or virological evidence of
past SARS-CoV-2 infection
Confirmed severe COVID-19
incidence per 1000 person-years offollow-up

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of the last
dose) of past SARS-CoV-2 infection
COVID-19 incidence per 1000
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Objectives

Estimands
Exploratory

To evaluate the immune responseover time to prophylactic BNT162b2
and persistence of immune response
in participants with and without
serological or virological evidence of
SARS-CoV-2 infection before
vaccination
To evaluate the immune response(non-S) to SARS-CoV-2 inparticipants with and without
confirmed COVID-19 during thestudy
To describe the serological responses
to the BNT vaccine candidate in casesof:
Confirmed COVID-19

Confirmed severe COVID-19

SARS-CoV-2 infection without
confirmed COVID-19

GMC/GMT, GMFR, and percentageof participants with titers greater thandefined threshold(s), at baseline and1, 6, 12, and 24 months after
completion of vaccination

Endpoints

SARS-CoV-2 NVA-specificbinding antibody



SARS-CoV-2 anti-S1 binding
antibody levels and/or anti-RBD
binding antibody levels
SARS-CoV-2 serum neutralizing
titers
SARS-CoV-2 NVA-specificbinding antibody
SARS-CoV-2 detection by
NAAT





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SARS-CoV-2 anti-S1 binding
antibody levels and/or anti-RBD
binding antibody levels
SARS-CoV-2 serum neutralizing
titersOverall Design
This is a Phase 1/2/3, randomized, placebo-controlled, observer-blind, dose-finding, vaccine
candidate–selection, and efficacy study in healthy adults.
The study consists of 2 parts: Phase 1: to identify preferred vaccine candidate(s) and doselevel(s); Phase 2/3: an expanded cohort and efficacy part. These parts, and the progression
between them, are detailed in the schema (Section 1.2).
The study will evaluate the safety, tolerability, and immunogenicity of 2 different
SARS-CoV-2 RNA vaccine candidates against COVID-19 and the efficacy of 1 candidate:

As a 2-dose (separated by 21 days) schedule;At various different dose levels in Phase 1;



In 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3: 18 to 85
years of age [stratified as ≤55 or >55 years of age]).

Dependent upon safety and/or immunogenicity data generated during the course of thisstudy, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
in Phase 1 may be started at the next highest dose, groups may not be started, groups may beterminated early, and/or groups may be added with dose levels below the lowest stated doseor intermediate between the lowest and highest stated doses.
The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.
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Number of Participants
Each group in Phase 1 will comprise 15 participants (12 receiving active vaccine and3 receiving placebo). In this phase, 13 groups will be studied, corresponding to a total of
195 participants.
The vaccine candidate selected for Phase 2/3, BNT162b2 at a dose of 30 µg, will comprise
14,643 vaccine recipients. It is intended that a minimum of 40% of participants will be in the
56- to 85-year stratum. An equal number of participants will receive placebo, ie, randomized
in a 1:1 ratio.
Intervention Groups and Duration

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)The study will evaluate a 2-dose (separated by 21 days) schedule of various different doselevels of 2 investigational RNA vaccine candidates for active immunization against
COVID-19 in 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3:
18 to 85 years of age [stratified as ≤55 or >55 years of age]):

BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 20 µg, 30 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 20 µg, 30 µg

The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.
Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Phase 1
dosing arms that are not evaluated in Phase 2/3.
Data Monitoring Committee or Other Independent Oversight Committee
The study will utilize an IRC, an internal Pfizer committee that will review data to allow
dose escalation or changes to continuation of specific groups.
An external data monitoring committee (DMC) will be formed and will review cumulative
unblinded data throughout the study.
Statistical Methods
The sample size for Phase 1 of the study is not based on any statistical hypothesis testing.
For Phase 2/3, the VE evaluation will be the primary objective. The VE is defined as
VE = 100 × (1 – IRR), where IRR is calculated as the ratio of the first confirmed COVID-19
illness rate in the vaccine group to the corresponding illness rate in the placebo group. Withassumptions of a true VE of 60% and 4 IAs planned, 164 COVID-19 cases will provide 90%
power to conclude true VE >30%. This would be achieved with a total 29,286 participants
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(14,643 vaccine recipients), based on the assumption of a 1.0% per year incidence in theplacebo group, and 20% of the participants being nonevaluable. If the attack rate is muchhigher, case accrual would be expected to be more rapid, enabling the study’s primary
endpoint to be evaluated much sooner. The total number of participants enrolled in Phase 2/3
may vary depending on the incidence of COVID-19 at the time of the enrollment, the true
underlying VE, and a potential early stop for efficacy or futility.
VE will be evaluated using a beta-binomial model and the posterior probability of VE being>30% will be assessed.
The primary safety objective will be evaluated by descriptive summary statistics for local
reactions, systemic events, AEs/SAEs, and abnormal hematology and chemistry laboratory
parameters (Phase 1 only), for each vaccine group. A 3-tier approach will be used tosummarize AEs in Phase 2/3.

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)The immunogenicity objectives will be evaluated descriptively by GMT, GMC, GMFR,
percentage of participants with ≥4-fold rise, and GMC ratio, and the associated 95%
confidence intervals (CIs), for SARS-CoV-2 serum neutralizing titers, SARS-CoV-2 anti-S1
binding antibody levels, and anti-RBD binding antibody levels at the various time points.

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1.2. Schema
Phase 1For each vaccine candidate(4:1 randomization active:placebo)

Age: 18-55 yAge: 65-85 y

Low-dose-level 2-dose group (n=15)
IRC (safety)

IRC (safety
after Dose 1)

Low-dose-level 2-dose group (n=15)

Mid-dose-level 2-dose group (n=15)
IRC (safety

IRC (safety)

after Dose 1)

Mid-dose-level 2-dose group (n=15)

High-dose-level 2-dose group (n=15)
IRC (safety
after Dose 1)

High-dose-level 2-dose group (n=15)

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IRC choice of group(s) for Phase 2/3(safety & immunogenicity after Doses 1 and 2)

Phase 2/3
Single vaccine candidate
Safety and immunogenicity analysis of
Age: 18-85
Phase 2 data (first 360 participants)(Stratified 18-55 or 56-85)
by unblinded team (these participants
BNT162b2 30 µg or placebo 2 doses
will also be included in Phase 3(n~14,643 per group, total n~29,286)
analyses)Abbreviation: IRC = internal review committee.

(1:1 randomization active:placebo)

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1.3. Schedule of Activities

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with theprotocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations orassessments required to protect the well-being of the participant.
1.3.1. Phase 1
An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 10 (24-month follow-up visit) that COVID-19 is suspected.
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

X

X

X

X

X

Obtain informed consent

X

Assign participant number

X

Obtain demography andmedical history data

X

Obtain details of medications
currently taken

X

Perform physical examination

X

2

3

4

5

6

7

8

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset

X

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Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

Measure vital signs(including body temperature)

X

X

X

X

X

X

Collect blood sample forhematology and chemistrylaboratory testsb~10 mL~10 mL~10 mL~10 mL~10 mL

Collect screening blood
sample for HIV, HBsAg,
HBc Ab, and HCV Ab tests~10 mL

Serological test for prior
COVID-19 infection~20 mL

Perform urine pregnancy test
(if appropriate)X

Obtain nasal (midturbinate)swab(s)c

2

3

4

X

X

X

X

Collect nonstudy vaccine
information

X

X

Confirm eligibility

X

X

Collect prohibited medication
use

X

X

Review temporary delay
criteria

X

X

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset
X

X
X

X

X

X

X

X

X
X

Review hematology andchemistry results

X

5

X

X

X

X

X

X

X

X

X

X

X

X

X

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Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

4

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

Confirm use of contraceptives(if appropriate)

X

X

X

X

X

X

~50 mL~50 mL

Obtain randomization number
and study intervention
allocation

X

Collect blood sample for
immunogenicity assessment~50 mL

Administer study intervention

X

X

Assess acute reactions for atleast 30 minutes after study
intervention administrationd

X

X

Explain participant
communication methods(including for e-diarycompletion), assist theparticipant with downloading
the app, or issue provisioned
device, if required

X

Provide thermometer andmeasuring device

X

5

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset
X

X~50 mL ~50 mL ~50 mL ~50 mL+++
optionale optionale optionale~170 mL ~170 mL ~170 mL~50 mL~50 mL~50 mL

X

Review reactogenicity e-diarydata (daily review is optimal
during the active diary period)

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Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 46 to 8Days
After
Visit 1

Review ongoingreactogenicity e-diary
symptoms and obtain stopdatesCollect AEs and SAEs as
appropriate

4

5

X

X

X

X

X

X

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset
X

X

X

X

X

Collect e-diary or assist theparticipant to delete
application

X

X

X

X

X

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Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 46 to 8Days
After
Visit 1

4

5

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset

Collection of COVID-19–
related clinical and laboratory
information (including local
diagnosis)

X

X

Abbreviations: e-diary = electronic diary; HBc Ab = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HCV Ab = hepatitis C virus antibody;
HIV = human immunodeficiency virus; NAAT = nucleic acid amplification test; vax = vaccination.

a.
b.
c.
d.
e.

The COVID-19 illness visit may be conducted as an in-person or telehealth visit.
Hematology: hemoglobin, complete blood count with differential, and platelets. Blood chemistry: alanine aminotransferase (ALT), aspartate
aminotransferase (AST), alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), and creatinine.
Two swabs will be taken at Visits 1 and 4. One will be tested (if possible at the site, otherwise at the central laboratory) within 24 hours and vaccination will
only proceed if it is NAAT-negative for SARS-CoV-2 genomes. The second will be sent to the central laboratory for potential later testing.
The first 5 participants in in each group will be observed at the site for at least 4 hours after study intervention administration. Further vaccination willcommence no sooner than 24 hours after the fifth participant received his or her vaccination.
An optional blood draw of ~170 mL will be taken at 1 of the visits (from selected participants who consent) for exploratory COVID-19 research.

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1.3.2. Phase 2/3
An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 6 (24-month follow-up visit) that COVID-19 is suspected.

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Visit Number
Visit Description

Visit Window (Days)1

Day 1bX

Assign participant number

X

Perform clinical assessment

c

3

4

5

6

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
Potential
COVID-19
COVID-19
Illness Visita ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

Vaccination 1 Vaccination 2

Obtain informed consent
Obtain demography and medical history data

2

Unplanned

X
X

Measure height and weightX

Perform urine pregnancy test (if appropriate)

X

X

Collect nonstudy vaccine information

X

X

X

X

X

X

X

X

X

~25 mL~25 mL~25 mL

Collect prohibited medication use
Confirm eligibility

X

X

Measure temperature (body)

X

X

Review temporary delay criteria

X

X

Confirm use of contraceptives (if appropriate)

X

X

Collect blood sample for immunogenicity
assessment

Unplanned~25 mL

Obtain nasal (midturbinate) swab

X

Obtain randomization number and study
intervention allocation

X

Administer study intervention

X

X

X

X
~25 mLX~50 mLX

X

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Visit Number

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Visit Description

2

3

4

5

6

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
Potential
COVID-19
COVID-19
Illness Visita ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

X

X

X

Vaccination 1 Vaccination 2

Visit Window (Days)

Day 1bAssess acute reactions for at least 30 minutes after
study intervention administration

X

Explain participant communication methods(including for e-diary completion), assist theparticipant with downloading the app, or issue
provisioned device, if required

X

Provide a thermometer (all participants) andmeasuring device (reactogenicity subset
participants only)

X

Unplanned

Unplanned

X

X

Review reactogenicity e-diary data (daily review is
optimal during the active diary period)dReview ongoing reactogenicity e-diary symptoms
and obtain stop datesd
Collect AEs and SAEs as appropriate

X

X

X

X

X

Collect e-diary or assist the participant to delete
application

X

X

X

X

X

Collection of COVID-19–related clinical andlaboratory information (including local diagnosis)
Abbreviation: e-diary = electronic diary.

a.
b.
c.
d.

The COVID-19 illness visit may be conducted as an in-person or telehealth visit.
The visit may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and exclusion criteria onwards must be conducted on thesame day.
Including, if indicated, a physical examination.
Reactogenicity subset participants only.

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2. INTRODUCTION
The BNT162 RNA-based COVID-19 vaccines are currently being investigated forprevention of COVID-19 in healthy adults.
2.1. Study Rationale
The purpose of the study is to rapidly describe the safety, tolerability, and immunogenicity of
2 BNT162 RNA-based COVID-19 vaccine candidates against COVID-19, and the efficacyof 1 candidate, in healthy adults. There are currently no licensed vaccines to prevent
infection with SARS-CoV-2 or COVID-19. Given the global crisis of COVID-19 and fast
expansion of the disease in the United States and elsewhere, the rapid development of aneffective vaccine is of utmost importance.

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2.2. Background
In December 2019, a pneumonia outbreak of unknown cause occurred in Wuhan, China.
In January 2020, it became clear that a novel coronavirus (2019-nCoV) was the underlying
cause. Later in January, the genetic sequence of the 2019-nCoV became available to theWorld Health Organization (WHO) and public (MN908947.3), and the virus was categorized
in the Betacoronavirus subfamily. By sequence analysis, the phylogenetic tree revealed acloser relationship to severe acute respiratory syndrome (SARS) virus isolates than to anothercoronavirus infecting humans, the Middle East respiratory syndrome (MERS) virus.
SARS-CoV-2 infections and the resulting disease, COVID-19, have spread globally,affecting a growing number of countries.
On 11 March 2020, the WHO characterized the COVID-19 outbreak as a pandemic.1
The WHO Situation Update Report dated 30 March 2020 noted 693,224 confirmed caseswith 33,106 deaths globally, including 142,081 confirmed cases with 2457 deaths in theAmericas.2 The United States currently has the most reported cases globally. At the time ofthis communication, the number of confirmed cases continues to rise globally. There are
currently no vaccines or effective antiviral drugs to treat SARS-CoV-2 infections or the
disease it causes, COVID-19.3
A prophylactic, RNA-based SARS-CoV-2 vaccine provides one of the most flexible andfastest approaches available to immunize against the emerging virus.4,5The development of an RNA-based vaccine encoding a viral antigen, which is then expressedby the vaccine recipient as a protein capable of eliciting protective immune responses,
provides significant advantages over more traditional vaccine approaches. Unlike live
attenuated vaccines, RNA vaccines do not carry the risks associated with infection and may
be given to people who cannot be administered live virus (eg, pregnant women andimmunocompromised persons). RNA-based vaccines are manufactured via a cell-free invitro transcription process, which allows an easy and rapid production and the prospect of
producing high numbers of vaccination doses within a shorter time period than achieved with

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traditional vaccine approaches. This capability is pivotal to enable the most effective
response in outbreak scenarios.
Two SARS-CoV-2–RNA lipid nanoparticle (RNA-LNP) vaccines based on a platform of
nucleoside-modified messenger RNA (modRNA, BNT162b) will be evaluated in this study.
Each vaccine candidate expresses 1 of 2 antigens: the SARS-CoV-2 full-length, P2 mutant,“heads up,” prefusion spike glycoprotein (P2 S) (version 9) or a trimerized SARS-CoV-2
spike glycoprotein-receptor binding domain (RBD) (version 5). The 2 SARS-CoV-2 vaccine
candidates that will be tested in this study are therefore:

BNT162b1 (variant RBP020.3): nucleoside-modified messenger RNA (modRNA) withblunted innate immune sensor–activating capacity and augmented expression encoding
the RBD.



BNT162b2 (variant RBP020.2): nucleoside-modified messenger RNA (modRNA) as
above, but encoding P2 S.

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2.
2.2.1. Clinical Overview
Prior to this study, given clinical data from other similarly formulated uRNA liposomal
vaccines from BioNTech in oncology trials6 and recent published results from clinical trials
using modRNA influenza vaccines by Moderna,7 the BNT162 vaccines were expected tohave a favorable safety profile with mild, localized, and transient effects. BNT162 vaccines
based on modRNA have now been administered to humans for the first time in this study andthe BNT162-01 study conducted in Germany by BioNTech, at doses between 1 µg and 100µg. The currently available safety and immunogenicity data are presented in the BNT162 IB.
2.3. Benefit/Risk Assessment
There is an ongoing global pandemic of COVID-19 with no preventative or therapeutic
options available. While there were no data available from clinical trials on the use of
BNT162 vaccines in humans at the outset of this study, available nonclinical data with thesevaccines, and data from nonclinical studies and clinical trials with the same or related RNAcomponents, or antigens, supported a favorable risk/benefit profile. Anticipated AEs after
vaccination were expected to be manageable using routine symptom-driven standard of careas determined by the investigators and, as a result, the profile of these vaccine candidates
supported initiation of this Phase 1/2/3 clinical study.
More detailed information about the known and expected benefits and risks and reasonably
expected AEs of BNT162 RNA-based COVID-19 vaccines may be found in the IB, which is
the SRSD for this study.

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2.3.1. Risk Assessment
Potential Risk of ClinicalSignificance

Summary of Data/Rationale for Risk

Mitigation Strategy

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Study Intervention: BNT162 RNA-Based COVID-19 Vaccine
Potential for local reactions (injection These are common adverse reactions seensite redness, injection site swelling, with other vaccines, as noted in the FDA
and injection site pain) and systemic Center for Biologics Evaluation andResearch (CBER) guidelines on toxicity
events (fever, fatigue, headache,
grading scales for healthy adult volunteers
chills, vomiting, diarrhea, muscle
pain, and joint pain) following
enrolled in preventive vaccine clinicalvaccination.
trials.8

The Phase 1 study design includes the use of controlled vaccination anddose escalation to closely monitor and limit the rate of enrollment to ensure
participant safety. The study employs the use of a reactogenicity e-diary tomonitor local reactions and systemic events in real time. Stopping rules arealso in place. The first 5 participants in each group in Phase 1 will beobserved for 4 hours after vaccination to assess any immediate AEs. Allother participants will be observed for at least 30 minutes after vaccination.

Unknown AEs and laboratory
abnormalities with a novel vaccine.

The Phase 1 study design includes the use of controlled vaccination andThis study is one of the first 2 parallelrunning clinical studies with the BNT162 dose escalation to closely monitor and limit the rate of enrollment to ensure
vaccine candidates and as such there are no participant safety. An IRC (in Phase 1) and DMC (throughout the study)
will also review safety data. Stopping rules are also in place. The first 5
clinical data available for this vaccine.
participants in each group in Phase 1 will be observed for 4 hours after
vaccination to assess any immediate AEs. All other participants will beobserved for at least 30 minutes after vaccination.

Potential for COVID-19
enhancement.

Disease enhancement has been seen
following vaccination with respiratorysyncytial virus (RSV), feline coronavirus,
and Dengue virus vaccines.

Phase 1 excludes participants with likely previous or current COVID-19. In
Phase 2/3, temporary delay criteria defer vaccination of participants withpossible current clinical COVID-19. All participants are followed for
SARS-CoV-2 antigen-specific antibody and SARS-CoV-2 serum
neutralizing titers, and COVID-19 illness, including markers of severity.

Study Procedures
Participants will be required to attend Without appropriate social distancing andhealthcare facilities during the global PPE, there is a potential for increased
exposure to SARS-CoV-2.
SARS-CoV-2 pandemic.
Venipuncture will be performed
during the study.

There is the risk of bleeding, bruising,hematoma formation, and infection at the
venipuncture site.

Pfizer will work with sites to ensure an appropriate COVID-19 prevention
strategy. Potential COVID-19 illness visits can be conducted via telehealth,without the need for an in-person visit, if required, with the participant
performing a self-swab.
Only appropriately qualified personnel would obtain the blood draw.

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2.3.2. Benefit Assessment
Benefits to individual participants may include:Receipt of a potentially efficacious COVID-19 vaccine during a global pandemicAccess to COVID-19 diagnostic and antibody testingContributing to research to help others in a time of global pandemic

2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in thisstudy, the potential risks identified in association with BNT162 RNA-based COVID-19
vaccine are justified by the anticipated benefits that may be afforded to healthy participants.
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS

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3.1. For Phase 1
Objectives

Estimands

Endpoints

Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Primary:
In participants receiving at least 1 doseof study intervention and having safety
data reported after any vaccination, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each doseAdverse events (AEs) from
Dose 1 to 1 month after the lastdose
 Serious AEs (SAEs) from Dose 1
to 6 months after the last dosePrimary:
Local reactions (pain at the
injection site, redness, andswelling)

Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs

In addition, the percentage ofHematology and chemistry laboratory
participants with:parameters detailed in Section 10.2
Abnormal hematology andchemistry laboratory values 1 and7 days after Dose 1; and 7 days
after Dose 2
Grading shifts in hematology andchemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2

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Objectives

Estimands

Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Secondary:In participants complying with the key
protocol criteria (evaluableparticipants) at the following time
points after receipt of study
intervention: 7 and 21 days after Dose
1; 7 and 14 days and 1, 6, 12, and 24
months after Dose 2







090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)

Endpoints
Secondary:

Geometric mean titers (GMTs) at SARS-CoV-2 serum neutralizing titers
each time point
Geometric mean fold rise (GMFR)
from before vaccination to eachsubsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
SARS-CoV-2 anti-S1 binding antibody
Geometric mean concentrations
levels and anti-RBD binding antibody(GMCs) at each time point
GMFR from prior to first dose of levels
study intervention to eachsubsequent time point
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
Geometric mean ratio (GMR),
estimated by the ratio of thegeometric mean of SARS-CoV-2
serum neutralizing titers to thegeometric mean of SARS-CoV-2
binding antibody levels at eachtime point

SARS-CoV-2 serum neutralizing
titers

SARS-CoV-2 anti-S1 binding
antibody levels



SARS-CoV-2 anti-RBD binding
antibody levels

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3.2. For Phase 2/3
Objectives
To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 in participants
without evidence of infection before
vaccination

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 in participants
with and without evidence of
infection before vaccination

Estimands
Primary Efficacy
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

Endpoints
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of the last
dose) of past SARS-CoV-2 infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT

Primary Safety
In participants receiving at least 1
dose of study intervention and havingsafety data reported after any
vaccination, the percentage ofparticipants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the last dose
SAEs from Dose 1 to 6 months
after the last dose

To define the safety profile ofprophylactic BNT162b2 in allparticipants randomized in Phase 2/3

In participants receiving at least
1 dose of study intervention andhaving safety data reported after any
vaccination, the percentage ofparticipants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the last dose
SAEs from Dose 1 to 6 months
after the last dose

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed severe COVID-19 inparticipants without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

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To define the safety profile ofprophylactic BNT162b2 in the first
360 participants randomized (Phase 2)



Local reactions (pain at the
injection site, redness, andswelling)
Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened
muscle pain, and new orworsened joint pain)
AEs
SAEs

AEs
SAEs
In a subset of at least 6000
participants:
o Local reactions (pain at the
injection site, redness, andswelling)o Systemic events (fever,fatigue, headache, chills,
vomiting, diarrhea, new orworsened muscle pain, andnew or worsened joint pain)

Secondary Efficacy
Confirmed severe COVID-19
incidence per 1000 person-years offollow-up in participants with noserological or virological evidence of
past SARS-CoV-2 infection

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Objectives

Estimands

Endpoints

To evaluate the efficacy ofprophylactic BNT162b2 against
confirmed severe COVID-19 inparticipants with and without
evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

Confirmed severe COVID-19
incidence per 1000 person-years offollow-up

To describe the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms) inparticipants without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of the last
dose) of past SARS-CoV-2 infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT

To describe the efficacy ofprophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms) inparticipants with and without
evidence of infection before
vaccination

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Exploratory
To evaluate the immune responseover time to prophylactic BNT162b2
and persistence of immune response
in participants with and without
serological or virological evidence of
SARS-CoV-2 infection before
vaccination

GMC/GMT, GMFR, and percentageof participants with titers greater thandefined threshold(s), at baseline and1, 6, 12, and 24 months after
completion of vaccination

SARS-CoV-2 anti-S1 binding
antibody levels and/or anti-RBD
binding antibody levels
SARS-CoV-2 serum neutralizing
titersTo evaluate the immune response(non-S) to SARS-CoV-2 inparticipants with and without
confirmed COVID-19 during the
study



SARS-CoV-2 NVA-specificbinding antibody

To describe the serological responses
to the BNT vaccine candidate in casesof:
Confirmed COVID-19

Confirmed severe COVID-19

SARS-CoV-2 infection without
confirmed COVID-19



SARS-CoV-2 anti-S1 binding
antibody levels and/or anti-RBD
binding antibody levels
SARS-CoV-2 serum neutralizing
titers
SARS-CoV-2 NVA-specificbinding antibody
SARS-CoV-2 detection by
NAAT





This protocol will use a group of internal case reviewers to determine whether certain
investigator-reported events meet the definition of disease-related efficacy endpoints, using
predefined endpoint criteria.
For those AEs that are handled as disease-related efficacy endpoints (which may include
death), a DMC will conduct unblinded reviews on a regular basis throughout the trial(see Section 9.6).

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Any AE that is determined by the internal case reviewers NOT to meet endpoint criteria isreported back to the investigator site of incidence. Refer to Section 8.3.1.1 for instructions
on how to report any such AE that meets the criteria for seriousness to Pfizer Safety.
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1/2/3, randomized, placebo-controlled, observer-blind, dose-finding, vaccine
candidate–selection, and efficacy study in healthy adults.
The study consists of 2 parts. Phase 1: to identify preferred vaccine candidate(s) and doselevel(s); Phase 2/3: an expanded cohort and efficacy part. These parts, and the progression
between them, are detailed in the schema (Section 1.2).

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)The study will evaluate the safety, tolerability, and immunogenicity of 2 different
SARS-CoV-2 RNA vaccine candidates against COVID-19 and the efficacy of 1 candidate:

As a 2-dose (separated by 21 days) schedule;At various different dose levels in Phase 1;



In 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3: 18 to 85
years of age [stratified as ≤55 or >55 years of age]).

Dependent upon safety and/or immunogenicity data generated during the course of thisstudy, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
in Phase 1 may be started at the next highest dose, groups may not be started, groups may beterminated early, and/or groups may be added with dose levels below the lowest stated doseor intermediate between the lowest and highest stated doses.
The study is observer-blinded, as the physical appearance of the investigational vaccine
candidates and the placebo may differ. The participant, investigator, study coordinator, andother site staff will be blinded. At the study site, only the dispenser(s)/administrator(s) are
unblinded.
To facilitate rapid review of data in real time, sponsor staff will be unblinded to vaccine
allocation for the participants in Phase 1.
4.1.1. Phase 1
Each group (vaccine candidate/dose level/age group) will comprise 15 participants;
12 participants will be randomized to receive active vaccine and 3 to receive placebo.
For each vaccine candidate/dose level/age group, the following apply:Additional safety assessments (see Section 8.2)

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Controlled enrollment (required only for the first candidate and/or dose level studied):No more than 5 participants (4 active, 1 placebo) can be vaccinated on the first day

The first 5 participants must be observed by blinded site staff for at least 4 hours after
vaccination for any acute reactions

Vaccination of the remaining participants will commence no sooner than 24 hours
after the fifth participant received his or her vaccination

Application of stopping rules

IRC review of safety data to determine escalation to the next dose level in the 18- to
55-year age cohort:Escalation between dose levels will be based on IRC review of at least 7-day
post–Dose 1 safety data in this study and/or the BioNTech study conducted inGermany (BNT162-01)

Note that, since both candidates are based upon the same RNA platform, dose
escalation for the second candidate studied may be based upon the safety profile ofthe first candidate studied being deemed acceptable at the same, or a higher, doselevel by the IRC

Groups of participants 65 to 85 years of age will not be started until safety data for the RNA
platform have been deemed acceptable at the same, or a higher, dose level in the 18- to
55-year age cohort by the IRC.
In this phase, 13 groups will be studied, corresponding to a total of 195 participants.
The IRC will select 1 vaccine candidate that, in Phase 1, has an established dose level per age
group based on induction of a post–Dose 2 immune response, including neutralizing
antibodies, which is expected to be associated with protection against COVID-19, forprogression into Phase 2/3.
4.1.2. Phase 2/3
On the basis of safety and/or immunogenicity data generated during the course of this study,
and/or the BioNTech study conducted in Germany (BNT162-01), 1 vaccine candidate wasselected to proceed into Phase 2/3. Participants in this phase will be 18 to 85 years of age,stratified as follows: 18 to 55 years or 56 to 85 years. It is intended that a minimum of 40%
of participants will be in the 56- to 85-year stratum. Commencement of each age stratum
will be based upon satisfactory post–Dose 2 safety and immunogenicity data from the 18- to
55-year and 65- to 85-year age groups in Phase 1, respectively. The vaccine candidate
selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.

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Phase 2/3 is event-driven. Under the assumption of a true VE rate of ≥60%, after the lastdose of investigational product, a target of 164 primary-endpoint cases of confirmed
COVID-19 due to SARS-CoV-2 occurring at least 7 days following the last dose of the
primary series of the candidate vaccine will be sufficient to provide 90% power to conclude
true VE >30% with high probability. The total number of participants enrolled in Phase 2/3
may vary depending on the incidence of COVID-19 at the time of the enrollment, the true
underlying VE, and a potential early stop for efficacy or futility.

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Assuming a COVID-19 attack rate of 1.0% per year in the placebo group, an estimated 20%
nonevaluable rate, and 1:1 randomization, the BNT162b2 vaccine candidate selected forPhase 2/3 is expected to comprise approximately 14,643 vaccine recipients. This is thenumber of participants initially targeted for Phase 2/3 and may be adjusted based on advice
from DMC analyses of case accumulation and the percentage of participants who areseropositive at baseline. Dependent upon the evolution of the pandemic, it is possible that
the COVID-19 attack rate may be much higher, in which case accrual would be expected tobe more rapid, enabling the study’s primary endpoint to be evaluated much sooner.
The first 360 participants enrolled (180 to active vaccine and 180 to placebo) will comprisethe “Phase 2” portion. Safety data through 7 days after Dose 2 and immunogenicity data
through 1 month after Dose 2 from these 360 participants will be analyzed by the unblindedstatistical team, reviewed by the DMC, and submitted to appropriate regulatory authorities
for review. Enrollment may continue during this period and these participants would be
included in the efficacy evaluation in the “Phase 3” portion of the study.
Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Phase 1
dosing arms that are not evaluated in Phase 2/3.
4.2. Scientific Rationale for Study Design
Additional surveillance for COVID-19 will be conducted as part of the study, given thepotential risk of disease enhancement. If a participant experiences symptoms, as detailed in
Section 8.13, a COVID-19 illness and subsequent convalescent visit will occur. As part ofthese visits, samples (nasal [midturbinate] swab and blood) will be taken for antigen andantibody assessment as well as recording of COVID-19–related clinical and laboratory
information (including local diagnosis).
Human reproductive safety data are not available for BNT162 RNA-based COVID-19
vaccines, but there is no suspicion of human teratogenicity based on the intended mechanismof action of the compound. Therefore, the use of a highly effective method of contraception
is required (see Appendix 4).
4.3. Justification for Dose
Because of the requirement for a rapid response to the newly emerged COVID-19 pandemic,
sufficient data were not available to experimentally validate the dose selection and initialstarting dose. Therefore, the original planned starting dose of 10 µg (for both BNT162b1 and
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BNT162b2) in this study was based on nonclinical experience with the same RNAs encoding
other viral antigens (such as influenza and HIV antigens). The general safety andeffectiveness of uRNA and modRNA platforms have been demonstrated in oncologicalclinical trials with different administration routes (NCT02410733, NCT03871348). Doses of
up to 400 µg total uRNA have been administered IV as RNA lipoplex (RNA-LPX) and dosesof up to 1000 µg total naked modRNA have been administered intratumorally, both without
signs of unpredictable overstimulation of the immune system.

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Based on nonclinical data of the RNA components, with other liposomes or in conjunction
with the lipid nanoparticles as will be tested clinically in this study, it was expected that
doses in the 1- to 5-µg range would be immunogenic and induce neutralizing antibodies;
however, it was anticipated that 3- to 10-fold higher doses would likely be required to elicit astronger antibody response. Based on previous clinical and nonclinical experience, it was
expected that doses of up to 100 µg would be well tolerated.
Update as part of protocol amendment 2: preliminary experience in this study and the
BioNTech study conducted in Germany (BNT162-01) suggests that, for vaccine candidates
based on the modRNA platform, a dose level between 30 µg and 100 µg warrants
consideration. Therefore, a 50-µg dose level is formally included for BNT162b1 and
BNT162b2.
Update as part of protocol amendment 3: as data have become available from this study andthe BNT162-01 study in Germany, it was decided:

To not study the BNT162a1 and BNT162c2 vaccine candidates at this time, so thesecandidates have been removed from the protocol; andThat lower dose levels of BNT162b1 and BNT162b2 warrant consideration. Therefore, a
20-µg dose level is formally included for both candidates.

Update as part of protocol amendment 4: the 50-µg dose level for BNT162b1 and BNT162b2
is removed and the 100-µg dose level for BNT162b2 is removed; similar dose levels of
BNT162b3 may be studied as for BNT162b1 and BNT162b2.
Update as part of protocol amendment 5: the vaccine candidate selected for Phase 2/3
evaluation is BNT162b2 at a dose of 30 µg. BNT162b3 will not be studied.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases ofthe study, including the last visit. Note that participants enrolled in Phase 1 in groups that do
not proceed to Phase 2/3 may be followed for fewer than 24 months (but no less than
6 months after the last vaccination).
The end of the study is defined as the date of last visit of the last participant in the study.

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5. STUDY POPULATIONThis study can fulfill its objectives only if appropriate participants are enrolled. The
following eligibility criteria are designed to select participants for whom participation in the
study is considered appropriate. All relevant medical and nonmedical conditions should betaken into consideration when deciding whether a particular participant is suitable for thisprotocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:

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1. Male or female participants between the ages of 18 and 55 years, inclusive, 65 and85 years, inclusive, or 18 and 85 years, inclusive, at randomization (dependent uponstudy phase).


Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female(Section 10.4.2) participants.

Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, vaccination
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Healthy participants who are determined by medical history, physical examination(if required), and clinical judgment of the investigator to be eligible for inclusion in the
study.
Note: Healthy participants with preexisting stable disease, defined as disease notrequiring significant change in therapy or hospitalization for worsening disease during
the 6 weeks before enrollment, can be included.
4. Participants who, in the judgment of the investigator, are at risk for acquiring COVID-19.
Informed Consent:
5. Capable of giving personal signed informed consent as described in Appendix 1, which
includes compliance with the requirements and restrictions listed in the ICD and in thisprotocol.

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5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Other medical or psychiatric condition including recent (within the past year) or active
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study
participation or, in the investigator’s judgment, make the participant inappropriate for the
study.
2. Known infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or
hepatitis B virus (HBV).
3. History of severe adverse reaction associated with a vaccine and/or severe allergic
reaction (eg, anaphylaxis) to any component of the study intervention(s).
4. Receipt of medications intended to prevent COVID-19.

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5. Previous clinical or microbiological diagnosis of COVID-19.
6. Phase 1 only: Individuals at high risk for severe COVID-19, including those with any of
the following risk factors:Hypertension

Diabetes mellitus

Chronic pulmonary diseaseAsthma

Current vaping or smoking

History of chronic smoking within the prior year

Chronic liver diseaseStage 3 or worse chronic kidney disease (glomerular filtration rate
<60 mL/min/1.73 m2)



Resident in a long-term facility

BMI >30 kg/m2

Anticipating the need for immunosuppressive treatment within the next 6 months

7. Phase 1 only: Individuals currently working in occupations with high risk of exposure to
SARS-CoV-2 (eg, healthcare worker, emergency response personnel).
8. Immunocompromised individuals with known or suspected immunodeficiency, as
determined by history and/or laboratory/physical examination.
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9. Phase 1 only: Individuals with a history of autoimmune disease or an active autoimmune
disease requiring therapeutic intervention, including but not limited to: systemic or
cutaneous lupus erythematosus, autoimmune arthritis/rheumatoid arthritis, Guillain-Barré
syndrome, multiple sclerosis, Sjögren’s syndrome, idiopathic thrombocytopenia purpura,glomerulonephritis, autoimmune thyroiditis, giant cell arteritis (temporal arteritis),
psoriasis, and insulin-dependent diabetes mellitus (type 1).
10. Bleeding diathesis or condition associated with prolonged bleeding that would, in theopinion of the investigator, contraindicate intramuscular injection.
11. Women who are pregnant or breastfeeding.
Prior/Concomitant Therapy:

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12. Previous vaccination with any coronavirus vaccine.
13. Individuals who receive treatment with immunosuppressive therapy, including cytotoxic
agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned
receipt throughout the study. If systemic corticosteroids have been administered shortterm (<14 days) for treatment of an acute illness, participants should not be enrolled into
the study until corticosteroid therapy has been discontinued for at least 28 days before
study intervention administration. Inhaled/nebulized (except for participants in
Phase 1 – see exclusion criterion 14), intra-articular, intrabursal, or topical (skin or eyes)corticosteroids are permitted.
14. Phase 1 only: Regular receipt of inhaled/nebulized corticosteroids.
15. Receipt of blood/plasma products or immunoglobulin, from 60 days before study
intervention administration or planned receipt throughout the study.
Prior/Concurrent Clinical Study Experience:
16. Participation in other studies involving study intervention within 28 days prior to study
entry and/or during study participation.
17. Previous participation in other studies involving study intervention containing lipid
nanoparticles.
Diagnostic Assessments:
18. Phase 1 only: Positive serological test for SARS-CoV-2 IgM and/or IgG antibodies atthe screening visit.
19. Phase 1 only: Any screening hematology and/or blood chemistry laboratory value thatmeets the definition of a ≥ Grade 1 abnormality.

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Note: With the exception of bilirubin, participants with any stable Grade 1 abnormalities(according to the toxicity grading scale) may be considered eligible at the discretion of
the investigator. (Note: A “stable” Grade 1 laboratory abnormality is defined as a reportof Grade 1 on an initial blood sample that remains ≤ Grade 1 upon repeat testing on asecond sample from the same participant.)
20. Phase 1 only: Positive test for HIV, hepatitis B surface antigen (HBsAg), hepatitis B
core antibodies (HBc Abs), or hepatitis C virus antibodies (HCV Abs) at the screening
visit.
21. Phase 1 only: SARS-CoV-2 NAAT-positive nasal swab within 24 hours before receipt ofstudy intervention.
Other Exclusions:
22. Investigator site staff or Pfizer employees directly involved in the conduct of the study,site staff otherwise supervised by the investigator, and their respective family members.

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5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm thatthe participant has selected an appropriate method of contraception for the individual
participant and his or her partner(s) from the permitted list of contraception methods(see Appendix 4, Section 10.4.4) and will confirm that the participant has been instructed inits consistent and correct use. At time points indicated in the SoA, the investigator ordesignee will inform the participant of the need to use highly effective contraception
consistently and correctly and document the conversation and the participant’s affirmation in
the participant’s chart (participants need to affirm their consistent and correct use of at least 1of the selected methods of contraception). In addition, the investigator or designee will
instruct the participant to call immediately if the selected contraception method is
discontinued or if pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but
are not subsequently randomly assigned to study intervention. A minimal set of screen
failure information is required to ensure transparent reporting of screen failure participants tomeet the CONSORT publishing requirements and to respond to queries from regulatory
authorities. Minimal information includes demography, screen failure details, eligibility
criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may berescreened under a different participant number.

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5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention
Administration
The following conditions are temporary or self-limiting and a participant may be vaccinatedonce the condition(s) has/have resolved and no other exclusion criteria are met.

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1. Current febrile illness (body temperature ≥100.4°F [≥38°C]) or other acute illness within
48 hours before study intervention administration. This includes current symptoms that
could represent a potential COVID-19 illness:

New or increased cough;

New or increased shortness of breath;Chills;

New or increased muscle pain;New loss of taste/smell;

Sore throat;

Diarrhea;Vomiting.

2. Receipt of any seasonal or pandemic influenza vaccine within 14 days, or any othernonstudy vaccine within 28 days, before study intervention administration.
3. Anticipated receipt of any seasonal or pandemic influenza vaccine within 14 days, or any
other nonstudy vaccine within 28 days, after study intervention administration.
4. Receipt of short-term (<14 days) systemic corticosteroids. Study intervention
administration should be delayed until systemic corticosteroid use has been discontinued
for at least 28 days. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin oreyes) corticosteroids are permitted.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s),placebo, medical device(s), or study procedure(s) intended to be administered to a study
participant according to the study protocol.
The study will evaluate a 2-dose (separated by 21 days) schedule of various different doselevels of 2 investigational RNA vaccine candidates for active immunization against
COVID-19 in 3 age groups (18 to 55 years of age, 65 to 85 years of age, and 18 to 85 yearsof age [stratified as ≤55 or >55 years of age]).
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These 2 investigational RNA vaccine candidates, with the addition of saline placebo, are the
3 potential study interventions that may be administered to a study participant:

BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 20 µg, 30 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 20 µg, 30 µgNormal saline (0.9% sodium chloride solution for injection)

The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.
6.1. Study Intervention(s) Administered
Intervention Name

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Type
Dose Formulation

BNT162b1(BNT162 RNA-LNP
vaccine utilizing
modRNA)
VaccinemodRNA

BNT162b2(BNT162 RNA-LNP
vaccine utilizing
modRNA)
VaccinemodRNA

Saline placebo

Placebo
Normal saline (0.9%sodium chloride solution
for injection)
Unit Dose Strength(s)250 µg/0.5 mL
250 µg/0.5 mL
N/Aa
Dosage Level(s)10-, 20-, 30-, 100-µg
10-, 20-, 30-µg
N/A
Route of Administration Intramuscular injection
Intramuscular injection
Intramuscular injection
Use
Experimental
Experimental
Placebo
IMP or NIMP
IMP
IMP
IMP
Sourcing
Provided centrally by the Provided centrally by the Provided centrally by thesponsorsponsorsponsorPackaging and Labeling Study intervention will be Study intervention will be Study intervention will be
provided in a glass vial as provided in a glass vial as provided in a glass or
open-label supply. Each
open-label supply. Each
plastic vial as open-labelvial will be labeled asvial will be labeled as
supply. Each vial will be
required per country
required per country
labeled as required per
requirement
requirement
country requirementa. Dependent upon safety and/or immunogenicity data generated during the course of this study, or the
BioNTech study conducted in Germany (BNT162-01), it is possible that groups may be started at the next
highest dose, groups may not be started, groups may be terminated early, and/or groups may be addedwith dose levels below the lowest stated dose or intermediate between the lowest and highest stated doses.

The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.
6.1.1. Administration
Participants will receive 1 dose of study intervention as randomized at each vaccination visit(Visits 1 and 4 for Phase 1 participants, Visits 1 and 2 for Phase 2/3 participants) inaccordance with the study’s SoA. The volume to be administered may vary by vaccine
candidate and dose level; full details are described in the IP manual.
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Study intervention should be administered intramuscularly into the deltoid muscle, preferablyof the nondominant arm, by an unblinded administrator.
Standard vaccination practices must be observed and vaccine must not be injected into bloodvessels. Appropriate medication and other supportive measures for management of an acute
hypersensitivity reaction should be available in accordance with local guidelines for standard
immunization practices.
Administration of study interventions should be performed by an appropriately qualified,
GCP-trained, and vaccine-experienced member of the study staff (eg, physician, nurse,
physician’s assistant, nurse practitioner, pharmacist, or medical assistant) as allowed by
local, state, and institutional guidance.
Study intervention administration details will be recorded on the CRF.
6.2. Preparation/Handling/Storage/Accountability

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1. The investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study interventions received and any discrepancies arereported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only
authorized site staff may supply or administer study intervention. All study interventions
must be stored in a secure, environmentally controlled, and monitored (manual or
automated recording) area in accordance with the labeled storage conditions with accesslimited to the investigator and authorized site staff. At a minimum, daily minimum andmaximum temperatures for all site storage locations must be documented and available
upon request. Data for nonworking days must indicate the minimum and maximum
temperatures since previously documented for all site storage locations upon return tobusiness.
3. Any excursions from the study intervention label storage conditions should be reported to
Pfizer upon discovery along with any actions taken. The site should actively pursue
options for returning the study intervention to the storage conditions described in thelabeling, as soon as possible. Once an excursion is identified, the study intervention must
be quarantined and not used until Pfizer provides permission to use the study
intervention. Specific details regarding the definition of an excursion and information thesite should report for each excursion will be provided to the site in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage conditions
stated on the label.
5. Study interventions should be stored in their original containers.
6. See the IP manual for storage conditions of the study intervention.

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7. The investigator, institution, or the head of the medical institution (where applicable) is
responsible for study intervention accountability, reconciliation, and record maintenance(ie, receipt, reconciliation, and final disposition records), such as the IPAL orsponsor-approved equivalent. All study interventions will be accounted for using a study
intervention accountability form/record.
8. Further guidance and information for the final disposition of unused study interventions
are provided in the IP manual. All destruction must be adequately documented. If
destruction is authorized to take place at the investigator site, the investigator must ensurethat the materials are destroyed in compliance with applicable environmental regulations,institutional policy, and any special instructions provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of
discovery as described in the IP manual.

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6.2.1. Preparation and Dispensing
See the IP manual for instructions on how to prepare the study intervention foradministration. Study intervention should be prepared and dispensed by an appropriately
qualified and experienced member of the study staff (eg, physician, nurse, physician’s
assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as allowed by
local, state, and institutional guidance. A second staff member will verify the dispensing.
Study intervention and placebo will be prepared by qualified unblinded site personnel
according to the IP manual. The study intervention will be administered in such a way toensure the participants remain blinded.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
Allocation (randomization) of participants to vaccine groups will proceed through the use of
an IRT system (IWR). The site personnel (study coordinator or specified designee) will be
required to enter or select information including but not limited to the user’s ID andpassword, the protocol number, and the participant number. The site personnel will then be
provided with a vaccine assignment and randomization number. The IRT system will
provide a confirmation report containing the participant number, randomization number, andstudy intervention allocation assigned. The confirmation report must be stored in the site’s
files.
The study-specific IRT reference manual and IP manual will provide the contact informationand further details on the use of the IRT system.

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6.3.2. Blinding of Site Personnel
In this observer blinded study, the study staff receiving, storing, dispensing, preparing, andadministering the study interventions will be unblinded. All other study and site personnel,
including the investigator, investigator staff, and participants, will be blinded to study
intervention assignments. In particular, the individuals who evaluate participant safety willbe blinded. Because the BNT162 RNA-based COVID-19 vaccine candidates and placebo
are different in physical appearance, the study intervention syringes will be administered in amanner that prevents the study participants from identifying the study intervention type basedon its appearance.
The responsibility of the unblinded dispenser and administrator must be assigned to anindividual or individuals who will not participate in the evaluation of any study participants.
Contact between the unblinded dispenser and study participants and unblinded administrator
and study participants should be kept to a minimum. The remaining site personnel must notknow study intervention assignments.

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6.3.3. Blinding of the Sponsor
To facilitate rapid review of data in real time, sponsor staff will be unblinded to study
intervention allocation for the participants in Phase 1. The majority of sponsor staff will beblinded to study intervention allocation in Phase 2/3. All laboratory testing personnel
performing serology assays will remain blinded to study intervention assigned/received
throughout the study. The following sponsor staff, who will have no part in the blinded
conduct of the study, will be unblinded in Phase 2/3 (further details will be provided in a data
blinding plan):

Those study team members who are involved in ensuring that protocol requirements forstudy intervention preparation, handling, allocation, and administration are fulfilled at thesite will be unblinded for the duration of the study (eg, unblinded study manager,
unblinded clinical research associate).

Unblinded clinician(s), who are not direct members of the study team and will notparticipate in any other study-related activities, will review unblinded protocol
deviations.

An unblinded team supporting interactions with, and analyses for, the DMC(see Section 9.6). This will comprise a statistician, programmer(s), and a medical
monitor who will review cases of severe COVID-19 as they are received, and will review
AEs at least weekly for additional potential cases of severe COVID-19(see Section 8.2.3).

An unblinded submissions team will be responsible for preparing unblinded analyses anddocuments to support regulatory activities that may be required while the study is
ongoing. All statistical analyses conducted on Phase 2/3 data while the study is ongoing,that are not in support of the DMC, will be performed by this team. This team will not
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have access to unblinded COVID-19 cases unless efficacy is achieved in either an interim
analysis or the final analysis, as determined by the DMC.
6.3.4. Breaking the Blind
The IRT will be programmed with blind-breaking instructions. In case of an emergency, theinvestigator has the sole responsibility for determining if unblinding of a participant’s study
intervention assignment is warranted. Participant safety must always be the firstconsideration in making such a determination. If the investigator decides that unblinding iswarranted, the investigator should make every effort to contact the sponsor prior to
unblinding a participant’s vaccine assignment unless this could delay further management of
the participant. If a participant’s vaccine assignment is unblinded, the sponsor must be
notified within 24 hours after breaking the blind. The date and reason that the blind was
broken must be recorded in the source documentation and CRF.
The study-specific IRT reference manual and IP manual will provide the contact informationand further details on the use of the IRT system.

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6.4. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from theinvestigator or designee, under medical supervision. The date and time of each dose
administered in the clinic will be recorded in the source documents and recorded in the CRF.
The dose of study intervention and study participant identification will be confirmed at thetime of dosing by a member of the study site staff other than the person administering thestudy intervention.
6.5. Concomitant Therapy
The following concomitant medications and vaccinations will be recorded in the CRF:
All vaccinations received from 28 days prior to study enrollment until the 6-monthfollow-up visit (Visit 8 for Phase 1 participants, and Visit 4 for Phase 2/3 participants).

Prohibited medications listed in Section 6.5.1 will be recorded, to include start and stop
dates, name of the medication, dose, unit, route, and frequency.

In addition, for participants enrolled in Phase 1, all current medication at baseline will berecorded, to include start date, name of the medication, dose, unit, route, and frequency.

6.5.1. Prohibited During the Study
Receipt of the following vaccines and medications during the time periods listed below may
exclude a participant from the per-protocol analysis from that point onwards, and may
require vaccinations to be discontinued in that participant; however, it is anticipated that theparticipant would not be withdrawn from the study (see Section 7). Medications should not
be withheld if required for a participant’s medical care.

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Unless considered medically necessary, no vaccines other than study intervention should be
administered within 28 days before and 28 days after each study vaccination. One exception
to this is that seasonal and pandemic influenza vaccine can be given at least 14 days after, orat least 14 days prior to, the administration of study intervention.
Receipt of chronic systemic treatment with known immunosuppressant medications, orradiotherapy, within 60 days before enrollment through conclusion of the study.
Receipt of systemic corticosteroids (≥20 mg/day of prednisone or equivalent) for ≥14 days is
prohibited from 28 days prior to enrollment to Visit 7 for Phase 1 participants, and Visit 3 forPhase 2/3 participants).
Receipt of inhaled/nebulized corticosteroids from 28 days prior to enrollment to Visit 7(1-month follow-up visit) for Phase 1 participants.
Receipt of blood/plasma products or immunoglobulins within 60 days before enrollment
through conclusion of the study.

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Receipt of any other (nonstudy) coronavirus vaccine at any time prior to or during study
participation is prohibited.
Prophylactic antipyretics and other pain medication to prevent symptoms associated withstudy intervention administration are not permitted. However, if a participant is taking a
medication for another condition, even if it may have antipyretic or pain-relieving properties,
it should not be withheld prior to study vaccination.
6.5.2. Permitted During the Study
The use of antipyretics and other pain medication to treat symptoms associated with study
intervention administration or ongoing conditions is permitted.
Medication other than that described as prohibited in Section 6.5.1 required for treatment ofpreexisting stable conditions is permitted.
Inhaled (except in Phase 1 participants – see Section 6.5.1), topical, or localized injections ofcorticosteroids (eg, intra-articular or intrabursal administration) are permitted.
6.6. Dose Modification
This protocol allows some alteration of vaccine dose for individual participants and/or dosegroups from the currently outlined dosing schedule. For reasons of reactogenicity,
tolerability, or safety, the IRC may recommend to reduce the second dose of study
intervention and/or increase the interval between doses.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.

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7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANTDISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study
intervention (definitive discontinuation). Reasons for definitive discontinuation of study
intervention may include the following: AEs; participant request; investigator request;
pregnancy; protocol deviation (including no longer meeting all the inclusion criteria, or
meeting 1 or more exclusion criteria).

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Note that discontinuation of study intervention does not represent withdrawal from the study.
Per the study estimands, if study intervention is definitively discontinued, the participant willremain in the study to be evaluated for safety, immunogenicity, and efficacy. See the SoA
for data to be collected at the time of discontinuation of study intervention and follow-up for
any further evaluations that need to be completed.
In the event of discontinuation of study intervention, it must be documented on theappropriate CRF/in the medical records whether the participant is discontinuing further
receipt of study intervention or also from study procedures, posttreatment study follow-up,
and/or future collection of additional information.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request. Reasons fordiscontinuation from the study may include the following:

Refused further follow-up;

Lost to follow-up;



Death;



Study terminated by sponsor;



AEs;



Participant request;

Investigator request;Protocol deviation.

If a participant does not return for a scheduled visit, every effort should be made to contact
the participant. All attempts to contact the participant and information received duringcontact attempts must be documented in the participant’s source document. In any
circumstance, every effort should be made to document participant outcome, if possible.
The investigator or his or her designee should capture the reason for withdrawal in the CRF
for all participants.

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If a participant withdraws from the study, he/she may request destruction of any remaining
samples taken and not tested, and the investigator must document any such requests in thesite study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1)
for disclosure of future information, no further evaluations should be performed and no
additional data should be collected. The sponsor may retain and continue to use any datacollected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not beviewed as protocol deviations so long as the participant’s safety was preserved.

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7.2.1. Withdrawal of Consent
Participants who request to discontinue receipt of study intervention will remain in the study
and must continue to be followed for protocol-specified follow-up procedures. The only
exception to this is when a participant specifically withdraws consent for any further contact
with him or her or persons previously authorized by the participant to provide thisinformation. Participants should notify the investigator in writing of the decision towithdraw consent from future follow-up, whenever possible. The withdrawal of consent
should be explained in detail in the medical records by the investigator, as to whether thewithdrawal is only from further receipt of study intervention or also from study procedures
and/or posttreatment study follow-up, and entered on the appropriate CRF page. In the eventthat vital status (whether the participant is alive or dead) is being measured, publicly
available information should be used to determine vital status only as appropriately directedin accordance with local law.
7.3. Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return forscheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to attend a required study visit:The site must attempt to contact the participant and reschedule the missed visit as soon as
possible and counsel the participant on the importance of maintaining the assigned visit
schedule and ascertain whether or not the participant wishes to and/or should continue inthe study;

Before a participant is deemed lost to follow-up, the investigator or designee must makeevery effort to regain contact with the participant (where possible, 3 telephone calls and,if necessary, a certified letter to the participant’s last known mailing address or local
equivalent methods). These contact attempts should be documented in the participant’s
medical record;Should the participant continue to be unreachable, he/she will be considered to havewithdrawn from the study.
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8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed anddated ICD before performing any study-specific procedures.
The full date of birth will be collected to critically evaluate the immune response and safety
profile by age.
Study procedures and their timing are summarized in the SoA. Protocol waivers or
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence orawareness to determine whether the participant should continue or discontinue study
intervention.

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Adherence to the study design requirements, including those specified in the SoA, is essential
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential
participants meet all eligibility criteria. The investigator will maintain a screening log torecord details of all participants screened and to confirm eligibility or record reasons forscreening failure, as applicable.
Every effort should be made to ensure that protocol-required tests and procedures arecompleted as described. However, it is anticipated that from time to time there may becircumstances outside the control of the investigator that may make it unfeasible to performthe test. In these cases, the investigator must take all steps necessary to ensure the safety andwell-being of the participant. When a protocol-required test cannot be performed, theinvestigator will document the reason for the missed test and any corrective and preventive
actions that he or she has taken to ensure that required processes are adhered to as soon as
possible. The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, andshipment instructions and contact information will be provided to the investigator site prior
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately
530 mL for participants in Phase 1 and 125 mL for Phase 2/3 participants. Additionally,
50 mL of blood will be taken at an unplanned convalescent visit at any time a participant
develops respiratory symptoms indicating a potential COVID-19 infection. Selectparticipants in Phase 1 will also be asked to provide an additional blood sample ofapproximately 170 mL at either Visit 5, 6, or 7. These participants would therefore have a
total blood sampling volume of 700 mL during the 24-month study period. Other additional
blood samples may be taken for safety assessments at times specified by Pfizer, provided thetotal volume taken during the study does not exceed 550 mL during any period of
60 consecutive days.
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8.1. Efficacy and/or Immunogenicity Assessments

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Efficacy will be assessed throughout a participant’s involvement in the study throughsurveillance for potential cases of COVID-19. If, at any time, a participant develops acuterespiratory illness (see Section 8.13), for the purposes of the study he or she will beconsidered to potentially have COVID-19 illness.9 In this circumstance, the participant
should contact the site, an in-person or telehealth visit should occur, and assessments should
be conducted as specified in the SoA. The assessments will include a nasal (midturbinate)swab, which will be tested at a central laboratory using a reverse transcription–polymerase
chain reaction (RT-PCR) test (Cepheid; FDA approved under EUA), or other equivalent
nucleic acid amplification–based test (ie, NAAT), to detect SARS-CoV-2. In addition,clinical information and results from local standard-of-care tests (as detailed in Section 8.13)
will be assessed. A local NAAT result will be considered acceptable if it was obtained using:An FDA-cleared (including Emergency Use Authorization) assay; orAn assay that is not FDA-cleared but was conducted in a laboratory that is currently
CLIA-certified; orAn assay performed by a laboratory accredited according to the ISO 15189 standard by anational or regional accreditation body.

Two definitions of SARS-CoV-2–related cases, and SARS-CoV-2–related severe cases, will
be considered (for both, the onset date of the case will be the date that symptoms were firstexperienced by the participant):Confirmed COVID-19: presence of at least 1 of the following symptoms and
SARS-CoV-2 NAAT positive at central laboratory or at a local testing facility (using an
acceptable test):Fever;

New or increased cough;

New or increased shortness of breath;Chills;

New or increased muscle pain;New loss of taste or smell;

Sore throat;

Diarrhea;

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The second definition, which may be updated as more is learned about COVID-19, will
include the following additional symptoms defined by the CDC (listed athttps://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html):

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Fatigue;Headache;

Nasal congestion or runny nose;Nausea.

Confirmed severe COVID-19: confirmed COVID-19 and presence of at least 1 of thefollowing:Clinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per minute,HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or PaO2/FiO2<300 mm Hg);

Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation,mechanical ventilation, or ECMO);

Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiring vasopressors);

Significant acute renal, hepatic, or neurologic dysfunction*;Admission to an ICU;Death.

The DMC may recommend modification of the definition of severe disease according toemerging information.
* Three blinded case reviewers (medically qualified Pfizer staff members) will review all
potential COVID-19 illness events. If a NAAT-confirmed case in Phase 2/3 may beconsidered severe, or not, solely on the basis of this criterion, the blinded data will be
reviewed by the case reviewers to assess whether the criterion is met; the majority opinion
will prevail.

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In addition, a serological definition will be used for participants without clinical presentationof COVID-19:


Confirmed seroconversion to SARS-CoV-2 without confirmed COVID-19: positive
SARS-CoV-2 NVA-binding antibody result in a participant with a prior negative
SARS-CoV-2 NVA-binding antibody result

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Serum samples will be obtained for immunogenicity testing at the visits specified in the SoA.
The following assays will be performed:

SARS-CoV-2 serum neutralization assay

SARS-CoV-2 anti-S1 IgG direct Luminex immunoassay

SARS-CoV-2 anti-RBD IgG direct Luminex immunoassay

Nonvaccine antigen (NVA) Ig direct Luminex immunoassay. The NVA will include a
SARS-CoV-2 target antigen that is not derived from the S glycoprotein, most likely anantigen derived from the SARS-CoV-2 nucleoprotein.

Note that all immunogenicity analyses will be based upon samples analyzed at the central
laboratory; the rapid test will only be performed at screening by all sites recruiting
participants in Phase 1 (see Section 8.11.1.1) to determine eligibility.
Serum obtained from the additional ~170-mL blood sample from select participants in Phase
1 at either Visit 5, 6, or 7 will be used for exploratory COVID-19 research, intended toestablish a surrogate endpoint that is reasonably likely to predict clinical benefit.
8.1.1. Biological Samples
Blood and nasal swab samples will be used only for scientific research. Each sample will belabeled with a code so that the laboratory personnel testing the samples will not know theparticipant’s identity. Samples that remain after performing assays outlined in the protocol
may be stored by Pfizer. Unless a time limitation is required by local regulations or ethicalrequirements, the samples will be stored for up to 15 years after the end of the study and thendestroyed. If allowed by the ICD, stored samples may be used for additional testing to better
understand the immune responses to the vaccine(s) under study in this protocol, to inform thedevelopment of other products, and/or for vaccine-related assay work supporting vaccine
programs. No testing of the participant’s DNA will be performed.
The participant may request that his or her samples, if still identifiable, be destroyed at any
time; however, any data already collected from those samples will still be used for thisresearch. The biological samples may be shared with other researchers as long asconfidentiality is maintained and no testing of the participant’s DNA is performed.

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8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinicallaboratory measurements may be obtained at any time during the study to assess any
perceived safety issues.
A clinical assessment, including medical history, will be performed on all participants at
his/her first visit to establish a baseline. Significant medical history and observations fromany physical examination, if performed, will be documented in the CRF.
AEs and SAEs are collected, recorded, and reported as defined in Section 8.3.
Acute reactions within the first 4 hours after administration of the study intervention (for the
first 5 participants vaccinated in each Phase 1 group), and within the first 30 minutes (for theremainder of participants), will be assessed and documented in the AE CRF.

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after administration of the study intervention. These prospectively self-collected occurrencesof local reactions and systemic events are graded as described in Section 8.2.2.
8.2.1. Clinical Safety Laboratory Assessments (Phase 1 Participants Only)
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for
the timing and frequency. All protocol-required laboratory assessments, as defined inAppendix 2, must be conducted in accordance with the laboratory manual and the SoA.
Unscheduled clinical laboratory measurements may be obtained at any time during the study
to assess any perceived safety issues.
The investigator must review the laboratory report, document this review, and record any
clinically relevant changes occurring during the study in the AE section of the CRF. See
Appendix 2 for the grading scale for assessment of clinically significant abnormal laboratory
findings. Clinically significant abnormal laboratory findings are those which are notassociated with the underlying disease, unless judged by the investigator to be more severe
than expected for the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during
participation in the study or within 28 days after the last dose of study intervention should be
repeated until the values return to normal or baseline or are no longer considered clinicallysignificant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 5 for suggested actions and follow-up assessments in the event of potential
drug-induced liver injury (DILI).

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8.2.2. Electronic Diary
Participants will be required to complete a reactogenicity e-diary through an application(see Section 8.14) installed on a provisioned device or on the participant’s own personal
device. All participants in Phase 1, and a subset of at least 6000 in Phase 2/3, will be asked
to monitor and record local reactions, systemic events, and antipyretic medication usage for7 days following administration of the study intervention. The reactogenicity e-diary allows
recording of these assessments only within a fixed time window, thus providing the accurate
representation of the participant’s experience at that time. Data on local reactions andsystemic events reported in the reactogenicity e-diary will be transferred electronically to athird-party vendor, where they will be available for review by investigators and the Pfizer
clinicians at all times via an internet-based portal.
At intervals agreed to by the vendor and Pfizer, these data will be transferred electronicallyinto Pfizer's database for analysis and reporting. These data do not need to be reported by theinvestigator in the CRF as AEs.

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Investigators (or designee) will be required to review the reactogenicity e-diary data online atfrequent intervals as part of the ongoing safety review.
The investigator or designee must obtain stop dates from the participant for any ongoing
local reactions, systemic events, or use of antipyretic medication on the last day that thereactogenicity e-diary was completed. The stop dates should be documented in the source
documents and the information entered in the CRF.
8.2.2.1. Grading Scales
The grading scales used in this study to assess local reactions and systemic events as
described below are derived from the FDA Center for Biologics Evaluation and Research(CBER) guidelines on toxicity grading scales for healthy adult volunteers enrolled inpreventive vaccine clinical trials.8
8.2.2.2. Local Reactions
During the reactogenicity e-diary reporting period, participants will be asked to assess
redness, swelling, and pain at the injection site and to record the symptoms in thereactogenicity e-diary. If a local reaction persists beyond the end of the reactogenicity
e-diary period following vaccination, the participant will be requested to report that
information. The investigator will enter this additional information in the CRF.
Redness and swelling will be measured and recorded in measuring device units(range: 1 to 21) and then categorized during analysis as absent, mild, moderate, or severe
based on the grading scale in Table 1. Measuring device units can be converted tocentimeters according to the following formula: 1 measuring device unit = 0.5 cm. Pain at
the injection site will be assessed by the participant as absent, mild, moderate, or severe
according the grading scale in Table 1.

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If a Grade 3 local reaction is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinicallyindicated. Only an investigator or medically qualified person is able to classify aparticipant’s local reaction as Grade 4. If a participant experiences a confirmed Grade 4 local
reaction, the investigator must immediately notify the sponsor and, if it is determined to berelated to the administration of the study intervention, further vaccinations will be
discontinued in that participant.
Table 1.

Local Reaction Grading Scale
Mild(Grade 1)

Pain at the
injection site

Does not interferewith activity

Interferes withactivity

Redness

2.0 cm to 5.0 cm(5 to 10 measuring
device units)
2.0 cm to 5.0 cm(5 to 10 measuring
device units)>5.0 cm to 10.0 cm(11 to 20 measuring
device units)>5.0 cm to 10.0 cm(11 to 20 measuring
device units)

Swelling

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Moderate(Grade 2)

Severe(Grade 3)

Potentially Life
Threatening(Grade 4)
Prevents daily activity Emergency room visit
or hospitalization forsevere pain
>10 cmNecrosis or(≥21 measuringexfoliative dermatitis
device units)>10 cmNecrosis(≥21 measuring
device units)

8.2.2.3. Systemic Events
During the reactogenicity e-diary reporting period, participants will be asked to assess
vomiting, diarrhea, headache, fatigue, chills, new or worsened muscle pain, and new orworsened joint pain and to record the symptoms in the reactogenicity e-diary. The symptoms
will be assessed by the participant as absent, mild, moderate, or severe according to thegrading scale in Table 2.
If a Grade 3 systemic event is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinicallyindicated. Only an investigator or medically qualified person is able to classify aparticipant’s systemic event as Grade 4. If a participant experiences a confirmed Grade 4
systemic event, the investigator must immediately notify the sponsor and, if it is determined
to be related to the administration of the study intervention, further vaccinations will be
discontinued in that participant.

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Table 2.

Systemic Event Grading Scale

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Mild(Grade 1)

Moderate(Grade 2)>2 times in
24 hours

Severe(Grade 3)

Vomiting

1-2 times in
24 hours

Requires IV
hydration

Diarrhea

2 to 3 loose stools 4 to 5 loose stools
in 24 hours
in 24 hours

6 or more loosestools in 24 hours

Headache

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Fatigue/tiredness

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Chills

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

New orworsened
muscle pain

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Does not interfere Some interference
New orwith activity
with activity
worsened
joint pain
Abbreviation: IV = intravenous.

Prevents daily
routine activity

Potentially Life
Threatening(Grade 4)
Emergency room visit or
hospitalization for
hypotensive shock
Emergency room visit or
hospitalization for severe
diarrhea
Emergency room visit or
hospitalization for severe
headache
Emergency room visit or
hospitalization for severe
fatigue
Emergency room visit or
hospitalization for severe
chillsEmergency room visit or
hospitalization for severe
new or worsened muscle
painEmergency room visit or
hospitalization for severe
new or worsened joint pain

8.2.2.4. Fever
In order to record information on fever, a thermometer will be given to participants with
instructions on how to measure oral temperature at home. Temperature will be collected in
the reactogenicity e-diary in the evening daily during the reactogenicity e-diary reporting
period. It will also be collected at any time during the reactogenicity e-diary data collection
periods when fever is suspected. Fever is defined as an oral temperature of ≥38.0°C(100.4°F). The highest temperature for each day will be recorded in the reactogenicity
e-diary. Temperature will be measured and recorded to 1 decimal place and then categorized
during analysis according to the scale shown in Table 3.
If a fever of ≥39.0°C (102.1°F) is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinicallyindicated. Only an investigator or medically qualified person is able to confirm aparticipant’s fever as >40.0°C (>104.0°F). If a participant experiences a confirmed fever>40.0°C (>104.0°F), the investigator must immediately notify the sponsor and, if it isdetermined to be related to the administration of the study intervention, further vaccinations
will be discontinued in that participant.

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Table 3.

Scale for Fever≥38.0-38.4°C (100.4-101.1°F)>38.4-38.9°C (101.2-102.0°F)>38.9-40.0°C (102.1-104.0°F)>40.0°C (>104.0°F)

8.2.2.5. Antipyretic Medication
The use of antipyretic medication to treat symptoms associated with study intervention
administration will be recorded in the reactogenicity e-diary daily during the reporting period(Day 1 to Day 7).

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8.2.3. Phase 1 Stopping Rules
The following stopping rules are in place for all Phase 1 participants, based on review of AE
data and e-diary reactogenicity data, until the start of Phase 2/3 or 30 days after the last doseof study intervention in Phase 1, whichever is later. These data will be monitored on an
ongoing basis by the investigator (or medically qualified designee) and sponsor in order topromptly identify and flag any event that potentially contributes to a stopping rule.
The sponsor study team will be unblinded during Phase 1, so will be able to assess whether
or not a stopping rule has been met on the basis of a participant’s individual study
intervention allocation.
In the event that sponsor personnel confirm that a stopping rule is met, the following actions
will commence:The IRC will review all appropriate data.

The stopping rule will PAUSE randomization and study intervention administration for
the impacted vaccine candidate all dose levels and age groups.



The DMC will review all appropriate data.

For all participants vaccinated, all other routine study conduct activities, including
ongoing data entry, reporting of AEs, participant reactogenicity e-diary completion,
blood sample collection, and participant follow-up, will continue during the pause.

A stopping rule is met if any of the following rules occur after administration of
investigational BNT162 vaccine; data from placebo recipients will not contribute to thestopping rules. Reactogenicity e-diary data confirmed by the investigator as being entered by
the participant in error will not contribute toward a stopping rule.
The BNT162b RNA platform will be evaluated for contribution to stopping rules overall;
vaccine candidate dose levels within the platform and age groups will contribute to stopping
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rules together. However, it is possible that the recommendations may include halting or
continuing randomization with any of the BNT162 vaccine candidates.
Stopping Rule Criteria for Each BNT162 Vaccine Candidate:
1. If any participant vaccinated with the BNT162 candidate (at any dose level) develops an
SAE that is assessed by the investigator as possibly related, or for which there is noalternative, plausible, attributable cause.
2. If any participant vaccinated with the BNT162 candidate (at any dose level) develops a
Grade 4 local reaction or systemic event after vaccination (see Section 8.2.2) that is
assessed as possibly related by the investigator, or for which there is no alternative,plausible, attributable cause.

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3. If any participant vaccinated with the BNT162 candidate (at any dose level) develops afever >40.0°C (>104.0°F) for at least 1 daily measurement after vaccination(see Section 8.2.2.4) that is assessed as possibly related by the investigator, or for which
there is no alternative, plausible, attributable cause.
4. If any 2 participants vaccinated with the BNT162 candidate (at any dose level) report thesame or similar severe (Grade 3) AE (including laboratory abnormalities) after
vaccination, assessed as possibly related by the investigator, or for which there is noalternative, plausible, attributable cause.
5. If any participant dies or requires ICU admission due to SARS-CoV-2 infection; if thisstopping rule is met, all available clinical and preclinical safety and immunogenicity data
should be reviewed to evaluate for enhanced COVID-19.
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19 and Phase 2/3
Stopping Rule
Participants in all phases of the study will be surveilled for potential COVID-19 illness from
Visit 1 onwards (see Section 8.13).
As this is a sponsor open-label study during Phase 1, the sponsor will conduct unblinded
reviews of the data during the course of the study, including for the purpose of safetyassessment. All NAAT-confirmed cases in Phase 1 will be reviewed contemporaneously by
the IRC and the DMC (see Section 9.6).
In Phase 2/3, the unblinded team supporting the DMC, including an unblinded medical
monitor, will review cases of severe COVID-19 as they are received and will review AEs atleast weekly for additional potential cases of severe COVID-19. At any point, the unblinded
team may discuss with the DMC chair whether the DMC should review cases for an adverse
imbalance of cases of COVID-19 and/or severe COVID-19 between the vaccine and placebogroups.

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The purpose of these reviews will be to identify whether any features of each case appear
unusual, in particular greater in severity, compared to available information at the time ofreview. Indicators of severity may include accelerated deterioration, need for hospitalization,need for ventilation, or death. Observed rates of these indicators will be compared with what
could be expected in a similar population to the study participants based upon available
information at the time of review.
Stopping and alert rules will be applied as follows. The stopping rule will be triggered whenthe 1-sided probability of observing the same or a more extreme case split is 5% or less when
the true incidence of severe disease is the same for vaccine and placebo participants, and alert
criteria are triggered when this probability is less than 11%. In addition, when the total
number of severe cases is low (15 or less), the unblinded team supporting the DMC will
implement the alert rule when a reverse case split of 2:1 or worse is observed. For example,
at 3 cases 2:1, at 4 cases 3:1, etc. Below 15 cases, this rule is more rigorous than requiring
the probability of an observed adverse split or worse be <11%. Further details can be foundin Section 10.7.

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8.2.5. Randomization and Vaccination After a Stopping Rule Is Met
Once the IRC (if in Phase 1) and DMC (all phases) have reviewed the safety data andprovided guidance, a notification will be sent from the sponsor to the sites with guidance on
how to proceed.
8.2.6. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA,
immediately before the administration of each vaccine dose. A negative pregnancy test result
will be required prior to the participant’s receiving the study intervention. Pregnancy tests
may also be repeated if requested by IRBs/ECs or if required by local regulations. In thecase of a positive confirmed pregnancy, the participant will be withdrawn fromadministration of study intervention but may remain in the study.

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8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or
the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, andrecording events that meet the definition of an AE or SAE and remain responsible to pursue
and obtain adequate information both to determine the outcome and to assess whether the
event meets the criteria for classification as an SAE or caused the participant to discontinue
the study intervention (see Section 7.1).
Each participant will be questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up
information in an expedited fashion.

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8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection
period”) for each participant begins from the time the participant provides informed consent,
which is obtained before the participant’s participation in the study (ie, before undergoing
any study-related procedure and/or receiving study intervention), through and including
Visit 7 for Phase 1 participants, and Visit 3 for Phase 2/3 participants. In addition, any AEs
occurring up to 48 hours after each subsequent blood draw must be recorded on the CRF.
SAEs will be collected from the time the participant provides informed consent toapproximately 6 months after the last dose of study intervention (Visit 8 for Phase 1
participants, and Visit 4 for Phase 2/3 participants).
Follow-up by the investigator continues throughout and after the active collection period anduntil the AE or SAE or its sequelae resolve or stabilize at a level acceptable to theinvestigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervention
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE
reported using the Vaccines SAE Report Form.
Investigators are not obligated to actively seek AEs or SAEs after the participant has
concluded study participation. However, if the investigator learns of any SAE, including a
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death, at any time after a participant has completed the study, and he/she considers the event
to be reasonably related to the study intervention, the investigator must promptly report the
SAE to Pfizer using the Vaccines SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in
Section 8.3.1 are reported to Pfizer Safety on the Vaccines SAE Report Form immediately
upon awareness and under no circumstance should this exceed 24 hours, as indicated inAppendix 3. The investigator will submit any updated SAE data to the sponsor within
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period,
which begins after obtaining informed consent as described in Section 8.3.1, will be recordedon the AE section of the CRF.

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)The investigator is to record on the CRF all directly observed and all spontaneously reported
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and theprocedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended andnonleading verbal questioning of the participant is the preferred method to inquire about
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow eachparticipant at subsequent visits/contacts. For each event, the investigator must pursue andobtain adequate information until resolution, stabilization, the event is otherwise explained,or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail toallow for a complete medical assessment of the case and independent determination of
possible causality. Any information relevant to the event, such as concomitant medications
and illnesses, must be provided. In the case of a participant death, a summary of available
autopsy findings must be submitted as soon as possible to Pfizer Safety.
Further information on follow-up procedures is given in Appendix 3.

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8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal
obligations and ethical responsibilities towards the safety of participants and the safety of astudy intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and otherregulatory agencies about the safety of a study intervention under clinical investigation. The
sponsor will comply with country-specific regulatory requirements relating to safety
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the
study and will notify the IRB/EC, if appropriate according to local requirements.

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8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding andoccupational exposure are reportable to Pfizer Safety within 24 hours of investigatorawareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if:A female participant is found to be pregnant while receiving or after discontinuing study
intervention.



A male participant who is receiving or has discontinued study intervention exposes afemale partner prior to or around the time of conception.



A female is found to be pregnant while being exposed or having been exposed to study
intervention due to environmental exposure. Below are examples of environmental
exposure during pregnancy:

A female family member or healthcare provider reports that she is pregnant after
having been exposed to the study intervention by inhalation or skin contact.

A male family member or healthcare provider who has been exposed to the study
intervention by inhalation or skin contact then exposes his female partner prior to or
around the time of conception.

The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s
awareness, irrespective of whether an SAE has occurred. The initial information submitted
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should include the anticipated date of delivery (see below for information related totermination of pregnancy).


If EDP occurs in a participant or a participant’s partner, the investigator must report thisinformation to Pfizer Safety on the Vaccines SAE Report Form and an EDP
Supplemental Form, regardless of whether an SAE has occurred. Details of thepregnancy will be collected after the start of study intervention and until 6 months after
the last dose of study intervention.



If EDP occurs in the setting of environmental exposure, the investigator must report
information to Pfizer Safety using the Vaccines SAE Report Form and EDP
Supplemental Form. Since the exposure information does not pertain to the participant
enrolled in the study, the information is not recorded on a CRF; however, a copy of thecompleted Vaccines SAE Report Form is maintained in the investigator site file.

Follow-up is conducted to obtain general information on the pregnancy and its outcome for
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as afollow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural
integrity of the neonate can be assessed at the time of birth. In the event of a termination, thereason(s) for termination should be specified and, if clinically possible, the structural
integrity of the terminated fetus should be assessed by gross visual inspection (unlesspreprocedure test findings are conclusive for a congenital anomaly and the findings arereported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meetsthe criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal
demise, neonatal death, or congenital anomaly), the investigator should follow the procedures
for reporting SAEs. Additional information about pregnancy outcomes that are reported to
Pfizer Safety as SAEs follows:

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard tocausality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs
when the investigator assesses the infant death as related or possibly related to exposure
to the study intervention.

Additional information regarding the EDP may be requested by the sponsor. Further
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on
preterm infants to identify developmental delays). In the case of paternal exposure, theinvestigator will provide the participant with the Pregnant Partner Release of Information
Form to deliver to his partner. The investigator must document in the source documents thatthe participant was given the Pregnant Partner Release of Information Form to provide to his
partner.
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8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if:A female participant is found to be breastfeeding while receiving or after discontinuing
study intervention.



A female is found to be breastfeeding while being exposed or having been exposed to
study intervention (ie, environmental exposure). An example of environmental exposure
during breastfeeding is a female family member or healthcare provider who reports that
she is breastfeeding after having been exposed to the study intervention by inhalation orskin contact.

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hoursof the investigator’s awareness, irrespective of whether an SAE has occurred. The
information must be reported using the Vaccines SAE Report Form. When exposure during
breastfeeding occurs in the setting of environmental exposure, the exposure information does
not pertain to the participant enrolled in the study, so the information is not recorded on a
CRF. However, a copy of the completed Vaccines SAE Report Form is maintained in theinvestigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specificallyapproved for use in breastfeeding women (eg, vitamins) is administered in accord withauthorized use. However, if the infant experiences an SAE associated with such a drug, theSAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with thestudy intervention, which may or may not lead to the occurrence of an AE. Such persons
may include healthcare providers, family members, and other roles that are involved in thetrial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of theinvestigator’s awareness, regardless of whether there is an associated SAE. The informationmust be reported using the Vaccines SAE Report Form. Since the information does not
pertain to a participant enrolled in the study, the information is not recorded on a CRF;
however, a copy of the completed Vaccines SAE Report Form is maintained in theinvestigator site file.
8.3.6. Cardiovascular and Death Events
Not applicable.

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8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs
or SAEs
Potential COVID-19 illness will not be reported according to the standard process forexpedited reporting of SAEs, even though the event may meet the definition of an SAE.
These events will be recorded on the COVID-19 illness pages in the participant’s CRF within
1 day.
Potential COVID-19 illness events will be reviewed by a group of internal blinded casereviewers. Any SAE that is determined by the internal case reviewers NOT to meet endpoint
criteria is reported back to the investigator site of incidence. The investigator must report the
SAE to Pfizer Safety within 24 hours of being made aware that the SAE did not meet
endpoint criteria. The investigator’s SAE awareness date is the date on which theinvestigator site of incidence receives the SAE back from the internal case reviewers.
8.3.8. Adverse Events of Special Interest
Not applicable.

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8.3.8.1. Lack of Efficacy
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.
8.3.9. Medical Device Deficiencies
Not applicable.
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as
medication errors.
Safety Event

Recorded on the CRF

Reported on the Vaccines SAE Report
Form to Pfizer Safety Within 24 Hours
of Awareness

Medication errors

All (regardless of whether
associated with an AE)

Only if associated with an SAE

Medication errors include:Medication errors involving participant exposure to the study intervention;

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do not involve the study participant;The administration of expired study intervention;

The administration of an incorrect study intervention;

The administration of an incorrect dosage;The administration of study intervention that has undergone temperature excursion fromthe specified storage range, unless it is determined by the sponsor that the study
intervention under question is acceptable for use.

Such medication errors occurring to a study participant are to be captured on the medication
error page of the CRF, which is a specific version of the AE page.

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In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by theinvestigator, the medication error is recorded on the medication error page of the CRF and, if
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a Vaccines SAE
Report Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of study intervention greater than 1 dose of study intervention within
a 24-hour time period will be considered an overdose.
Pfizer does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs.
3. Document the quantity of the excess dose as well as the duration of the overdose in the
CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the medical monitor based on the clinical evaluation of the participant.

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8.5. Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7. Genetics
Genetics (specified analyses) are not evaluated in this study.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.9. Immunogenicity Assessments
Immunogenicity assessments are described in Section 8.1.

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8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are notevaluated in this study.
8.11. Study Procedures
8.11.1. Phase 1
8.11.1.1. Screening: (0 to 28 Days Before Visit 1)
Before enrollment and before any study-related procedures are performed, voluntary, written
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.
It is anticipated that the procedures below will be conducted in a stepwise manner; however,the visit can occur over more than 1 day.
Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance.

Obtain details of any medications currently taken.

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Perform physical examination including vital signs (weight, height, body temperature,pulse rate, and seated blood pressure), evaluating any clinically significant abnormalities
within the following body systems: general appearance; skin; head, eyes, ears, nose, andthroat; heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph
nodes.



Collect a blood sample (approximately 20 mL) for potential future serological assessment
and to perform a rapid test for prior COVID-19 infection.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.

Collect a blood sample (approximately 10 mL) for HIV, HBsAg, HBc Ab, and HCV Ab
tests.



Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Record AEs as described in Section 8.3. AEs that occur prior to dosing should be notedon the Medical History CRF.



Ask the participant to contact the site staff or investigator immediately if any significant
illness or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

Complete the CRF.

8.11.1.2. Visit 1 – Vaccination 1: (Day 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.
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

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Review screening laboratory results (hematology and chemistry, and HIV, HBsAg,
HBc Ab, and HCV Ab tests).

Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested(if possible at the site, otherwise at the central laboratory) within 24 hours andvaccination will proceed only if it is NAAT-negative for SARS-CoV-2 genomes.
The second will be sent to the central laboratory for potential later testing.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Obtain the participant’s randomization number and study intervention allocation using
the IRT system. Only an unblinded site staff member may obtain this information.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.



The first 5 participants vaccinated in each group must be observed by blinded site staff
for any acute reactions for at least 4 hours after vaccination. For participants enrolled
thereafter, blinded site staff must observe the participant for at least 30 minutes after
study intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Issue a measuring device to measure local reactions at the injection site and athermometer for recording daily temperatures and provide instructions on their use.

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Explain the e-diary technologies available for this study (see Section 8.14), and assist theparticipant in downloading the study application onto the participant’s own device orissue a provisioned device if required. Provide instructions on e-diary completion andask the participant to complete the reactogenicity e-diary from Day 1 to Day 7, with
Day 1 being the day of vaccination and, if utilized, the COVID-19 illness e-diary (to becompleted if the participant is diagnosed with COVID-19 or has possible new orincreased symptoms, and when he/she receives a reminder, at least weekly).



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

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8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1 to 3 Days After Visit 1)

Record AEs as described in Section 8.3.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.

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The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

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8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to 8 Days After Visit 1)

Record AEs as described in Section 8.3.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.

Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.
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

Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

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8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary wascompleted and record stop dates in the CRF if required.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

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Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested (ifpossible at the site, otherwise at the central laboratory) within 24 hours and vaccination
will only proceed if it is NAAT-negative for SARS-CoV-2 genomes. The second will besent to the central laboratory for potential later testing.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met. If not, the participant should not receive further study intervention but willremain in the study to be evaluated for safety, immunogenicity, and efficacy(see Section 7.1).

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection
site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and ask the participant to complete thereactogenicity e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.
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

Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to 8 Days After Visit 4)

Record AEs as described in Section 8.3.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

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If the participant (select participants only, details will be provided by the sponsor)
consents, collect an additional 170 mL blood sample for exploratory COVID-19 research.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to 16 Days After Visit 4)

Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary wascompleted and record stop dates in the CRF if required.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

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

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



If not collected at Visit 5, and the participant (select participants only, details will be
provided by the sponsor) consents, collect an additional 170-mL blood sample for
exploratory COVID-19 research.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately (this could be via
the COVID-19 illness e-diary) if he or she experiences any respiratory symptoms as
detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After Visit 4)

Record AEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

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If not collected at Visit 5 or 6, and the participant (select participants only, details will be
provided by the sponsor) consents, collect an additional 170-mL blood sample for
exploratory COVID-19 research.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (154 to 168 Days After Visit 4)

Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.1.10. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 4)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.1.11. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 4)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect the participant’s e-diary or assist the participant to remove the study applicationfrom his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.2. Phase 2/3
8.11.2.1. Visit 1 – Vaccination 1: (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written,
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.

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It is anticipated that the procedures below will be conducted in a stepwise manner. The visit
may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion andexclusion criteria onwards must be conducted on the same day.
Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance.



Perform a clinical assessment. If the clinical assessment indicates that a physicalexamination is necessary to comprehensively evaluate the participant, perform a physicalexamination and record any findings in the source documents and, if clinicallysignificant, record on the medical history CRF.

Measure the participant’s height and weight.

Measure the participant’s body temperature.

Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.



Record AEs as described in Section 8.3.

Collect a blood sample (approximately 25 mL) for immunogenicity testing.
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Obtain a nasal (midturbinate) swab (collected by site staff).

Obtain the participant’s randomization number and study intervention allocation number
using the IRT system. Only an unblinded site staff member may obtain this information.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

For participants in the reactogenicity subset, issue a measuring device to measure local
reactions at the injection site and a thermometer for recording daily temperatures andprovide instructions on their use.

For participants not in the reactogenicity subset, issue a thermometer to monitor for fever(for COVID-19 surveillance) and provide instructions on its use.



Explain the e-diary technologies available for this study (see Section 8.14), and assist theparticipant in downloading the study application onto the participant’s own device orissue a provisioned device if required.



For participants in the reactogenicity subset, provide instructions on reactogenicity
e-diary completion and ask the participant to complete the reactogenicity e-diary fromDay 1 to Day 7, with Day 1 being the day of vaccination.

For all participants, provide instructions on COVID-19 illness e-diary completion andask the participant to complete the COVID-19 illness e-diary if he/she is diagnosed
with COVID-19 or has possible new or increased symptoms, and when he/she
receives a reminder, at least weekly. See Section 8.14 for further details.

If the participant is part of the reactogenicity subset, ask the participant to contact the site
staff or investigator immediately if he or she experiences any of the following from Day
1 to Day 7 after vaccination (where Day 1 is the day of vaccination) to determine if anunscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.
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Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.

If the participant is part of the reactogenicity subset, the investigator or appropriately
qualified designee reviews the reactogenicity e-diary data online following vaccination toevaluate participant compliance and as part of the ongoing safety review. Daily review is
optimal during the active diary period.
8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days After Visit 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



If the participant is part of the reactogenicity subset, review the participant’s
reactogenicity e-diary data. Collect stop dates of any reactogenicity e-diary events
ongoing on the last day that the reactogenicity e-diary was completed and record stop
dates in the CRF if required.



Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met. If not, the participant should not receive further study intervention but will
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remain in the study to be evaluated for safety, immunogenicity, and efficacy(see Section 7.1).
Measure the participant’s body temperature.

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection
site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and, if the participant is part of thereactogenicity subset, ask the participant to complete the reactogenicity e-diary fromDay 1 to Day 7, with Day 1 being the day of vaccination.



If the participant is part of the reactogenicity subset, ask the participant to contact the site
staff or investigator immediately if he or she experiences any of the following fromDay 1 to Day 7 after vaccination (where Day 1 is the day of vaccination) to determine if
an unscheduled reactogenicity visit is required:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.

Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

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

Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.

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If the participant is part of the reactogenicity subset, the investigator or appropriately
qualified designee reviews the reactogenicity e-diary data online following vaccination toevaluate participant compliance and as part of the ongoing safety review. Daily review is
optimal during the active diary period.
8.11.2.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2): (28 to 35 Days After
Visit 2)


Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. If the participant is part of thereactogenicity subset, review the participant’s reactogenicity e-diary data. Collect stop
dates of any reactogenicity e-diary events ongoing on the last day that the reactogenicity
e-diary was completed and record stop dates in the CRF if required.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 25 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

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Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.2.4. Visit 4 – 6-Month Follow-up Visit: (154 to 168 Days After Visit 2)

Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.

Collect a blood sample (approximately 25 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.3.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.11.2.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 2)Collect a blood sample (approximately 25 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.2.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 2)Collect a blood sample (approximately 25 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect the participant’s e-diary or assist the participant to remove the study applicationfrom his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction
If a Grade 3 local reaction (Section 8.2.2.2), systemic event (Section 8.2.2.3), or fever(Section 8.2.2.4) is reported in the reactogenicity e-diary, a telephone contact should occur toascertain further details and determine whether a site visit is clinically indicated. If suspected
Grade 4 local reaction (Section 8.2.2.2), systemic event (Section 8.2.2.3), or fever(Section 8.2.2.4) is reported in the reactogenicity e-diary, a telephone contact or site visit
should occur to confirm whether the event meets the criteria for Grade 4.
A site visit must be scheduled as soon as possible to assess the participant unless any of thefollowing is true:The participant is unable to attend the unscheduled visit.

The local reaction/systemic event is no longer present at the time of the telephone
contact.



The participant recorded an incorrect value in the reactogenicity e-diary (confirmation ofa reactogenicity e-diary data entry error).



The PI or authorized designee determined it was not needed.

This telephone contact will be recorded in the participant’s source documentation and theCRF.
If the participant is unable to attend the unscheduled visit, or the PI or authorized designee
determined it was not needed, any ongoing local reactions/systemic events must be assessedat the next study visit.

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During the unscheduled visit, the reactions should be assessed by the investigator or a
medically qualified member of the study staff such as a study physician or a study nurse, asapplicable to the investigator’s local practice, who will:Measure body temperature (°F/°C).

Measure minimum and maximum diameters of redness (if present).

Measure minimum and maximum diameters of swelling (if present).



Assess injection site pain (if present) in accordance with the grades provided in
Section 8.2.2.2.

Assess systemic events (if present) in accordance with the grades provided in
Section 8.2.2.3.

Assess for other findings associated with the reaction and record on the AE page of the
CRF, if appropriate.

The investigator or an authorized designee will complete the unscheduled visit assessment
page of the CRF.
8.13. COVID-19 Surveillance (All Participants)
If a participant experiences any of the following, he or she is instructed to contact the site
immediately and, if confirmed, participate in an in-person or telehealth visit as soon as
possible, optimally within 3 days of symptom onset. During the 7 days following eachvaccination, potential COVID-19 symptoms that overlap with solicited systemic events(ie, fever, chills, new or increased muscle pain, diarrhea, vomiting) should not trigger apotential COVID-19 illness visit unless, in the investigator’s opinion, the clinical picture ismore indicative of a possible COVID-19 illness than vaccine reactogenicity. Participants may
utilize a COVID-19 illness e-diary through an application (see Section 8.14) installed on aprovisioned device or on the participant’s own personal device to prompt him/her to reportany symptoms. Note that this does not substitute for a participant’s routine medical care.
Therefore, participants should be encouraged to seek care, if appropriate, from their usual
provider.


A diagnosis of COVID-19;



Fever;

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New or increased muscle pain;New loss of taste/smell;

Sore throat;

Diarrhea;Vomiting.

8.13.1. Potential COVID-19 Illness Visit: (Optimally Within 3 Days After Potential
COVID-19 Illness Onset)
This visit may be conducted as an in-person or telehealth visit; a telehealth visit involves thesharing of healthcare information and services via telecommunication technologies (eg,audio, video, video-conferencing software) remotely, thus allowing the participant andinvestigator to communicate on aspects of clinical care.

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)As a participant’s COVID-19 illness may evolve over time, several contacts may be required
to obtain the following information:


Record AEs, as appropriate as described in Section 8.3.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



If the visit is conducted in person, obtain a nasal (midturbinate) swab (collected by site
staff). Alternatively, if conducted by telehealth, instruct the participant to self-collect a
nasal (midturbinate) swab and ship for assessment at the central laboratory. The result
from this swab will be provided to the site once it is available, but this will not be in realtime, and cannot be relied upon to direct clinical care. Therefore, the participant should
be encouraged to seek care, if appropriate, from his or her usual provider.

Collect COVID-19–related standard-of-care clinical and laboratory information. This
includes, but is not limited to:Symptoms and signs, includingClinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per
minute, HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or
PaO2/FiO2 <300 mm Hg)



Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiringvasopressors)Significant acute renal, hepatic, or neurologic dysfunction
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Respiratory failure (defined as needing high-flow oxygen, noninvasive
ventilation, mechanical ventilation, or ECMO)

Clinical diagnosis

Local laboratory COVID-19 test resultFull blood count

Blood chemistry, specifically creatinine, urea, liver function tests, and C-reactive
protein

Imaging results (eg, CT or MRI scan) to document neurologic dysfunction

Number and type of any healthcare contact; duration of hospitalization and ICU stay



Death



Schedule an appointment for the participant to return for the potential COVID-19
convalescent visit once he or she has recovered.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After Potential
COVID-19 Illness Visit)

Record AEs, as appropriate as described in Section 8.3.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Collect/update COVID-19–related clinical and laboratory information (detailed in
Section 8.13.1).

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.14. Communication and Use of Technology

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In a study of this nature that requires illness events to be reported outside of scheduled study
visits, it is vital that communication between the study site and the participant is maintained
to ensure that endpoint events are not missed. This study will employ various methods,
tailored to the individual participant, to ensure that communication is maintained and study
information can be transmitted securely. Using appropriate technology, such as a study
application, a communication pathway between the participant and the study site staff will beestablished. The participant may be able to utilize his or her own devices to access thistechnology, or use a device provided by the sponsor. Traditional methods of telephone
communication will also be available. The technology solution may facilitate the following:Contact with the investigator, including the ability of the participant to report whether or
not he or she has experienced symptoms that could represent a potential COVID-19
illness (COVID-19 illness e-diary; see Section 8.13).

An alert in the event that the participant is hospitalized.



Visit reminders.



Messages of thanks and encouragement from the study team.



A platform for recording local reactions and systemic events (reactogenicity e-diary) –see Section 8.2.2.

If a participant is not actively completing either the reactogenicity or COVID-19 illness
e-diary, the investigator or designee is required to contact the participant to ascertain why
and also to obtain details of any missed events.
9. STATISTICAL CONSIDERATIONS
Methodology for summary and statistical analyses of the data collected in this study is
described here and further detailed in a statistical analysis plan (SAP), which will bemaintained by the sponsor. The SAP may modify what is outlined in the protocol whereappropriate; however, any major modifications of the primary endpoint definitions or theiranalyses will also be reflected in a protocol amendment.
9.1. Estimands and Statistical Hypotheses
9.1.1. Estimands
The estimand corresponding to each primary, secondary, and tertiary/exploratory objective is
described in the table in Section 3.
In the primary safety objective evaluations, missing reactogenicity e-diary data will not be
imputed. Missing AE dates will be imputed according to Pfizer safety rules. No othermissing information will be imputed in the safety analysis.

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The estimands to evaluate the immunogenicity objectives are based on evaluable populations
for immunogenicity (Section 9.3). These estimands estimate the vaccine effect in the
hypothetical setting where participants follow the study schedules and protocol requirements
as directed. Missing antibody results will not be imputed. Immunogenicity results that are
below the LLOQ will be set to 0.5 × LLOQ in the analysis; this may be adjusted once
additional data on the assay characteristics become available.
The estimands to evaluate the efficacy objectives are based on evaluable populations for
efficacy (Section 9.3). These estimands estimate the vaccine effect in the hypotheticalsetting where participants follow the study schedules and protocol requirements as directed.
In addition, VE will be analyzed by all--available efficacy population. Missing laboratory
results will not be imputed for the primary analysis, but missing data imputation for theefficacy endpoint may be performed as a sensitivity analysis.

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9.1.2. Statistical Hypotheses
Phase 2/3 of the study has 2 primary efficacy endpoints evaluating VE, which is defined as
VE = 100 × (1 – IRR). IRR is calculated as the ratio of first confirmed COVID-19 illness ratein the vaccine group to the corresponding illness rate in the placebo group. In Phase 2/3, theassessment of VE will be based on posterior probabilities of VE1 > 30% and VE2 > 30%.
VE1 represents VE for prophylactic BNT162b2 against confirmed COVID-19 in participants
without evidence of infection before vaccination, and VE2 represents VE for prophylactic
BNT162b2 against confirmed COVID-19 in all participants after vaccination.
For participants with multiple confirmed cases, only the first case will contribute to the VE
calculation for each hypothesis. VE1 and VE2 will be evaluated sequentially to control theoverall type I error to the desired level of 2.5%. VE is demonstrated if there is sufficientevidence (posterior probability) that either VE1 >30% or both VE1 and VE2 are >30%. The
assessment for the primary analysis will be based on posterior probability using a Bayesianmodel.
9.2. Sample Size Determination
The study sample size for Phase 1 of the study is not based on any statistical hypothesis
testing. Phase 1 comprises 15 participants (randomization ratio of 4:1 so that 12 receive
active vaccine and 3 receive placebo) per group; 13 vaccine groups are studied,corresponding to a total of 195 participants.
For Phase 2/3, with assumptions of a true VE of 60% after the last dose of investigational
product, a total of approximately 164 first confirmed COVID-19 illness cases will provide
90% power to conclude true VE >30% with high probability, allowing early stopping for
efficacy at the IA. This would be achieved with 11,714 evaluable participants per group or
14,643 vaccine recipients randomized in a 1:1 ratio with placebo, for a total sample size of
29,286, based on the assumption of a 1.0% illness rate per year in the placebo group, and
20% of the participants being nonevaluable or having serological evidence of prior infection
with SARS-CoV-2, potentially making them immune to further infection. Dependent upon
the evolution of the pandemic, it is possible that the COVID-19 attack rate may be much
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higher, in which case accrual would be expected to be more rapid, enabling the study’s
primary endpoint to be evaluated much sooner. The total number of participants enrolled inPhase 2/3 may vary depending on the incidence of COVID-19 at the time of the enrollment,
the true underlying VE, and a potential early stop for efficacy or futility.
For safety outcomes, Table 4 shows the probability of observing at least 1 AE for a given
true event rate of a particular AE, for various sample sizes. For example, if the true AE rate
is 10%, with 12 participants in a vaccine group, there is 72% probability of observing at least
1 AE.

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Table 4.

Probability of Observing at Least 1 AE by Assumed True Event Rates
With Different Sample Sizes

Assumed True
Event Rate of
an AE
0.01%
0.02%
0.04%
0.06%
0.08%
0.10%
0.15%
0.20%
0.25%
0.30%
0.35%
0.50%
1.00%
2.00%
3.00%
5.00%
7.00%
10.00%

N=12

N=45

N=180

N=3000N=6000N=9000N=15000

0.00
0.00
0.00
0.01
0.01
0.01
0.02
0.02
0.03
0.04
0.04
0.06
0.11
0.22
0.31
0.46
0.58
0.72

0.00
0.01
0.02
0.03
0.04
0.04
0.07
0.09
0.11
0.13
0.15
0.20
0.36
0.60
0.75
0.90
0.96
0.99

0.02
0.04
0.07
0.10
0.13
0.16
0.24
0.30
0.36
0.42
0.47
0.59
0.84
0.97
>0.99
>0.99
>0.99
>0.99

0.26
0.45
0.70
0.83
0.91
0.95
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

0.45
0.70
0.91
0.97
0.99
0.99
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

0.59
0.83
0.97
0.99
0.99
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

0.78
0.95
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

9.3. Analysis Sets
For purposes of analysis, the following populations are defined:
Population
Enrolled
Randomized
Dose 1 evaluable
immunogenicity

Description
All participants who have a signed ICD.
All participants who are assigned a randomization number in
the IWR system.
All eligible randomized participants who receive the vaccine
to which they are randomly assigned at the first dose, have atleast 1 valid and determinate immunogenicity result 21 days
after Dose 1, have blood collection within an appropriate

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Population
Dose 2 evaluable
immunogenicity

Dose 1 all-available
immunogenicity
Dose 2 all-available
immunogenicity

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Evaluable efficacy

All-available efficacy

Description
window after Dose 1, and have no other major protocol
deviations as determined by the clinician.
All eligible randomized participants who receive 2 doses ofthe vaccine to which they are randomly assigned, within thepredefined window, have at least 1 valid and determinate
immunogenicity result after Dose 2, have blood collection
within an appropriate window after Dose 2, and have no othermajor protocol deviations as determined by the clinician.
All participants who receive at least 1 dose of the study
intervention with at least 1 valid and determinate
immunogenicity result after Dose 1 but before Dose 2.
All participants who receive at least 1 dose of the study
intervention with at least 1 valid and determinate
immunogenicity result after Dose 2.
All eligible randomized participants who receive all
vaccination(s) as randomized within the predefined window,
have the efficacy measurement after the last dose of study
intervention, and have no other major protocol deviations as
determined by the clinician. A major protocol deviation will
exclude a participant from the evaluable efficacy populationfrom the date that it occurs through the participant’s remaining
follow-up.
All eligible randomized participants who receive at least
1 vaccination and have the efficacy measurement at any timeafter Dose 1.
All eligible randomized participants who complete
2 vaccination doses and have the efficacy measurement at any
time after Dose 2.

SafetyAll randomized participants who receive at least 1 dose of thestudy intervention.

9.4. Statistical Analyses
The SAP will be developed and finalized before database lock for any of the planned
analyses in Section 9.5.1. It will describe the participant populations to be included in theanalyses and the procedures for accounting for missing, unused, and spurious data. Thissection provides a summary of the planned statistical analyses of the primary, secondary, andtertiary/exploratory endpoints.

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9.4.1. Immunogenicity Analyses
Immunogenicity samples will be drawn for all participants. Immunogenicity analyses will bebased upon results from appropriately sized subsets of samples, according to the purpose.
The statistical analysis of immunogenicity results will be primarily based on the evaluable
immunogenicity populations as defined in Section 9.3.
An additional analysis will be performed based on the all-available populations if there is alarge enough difference in sample size between the all-available immunogenicity populationand the evaluable immunogenicity population. Participants will be summarized according to
the vaccine group to which they were randomized.

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Endpoint
Secondaryimmunogenicity

Statistical Analysis Methods
Geometric mean titers/concentrations (GMTs/GMCs) of
SARS-CoV-2 serum neutralizing titers and SARS-CoV-2 anti-S1
binding antibody and anti-RBD binding antibody
For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2 anti-S1
binding antibody levels and anti-RBD binding antibody levels,
GMTs/GMCs and 2-sided 95% CIs will be provided for each
investigational product within each group before vaccination and ateach of the following time points:Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1, 6, 12
and 24 months after Dose 2

Geometric means will be calculated as the mean of the assay results
after making the logarithm transformation and then exponentiating themean to express results on the original scale. Two-sided 95% CIs will
be obtained by taking natural log transforms of concentrations/titers,
calculating the 95% CI with reference to the t-distribution, and thenexponentiating the confidence limits.
GMFRs of SARS-CoV-2 serum neutralizing titers and
SARS-CoV-2 anti-S1 binding antibody and anti-RBD binding
antibody
For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2 anti-S1
binding antibody levels and anti-RBD binding antibody levels, the
GMFRs and 2-sided 95% CIs will be provided for each investigational
product within each group at each of the following time points:Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1, 6, 12,
and 24 months after Dose 2

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Endpoint

Statistical Analysis Methods
GMFRs will be limited to participants with nonmissing values prior to
the first dose and at the postvaccination time point. The GMFR will becalculated as the mean of the difference of logarithmically transformed
assay results (later time point – earlier time point) and exponentiating
the mean. The associated 2-sided CIs will be obtained by calculating
CIs using Student’s t-distribution for the mean difference of thelogarithmically transformed assay results and exponentiating theconfidence limits.
Percentage of participants with ≥4-fold rise in SARS-CoV-2 serum
neutralizing titers and SARS-CoV-2 anti-S1 binding antibody andanti-RBD binding antibody

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2 anti-S1
binding antibody levels and anti-RBD binding antibody levels,
percentages (and 2-sided 95% CIs) of participants with ≥4-fold rise
will be provided for each investigational product within each group ateach of the following time points:Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1, 6, 12,
and 24 months after Dose 2

The Clopper-Pearson method will be used to calculate the CIs.
GMR of SARS-CoV-2 serum neutralizing titer to SARS-CoV-2
anti-S1 binding antibody and SARS-CoV-2 anti-RBD binding
antibody
For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2 anti-S1
binding antibody levels and anti-RBD binding antibody levels, theGMRs and 2-sided 95% CIs will be provided for each investigational
product within each group at each of the following time points:Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1, 6, 12,
and 24 months after Dose 2

GMRs will be limited to participants with nonmissing values for both
SARS-CoV-2 serum neutralizing titers and SARS-CoV-2 anti-S1
binding antibody/SARS-CoV-2 anti-RBD binding antibody at eachtime point. The GMR will be calculated as the mean of the differenceof logarithmically transformed assay results (eg, SARS-CoV-2 serum
neutralizing titers minus SARS-CoV-2 anti-S1 binding antibody foreach participant) and exponentiating the mean. Two-sided CIs will beobtained by calculating CIs using Student’s t-distribution for the mean
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Endpoint

Statistical Analysis Methods
difference of the logarithmically transformed assay results andexponentiating the confidence limits.
For all the immunogenicity endpoints, the analysis will be based on the
Dose 1 and Dose 2 evaluable immunogenicity populations. An
additional analysis will be performed based on the all-available
immunogenicity populations if there is a large enough difference insample size between the all-available immunogenicity populations andthe evaluable immunogenicity populations. Participants will besummarized according to the vaccine group to which they wererandomized. Missing serology data will not be imputed.

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Exploratory
immunogenicity

Geometric mean titers/concentrations (GMTs/GMCs) of SARSCoV-2 serum neutralizing titers and SARS-CoV-2 anti-S1 binding
antibody and anti-RBD binding antibody
For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2 anti-S1
binding antibody levels and anti-RBD binding antibody levels,
GMTs/GMCs and 2-sided 95% CIs will be provided for each
investigational product within each group before vaccination and ateach of the following time points in Phase 2/3:


1, 6, 12, and 24 months after completion of vaccination inparticipants with and without serological or virological evidence of
SARS-CoV-2 infection before vaccination

Geometric means will be calculated as the mean of the assay results
after making the logarithm transformation and then exponentiating themean to express results on the original scale. Two-sided 95% CIs will
be obtained by taking natural log transforms of concentrations/titers,
calculating the 95% CI with reference to the t-distribution, and thenexponentiating the confidence limits.
GMFRs of SARS-CoV-2 serum neutralizing titers and SARS-CoV2 anti-S1 binding antibody and anti-RBD binding antibody
For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2 anti-S1
binding antibody levels and anti-RBD binding antibody levels, the
GMFRs and 2-sided 95% CIs will be provided for each investigational
product within each group at each of the following time points in Phase
2/3:

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Endpoint

Statistical Analysis Methods
1, 6, 12, and 24 months after completion of vaccination inparticipants with and without serological or virologicalevidence of SARS-CoV-2 infection before vaccination

GMFRs will be limited to participants with nonmissing values prior to
the first dose and at the postvaccination time point. The GMFR will becalculated as the mean of the difference of logarithmically transformed
assay results (later time point – earlier time point) and exponentiating
the mean. The associated 2-sided CIs will be obtained by calculating
CIs using Student’s t-distribution for the mean difference of thelogarithmically transformed assay results and exponentiating theconfidence limits.

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Percentage of participants with antibody levels ≥ predefined
threshold(s) for SARS-CoV-2 serological parameters
For SARS-CoV-2 serum neutralizing titers, SARS-CoV-2 anti-S1
binding antibody levels and/or anti-RBD binding antibody levels,
SARS-CoV-2 NVA-specific binding antibody, and SARS-CoV-2
detection by NAAT, percentages (and 2-sided 95% CIs) of participants
with antibody levels ≥ predefined threshold(s) will be provided foreach investigational product within each group at baseline and each of
the following time points in Phase 2/3:


1, 6, 12, and 24 months after completion of vaccination inparticipants with and without serological or virological evidence of
SARS-CoV-2 infection before vaccination

The Clopper-Pearson method will be used to calculate the CIs.
Percentage of participants with the immune response (non-S) to
SARS-CoV-2 for SARS-CoV-2 NVA-specific binding antibody at
the time points when data are available
The Clopper-Pearson method will be used to calculate the CIs.
For all of the immunogenicity endpoints, the analysis will be based on
the Dose 1 and Dose 2 evaluable immunogenicity populations. An
additional analysis will be performed based on the all-available
immunogenicity populations if there is a large enough difference insample size between the all-available immunogenicity populations andthe evaluable immunogenicity populations. Participants will besummarized according to the vaccine group to which they wererandomized. Missing serology data will not be imputed.
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Endpoint

Statistical Analysis Methods
RCDCs for immunogenicity results
Empirical RCDCs will be provided for SARS-CoV-2 serum
neutralizing titers, SARS-CoV-2 S1-specific binding antibody, andRBD-specific binding antibody after Dose 1 and after Dose 2.

9.4.2. Efficacy Analyses
The statistical analysis of efficacy will be based on the evaluable efficacy population(primary analysis) and the all-available efficacy population as defined in Section 9.3.

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Endpoint
Primary efficacy

Statistical Analysis Methods
Ratio of confirmed COVID-19 illness per 1000 person-years offollow-up in participants without evidence of infection before
vaccination for the active vaccine group to the placebo group
VE will be estimated by 100 × (1 – IRR), where IRR is the calculated
ratio of confirmed COVID-19 illness per 1000 person-years follow-up
in the active vaccine group to the corresponding illness rate in theplacebo group 7 days after the last dose. VE will be analyzed using abeta-binomial model.
After the above objective is met, the second primary endpoint will be
evaluated as below.
Ratio of confirmed COVID-19 illness per 1000 person-years offollow-up in participants with and without evidence of infection
before vaccination for the active vaccine group to the placebogroup
VE will be estimated by 100 × (1 – IRR), where IRR is the calculated
ratio of confirmed COVID-19 illness per 1000 person-years follow-up
in the active vaccine group to the corresponding illness rate in theplacebo group after 7 days after the last dose. VE will be analyzed
using a beta-binomial model.
The efficacy analysis for the first primary objective evaluation will bebased on the participants without evidence of infection before
vaccination and included in the evaluable efficacy population and in
the all-available efficacy population.

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Endpoint

Statistical Analysis Methods
The efficacy analysis for the second primary objective evaluation will
be based on all participants included in the evaluable efficacy
population and in the all-available efficacy population.
For the primary endpoint analysis, missing efficacy data will not be
imputed. A sensitivity analysis will be performed by imputing missing
values; details will be provided in the SAP.

Secondary

Ratio of confirmed severe COVID-19 illness per 1000 person-years
of follow-up in participants without evidence of infection before
vaccination for the active vaccine group to the placebo group

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Ratio of confirmed severe COVID-19 illness per 1000 person-years
of follow-up for the active vaccine group to the placebo group
These secondary efficacy objectives will be evaluated after the primaryobjectives are met. The analysis will be based on the evaluable efficacy
population and the all-available efficacy population. The analysis
methodology used for the primary efficacy endpoints will be applied
for the analysis of the above secondary efficacy endpoints.
The following secondary efficacy endpoints will be evaluateddescriptively with 95% CIs.
Ratio of confirmed COVID-19 illness (according to the
CDC-defined symptoms) per 1000 person-years of follow-up inparticipants without evidence of infection before vaccination for
the active vaccine group to the placebo group
Ratio of confirmed COVID-19 illness (according to the
CDC-defined symptoms) per 1000 person-years of follow-up inparticipants with and without evidence of infection before
vaccination for the active vaccine group to the placebo group
VE = 100 × (1 – IRR) will be estimated with confirmed COVID-19
illness according to the CDC-defined symptoms after 7 days after thelast dose. The 2-sided 95% CI for VE will be derived using the
Clopper-Pearson method as described by Agresti.9
Missing efficacy data will not be imputed.

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9.4.3. Safety Analyses
Endpoint
Primary

Statistical Analysis Methods
Descriptive statistics will be provided for each reactogenicity endpoint
for each dose and vaccine group. Local reactions and systemic eventsfrom Day 1 through Day 7 after each vaccination will be presented byseverity cumulatively across severity levels. Descriptive summary
statistics will include counts and percentages of participants with theindicated endpoint and the associated Clopper-Pearson 95% CIs.

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)For Phase 1, descriptive statistics will be provided for abnormal
hematology and chemistry laboratory values at 1 and 7 days after
Dose 1 and 7 days after Dose 2, including grading shifts inhematology and chemistry laboratory assessments between baseline
and 1 and 7 days after Dose 1, and before Dose 2 and 7 days after
Dose 2. Descriptive summary statistics will include counts andpercentages of participants with the indicated endpoint and theassociated Clopper-Pearson 2-sided 95% CIs.
AEs will be categorized according to the Medical Dictionary forRegulatory Activities (MedDRA) terms. A 3-tier approach will be
used to summarize AEs in Phase 2/3. Under this approach AEs areclassified into 1 of 3 tiers: (1) Tier 1 events are prespecified events ofclinical importance and are identified in a list in the product’s safety
review plan; (2) Tier 2 events are those that are not Tier 1 but areconsidered “relatively common”; a MedDRA preferred term is defined
as a Tier 2 event if there are at least 1% of participants in at least 1
vaccine group reporting the event; and (3) Tier 3 events are those thatare neither Tier 1 nor Tier 2 events. For both Tier 1 and Tier 2 events,
2-sided 95% CIs for the difference between the vaccine and placebogroups in the percentage of participants reporting the events based on
the Miettinen and Nurminen method10 will be provided. In addition,
for Tier 1 events, the asymptotic p-values will also be presented forthe difference between groups in the percentage of participants
reporting the events, based on the same test statistic and under theassumption that the test statistic is asymptotically normally
distributed.
Descriptive summary statistics (counts, percentages, and associatedClopper-Pearson 95% CIs) will be provided for any AE events foreach vaccine group.
SAEs will be categorized according to MedDRA terms. Counts,
percentages, and the associated Clopper-Pearson 95% CIs of SAEs

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Endpoint

Statistical Analysis Methods
from Dose 1 to 6 months after last dose will be provided for eachvaccine group.
The safety analyses are based on the safety population. Participants
will be summarized by vaccine group according to the investigational
products they actually received. Missing reactogenicity e-diary data
will not be imputed; missing AE dates will be handled according to
the Pfizer safety rules.

SecondaryNot applicable (N/A)

Exploratory

N/A

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9.4.4. Other Analyses
The ratios of (GMFR A to GMFR B) and (GMFR A to GMFR C) may be explored, where
GMFR A is the geometric mean of the ratio of the SARS-CoV-2 serum neutralizing titer at
the postvaccination time point to the corresponding titer at the prevaccination time point,
GFMR B is the geometric mean of the ratio of the SARS-CoV-2 S1-specific binding
antibody level at the postvaccination time point to the corresponding antibody level at theprevaccination time point, and GMFR C is the geometric mean of the ratio of the
SARS-CoV-2 RBD-specific binding antibody level at the postvaccination time point to thecorresponding antibody level at the prevaccination time point.
9.5. Interim Analyses
As this is a sponsor open-label study during Phase 1, the sponsor may conduct unblinded
reviews of the data during the course of the study for the purpose of safety assessment,
facilitating dose escalation decisions, and/or supporting clinical development.
During Phase 2/3, 4 IAs are planned and will be performed by an unblinded statistical teamafter accrual of 32, 62, 92, and 120 cases. At each IA:

VE for the first primary objective will be evaluated . Overwhelming efficacy will bedeclared if the first primary study objective is met. The criteria for success at an interim
analysis are based on the posterior probability (ie, P[VE >30%|data]) at the current
number of cases. Overwhelming efficacy will be declared if the posterior probability ishigher than the success threshold. The success threshold for each interim analysis will becalibrated to protect overall type I error at 2.5%. Additional details about the successthreshold or boundary calculation at each interim analysis will be provided in the SAP.

The study will stop for lack of benefit (futility) if the predicted probability of success at
the final analysis or study success is <5%. The posterior predictive POS will becalculated using a beta-binomial model. The futility assessment will be performed for the
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first primary endpoint and the futility boundary may be subject to change to reflectsubsequent program-related decisions by the sponsor.
Efficacy and futility boundaries will be applied in a nonbinding way.

Bayesian approaches require specification of a prior distribution for the possible values of theunknown vaccine effect, thereby accounting for uncertainty in its value. A minimally
informative beta prior, beta (0.700102, 1), is proposed for θ = (1-VE)/(2-VE). The prior iscentered at θ = 0.4118 (VE=30%) which can be considered pessimistic. The prior allows
considerable uncertainty; the 95% interval for θ is (0.005, 0.964) and the corresponding 95%
interval for VE is (-26.2, 0.995).
Table 5 illustrates the boundary for efficacy and futility if IAs are performed after accrual of
32 62, 92, and 120 cases in participants without evidence of infection before vaccination.
Table 5.

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AnalysisInterim Analysis Plan and Boundaries for Efficacy and Futility
Number of
Cases

Success Criteriaa

Futility Boundary

VE Point Estimate
VE Point Estimate(Case Split)(Case Split)
IA1
32
76.9% (6:26)
11.8% (15:17)
IA2
6268.1% (15:47)
27.8% (26:36)
IA3
92
62.7% (25:67)
38.6% (35:57)
IA4120
58.8% (35:85)
N/A
Final
164
52.3% (53:111)
Abbreviations: IA = interim analysis; N/A = not applicable; VE = vaccine efficacy.
Note: Case split = vaccine : placebo.
a. Interim efficacy claim: P(VE >30%|data) > 0.995; success at the final analysis: P(VE >30%|data)> 0.986.

Additional design operating characteristics (the boundary based on the number of cases
observed in the vaccine group; the probabilities for efficacy and futility given assumed
various VEs with a 1:1 randomization ratio) are listed in Table 6 and Table 7.

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Table 6.

Statistical Design Operating Characteristics: Probability of Success or
Failure for Interim Analyses

VaccineEfficacy(%)

Interim Analysis 1(Total Cases = 32)

30
50
60
70
80

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Table 7.

Probabilityof Success(Cases in
VaccineGroup ≤6)
0.006
0.054
0.150
0.368
0.722

Probabilityof Failure(Cases in
VaccineGroup ≥15)
0.315
0.078
0.021
0.003
<0.001

Interim Analysis 2(Total Cases = 62)
Probabilityof Success(Cases in
VaccineGroup ≤15)
0.003
0.051
0.160
0.310
0.238

Probabilityof Failure(Cases in
VaccineGroup ≥26)
0.231
0.056
0.010
<0.001<0.001

Interim Analysis 3(Total Cases = 92)
Probabilityof Success(Cases in
VaccineGroup ≤25)
0.002
0.063
0.175
0.195
0.037

Probabilityof Failure(Cases in
VaccineGroup ≥35)
0.239
0.103
0.019
0.001
<0.001

InterimAnalysis 4(Total Cases= 120)
Probability of
Success(CasesVaccineGroup ≤35)
0.002
0.075
0.160
0.085
0.003

Statistical Design Operating Characteristics: Probability of Success for
Final Analysis and Overall

Vaccine Efficacy (%)

30
50
60
70
80

Final Analysis(Total Cases = 164)
Probability of Success (Cases in Vaccine
Group ≤53)
0.007
0.196
0.220
0.036
<0.001

Overall Probability of Success

0.021
0.439
0.866
>0.999>0.999If neither success nor futility has been declared after all IAs, the final analysis will be
performed and the first primary objective will have been met if there are 53 or fewer cases
observed in the vaccine group out of a total of 164 first confirmed cases from 7 days after
receipt of the last dose of investigational product onwards.
After the primary objectives are met, the secondary VE endpoints (confirmed severe
COVID-19 in participants without evidence of infection before vaccination and confirmed
severe COVID-19 in all participants) will be evaluated sequentially, by the same method
used for the primary VE endpoint evaluation. Success thresholds for secondary VE will beappropriately chosen to control overall Type I error at 2.5%. Further details will be provided
in the SAP. The remaining secondary VE endpoints will be evaluated descriptively to
calculate the observed VE with 95% CIs.

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9.5.1. Analysis Timing

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Statistical analyses will be carried out when the following data are available:Complete safety and immunogenicity analysis approximately 1 month after Dose 2 forPhase 1.



Safety data through 7 days after Dose 2 and immunogenicity data through 1 month after
Dose 2 from the first 360 participants enrolled (180 to active vaccine and 180 to placebo)in Phase 2/3.



Safety and immunogenicity data through 1 month after Dose 2 from the first 6000
participants enrolled (3000 to active vaccine and 3000 to placebo) in Phase 2/3.



IAs for efficacy at 32, 62, 92, and 120 cases and futility at 32, 62, and 92 cases.

Complete safety and immunogenicity analysis approximately 6 months after Dose 2 for
all participants in Phase 2/3.

Complete efficacy and persistence-of-immunogenicity analysis after complete data are
available at the end of the study.

All analyses conducted on Phase 2/3 data while the study is ongoing will be performed by an
unblinded statistical team.
9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will use an IRC, a DMC, and a group of internal case reviewers. The IRC is
independent of the study team and includes only internal members. The DMC is independentof the study team and includes only external members. The IRC and DMC charters describe
the role of the IRC and DMC in more detail.
The responsibilities of the IRC are only in Phase 1 and will include:

Review of safety data to permit dose escalations in the 18- to 55-year age cohort



Review of safety data in the case of a stopping rule being met

Review of safety and/or immunogenicity data to:Allow groups of participants of 65 to 85 years of age to proceed

Select vaccine candidate/dose level(s) to proceed into Phase 2/3. Data supporting theselection, including results for both binding antibody levels and serum neutralizing
titers, and the ratio between them, will also be submitted to the FDA for review

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

Review of any available safety and/or immunogenicity data generated during the courseof this study, or the BioNTech study conducted in Germany, to determine:Whether any groups may not be started



Whether any groups may be terminated earlyWhether any groups may be added with dose levels below the lowest stated dose orintermediate between the lowest and highest stated doses

Contemporaneous review of all NAAT-confirmed COVID-19 illnesses in Phase 1090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)The DMC will be responsible for ongoing monitoring of the safety of participants in the
study according to the charter. This may include, but is not limited to:Contemporaneous review of related AEs up to 1 month after completion of thevaccination scheduleContemporaneous review of all SAEs up to 6 months after completion of the vaccination
schedule

Contemporaneous review of all NAAT-confirmed COVID-19 illnesses in Phase 1

At the time of the planned IAs, and ad hoc if requested by the unblinded team, review ofcases of COVID-19 for an adverse imbalance of cases of COVID-19 and/or severe
COVID-19 between the vaccine and placebo groups

The recommendations made by the DMC to alter the conduct of the study will be forwarded
to the appropriate Pfizer personnel for final decision. Pfizer will forward such decisions,which may include summaries of aggregate analyses of safety data, to regulatory authorities,
as appropriate.
Three blinded case reviewers (medically qualified Pfizer staff members) will review all
potential COVID-19 illness events. If a NAAT-confirmed case in Phase 2/3 may beconsidered severe, or not, solely on the basis of “significant acute renal, hepatic, orneurologic dysfunction,” the blinded data will be reviewed by the case reviewers to assess
whether the criterion is met; the majority opinion will prevail.

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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:Consensus ethical principles derived from international guidelines including the
Declaration of Helsinki and CIOMS International Ethical Guidelines;Applicable ICH GCP guidelines;Applicable laws and regulations, including applicable privacy laws.

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents(eg, advertisements) must be reviewed and approved by the sponsor and submitted to an
IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study is
initiated.
Any amendments to the protocol will require IRB/EC approval before implementation ofchanges made to the study design, except for changes necessary to eliminate an immediate
hazard to study participants.
The investigator will be responsible for the following:Providing written summaries of the status of the study to the IRB/EC annually or more
frequently in accordance with the requirements, policies, and procedures established by
the IRB/EC;



Notifying the IRB/EC of SAEs or other significant safety findings as required by IRB/EC
procedures;Providing oversight of the conduct of the study at the site and adherence to requirementsof 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014 for clinicalstudies (if applicable), and all other applicable local regulations.

10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicableregulatory authority in any area of the world, or if the investigator is aware of any new
information that might influence the evaluation of the benefits and risks of the study
intervention, Pfizer should be informed immediately.
In addition, the investigator will inform Pfizer immediately of any urgent safety measurestaken by the investigator to protect the study participants against any immediate hazard, andof any serious breaches of this protocol or of ICH GCP that the investigator becomes awareof.
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10.1.2. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to theparticipant and answer all questions regarding the study. The participant should be given
sufficient time and opportunity to ask questions and to decide whether or not to participate in
the trial.
Participants must be informed that their participation is voluntary. Participants will be
required to sign a statement of informed consent that meets the requirements of 21 CFR 50,
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/EC
or study center.
The investigator must ensure that each study participant is fully informed about the natureand objectives of the study, the sharing of data related to the study, and possible risks
associated with participation, including the risks associated with the processing of theparticipant’s personal data.

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)The participant must be informed that his/her personal study-related data will be used by thesponsor in accordance with local data protection law. The level of disclosure must also be
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical
Quality Assurance auditors or other authorized personnel appointed by the sponsor, byappropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or
her right to access and correct his or her personal data and to withdraw consent for theprocessing of his or her personal data.
The medical record must include a statement that written informed consent was obtained
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their
participation in the study.
A copy of the ICD(s) must be provided to the participant. Participants who are rescreened are
required to sign a new ICD.
Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate
section that addresses the use of samples for optional additional research. The optional
additional research does not require the collection of any further samples. The investigator
or authorized designee will explain to each participant the objectives of the additional
research. Participants will be told that they are free to refuse to participate and may
withdraw their consent at any time and for any reason during the storage period.

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10.1.3. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementationof organizational and technical measures to ensure protection of participant data.

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Participants’ personal data will be stored at the study site in encrypted electronic and/or paper
form and will be password protected or secured in a locked room to ensure that only
authorized study staff have access. The study site will implement appropriate technical andorganizational measures to ensure that the personal data can be recovered in the event ofdisaster. In the event of a potential personal data breach, the study site will be responsiblefor determining whether a personal data breach has in fact occurred and, if so, providing
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personaldata, participants will be assigned a single, participant-specific numerical code. Any
participant records or data sets that are transferred to the sponsor will contain the numericalcode; participant names will not be transferred. All other identifiable data transferred to thesponsor will be identified by this single, participant-specific code. The study site will
maintain a confidential list of participants who participated in the study, linking eachparticipant’s numerical code to his or her actual identity and medical record identification. In
case of data transfer, the sponsor will protect the confidentiality of participants’ personal dataconsistent with the clinical study agreement and applicable privacy laws.
10.1.4. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting theresults of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or
www.pfizer.com, and other public registries in accordance with applicable local
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, andcomplete manner and are reported regardless of the outcome of the study or the country inwhich the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional
studies (conducted in patients) that evaluate the safety and/or efficacy of a product,
regardless of the geographical location in which the study is conducted. These results are
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies inaccordance with the format and timelines set forth by EU requirements.

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www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used
to identify individual participants have been removed) on www.pfizer.com for
Pfizer-sponsored interventional studies at the same time the corresponding study results areposted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinicaldata to the EMA website. Clinical data, under Phase 1 of this policy, includes clinicaloverviews, clinical summaries, CSRs, and appendices containing the protocol and protocol
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of thispolicy, includes the publishing of individual participant data. Policy 0070 applies to newmarketing authorization applications submitted via the centralized procedure since
01 January 2015 and applications for line extensions and for new indications submitted via
the centralized procedure since 01 July 2015.

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Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposesof “bona-fide scientific research” that contributes to the scientific understanding of thedisease, target, or compound class. Pfizer will make available data from these trials
24 months after study completion. Patient-level data will be anonymized in accordance withapplicable privacy laws and regulations. CSRs will have personally identifiable information
redacted.
Data requests are considered from qualified researchers with the appropriate competencies toperform the proposed analyses. Research teams must include a biostatistician. Data will not
be provided to applicants with significant conflicts of interest, including individuals
requesting access for commercial/competitive or legal purposes.
10.1.5. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unlesstransmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is
responsible for verifying that data entries are accurate and correct by physically orelectronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports theinformation entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted
electronic and/or paper form and are password protected or secured in a locked room toprevent access by unauthorized third parties.

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The investigator must permit study-related monitoring, audits, IRB/EC review, andregulatory agency inspections and provide direct access to source data documents. This
verification may also occur after study completion. It is important that the investigator(s)and their relevant personnel are available during the monitoring visits and possible audits orinspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality
such as risk management and mitigation strategies and analytical risk-based monitoring),
methods, responsibilities, and requirements, including handling of noncompliance issues andmonitoring techniques (central, remote, or on-site monitoring), are provided in themonitoring plan.

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)The sponsor or designee is responsible for the data management of this study, including
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data enteredinto the CRF by authorized site personnel are accurate, complete, and verifiable from source
documents; that the safety and rights of participants are being protected; and that the study is
being conducted in accordance with the currently approved protocol and any other study
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must
be retained by the investigator for 15 years after study completion unless local regulations or
institutional policies require a longer retention period. No records may be destroyed during
the retention period without the written approval of the sponsor. No records may betransferred to another location or party without written notification to the sponsor. The
investigator must ensure that the records continue to be stored securely for as long as they are
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of suchdata are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory
inspection notification in relation to the study. Furthermore, the investigator will cooperatewith the sponsor or its agents to prepare the investigator site for the inspection and will allow
the sponsor or its agent, whenever feasible, to be present during the inspection. The
investigator site and investigator will promptly resolve any discrepancies that are identified
between the study data and the participant's medical records. The investigator will promptly
provide copies of the inspection findings to the sponsor or its agent. Before response
submission to the regulatory authorities, the investigator will provide the sponsor or its
agents with an opportunity to review and comment on responses to any such findings.

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10.1.6. Source Documents
Source documents provide evidence for the existence of the participant and substantiate theintegrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be
consistent with the source documents or the discrepancies must be explained. The
investigator may need to request previous medical records or transfer records, depending on
the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the study monitoring plan.
Description of the use of computerized system is documented in the Data Management Plan.
10.1.7. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment ofparticipants.

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)The first act of recruitment is the date of the first participant’s first visit and will be the study
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any
time for any reason at the sole discretion of the sponsor. Study sites will be closed uponstudy completion. A study site is considered closed when all required documents and study
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor
or designee if requested to do so by the responsible IRB/EC or if such termination is required
to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limitedto:

Failure of the investigator to comply with the protocol, the requirements of the IRB/EC
or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.

If the study is prematurely terminated or suspended, the sponsor shall promptly inform theinvestigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of
the reason for termination or suspension, as specified by the applicable regulatory
requirements. The investigator shall promptly inform the participant and should assure
appropriate participant therapy and/or follow-up.

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Study termination is also provided for in the clinical study agreement. If there is any conflict
between the contract and this protocol, the contract will control as to termination rights.
10.1.8. Sponsor’s Qualified Medical Personnel

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)The contact information for the sponsor's appropriately qualified medical personnel for the
study is documented in the study contact list located in the supporting study documentation.
To facilitate access to appropriately qualified medical personnel on study-related medical
questions or problems, participants are provided with a contact card at the time of informed
consent. The contact card contains, at a minimum, protocol and study intervention
identifiers, participant numbers, contact information for the investigator site, and contact
details for a contact center in the event that the investigator site staff cannot be reached toprovide advice on a medical question or problem originating from another healthcare
professional not involved in the participant’s participation in the study. The contact number
can also be used by investigator staff if they are seeking advice on medical questions or
problems; however, it should be used only in the event that the established communication
pathways between the investigator site and the study team are not available. It is therefore
intended to augment, but not replace, the established communication pathways between theinvestigator site and the study team for advice on medical questions or problems that may
arise during the study. The contact number is not intended for use by the participant directly,
and if a participant calls that number, he or she will be directed back to the investigator site.

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10.2. Appendix 2: Clinical Laboratory Tests

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)The following safety laboratory tests will be performed at times defined in the SoA section ofthis protocol. Additional laboratory results may be reported on these samples as a result of
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived
from calculated values. These additional tests would not require additional collection ofblood. Unscheduled clinical laboratory measurements may be obtained at any time during
the study to assess any perceived safety issues.
Hematology
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet countWBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)Basophils (Abs)
Lymphocytes (Abs)

Chemistry
BUN and creatinine
AST, ALT
Total bilirubin
Alkaline phosphatase

Other Urine pregnancy test (β-hCG)
At screening only: Hepatitis B core antibody
 Hepatitis B surface antigen
 Hepatitis C antibody
 Human immunodeficiency virus

Investigators must document their review of each laboratory safety report.
Clinically significant abnormal laboratory findings should be recorded in the AE CRF in
accordance with the following grading scale (Table 8).
Table 8.

Laboratory Abnormality Grading Scale

Hematology

Mild (Grade 1)

Hemoglobin
11.0 – 12.0
(Female) - g/dL
Hemoglobin
12.5 – 13.5
(Male) - g/dL
WBC increase 10,800 – 15,000
cells/mm3
WBC decrease 2,500 – 3,500
cells/mm3
Lymphocytes
750 – 1,000
decrease - cells/mm3
Neutrophils decrease 1,500 – 2,000- cells/mm3
Eosinophils 650 – 1500
cells/mm3
Platelets decreased - 125,000 – 140,000
cells/mm3

Moderate(Grade 2)

Severe (Grade 3)

9.5 – 10.9

8.0 – 9.4

Potentially Life
Threatening(Grade 4)<8.0

10.5 – 12.4

8.5 – 10.4

<8.5

15,001 – 20,000

20,001 – 25, 000>25,000

1,500 – 2,499

1,000 – 1,499<1,000500 – 749

250 – 499

<250

1,000 – 1,499

500 – 999

<500

1501 - 5000

>5000

Hypereosinophilic

100,000 – 124,000

25,000 – 99,000<25,000

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Table 8.

Laboratory Abnormality Grading Scale

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Chemistry

Mild (Grade 1)

Moderate(Grade 2)

Severe(Grade 3)

BUN - mg/dL
Creatinine – mg/dL

23 – 26
1.5 – 1.7

27 – 31
1.8 – 2.0> 31
2.1 – 2.5

Alkaline
phosphate –increase by factor
Liver function tests– ALT, AST
increase by factor
Bilirubin – whenaccompanied
by any increase inliver function test increase by factor
Bilirubin – whenliver function test is
normal - increase byfactor

1.1 – 2.0 x ULN

2.1 – 3.0 x ULN

3.1 – 10 x ULN

Potentially Life
Threatening(Grade 4)
Requires dialysis> 2.5 or requires
dialysis>10 x ULN

1.1 – 2.5 x ULN

2.6 – 5.0 x ULN

5.1 – 10 x ULN>10 x ULN

1.1 – 1.25 x ULN

1.26 – 1.5 x ULN

1.51 – 1.75 x ULN>1.75 x ULN

1.1 – 1.5 x ULN

1.6 – 2.0 x ULN

2.0 – 3.0 x ULN>3.0 x ULN

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen;
ULN = upper limit of normal; WBC = white blood cell.

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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition


An AE is any untoward medical occurrence in a patient or clinical study participant,temporally associated with the use of study intervention, whether or not consideredrelated to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including anabnormal laboratory finding), symptom, or disease (new or exacerbated) temporally
associated with the use of study intervention.

Events Meeting the AE Definition

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Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis)or other safety assessments (eg, ECG, radiological scans, vital sign measurements),
including those that worsen from baseline, considered clinically significant in the
medical and scientific judgment of the investigator Any abnormal laboratory test
results that meet any of the conditions below must be recorded as an AE:
Is associated with accompanying symptoms.



Requires additional diagnostic testing or medical/surgical intervention.



Leads to a change in study dosing (outside of any protocol-specified dose
adjustments) or discontinuation from the study, significant additional
concomitant drug treatment, or other therapy.



Exacerbation of a chronic or intermittent preexisting condition including either anincrease in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration eventhough it may have been present before the start of the study.



Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.



Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
intervention or a concomitant medication. Overdose per se will not be reported as
an AE/SAE unless it is an intentional overdose taken with possible suicidal/selfharming intent. Such overdoses should be reported regardless of sequelae.

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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safetyassessments which are associated with the underlying disease, unless judged by theinvestigator to be more severe than expected for the participant’s condition.



The disease/disorder being studied or expected progression, signs, or symptoms ofthe disease/disorder being studied, unless more severe than expected for theparticipant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).



Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present
or detected at the start of the study that do not worsen.

10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:a. Results in deathb. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which theparticipant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.
c. Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving
at least an overnight stay) at the hospital or emergency ward for observation and/or
treatment that would not have been appropriate in the physician’s office or outpatientsetting. Complications that occur during hospitalization are AEs. If a complication
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in
doubt as to whether “hospitalization” occurred or was necessary, the AE should beconsidered serious.
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Hospitalization for elective treatment of a preexisting condition that did not worsen frombaseline is not considered an AE.
d. Results in persistent disability/incapacity


The term disability means a substantial disruption of a person’s ability to conduct
normal life functions.

This definition is not intended to include experiences of relatively minor medicalsignificance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza,
and accidental trauma (eg, sprained ankle) which may interfere with or prevent
everyday life functions but do not constitute a substantial disruption.

e. Is a congenital anomaly/birth defect090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)

f. Other situations:Medical or scientific judgment should be exercised in deciding whether SAE
reporting is appropriate in other situations such as important medical events that
may not be immediately life-threatening or result in death or hospitalization but may
jeopardize the participant or may require medical or surgical intervention to prevent
one of the other outcomes listed in the above definition. These events should
usually be considered serious.



Examples of such events include invasive or malignant cancers, intensive treatment
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or
convulsions that do not result in hospitalization, or development of drug dependency
or drug abuse.

Suspected transmission via a Pfizer product of an infectious agent, pathogenic or
nonpathogenic, is considered serious. The event may be suspected from clinicalsymptoms or laboratory findings indicating an infection in a patient exposed to a
Pfizer product. The terms “suspected transmission” and “transmission” areconsidered synonymous. These cases are considered unexpected and handled asserious expedited cases by pharmacovigilance personnel. Such cases are also
considered for reporting as product defects, if appropriate.

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10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF andfor reporting serious adverse events on the Vaccines SAE Report Form to Pfizer Safety.
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious adverse
events (AEs); and (3) exposure to the study intervention under study during pregnancy orbreastfeeding, and occupational exposure.

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)It should be noted that the Vaccines SAE Report Form for reporting of SAE information is
not the same as the AE page of the CRF. When the same data are collected, the forms must
be completed in a consistent manner. AEs should be recorded using concise medical
terminology and the same AE term should be used on both the CRF and the Vaccines SAE
Report Form for reporting of SAE information.
Safety Event

Recorded on the CRF

SAE
Nonserious AE
Exposure to the study
intervention under study
during pregnancy orbreastfeeding, andoccupational exposure

All
All
All AEs/SAEs associatedwith exposure during
pregnancy or breastfeeding

Reported on the Vaccines
SAE Report Form to
Pfizer Safety Within 24
Hours of Awareness

All
None
All (and EDP supplemental
form for EDP)
Note: Include all SAEs
associated with exposure
Occupational exposure is not during pregnancy orbreastfeeding. Include allrecorded.
AEs/SAEs associated withoccupational exposure.

When an AE/SAE occurs, it is the responsibility of the investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostic
reports) related to the event.



The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s
medical records to Pfizer Safety in lieu of completion of the Vaccines SAE Report
Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases arerequested by Pfizer Safety. In this case, all participant identifiers, with the
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exception of the participant number, will be redacted on the copies of the medical
records before submission to Pfizer Safety.


The investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. Whenever possible, the diagnosis(not the individual signs/symptoms) will be documented as the AE/SAE.

Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during
the study and assign it to 1 of the following categories:

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)GRADE If required on the AE page of the CRF, the investigator will use theadjectives MILD, MODERATE, SEVERE, or LIFE-THREATENING todescribe the maximum intensity of the AE. For purposes of consistency,
these intensity grades are defined as follows:
1

MILD

Does not interfere with participant's usualfunction.

2

MODERATE

Interferes to some extent with participant's usualfunction.

3

SEVEREInterferes significantly with participant's usualfunction.

4

LIFE-THREATENING Life-threatening consequences; urgent
intervention indicated.

Assessment of Causality

The investigator is obligated to assess the relationship between study intervention
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence,
and/or arguments to suggest a causal relationship, rather than a relationship cannot
be ruled out.

The investigator will use clinical judgment to determine the relationship.



Alternative causes, such as underlying disease(s), concomitant therapy, and otherrisk factors, as well as the temporal relationship of the event to study intervention
administration, will be considered and investigated.

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The investigator will also consult the IB and/or product information, for marketed
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she
has reviewed the AE/SAE and has provided an assessment of causality.



There may be situations in which an SAE has occurred and the investigator has
minimal information to include in the initial report to the sponsor. However, it isvery important that the investigator always make an assessment of causality forevery event before the initial transmission of the SAE data to the sponsor.



The investigator may change his/her opinion of causality in light of follow-up
information and send an SAE follow-up report with the updated causality
assessment.



The causality assessment is one of the criteria used when determining regulatory
reporting requirements.



If the investigator does not know whether or not the study intervention caused theevent, then the event will be handled as “related to study intervention” for reporting
purposes, as defined by the sponsor. In addition, if the investigator determines thatan SAE is associated with study procedures, the investigator must record this causal
relationship in the source documents and CRF, and report such an assessment in the
dedicated section of the Vaccines SAE Report Form and in accordance with the
SAE reporting requirements.

Follow-up of AEs and SAEs


The investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by thesponsor to elucidate the nature and/or causality of the AE or SAE as fully as
possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other healthcare providers.



If a participant dies during participation in the study or during a recognizedfollow-up period, the investigator will provide Pfizer Safety with a copy of any
postmortem findings including histopathology.



New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours ofreceipt of the information.

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10.3.4. Reporting of SAEs

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SAE Reporting to Pfizer Safety via Vaccines SAE Report Form

Facsimile transmission of the Vaccines SAE Report Form is the preferred method totransmit this information to Pfizer Safety.



In circumstances when the facsimile is not working, notification by telephone isacceptable with a copy of the Vaccines SAE Report Form sent by overnight mail orcourier service.

Initial notification via telephone does not replace the need for the investigator tocomplete and sign the Vaccines SAE Report Form pages within the designatedreporting time frames.

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10.4. Appendix 4: Contraceptive Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during
the intervention period and for at least 28 days after the last dose of study intervention, whichcorresponds to the time needed to eliminate reproductive safety risk of the study
intervention(s):Refrain from donating sperm.

PLUS either:Be abstinent from heterosexual intercourse with a female of childbearing potential as
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) andagree to remain abstinent.

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)OR

Must agree to use a male condom when engaging in any activity that allows for passageof ejaculate to another person.



In addition to male condom use, a highly effective method of contraception may beconsidered in WOCBP partners of male participants (refer to the list of highly effective
methods below in Section 10.4.4).

10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using an acceptable contraceptive method as described below during
the intervention period (for a minimum of 28 days after the last dose of study
intervention). The investigator should evaluate the effectiveness of the contraceptive
method in relationship to the first dose of study intervention.

The investigator is responsible for review of medical history, menstrual history, and recent
sexual activity to decrease the risk for inclusion of a woman with an early undetected
pregnancy.

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10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot
be confirmed before the first dose of study intervention, additional evaluation should beconsidered.
Women in the following categories are not considered WOCBP:

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1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.

For individuals with permanent infertility due to an alternate medical cause other than theabove, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should beapplied to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s
review of the participant’s medical records, medical examination, or medical history
interview. The method of documentation should be recorded in the participant’s medical
record for the study.
2. Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause. In addition, ahigh FSH level in the postmenopausal range must be used to confirm apostmenopausal state in women under 60 years of age and not using hormonal
contraception or HRT.



Female on HRT and whose menopausal status is in doubt will be required to use
one of the nonestrogen hormonal highly effective contraception methods if theywish to continue their HRT during the study. Otherwise, they must discontinue
HRT to allow confirmation of postmenopausal status before study enrollment.

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10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations
regarding the use of contraceptive methods for those participating in clinical trials.
1. Implantable progestogen-only hormone contraception associated with inhibition ofovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner:

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)

Vasectomized partner is a highly effective contraceptive method provided that thepartner is the sole sexual partner of the woman of childbearing potential and theabsence of sperm has been confirmed. If not, an additional highly effective methodof contraception should be used. The spermatogenesis cycle is approximately
90 days.

6. Combined (estrogen- and progestogen-containing) hormonal contraception associatedwith inhibition of ovulation:


Oral;



Intravaginal;Transdermal;



Injectable.

7. Progestogen-only hormone contraception associated with inhibition of ovulation:


Oral;



Injectable.

8. Sexual abstinence:Sexual abstinence is considered a highly effective method only if defined as
refraining from heterosexual intercourse during the entire period of risk associatedwith the study intervention. The reliability of sexual abstinence needs to be evaluatedin relation to the duration of the study and the preferred and usual lifestyle of theparticipant.

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9. Progestogen-only oral hormonal contraception where inhibition of ovulation is not the
primary mode of action.
10. Male or female condom with or without spermicide.
11. Cervical cap, diaphragm, or sponge with spermicide.

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12. A combination of male condom with either cervical cap, diaphragm, or sponge with
spermicide (double-barrier methods).

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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations intransaminases) are termed “tolerators,” while those who show transient liver injury, but adapt
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of amore serious potential outcome. These participants fail to adapt and therefore are"susceptible" to progressive and serious liver injury, commonly referred to as DILI.
Participants who experience a transaminase elevation above 3 × ULN should be monitored
more frequently to determine if they are an “adaptor” or are “susceptible.”

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LFTs are not required as a routine safety monitoring procedure for all participants in thisstudy. However, should an investigator deem it necessary to assess LFTs because aparticipant presents with clinical signs/symptoms, such LFT results should be managed andfollowed as described below.
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will beelevated within the same laboratory sample). In rare instances, by the time TBili elevations
are detected, AST/ALT values might have decreased. This occurrence is still regarded as apotential DILI. Therefore, abnormal elevations in either AST OR ALT in addition to TBili
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law
criteria) cases and should always be considered important medical events, even before allother possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on theparticipant’s individual baseline values and underlying conditions. Participants who present
with the following laboratory abnormalities should be evaluated further as potential DILI
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:Participants with AST/ALT and TBili baseline values within the normal range who
subsequently present with AST OR ALT values >3 × ULN AND a TBili value >2 × ULN
with no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or notavailable.

For participants with baseline AST OR ALT OR TBili values above the ULN, thefollowing threshold values are used in the definition mentioned above, as needed,
depending on which values are above the ULN at baseline:Preexisting AST or ALT baseline values above the normal range: AST or ALT values>2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is smaller).

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Rises in AST/ALT and TBili separated by more than a few weeks should be assessedindividually based on clinical judgment; any case where uncertainty remains as to whether it
represents a potential Hy’s law case should be reviewed with the sponsor.

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)The participant should return to the investigator site and be evaluated as soon as possible,
preferably within 48 hours from awareness of the abnormal results. This evaluation should
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili for suspected cases ofHy’s law, additional laboratory tests should include albumin, CK, direct and indirect
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should
also be given to drawing a separate tube of clotted blood and an anticoagulated tube of bloodfor further testing, as needed, for further contemporaneous analyses at the time of therecognized initial abnormalities to determine etiology. A detailed history, including relevant
information, such as review of ethanol, acetaminophen/paracetamol (either by itself or as a
coformulated product in prescription or over-the-counter medications), recreational drug,
supplement (herbal) use and consumption, family history, sexual history, travel history,
history of contact with a jaundiced person, surgery, blood transfusion, history of liver orallergic disease, and potential occupational exposure to chemicals, should be collected.
Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary
tract) and collection of serum samples for acetaminophen/paracetamol drug and/or protein
adduct levels may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if noother reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law)cases are to be reported as SAEs, irrespective of availability of all the results of theinvestigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results ofreasonable investigations have been received and have excluded an alternative etiology.

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10.6. Appendix 6: Abbreviations

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)The following is a list of abbreviations that may be used in the protocol.
Abbreviation
2019-nCoV
Abs
AE
ALT
AST
-hCG
BMI
BUN
CBER
CDC
CFR
CI
CIOMS
CLIA
CONSORT
COVID-19
CRF
CRO
CSR
CT
DBP
DILI
DMC
DNA
DU
EC
ECMO
ECG
eCRF
e-diary
EDP
EMA
EU
EUA
EudraCT
FDA
FiO2
FSH
GCP

Term
novel coronavirus 2019absolute (in Appendix 2)
adverse event
alanine aminotransferase
aspartate aminotransferase
beta-human chorionic gonadotropin
body mass index
blood urea nitrogen
Center for Biologics Evaluation and ResearchCenters for Disease Control and Prevention (United States)
Code of Federal Regulations
confidence interval
Council for International Organizations of Medical Sciences
Clinical Laboratory Improvement Amendments
Consolidated Standards of Reporting Trials
coronavirus disease 2019case report form
contract research organization
clinical study reportcomputed tomography
diastolic blood pressuredrug-induced liver injury
data monitoring committee
deoxyribonucleic aciddosing unit
ethics committee
extracorporeal membrane oxygenationelectrocardiogram
electronic case report form
electronic diary
exposure during pregnancy
European Medicines Agency
European Union
emergency use application
European Clinical Trials Database
Food and Drug Administration
fraction of inspired oxygenfollicle-stimulating hormone
Good Clinical Practice

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Abbreviation
GGT
GMC
GMFR
GMR
GMT
HBc Ab
HBsAg
HBV
HCV
HCV Ab
HIPAA
HIV
HR
HRT
IA
IB
ICD
ICH
ICU
ID
Ig
IgG
IgM
IMP
IND
INR
IP manual
IPAL
IRB
IRC
IRR
IRT
ISO
IV
IWR
LFT
LL
LLOQ
LNP
LPX
MCH
MCHC

Term
gamma-glutamyl transferase
geometric mean concentrationgeometric mean fold risegeometric mean ratio
geometric mean titerhepatitis B core antibody
hepatitis B surface antigen
hepatitis B virus
hepatitis C virus
hepatitis C virus antibody
Health Insurance Portability and Accountability Act
human immunodeficiency virus
heart rate
hormone replacement therapy
interim analysis
investigator’s brochure
informed consent document
International Council for Harmonisation
intensive care unit
identification
immunoglobulin
immunoglobulin G
immunoglobulin M
investigational medicinal productinvestigational new druginternational normalized ratio
investigational product manual
Investigational Product Accountability Log
institutional review board
internal review committee
illness rate ratio
interactive response technology
International Organization for Standardization
intravenous(ly)interactive Web-based response
liver function test
lower limit
lower limit of quantitation
lipid nanoparticle
lipoplexmean corpuscular hemoglobinmean corpuscular hemoglobin concentration

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Abbreviation
MCV
MedDRAMERS
modRNA
MRI
N/A
NAAT
non-S
NVA
P2 S
PaO2
PCR
PI
POS
PPE
PT
RBC
RBD
RCDC
RNA
RR
RSV
RT-PCR
S1
SAE
SAP
saRNA
SARS
SARS-CoV-2
SBP
SoA
SOP
SpO2
SRSD
SUSAR
TBD
TBili
ULN
uRNA
US
vax

Term
mean corpuscular volume
Medical Dictionary for Regulatory Activities
Middle East respiratory syndrome
nucleoside-modified messenger ribonucleic acidmagnetic resonance imaging
not applicable
nucleic acid amplification test
nonspike protein
nonvaccine antigen
SARS-CoV-2 full-length, P2 mutant, “heads up,” prefusion spikeglycoprotein
partial pressure of oxygen, arterial
polymerase chain reaction
principal investigatorprobability of successpersonal protective equipment
prothrombin time
red blood cell
receptor-binding domain
reverse cumulative distribution curve
ribonucleic acidrespiratory rate
respiratory syncytial virus
reverse transcription–polymerase chain reaction
spike protein S1 subunit
serious adverse event
statistical analysis planself-amplifying messenger ribonucleic acidsevere acute respiratory syndrome
severe acute respiratory syndrome coronavirus 2
systolic blood pressureschedule of activities
standard operating procedureoxygen saturation as measured by pulse oximetry
single reference safety document
suspected unexpected serious adverse reaction
to be determinedtotal bilirubin
upper limit of normal
unmodified messenger ribonucleic acid
United States
vaccination

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Abbreviation
VE
WBC
WHO
WOCBP

Term
vaccine efficacy
white blood cell
World Health Organization
woman/women of childbearing potential

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10.7. Appendix 7: Stopping and Alert Rules for Enhanced COVID-19
In Phase 2/3, the unblinded team supporting the DMC (reporting team), including an
unblinded medical monitor, will review cases of severe COVID-19 as they are received, andwill review AEs at least weekly for additional potential cases of severe COVID-19 and willcontact the DMC in the event that the stopping rule or an alert is met. Specifically, theunblinded reporting team will contact the DMC chair, who will then convene the full DMC
as soon as possible. The DMC will review all available safety and/or efficacy data at thetime of the review. The DMC will make one of the following recommendations to Pfizer:
withhold final recommendation until further information/data are provided, continue thestudy as designed, modify the study and continue, or stop the study. The final decision toaccept or reject the committee’s recommendation resides with Pfizer management and will be
communicated to the committee chairperson in writing.

090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)

At any point the unblinded team may discuss with the DMC chair whether the DMC should
review cases for an adverse imbalance of cases of COVID-19 and/or severe COVID-19
between the vaccine and placebo groups (see Section 9.6). In addition, at the time of the IAs
at 32, 62, 92, and 120 cases, the number of severe COVID-19 cases in the vaccine andplacebo groups will be assessed.
Stopping and alert rules will be applied as follows. The stopping rule will be triggered whenthe 1-sided probability of observing the same or a more extreme case split is 5% or less when
the true incidence of severe disease is the same for vaccine and placebo participants, and alert
criteria are triggered when this probability is less than 11%. In addition, when the total
number of severe cases is low (15 or less), the unblinded team supporting the DMC will
implement the alert rule when a reverse case split of 2:1 or worse is observed. For example,
at 3 cases 2:1, at 4 cases 3:1, etc. Below 15 cases, this rule is more rigorous than requiring
the probability of an observed adverse split or worse be <11%.
The stopping rule and alert rules are illustrated in Table 9 and Table 10, respectively, when
the total number of severe cases is 20 or less. For example, when there are 7 severe cases,
the adverse split has to be 7:0 to stop the study, but a split of 5:2 would trigger the alert rule.
Similarly, when there is a total of 9 severe cases, an adverse split of 9:0 triggers the stopping
rule, while a split of 6:3 or worse triggers the alert rule. The alert rule may be triggered withas few as 2 cases, with a split of 2:0.

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Table 9.

Stopping Rule: Enrollment Is Stopped if the Number of Severe Cases inthe Vaccine Group Is Greater Than or Equal to the Prespecified Stopping
Rule Value (S)090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)

Total Severe Cases

Prespecified Stopping Rule Value(S): Number of Severe Cases in the
Vaccine Group to Stop

4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Abbreviation: N/A = not applicable.

4
5
6
7
7
8
9
9
10
10
11
12
12
13
13
14
15

If the True Ratio of Severe Cases
Between Vaccine and PlaceboGroups Is 1:1, Probability of S or
More Being Observed in the Vaccine
Group
N/A
3.13%
1.56%
0.78%
3.52%
1.95%
1.07%
3.27%
1.93%
4.61%
2.87%
1.76%
3.84%
2.45%
4.81%
3.18%
2.07%

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Table 10. Alert Rule: Further Action Is Taken if the Number of Severe Cases in the
Vaccine Group Is Greater Than or Equal to the Prespecified Alert Rule
Value (A)
Total
SevereCases

Prespecified AlertRule Value(A):
Number of
SevereCases in the
VaccineGroup toTrigger
Further
ActionIf the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
1:1,
Probabilityof A Being
Observed inthe Vaccine
Group

2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20

2
2
3
4
4
5
6
6
7
8
8
9
10
10
11
12
13
13
14

25.00%
37.50%
25.00%
15.63%
23.44%
16.41%
10.94%
16.41%
11.72%
8.06%
12.08%
8.73%
6.11%
9.16%
6.67%
4.72%
3.27%
5.18%
3.70%

If the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
1:1,
Probabilityof A or More
Being
Observed inthe Vaccine
Group
25.00%
50.00%
31.25%
18.75%
34.38%
22.66%
14.45%
25.39%
17.19%
11.33%
19.38%
13.34%
8.98%
15.09%
10.51%
7.17%
4.81%
8.35%
5.77%

If the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
2:1,
Probabilityof A or More
Being
Observed inthe Vaccine
Group44.49%
74.12%
59.32%
46.16%
68.10%
57.14%
46.90%
65.11%
56.02%
47.35%
63.25%
55.31%
47.66%
61.94%
54.81%
47.88%
41.34%
54.43%
48.06%

If the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
3:1,
Probabilityof A or More
Being
Observed inthe Vaccine
Group56.25%
84.38%
73.83%
63.28%
83.06%
75.64%
67.85%
83.43%
77.59%
71.33%
84.24%
79.40%
74.15%
85.16%
81.03%
76.53%
71.75%
82.51%
78.58%

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If the True
Ratio ofSevere Cases
Between the
Vaccine andPlacebo
Groups Is
4:1,
Probabilityof A or More
Being
Observed inthe VaccineGroup64.00%
89.60%
81.92%
73.73%
90.11%
85.20%
79.69%
91.44%
87.91%
83.89%
92.74%
90.09%
87.02%
93.89%
91.83%
89.43%
86.71%
93.24%
91.33%

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Protocol Amendment 5, 24 July 2020090177e1947b6a02\Approved\Approved On: 24-Jul-2020 13:05 (GMT)

11. REFERENCES
1

World Health Organization. WHO Director-General's opening remarks at the media
briefing on COVID-19. Available from: https://www.who.int/dg/speeches/detail/whodirector-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march2020. Published: 11 Mar 2020. Accessed: 01 Apr 2020.

2

World Health Organization. Coronavirus disease 2019 (COVID-19) situation report - 70.
In: Data as reported by national authorities by 10:00 CET 30 March 2020. Geneva,
Switzerland: World Health Organization; 2020.

3

Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19):
information for clinicians on investigational therapeutics for patients with COVID-19.
Available from: https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeuticoptions.html. Updated: 25 Apr 2020. Accessed: 26 Jun 2020.

4

Rauch S, Jasny E, Schmidt KE, et al. New vaccine technologies to combat outbreaksituations. Front Immunol 2018;9:1963.

5

Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics—developing a new class ofdrugs. Nat Rev Drug Discov 2014;13(10):759-80.

6

BioNTech RNA Pharmaceuticals GmbH. CorVAC/BNT162 Investigator’s Brochure.
Mainz, Germany: BioNTech RNA Pharmaceuticals GmbH; 25 Mar 2020.

7

Feldman RA, Fuhr R, Smolenov I, et al. mRNA vaccines against H10N8 and H7N9
influenza viruses of pandemic potential are immunogenic and well tolerated in healthy
adults in phase 1 randomized clinical trials. Vaccine. 2019;37(25):3326-34.

8

US Food and Drug Administration. Guidance for industry: toxicity grading scale forhealthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials.
Rockville, MD: Center for Biologics Evaluation and Research; September 2007.

9

Agresti A. Introduction: distributions and inference for categorical data. In: Agresti A,
ed. Categorical data analysis. 2nd ed. Hoboken, NJ: John Wiley & Sons; 2002:1-35.

10

Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med
1985;4(2):213-26.

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Document Approval Record
Document Name:

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Page 744

FDA-CBER-2021-5683-0014797

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Protocol Amendment 4, 30 June 2020090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)A PHASE 1/2/3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLIND,
DOSE-FINDING STUDY TO EVALUATE THE SAFETY, TOLERABILITY,IMMUNOGENICITY, AND EFFICACY OF SARS-COV-2 RNA VACCINECANDIDATES AGAINST COVID-19 IN HEALTHY ADULTS

Study Sponsor:

BioNTechStudy Conducted By:

PfizerStudy Intervention Number:

PF-07302048

Study Intervention Name:

RNA-Based COVID-19 Vaccines

US IND Number:

19736

EudraCT Number:2020-002641-42

Protocol Number:

C4591001

Phase:
1/2/3
Short Title: A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, andEfficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Adults

This document and accompanying materials contain confidential information belonging to Pfizer. Except asotherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold thisinformation in confidence and not copy or disclose it to others (except where required by applicable law) or
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer
must be promptly notified.

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Protocol Amendment 4, 30 June 2020

Protocol Amendment Summary of Changes Table
Document History
Document

Version Date

Summary and Rationale for Changes

Protocol amendment 4

30 June 2020

Given the rapidly evolving pandemic situation, andthe need to demonstrate VE as soon as possible, theprotocol has been amended to be powered to meet
new efficacy objectives. These new efficacy
objectives and corresponding endpoints have been
added to Section 3.
Further nonclinical data are available to support the
study of the BNT162b3 candidate in humans, and thecandidate has been added to the protocol.

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)The 6-month safety follow-up telephone contact has
been changed to an in-person visit for Stage 3
participants, to allow collection of an
immunogenicity blood sample.
The COVID-19 illness visit has now added
flexibility to permit a remote or in-person visit.
The COVID-19 illness symptoms have been updated
to align with the FDA-accepted definitions; thischange is also reflected in the criteria for temporary
delay of enrollment.
AEs that occur between consent and dosing will now
be reported on the AE (rather than Medical History)
CRF, to align with the latest Pfizer protocol
template.
Changes have been made to the headings to alignwith the latest Pfizer protocol template.
Clarified that only an unblinded site staff member
may obtain the participant’s randomization number
and study intervention allocation.
Additional interim analyses have been added toevaluate VE and futility during the study.

Protocol amendment 3

10 June 2020

As a result of regulatory feedback, an appendix has
been added to outline the stopping and alert rules tomonitor for potential enhanced COVID-19 disease.
As data have become available from this study andthe BNT162-01 study in Germany, the following
decisions were made: Not to study the BNT162a1 and BNT162c2
vaccine candidates at this time. Therefore, these

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candidates have been removed from theprotocol.
To study further lower dose levels of the
modRNA candidates. Therefore, a 20-µg doselevel is formally included for BNT162b1 and
BNT162b2.
To permit individual and group dosing
alterations for the second dose of study
intervention.

Following regulatory feedback, the BNT162b3
vaccine candidate has been removed from theprotocol until further nonclinical data are available tosupport study in humans.

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)

Given the rapidly evolving pandemic situation,
additional blood draws for exploratory COVID-19
research, intended to establish an immunologicalsurrogate of protection, will be taken from selectedparticipants who consent.
In order to increase flexibility enrolling participants,
an extended screening window (increased from 14 to
28 days) for sentinel participants in Stage 1 has been
added. This is considered acceptable since eligible
participants are expected to be either healthy or havestable medical conditions.
To increase the number of doses that can be obtained
from available vaccine vials, not all dose levels will
result in a dosing volume of 0.5 mL. Precise dosing
instructions will be provided in the IP manual.

Protocol amendment 2

27 May 2020

To facilitate the reporting of COVID-19 illness
diagnoses and potential symptoms to theinvestigator, participants may utilize a COVID-19
illness e-diary.
Given the urgent nature of the pandemic situation,
the following changes allow determination of theappropriate human dose level for both younger andolder adults to move speedily into the next phase ofclinical evaluation:
 Added a new vaccine candidate, BNT162b3,
modRNA encoding a membrane-anchored RBD
 Added a 50-µg dose level for vaccine candidates
based on the modRNA platform (ie, BNT162b1,
BNT162b2, and BNT162b3)
 Modified the criteria required for the IRC todetermine dose escalation in the 18- to 55-year
age cohort and advancement to groups ofparticipants 65 to 85 years of age
In addition:

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Protocol amendment 1

13 May 2020









090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)

Removed hemoglobin change-from-baseline
abnormalities from the laboratory abnormality
grading scale as abnormalities should be gradedbased upon absolute values
Following regulatory feedback:
Modified exclusion criteria and prohibitedinhaled/nebulized corticosteroids for sentinel
participants in Stage 1
Clarified that the rapid test for prior COVID-19
infection for sentinel participants in Stage 1 will
be used only for screening purposes
Removed time frames for stopping rules
Stated that data supporting the selection of
vaccine candidate(s)/dose level(s) andschedule(s) for Stages 2 and 3 will be submitted
to the FDA for review
Following preliminary experience in the
BioNTech study conducted in Germany(BNT162-01):
Decreased the dose levels for BNT162a1 and
BNT162c2

Additionally: Clarified the roles of BioNTech and Pfizer
 Amended text so that the IRC decision toprogress group(s) into Stages 2 and 3 can bebased upon safety and immunogenicity data
after Dose 1 or 2
 Clarified safety data requirements to permit dose
escalation
 Amended text so that the progression toparticipants 65 to 85 years of age can be based
upon data from the same RNA platform Incorporated a protocol administrative change tocorrect the variant designation and the encoded
antigen to BNT162c2
 Clarified that the SARS-CoV-2 neutralizing
assay does not employ wild-type virus
 Clarified that the SARS-CoV-2 spike protein–binding antibody assay is specific for the S1subunit Clarified that efficacy against COVID-19 isbased upon illness (not infection) rate ratio Incorporated a protocol administrative change tostate that the study placebo may be supplied in a
glass or plastic vial Corrected a typographical error in Section 6.5.1
regarding the time frame for prior receipt ofblood/plasma products or immunoglobulins
 Corrected a typographical error in Table 2
regarding the lower limit of diameter (cm) for
mild redness and swelling
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







090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)

Original protocol

15 April 2020

Updated the °C fever scale in Table 4 to ensurethat all potential °F values are correctly assigned
Incorporated a protocol administrative change toclarify that a rapid test for prior COVID-19
infection will be performed for sentinel
participants in Stage 1, and a serum sample will
be drawn for potential future assessment
Clarified that, after screening, physicalexaminations in sentinel participants in Stage 1
will be directed
Clarified the descriptions of the populations foranalysis to align with the statistical analysis plan
Added a complete safety and immunogenicity
analysis approximately 6 months after Dose 2
for all participants in Stage 3
Amended text so that the stopping rules apply to
an RNA platform rather than a specific vaccine
candidate

N/A

This amendment incorporates all revisions to date, including amendments made at therequest of country health authorities and IRBs/ECs.

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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................12
1. PROTOCOL SUMMARY...................................................................................................13
1.1. Synopsis ..................................................................................................................13
1.2. Schema ....................................................................................................................20
1.3. Schedule of Activities .............................................................................................21
1.3.1. Stage 1 Sentinel Cohorts.............................................................................21
1.3.2. Stage 1 Nonsentinel Cohorts and Stage 2 Cohorts .....................................26
1.3.3. Stage 3 Cohort(s) ........................................................................................29
2. INTRODUCTION ...............................................................................................................312.1. Study Rationale .......................................................................................................31090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)

2.2. Background .............................................................................................................312.2.1. Clinical Overview.......................................................................................32
2.3. Benefit/Risk Assessment.........................................................................................32
2.3.1. Risk Assessment .........................................................................................33
2.3.2. Benefit Assessment.....................................................................................34
2.3.3. Overall Benefit/Risk Conclusion................................................................34
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................34
3.1. For Stages 1 and 2 ...................................................................................................34
3.2. For Stage 3 ..............................................................................................................36
4. STUDY DESIGN.................................................................................................................38
4.1. Overall Design.........................................................................................................38
4.1.1. Stage 1 ........................................................................................................38
4.1.2. Stage 2 ........................................................................................................40
4.1.3. Stage 3 ........................................................................................................40
4.2. Scientific Rationale for Study Design .....................................................................41
4.3. Justification for Dose ..............................................................................................41
4.4. End of Study Definition ..........................................................................................42
5. STUDY POPULATION ......................................................................................................425.1. Inclusion Criteria.....................................................................................................43
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5.2. Exclusion Criteria....................................................................................................43
5.3. Lifestyle Considerations..........................................................................................46
5.3.1. Contraception..............................................................................................46
5.4. Screen Failures ........................................................................................................46
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study
Intervention Administration ......................................................................................46
6. STUDY INTERVENTION..................................................................................................47
6.1. Study Intervention(s) Administered ........................................................................50
6.1.1. Administration ............................................................................................50
6.2. Preparation/Handling/Storage/Accountability ........................................................51
6.2.1. Preparation and Dispensing ........................................................................52
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................52
6.3.1. Allocation to Study Intervention ................................................................52
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6.3.2. Blinding of Site Personnel ..........................................................................52
6.3.3. Blinding of the Sponsor ..............................................................................53
6.3.4. Breaking the Blind......................................................................................53
6.4. Study Intervention Compliance...............................................................................53
6.5. Concomitant Therapy..............................................................................................53
6.5.1. Prohibited During the Study .......................................................................54
6.5.2. Permitted During the Study ........................................................................54
6.6. Dose Modification...................................................................................................55
6.7. Intervention After the End of the Study ..................................................................55
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANTDISCONTINUATION/WITHDRAWAL...........................................................................55
7.1. Discontinuation of Study Intervention ....................................................................55
7.2. Participant Discontinuation/Withdrawal From the Study .......................................55
7.2.1. Withdrawal of Consent ...............................................................................56
7.3. Lost to Follow-up ....................................................................................................57
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................57
8.1. Efficacy and/or Immunogenicity Assessments .......................................................58
8.1.1. Biological Samples .....................................................................................61
8.2. Safety Assessments .................................................................................................61
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8.2.1. Clinical Safety Laboratory Assessments (Sentinel-Cohort
Participants Only) ............................................................................................61
8.2.2. Electronic Diary..........................................................................................62
8.2.2.1. Grading Scales...........................................................................62
8.2.2.2. Local Reactions .........................................................................63
8.2.2.3. Systemic Events ........................................................................63
8.2.2.4. Fever..........................................................................................64
8.2.2.5. Antipyretic Medication .............................................................65
8.2.3. Stopping Rules............................................................................................65
8.2.3.1. Randomization and Vaccination After a Stopping Rule Is
Met.....................................................................................................67
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19
Disease .............................................................................................................67

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8.2.5. Pregnancy Testing ......................................................................................67
8.3. Adverse Events and Serious Adverse Events..........................................................68
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......68
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................69
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................69
8.3.2. Method of Detecting AEs and SAEs ..........................................................69
8.3.3. Follow-up of AEs and SAEs.......................................................................69
8.3.4. Regulatory Reporting Requirements for SAEs...........................................70
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational
Exposure ..........................................................................................................70
8.3.5.1. Exposure During Pregnancy......................................................70
8.3.5.2. Exposure During Breastfeeding ................................................72
8.3.5.3. Occupational Exposure .............................................................72
8.3.6. Cardiovascular and Death Events...............................................................72
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not
Qualifying as AEs or SAEs..............................................................................72
8.3.8. Adverse Events of Special Interest .............................................................73
8.3.8.1. Lack of Efficacy ........................................................................73
8.3.9. Medical Device Deficiencies......................................................................73
8.3.10. Medication Errors .....................................................................................73
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8.4. Treatment of Overdose............................................................................................74
8.5. Pharmacokinetics ....................................................................................................74
8.6. Pharmacodynamics..................................................................................................74
8.7. Genetics ...................................................................................................................74
8.8. Biomarkers ..............................................................................................................74
8.9. Immunogenicity Assessments .................................................................................74
8.10. Health Economics .................................................................................................75
8.11. Study Procedures...................................................................................................75
8.11.1. Stage 1 Sentinel Cohorts...........................................................................75
8.11.1.1. Screening: (0 to 28 Days Before Visit 1) ................................75
8.11.1.2. Visit 1 – Vaccination 1: (Day 1) .............................................76090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)

8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1to 3 Days After Visit 1) .....................................................................78
8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to
8 Days After Visit 1) .........................................................................79
8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1) ...........80
8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to
8 Days After Visit 4) .........................................................................83
8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to
16 Days After Visit 4) .......................................................................84
8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After
Visit 4) ...............................................................................................85
8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (154 to 168 Days
After Visit 4)......................................................................................86
8.11.1.10. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 4)......................................................................................86
8.11.1.11. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 4)......................................................................................87
8.11.2. Stage 1 Nonsentinel Cohorts and Stage 2 Cohorts ...................................87
8.11.2.1. Visit 1 – Vaccination 1: (Day 1) .............................................87
8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days or 56 to 70 Days
After Visit 1)......................................................................................89
8.11.2.3. Visit 3 – 2-Week Follow-up Visit: (12 to 16 Days After
Visit 2) ...............................................................................................91

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8.11.2.4. Visit 4 – 1-Month Follow-up Visit: (28 to 35 Days After
Visit 2) ...............................................................................................92
8.11.2.5. Visit 5 – 6-Month Follow-up Visit: (154 to 168 Days
After Visit 2)......................................................................................92
8.11.2.6. Visit 6 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 2)......................................................................................93
8.11.2.7. Visit 7 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 2)......................................................................................93
8.11.3. Stage 3 Cohort(s) ......................................................................................94
8.11.3.1. Visit 1 – Vaccination 1: (Day 1) .............................................94
8.11.3.2. Visit 2 – Vaccination 2: (19 to 23 Days or 56 to 70 Days
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8.11.3.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2):(28 to 35 Days After Visit 2).............................................................98
8.11.3.4. Visit 4 – 6-Month Follow-up Visit: (154 to 168 Days
After Visit 2)......................................................................................99
8.11.3.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 2)......................................................................................99
8.11.3.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 2)....................................................................................100
8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction ......................100
8.13. COVID-19 Disease Surveillance (All Participants)............................................101
8.13.1. Potential COVID-19 Illness Visit: (Optimally Within 3 Days After
Potential COVID-19 Illness Onset) ...............................................................102
8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After
Potential COVID-19 Illness Visit)................................................................103
8.14. Communication and Use of Technology.............................................................103
9. STATISTICAL CONSIDERATIONS ..............................................................................104
9.1. Estimands and Statistical Hypotheses ...................................................................104
9.1.1. Estimands..................................................................................................104
9.1.2. Statistical Hypotheses...............................................................................105
9.2. Sample Size Determination...................................................................................105
9.3. Analysis Sets .........................................................................................................106
9.4. Statistical Analyses ...............................................................................................107
9.4.1. Immunogenicity Analyses ........................................................................107
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9.4.2. Efficacy Analyses .....................................................................................112
9.4.3. Safety Analyses ........................................................................................114
9.4.4. Other Analyses..........................................................................................115
9.5. Interim Analyses ...................................................................................................115
9.5.1. Analysis Timing........................................................................................118
9.6. Data Monitoring Committee or Other Independent Oversight Committee...........118
10. SUPPORTING DOCUMENTATION AND OPERATIONALCONSIDERATIONS ........................................................................................................120
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .............120
10.1.1. Regulatory and Ethical Considerations ..................................................120
10.1.1.1. Reporting of Safety Issues and Serious Breaches of theProtocol or ICH GCP.......................................................................120
10.1.2. Informed Consent Process ......................................................................121
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10.1.3. Data Protection .......................................................................................122
10.1.4. Dissemination of Clinical Study Data ....................................................122
10.1.5. Data Quality Assurance ..........................................................................123
10.1.6. Source Documents ..................................................................................125
10.1.7. Study and Site Start and Closure ............................................................125
10.1.8. Sponsor’s Qualified Medical Personnel .................................................126
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................127
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting ....................................................................129
10.3.1. Definition of AE .....................................................................................129
10.3.2. Definition of SAE ...................................................................................130
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.....................132
10.3.4. Reporting of SAEs..................................................................................135
10.4. Appendix 4: Contraceptive Guidance .................................................................136
10.4.1. Male Participant Reproductive Inclusion Criteria ..................................136
10.4.2. Female Participant Reproductive Inclusion Criteria...............................136
10.4.3. Woman of Childbearing Potential ..........................................................137
10.4.4. Contraception Methods...........................................................................138
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ......140
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10.6. Appendix 6: Abbreviations .................................................................................142
10.7. Appendix 7: Stopping and Alert Rules for Enhanced COVID-19 ......................146
11. REFERENCES ................................................................................................................148

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LIST OF TABLES
Table 1.

Potential Groups in Stage 1 ......................................................................48

Table 2.

Local Reaction Grading Scale ..................................................................63

Table 3.

Systemic Event Grading Scale..................................................................64

Table 4.

Scale for Fever..........................................................................................65

Table 5.

Probability of Observing at Least 1 AE by Assumed True Event
Rates With Different Sample Sizes ........................................................106

Table 6.

Interim Analysis Plan and Boundaries for Efficacy and Futility............116

Table 7.

Statistical Design Operating Characteristics: Probability of Successor Failure for Interim Analyses...............................................................117

Table 8.

Statistical Design Operating Characteristics: Probability of Successfor Final Analysis and Overall................................................................117

Table 9.

Laboratory Abnormality Grading Scale .................................................127

Table 10.

For 2 to 20 Cases of Severe COVID-19, Probability of Observing
This Number or More of Severe Cases in the Vaccine Group at a
Range of True Adverse Ratios From 1:1 to 4:1......................................146

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1. PROTOCOL SUMMARY
1.1. Synopsis
Short Title: A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, andEfficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Adults
Rationale

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A pneumonia of unknown cause detected in Wuhan, China, was first reported in
December 2019. On 08 January 2020, the pathogen causing this outbreak was identified as anovel coronavirus 2019. The outbreak was declared a Public Health Emergency ofInternational Concern on 30 January 2020. On 12 February 2020, the virus was officiallynamed as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the WHO
officially named the disease caused by SARS-CoV-2 as coronavirus disease 2019
(COVID-19). On 11 March 2020, the WHO upgraded the status of the COVID-19 outbreakfrom epidemic to pandemic, which is now spreading globally at high speed.
There are currently no licensed vaccines to prevent infection with SARS-CoV-2 or antiviraldrugs to treat COVID-19. Given the rapid transmission of COVID-19 and incidence ofdisease in the United States and elsewhere, the rapid development of an effective vaccine isof utmost importance.
BioNTech has developed RNA-based vaccine candidates using a platform approach thatenables the rapid development of vaccines against emerging viral diseases, including
SARS-CoV-2. Each vaccine candidate is based on a platform of nucleoside-modified
messenger RNA (modRNA, BNT162b). Each vaccine candidate expresses 1 of 3 antigens:the SARS-CoV-2 full-length, P2 mutant, “heads up,” prefusion spike glycoprotein (P2 S)(version 9), a trimerized SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD)(version 5), or a membrane-anchored trimerized SARS-CoV-2 RBD. The 3 SARS-CoV-2
vaccine candidates that may be tested in this study are therefore:
BNT162b1 (variant RBP020.3): a modRNA encoding the RBD;
BNT162b2 (variant RBP020.2): a modRNA encoding P2 S;
BNT162b3 (variant RBP020.8): a modRNA encoding a membrane-anchored RBD.
All candidates are formulated in the same lipid nanoparticle (LNP) composition. This study
is intended to investigate the safety, immunogenicity, and efficacy of these prophylactic
BNT162 vaccines against COVID-19.

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It is expected that the various candidate vaccines may not all be available from the start ofthe study, in which case they will be rolled into the study in a consecutive fashion as they are
released. A Phase 1/2 study of the same vaccine candidates (BNT162-01), conducted inGermany by BioNTech in adults 18 to 55 years of age, started in April 2020.
Study C4591001 is designed to complement and expand upon the German study and confirm
the optimal vaccine candidate(s), dose level(s), number of doses, and schedule ofadministration.
Objectives, Estimands, and Endpoints

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)For Stages 1 and 2
Objectives

Estimands

Endpoints

Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Primary:
In participants receiving at least 1 doseof study intervention and having safety
data reported after any vaccination, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each doseAdverse events (AEs) from
Dose 1 to 1 month after the lastdose
 Serious AEs (SAEs) from Dose 1
to 6 months after the last doseIn addition, in sentinel cohorts from
Stage 1, the percentage of participantswith:
Abnormal hematology andchemistry laboratory values 1 and7 days after Dose 1; and 7 days
after Dose 2
Grading shifts in hematology andchemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2
Secondary:In participants complying with the key
protocol criteria (evaluableparticipants) at the following time
points after receipt of study
intervention:

Primary:
Local reactions (pain at the
injection site, redness, andswelling)

Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs

Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Hematology and chemistry laboratory
parameters detailed in Section 10.2

Secondary:Stage 1 Sentinel Cohorts: 7 and21 days after Dose 1; 7 and 14 days and1, 6, 12, and 24 months after Dose 2
Stage 1 Nonsentinel Cohorts andStage 2 Cohorts: 21 days after Dose 1;
14 days and 1, 6, 12, and 24 months
after Dose 2

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Objectives

Estimands










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Endpoints

Geometric mean titers (GMTs) at SARS-CoV-2 serum neutralizing titers
each time point
Geometric mean fold rise (GMFR)
from before vaccination to eachsubsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
SARS-CoV-2 anti-S1 binding antibody
Geometric mean concentrations
levels and anti-RBD binding antibody(GMCs) at each time point
GMFR from before vaccination to levels
each subsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
SARS-CoV-2 serum neutralizing
Geometric mean ratio (GMR),
titersestimated by the ratio of thegeometric mean of SARS-CoV-2 
SARS-CoV-2 anti-S1 binding
serum neutralizing titers to theantibody levels
geometric mean of SARS-CoV-2– 
SARS-CoV-2 anti-RBD binding
binding antibody levels at eachantibody levels
time point

For Stage 3
Objectives

Estimands
Primary Efficacy

Endpoints

To evaluate the efficacies ofindividual prophylactic BNT162
vaccines against confirmed
COVID-19 in participants without
evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of the last
dose) of past SARS-CoV-2 infection

To evaluate the efficacies ofindividual prophylactic BNT162
vaccines against confirmed
COVID-19 in participants with andwithout evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

COVID-19 incidence per 1000
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Objectives

Estimands
Primary Safety

To define the safety profiles ofindividual prophylactic BNT162
vaccines in the first 360 participants
randomized in Stage 3

In participants receiving at least 1
dose of study intervention and havingsafety data reported after any
vaccination, the percentage ofparticipants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the last dose
SAEs from Dose 1 to 6 months
after the last dose
In participants receiving at least
1 dose of study intervention andhaving safety data reported after any
vaccination, the percentage ofparticipants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the last dose
 SAEs from Dose 1 to 6 months
after the last dose

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To define the safety profiles ofindividual prophylactic BNT162
vaccines in all participants
randomized in Stage 3

Endpoints










Local reactions (pain at the
injection site, redness, andswelling)
Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened
muscle pain, and new orworsened joint pain)
AEs
SAEs

AEs
SAEs
In a subset of at least 6000
participants:
o Local reactions (pain at the
injection site, redness, andswelling)o Systemic events (fever,fatigue, headache, chills,
vomiting, diarrhea, new orworsened muscle pain, andnew or worsened joint pain)

Secondary Efficacy
To evaluate the efficacies ofindividual prophylactic BNT162
vaccines against confirmed severe
COVID-19 in participants without
evidence of infection before
vaccination
To evaluate the efficacies ofindividual prophylactic BNT162
vaccines against confirmed severe
COVID-19 in participants with andwithout evidence of infection before
vaccination
To describe the efficacies ofindividual prophylactic BNT162
vaccines against confirmed
COVID-19 (according to the
CDC-defined symptoms) inparticipants without evidence of
infection before vaccination
To describe the efficacies ofindividual prophylactic BNT162
vaccines against confirmed
COVID-19 (according to the
CDC-defined symptoms) inparticipants with and without
evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

Confirmed severe COVID-19
incidence per 1000 person-years offollow-up in participants with noserological or virological evidence of
past SARS-CoV-2 infection
Confirmed severe COVID-19
incidence per 1000 person-years offollow-up

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of the last
dose) of past SARS-CoV-2 infection
COVID-19 incidence per 1000
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Objectives

Estimands
Secondary Immunogenicity

To evaluate the immune responseover time to BNT162 prophylactic
vaccines and persistence of immune
response in participants with andwithout serological or virologicalevidence of SARS-CoV-2 infection
before vaccination

GMT, GMFR, and percentage ofparticipants with titers greater thandefined threshold(s), at baseline and1, 6, 12, and 24 months after
completion of vaccination

Endpoints

SARS-CoV-2 anti-S1 binding
antibody levels and/or anti-RBD
binding antibody levels
SARS-CoV-2 serum neutralizing
titersExploratory
To evaluate the immune response(non-S) to SARS-CoV-2 inparticipants with and without
confirmed COVID-19 during thestudy
To describe the serological responses
to the BNT vaccine candidate in casesof:
Confirmed COVID-19

Confirmed severe COVID-19

SARS-CoV-2 infection without
confirmed COVID-19



SARS-CoV-2 NVA-specificbinding antibody



SARS-CoV-2 anti-S1 binding
antibody levels and/or anti-RBD
binding antibody levels
SARS-CoV-2 serum neutralizing
titers
SARS-CoV-2 NVA-specificbinding antibody
SARS-CoV-2 detection by
NAAT




090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)Overall Design
This is a Phase 1/2/3, randomized, placebo-controlled, observer-blind, dose-finding, andvaccine candidate–selection study in healthy adults.
The study will evaluate the safety, tolerability, immunogenicity, and efficacy of 3 different
SARS-CoV-2 RNA vaccine candidates against COVID-19:


As a 2-dose (separated by 21 or 60 days) or single-dose schedule

At various different dose levels

In 3 age groups (18 to 55 years of age, 65 to 85 years of age, and 18 to 85 years of age[stratified as ≤55 or >55 years of age])

Dependent upon safety and/or immunogenicity data generated during the course of thisstudy, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
may be started at the next highest dose, groups may not be started, groups may be terminatedearly, and/or groups may be added with dose levels below the lowest stated dose orintermediate between the lowest and highest stated doses.
The study consists of 3 stages. Stage 1: to identify preferred vaccine candidate(s), doselevel(s), number of doses, and schedule of administration (with the first 15 participants ateach dose level of each vaccine candidate comprising a sentinel cohort); Stage 2: an

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expanded-cohort stage; and Stage 3: an efficacy stage. These stages, and the progression
between them, are detailed in the schema (Section 1.2).
A vaccine candidate/dose level that, in Stage 1, has an established dose level andimmunization schedule based on induction of an immune response in the sentinel evaluation,
including neutralizing antibodies, and is expected to be associated with protection against
COVID-19, can progress directly into Stage 3.
Vaccine candidate(s) that have preliminary evidence to support a dose and schedule and toshow that the candidate is safe and has evidence of vaccine-elicited antibody, but require
further safety and immunogenicity data to support progression to Stage 3, can progress toStage 2.
Number of Participants

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Each group in Stage 1 will comprise 15 participants (12 receiving active vaccine and3 receiving placebo). In this stage, assuming 2 dose levels are selected following the initial
dose escalation, up to 42 potential groups are foreseen; if all groups are fully enrolled, thiscorresponds to a total of 630 participants.
Each group in Stage 2 will comprise 225 participants (180 receiving active vaccine and
45 receiving placebo). The total number of participants to be enrolled in this stage depends
on the number of groups to be pursued.
Each vaccine candidate/dose level selected for Stage 3 will comprise 14,643 vaccine
recipients. An equal number of participants will receive placebo, ie, randomized in a 1:1
ratio.
Intervention Groups and Duration
The study may evaluate single-dose and 2-dose (separated by 21 or 60 days) schedules ofvarious different dose levels of 3 investigational RNA vaccine candidates for active
immunization against COVID-19 in 3 age groups (18 to 55 years of age, 65 to 85 years ofage, and 18 to 85 years of age [stratified as ≤55 or >55 years of age]):

BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 20 µg, 30 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 20 µg, 30 µg



BNT162b3 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding a membraneanchored RBD): 10 µg, 20 µg, 30 µg

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Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Stage 1 andStage 2 dosing arms that are not evaluated in Stage 3.
Data Monitoring Committee or Other Independent Oversight Committee
The study will utilize an IRC, an internal Pfizer committee that will review data to allow
dose escalation or changes to continuation of specific groups.
An external data monitoring committee (DMC) will be formed and will review cumulative
unblinded data throughout the study.
Statistical Methods

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)The study sample size for the first 2 stages of the study is not based on any statistical
hypothesis testing.
For the third stage, the VE evaluation will be the primary objective. The VE is defined as
VE = 100 × (1 – IRR), where IRR is calculated as the ratio of the first confirmed COVID-19
illness rate in the vaccine group to the corresponding illness rate in the placebo group. Withassumptions of a true VE of 60% and 4 IAs planned, 164 COVID-19 cases will provide 90%
power to conclude true VE >30%. This would be achieved with a total 29,286 participants(14,643 vaccine recipients), based on the assumption of a 1.0% per year incidence in theplacebo group, and 20% of the participants being nonevaluable. If the attack rate is muchhigher, case accrual would be expected to be more rapid, enabling the study’s primary
endpoint to be evaluated much sooner. The total number of participants enrolled in Stage 3
may vary depending on the incidence of COVID-19 at the time of the enrollment, the numberof candidate vaccines evaluated, the true underlying VE, and a potential early stop for
efficacy or futility.
VE will be evaluated using a beta-binomial model and the posterior probability of VE being>30% will be assessed.
The primary safety objective will be evaluated by descriptive summary statistics for local
reactions, systemic events, AEs/SAEs, and abnormal hematology and chemistry laboratory
parameters (sentinel cohorts only), for each vaccine group. A 3-tier approach will be used tosummarize AEs.
The secondary immunogenicity objectives will be evaluated descriptively by GMT, GMC,
GMFR, percentage of participants with ≥4-fold rise, and GMC ratio, and the associated 95%
confidence intervals (CIs), for SARS-CoV-2 serum neutralizing titers, SARS-CoV-2 anti-S1
binding antibody levels, and anti-RBD binding antibody levels at the various time points.

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1.2. SchemaStage 1

(4:1 randomization active:placebo)

For each vaccine candidate
Age: 18-55 yAge: 65-85 y

Low-dose-level 2-dose group (n=15):
SENTINEL
IRC (safety

IRC (safety)

Low-dose-level 2-dose group (n=15):
SENTINEL

after Dose 1)

Mid-dose-level 2-dose group (n=15):
SENTINEL
IRC (safety

IRC (safety)

Mid-dose-level 2-dose group (n=15):
SENTINEL

after Dose 1)

High-dose-level 2-dose group (n=15):
SENTINEL
IRC (safety

High-dose-level 2-dose group (n=15):
SENTINEL

after Dose 1)

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)

IRC choice of group(s) for Stage 2 or 3
(safety & immunogenicity after Dose 1 or 2)
Dose level(s) selected for Stage 2: 2dose (60 days apart) group(s) (n=15)&
Dose level(s) selected for Stage 2: 1dose group(s) (n=15)
Stage 2

Dose level(s) selected for Stage 2: 2dose (60 days apart) group(s) (n=15)

Directprogression toStage 3 if Stage 1
data support
selection of asinglecandidate/dose
level&
Dose level(s) selected for Stage 2: 1dose group(s) (n=15)(4:1 randomization active:placebo)

Age: 18-85(Stratified 18-55 or 56-85)
Group for each selected vaccine
candidate/dose level(n=180 per active group)
IRC choice of group for Stage 3(safety & immunogenicity after Dose 1 or 2)
Stage 3
Safety and immunogenicity analysis of
Age: 18-85
data for first 360 participants by(Stratified 18-55 or 56-85)
unblinded team if candidate
Selected vaccine candidate/dose level
progressed directly from Stage 1 to(n~14,643 per group)Stage 3Abbreviation: IRC = internal review committee.

(1:1 randomization active:placebo)

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1.3. Schedule of Activities

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with theprotocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations orassessments required to protect the well-being of the participant.
1.3.1. Stage 1 Sentinel Cohorts
An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 10 (24-month follow-up visit) that COVID-19 is suspected.
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

X

X

X

X

X

Obtain informed consent

X

Assign participant number

X

Obtain demography andmedical history data

X

Obtain details of medications
currently taken

X

Perform physical examination

X

2

3

4

5

6

7

8

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset

X

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Protocol C4591001
Protocol Amendment 4, 30 June 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

Measure vital signs(including body temperature)

X

X

X

X

X

X

Collect blood sample forhematology and chemistrylaboratory testsb~10 mL~10 mL~10 mL~10 mL~10 mL

Collect screening blood
sample for HIV, HBsAg,
HBc Ab, and HCV Ab tests~10 mL

Serological test for prior
COVID-19 infection~20 mL

Perform urine pregnancy test
(if appropriate)X

Obtain nasal (midturbinate)swab(s)c

2

3

4

X

X

X

X

Collect nonstudy vaccine
information

X

X

Confirm eligibility

X

X

Collect prohibited medication
use

X

X

Review temporary delay
criteria

X

X

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset
X

X
X

X

X

X

X

X

X
X

Review hematology andchemistry results

X

5

X

X

X

X

X

X

X

X

X

X

X

X

X

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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Protocol Amendment 4, 30 June 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

4

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

Confirm use of contraceptives(if appropriate)

X

X

X

X

X

X

~50 mL~50 mL

Obtain randomization number
and study intervention
allocation

X

Collect blood sample for
immunogenicity assessment~50 mL

Administer study intervention

X

X

Assess acute reactions for atleast 30 minutes after study
intervention administrationd

X

X

Explain participant
communication methods(including for e-diarycompletion), assist theparticipant with downloading
the app, or issue provisioned
device, if required

X

Provide thermometer andmeasuring device

X

5

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset
X

X~50 mL ~50 mL ~50 mL ~50 mL+++
optionale optionale optionale~170 mL ~170 mL ~170 mL~50 mL~50 mL~50 mL

X

Review reactogenicity e-diarydata (daily review is optimal
during the active diary period)

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Protocol C4591001
Protocol Amendment 4, 30 June 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 46 to 8Days
After
Visit 1

Review ongoingreactogenicity e-diary
symptoms and obtain stopdatesCollect AEs and SAEs as
appropriate

4

5

X

X

X

X

X

X

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset
X

X

X

X

X

Collect e-diary or assist theparticipant to delete
application

X

X

X

X

X

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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Protocol Amendment 4, 30 June 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit
VisitaVisit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 46 to 8Days
After
Visit 1

4

5

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset

Collection of COVID-19–
related clinical and laboratory
information (including local
diagnosis)

X

X

Abbreviations: e-diary = electronic diary; HBc Ab = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HCV Ab = hepatitis C virus antibody;
HIV = human immunodeficiency virus; NAAT = nucleic acid amplification test; vax = vaccination.

a.
b.
c.
d.
e.

The COVID-19 illness visit may be conducted as an in-person or telehealth visit.
Hematology: hemoglobin, complete blood count with differential, and platelets. Blood chemistry: alanine aminotransferase (ALT), aspartate
aminotransferase (AST), alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), and creatinine.
Two swabs will be taken at Visits 1 and 4. One will be tested (if possible at the site, otherwise at the central laboratory) within 24 hours and vaccination will
only proceed if it is NAAT-negative for SARS-CoV-2 genomes. The second will be sent to the central laboratory for potential later testing.
The first 5 participants in in each sentinel group will be observed at the site for at least 4 hours after study intervention administration. Further vaccination
will commence no sooner than 24 hours after the fifth participant received his or her vaccination.
An optional blood draw of ~170 mL will be taken at 1 of the visits (from selected participants who consent) for exploratory COVID-19 research.

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1.3.2. Stage 1 Nonsentinel Cohorts and Stage 2 Cohorts
An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 7 (24-month follow-up visit) that COVID-19 is suspected.

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)

Visit Number
Visit Description

Visit Window (Days)

1

2

3

4

5

6

7

2-WeekFollow-up
Visit

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
Potential
COVID-19
COVID-19
Illness Visita ConvalescentVisit

19 to 23 Days 12 to 16 Days 28 to 35 Days
After Visit 1 After Visit 2 After Visit 2
or56 to 70 Days
After Visit 1b

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19 Illness Visit
Illness Onset

X

X

Vaccination 1 Vaccination 2

Day 1

Obtain informed consent

X

Assign participant number

X

Obtain demography and medical
history data

X

Perform physical examination

X

Measure vital signs

X

Perform urine pregnancy test
(if appropriate)

X

X

Collect nonstudy vaccine information

X

X

X

X

X

X

X

X

X

X

X

Collect prohibited medication use
Confirm eligibility

X

X

Measure temperature (body)

X

X

Review temporary delay criteria

X

X

Confirm use of contraceptives(if appropriate)

X

X

Obtain randomization number andstudy intervention allocation

X

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Unplanned

X

Unplanned

X

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Visit Number
Visit Description

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)

Visit Window (Days)

Collect blood sample for
immunogenicity assessment

1

2

3

4

5

6

7

2-WeekFollow-up
Visit

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
Potential
COVID-19
COVID-19
Illness Visita ConvalescentVisit

19 to 23 Days 12 to 16 Days 28 to 35 Days
After Visit 1 After Visit 2 After Visit 2
or56 to 70 Days
After Visit 1b

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19 Illness Visit
Illness Onset~25 mL~25 mL~25 mL

Vaccination 1 Vaccination 2

Day 1~25 mL~25 mL

Obtain nasal (midturbinate) swab

X

X

Administer study intervention

X

X

Assess acute reactions for at least 30
minutes after study intervention
administration

X

X

Explain participant communication
methods (including for e-diarycompletion), assist the participant withdownloading the app, or issue
provisioned device, if required

X

Provide participant with thermometerand measuring deviceX~25 mL~25 mL

Unplanned

Unplanned~50 mL
X

X

Review reactogenicity e-diary data
(daily review is optimal during theactive diary period)
Review ongoing reactogenicity e-diary
symptoms and obtain stop dates
Collect AEs and SAEs as appropriate

X

X

X

X

X

X

X

X

Collect e-diary or assist the participant
to delete application

X

X

X

X

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Protocol Amendment 4, 30 June 2020
Visit Number
Visit Description

1

Visit Window (Days)

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)

2

3

4

5

6

7

2-WeekFollow-up
Visit

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
Potential
COVID-19
COVID-19
Illness Visita ConvalescentVisit

19 to 23 Days 12 to 16 Days 28 to 35 Days
After Visit 1 After Visit 2 After Visit 2
or56 to 70 Days
After Visit 1b

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19 Illness Visit
Illness Onset

Vaccination 1 Vaccination 2

Day 1

Collection of COVID-19–related
clinical and laboratory information(including local diagnosis)

Unplanned

X

UnplannedX

Abbreviation: e-diary = electronic diary.

a.
b.

The COVID-19 illness visit may be conducted as an in-person or telehealth visit.
The window for Visit 2 is dependent on the dosing schedule for the assigned group.

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1.3.3. Stage 3 Cohort(s)An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 6 (24-month follow-up visit) that COVID-19 is suspected.

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)

Visit Number
Visit Description

Visit Window (Days)

1

2

3

4

5

6

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
Potential
COVID-19
COVID-19
Illness Visita ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2
or56 to 70 Days
After Visit 1b

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

Vaccination 1 Vaccination 2

Day 1

Obtain informed consent

X

Assign participant number

X

Obtain demography and medical history data

X

Perform clinical assessmentc

X

Measure height and weightX

Perform urine pregnancy test (if appropriate)

X

X

Collect nonstudy vaccine information

X

X

X

X

X

X

X

X

X

~25 mL~25 mL~25 mL

Collect prohibited medication use
Confirm eligibility

X

X

Measure temperature (body)

X

X

Review temporary delay criteria

X

X

Confirm use of contraceptives (if appropriate)

X

X

Obtain randomization number and study
intervention allocation

X

Collect blood sample for immunogenicity
assessment~25 mL
X

X

Administer study intervention

X

X

X

Unplanned

XX~25 mL

Obtain nasal (midturbinate) swab

Unplanned~50 mLX

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Visit Number

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Visit Description

2

3

4

5

6

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
Potential
COVID-19
COVID-19
Illness Visita ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2
or56 to 70 Days
After Visit 1b

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

X

X

X

Vaccination 1 Vaccination 2

Visit Window (Days)

Day 1

Assess acute reactions for at least 30 minutes after
study intervention administration

X

Explain participant communication methods(including for e-diary completion), assist theparticipant with downloading the app, or issue
provisioned device, if required

X

Provide a thermometer (all participants) andmeasuring device (reactogenicity subset
participants only)

X

Unplanned

Unplanned

X

X

Review reactogenicity e-diary data (daily review is
optimal during the active diary period)dReview ongoing reactogenicity e-diary symptoms
and obtain stop datesd
Collect AEs and SAEs as appropriate

X

X

X

X

X

Collect e-diary or assist the participant to delete
application

X

X

X

X

X

Collection of COVID-19–related clinical andlaboratory information (including local diagnosis)
Abbreviation: e-diary = electronic diary.

a.
b.
c.
d.

The COVID-19 illness visit may be conducted as an in-person or telehealth visit.
The window for Visit 2 is dependent on the dosing schedule(s) selected for Stage 3.
Including, if indicated, a physical examination.
Reactogenicity subset participants only.

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2. INTRODUCTION
The BNT162 RNA-based COVID-19 vaccines are currently being investigated forprevention of COVID-19 in healthy adults.
2.1. Study Rationale
The purpose of the study is to rapidly describe the safety, tolerability, immunogenicity, andefficacy of 3 BNT162 RNA-based COVID-19 vaccine candidates against COVID-19 in
healthy adults. There are currently no licensed vaccines to prevent infection with
SARS-CoV-2 or antiviral drugs to treat COVID-19. Given the global crisis of COVID-19
and fast expansion of the disease in the United States and elsewhere, the rapid developmentof an effective vaccine is of utmost importance.

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)

2.2. Background
In December 2019, a pneumonia outbreak of unknown cause occurred in Wuhan, China.
In January 2020, it became clear that a novel coronavirus (2019-nCoV) was the underlying
cause. Later in January, the genetic sequence of the 2019-nCoV became available to theWorld Health Organization (WHO) and public (MN908947.3), and the virus was categorized
in the Betacoronavirus subfamily. By sequence analysis, the phylogenetic tree revealed acloser relationship to severe acute respiratory syndrome (SARS) virus isolates than to anothercoronavirus infecting humans, the Middle East respiratory syndrome (MERS) virus.
SARS-CoV-2 infections and the resulting disease, COVID-19, have spread globally,affecting a growing number of countries.
On 11 March 2020, the WHO characterized the COVID-19 outbreak as a pandemic.1
The WHO Situation Update Report dated 30 March 2020 noted 693,224 confirmed caseswith 33,106 deaths globally, including 142,081 confirmed cases with 2457 deaths in theAmericas.2 The United States currently has the most reported cases globally. At the time ofthis communication, the number of confirmed cases continues to rise globally. There are
currently no vaccines or effective antiviral drugs to treat SARS-CoV-2 infections or the
disease it causes, COVID-19.3
A prophylactic, RNA-based SARS-CoV-2 vaccine provides one of the most flexible andfastest approaches available to immunize against the emerging virus.4,5The development of an RNA-based vaccine encoding a viral antigen, which is then expressedby the vaccine recipient as a protein capable of eliciting protective immune responses,
provides significant advantages over more traditional vaccine approaches. Unlike live
attenuated vaccines, RNA vaccines do not carry the risks associated with infection and may
be given to people who cannot be administered live virus (eg, pregnant women andimmunocompromised persons). RNA-based vaccines are manufactured via a cell-free invitro transcription process, which allows an easy and rapid production and the prospect of
producing high numbers of vaccination doses within a shorter time period than achieved with

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traditional vaccine approaches. This capability is pivotal to enable the most effective
response in outbreak scenarios.

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)Three SARS-CoV-2–RNA lipid nanoparticle (RNA-LNP) vaccines based on a platform of
nucleoside-modified messenger RNA (modRNA, BNT162b) may be evaluated in this study.
Each vaccine candidate expresses 1 of 3 antigens: the SARS-CoV-2 full-length, P2 mutant,“heads up,” prefusion spike glycoprotein (P2 S) (version 9), a trimerized SARS-CoV-2 spikeglycoprotein-receptor binding domain (RBD) (version 5), or a membrane-anchoredtrimerized SARS-CoV-2 RBD. The 3 SARS-CoV-2 vaccine candidates that may be tested inthis study are therefore:

BNT162b1 (variant RBP020.3): nucleoside-modified messenger RNA (modRNA) withblunted innate immune sensor–activating capacity and augmented expression encoding
the RBD.



BNT162b2 (variant RBP020.2): nucleoside-modified messenger RNA (modRNA) as
above, but encoding P2 S.



BNT162b3 (variant RBP020.8): nucleoside-modified messenger RNA (modRNA) as
above, but encoding a membrane-anchored RBD.

2.2.1. Clinical Overview
Prior to this study, given clinical data from other similarly formulated uRNA liposomal
vaccines from BioNTech in oncology trials6 and recent published results from clinical trials
using modRNA influenza vaccines by Moderna,7 the BNT162 vaccines were expected tohave a favorable safety profile with mild, localized, and transient effects. BNT162 vaccines
based on modRNA have now been administered to humans for the first time in this study andthe BNT162-01 study conducted in Germany by BioNTech, at doses between 1 µg and 100µg. The currently available safety and immunogenicity data are presented in the BNT162 IB.
2.3. Benefit/Risk Assessment
There is an ongoing global pandemic of COVID-19 with no preventative or therapeutic
options available. While there were no data available from clinical trials on the use of
BNT162 vaccines in humans at the outset of this study, available nonclinical data with thesevaccines, and data from nonclinical studies and clinical trials with the same or related RNAcomponents, or antigens, supported a favorable risk/benefit profile. Anticipated AEs after
vaccination were expected to be manageable using routine symptom-driven standard of careas determined by the investigators and, as a result, the profile of these vaccine candidates
supported initiation of this Phase 1/2/3 clinical study.
More detailed information about the known and expected benefits and risks and reasonably
expected AEs of BNT162 RNA-based COVID-19 vaccines may be found in the IB, which is
the SRSD for this study.

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2.3.1. Risk Assessment
Potential Risk of ClinicalSignificance

Summary of Data/Rationale for Risk

Mitigation Strategy

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Study Intervention: BNT162 RNA-Based COVID-19 Vaccine
Potential for local reactions (injection These are common adverse reactions seensite redness, injection site swelling, with other vaccines, as noted in the FDA
and injection site pain) and systemic Center for Biologics Evaluation andResearch (CBER) guidelines on toxicity
events (fever, fatigue, headache,
grading scales for healthy adult volunteers
chills, vomiting, diarrhea, muscle
pain, and joint pain) following
enrolled in preventive vaccine clinicalvaccination.
trials.8

The study design includes the use of sentinel cohorts and dose escalation toclosely monitor and limit the rate of enrollment to ensure participant safety.
The study employs the use of a reactogenicity e-diary to monitor local
reactions and systemic events in real time. Stopping rules are also in place
for sentinel cohorts. The first 5 sentinel-cohort participants in each groupwill be observed for 4 hours after vaccination to assess any immediate AEs.

Unknown AEs and laboratory
abnormalities with a novel vaccine.

The study design includes the use of sentinel cohorts and dose escalation toThis study is one of the first 2 parallelrunning clinical studies with the BNT162 closely monitor and limit the rate of enrollment to ensure participant safety.
vaccine candidates and as such there are no An IRC and DMC will also review safety data throughout the study.
Stopping rules are also in place for sentinel cohorts. The first 5 sentinelclinical data available for this vaccine.
cohort participants in each group will be observed for 4 hours after
vaccination to assess any immediate AEs.

Potential for COVID-19 diseaseenhancement.

Disease enhancement has been seen
following vaccination with respiratorysyncytial virus (RSV), feline coronavirus,
and Dengue virus vaccines.

Stages 1 and 2 exclude participants with likely previous or current COVID19. In Stage 3, temporary delay criteria defer vaccination of participants
with possible current clinical COVID-19. All participants are followed for
SARS-CoV-2 antigen-specific antibody and SARS-CoV-2 serum
neutralizing titers, and COVID-19 illness, including markers of severity.

Study Procedures
Participants will be required to attend Without appropriate social distancing andhealthcare facilities during the global PPE, there is a potential for increased
exposure to SARS-CoV-2.
SARS-CoV-2 pandemic.
Venipuncture will be performed
during the study.

There is the risk of bleeding, bruising,hematoma formation, and infection at the
venipuncture site.

Pfizer will work with sites to ensure an appropriate COVID-19 prevention
strategy.
Only appropriately qualified personnel would obtain the blood draw.

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2.3.2. Benefit Assessment
Benefits to individual participants may include:Receipt of a potentially efficacious COVID-19 vaccine during a global pandemicAccess to COVID-19 diagnostic and antibody testingContributing to research to help others in a time of global pandemic

2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in thisstudy, the potential risks identified in association with BNT162 RNA-based COVID-19
vaccine are justified by the anticipated benefits that may be afforded to healthy participants.
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS

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3.1. For Stages 1 and 2
Objectives

Estimands

Endpoints

Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Primary:
In participants receiving at least 1 doseof study intervention and having safety
data reported after any vaccination, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each doseAdverse events (AEs) from
Dose 1 to 1 month after the lastdose
 Serious AEs (SAEs) from Dose 1
to 6 months after the last dosePrimary:
Local reactions (pain at the
injection site, redness, andswelling)

Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs

In addition, in sentinel cohorts from
Hematology and chemistry laboratory
Stage 1, the percentage of participants parameters detailed in Section 10.2
with:

Abnormal hematology andchemistry laboratory values 1 and7 days after Dose 1; and 7 days
after Dose 2
Grading shifts in hematology andchemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2

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Objectives

Estimands

Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Secondary:In participants complying with the key
protocol criteria (evaluableparticipants) at the following time
points after receipt of study
intervention:

Endpoints
Secondary:Stage 1 Sentinel Cohorts: 7 and21 days after Dose 1; 7 and 14 days and1, 6, 12, and 24 months after Dose 2
Stage 1 Nonsentinel Cohorts andStage 2 Cohorts: 21 days after Dose 1;
14 days and 1, 6, 12, and 24 months
after Dose 2
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







Geometric mean titers (GMTs) at SARS-CoV-2 serum neutralizing titers
each time point
Geometric mean fold rise (GMFR)
from before vaccination to eachsubsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
SARS-CoV-2 anti-S1 binding antibody
Geometric mean concentrations
levels and anti-RBD binding antibody(GMCs) at each time point
GMFR from prior to first dose of levels
study intervention to eachsubsequent time point
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
Geometric mean ratio (GMR),
estimated by the ratio of thegeometric mean of SARS-CoV-2
serum neutralizing titers to thegeometric mean of SARS-CoV-2
binding antibody levels at eachtime point

SARS-CoV-2 serum neutralizing
titers

SARS-CoV-2 anti-S1 binding
antibody levels



SARS-CoV-2 anti-RBD binding
antibody levels

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3.2. For Stage 3
Objectives
To evaluate the efficacies ofindividual prophylactic BNT162
vaccines against confirmed
COVID-19 in participants without
evidence of infection before
vaccination
To evaluate the efficacies ofindividual prophylactic BNT162
vaccines against confirmed
COVID-19 in participants with andwithout evidence of infection before
vaccination

Estimands
Primary Efficacy
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

Endpoints
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of the last
dose) of past SARS-CoV-2 infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT

Primary Safety
In participants receiving at least 1
dose of study intervention and havingsafety data reported after any
vaccination, the percentage ofparticipants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the last dose
SAEs from Dose 1 to 6 months
after the last dose

To define the safety profiles ofindividual prophylactic BNT162
vaccines in all participants
randomized in Stage 3

In participants receiving at least
1 dose of study intervention andhaving safety data reported after any
vaccination, the percentage ofparticipants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 monthafter the last dose
SAEs from Dose 1 to 6 months
after the last dose

To evaluate the efficacies ofindividual prophylactic BNT162
vaccines against confirmed severe
COVID-19 in participants without
evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

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To define the safety profiles ofindividual prophylactic BNT162
vaccines in the first 360 participants
randomized in Stage 3

Local reactions (pain at the
injection site, redness, andswelling)
Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened
muscle pain, and new orworsened joint pain)
AEs
SAEs

AEs
SAEs
In a subset of at least 6000
participants:
o Local reactions (pain at the
injection site, redness, andswelling)o Systemic events (fever,fatigue, headache, chills,
vomiting, diarrhea, new orworsened muscle pain, andnew or worsened joint pain)

Secondary Efficacy
Confirmed severe COVID-19
incidence per 1000 person-years offollow-up in participants with noserological or virological evidence of
past SARS-CoV-2 infection

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Objectives

Estimands

Endpoints

To evaluate the efficacies ofindividual prophylactic BNT162
vaccines against confirmed severe
COVID-19 in participants with andwithout evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

Confirmed severe COVID-19
incidence per 1000 person-years offollow-up

To describe the efficacies ofindividual prophylactic BNT162
vaccines against confirmed
COVID-19 (according to the
CDC-defined symptoms) inparticipants without evidence of
infection before vaccination
To describe the efficacies ofindividual prophylactic BNT162
vaccines against confirmed
COVID-19 (according to the
CDC-defined symptoms) inparticipants with and without
evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluableparticipants) at least 7 days after
receipt of the last dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT in participants withno serological or virological evidence(up to 7 days after receipt of the last
dose) of past SARS-CoV-2 infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locallyconfirmed NAAT

To evaluate the immune responseover time to BNT162 prophylactic
vaccines and persistence of immune
response in participants with andwithout serological or virologicalevidence of SARS-CoV-2 infection
before vaccination

GMT, GMFR, and percentage ofparticipants with titers greater thandefined threshold(s), at baseline and1, 6, 12, and 24 months after
completion of vaccination

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Secondary Immunogenicity

SARS-CoV-2 anti-S1 binding
antibody levels and/or anti-RBD
binding antibody levels
SARS-CoV-2 serum neutralizing
titersExploratory
To evaluate the immune response(non-S) to SARS-CoV-2 inparticipants with and without
confirmed COVID-19 during the
study



SARS-CoV-2 NVA-specificbinding antibody

To describe the serological responses
to the BNT vaccine candidate in casesof:
Confirmed COVID-19

Confirmed severe COVID-19

SARS-CoV-2 infection without
confirmed COVID-19



SARS-CoV-2 anti-S1 binding
antibody levels and/or anti-RBD
binding antibody levels
SARS-CoV-2 serum neutralizing
titers
SARS-CoV-2 NVA-specificbinding antibody
SARS-CoV-2 detection by
NAAT





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4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1/2/3, randomized, placebo-controlled, observer-blind, dose-finding, andvaccine candidate–selection study in healthy adults.

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)The study will evaluate the safety, tolerability, immunogenicity, and efficacy of 3 different
SARS-CoV-2 RNA vaccine candidates against COVID-19:


As a 2-dose (separated by 21 or 60 days) or single-dose schedule

At various different dose levels

In 3 age groups (18 to 55 years of age, 65 to 85 years of age, and 18 to 85 years of age[stratified as ≤55 or >55 years of age])

Dependent upon safety and/or immunogenicity data generated during the course of thisstudy, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
may be started at the next highest dose, groups may not be started, groups may be terminatedearly, and/or groups may be added with dose levels below the lowest stated dose orintermediate between the lowest and highest stated doses.
The study consists of 3 stages. Stage 1: to identify preferred vaccine candidate(s), doselevel(s), number of doses, and schedule of administration (with the first 15 participants ateach dose level of each vaccine candidate comprising a sentinel cohort); Stage 2: an
expanded-cohort stage; and Stage 3: an efficacy stage. These stages, and the progression
between them, are detailed in the schema (Section 1.2).
Stages 1 and 2 represent a Phase 1/2a assessment of a number of BNT162 vaccine candidates
and dose levels. Stage 3 is a seamless Phase 2b/3 assessment of one (or possibly more)
selected BNT162 vaccine candidate/dose level, powered to demonstrate efficacy.
The study is observer-blinded, as the physical appearance of the investigational vaccine
candidates and the placebo may differ. The participant, investigator, study coordinator, andother site staff will be blinded. At the study site, only the dispenser(s)/administrator(s) are
unblinded.
To facilitate rapid review of data in real time, sponsor staff will be unblinded to vaccine
allocation for the participants in Stage 1 and Stage 2.
4.1.1. Stage 1
Each group (vaccine candidate/dose level/age group/number of doses) will comprise
15 participants; 12 participants will be randomized to receive active vaccine and 3 to receive
placebo. On Day 22, those in 2-dose groups will receive the same vaccine they received on
Day 1; for those in single-dose groups, all will receive placebo. Full details of all potential
groups in Stage 1 may be found in Table 1.
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Protocol Amendment 4, 30 June 2020090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)For each vaccine candidate/dose level/age group, the 15 participants randomized into each2-dose group will comprise a sentinel cohort, to which the following apply:Additional safety assessments (see Section 8.2)

Controlled enrollment (required only for the first candidate and/or dose level studied):No more than 5 participants (4 active, 1 placebo) can be vaccinated on the first day

The first 5 participants must be observed by blinded site staff for at least 4 hours after
vaccination for any acute reactions

Vaccination of the remaining participants will commence no sooner than 24 hours
after the fifth participant received his or her vaccination

Application of stopping rules

IRC review of safety data to determine escalation to the next dose level in the 18- to
55-year age cohort:Escalation between dose levels will be based on IRC review of at least 7-day
post–Dose 1 safety data in this study and/or the BioNTech study conducted inGermany (BNT162-01)

Note that, since all candidates are based upon the same RNA platform, dose
escalation for the second and subsequent candidate(s) studied may be based upon thesafety profile of the first candidate studied being deemed acceptable at the same, or ahigher, dose level by the IRC

Groups of participants 65 to 85 years of age will not be started until safety data for the RNA
platform have been deemed acceptable at the same, or a higher, dose level in the 18- to
55-year age cohort by the IRC.
Once the IRC has selected a vaccine candidate/dose level to proceed into a later stage, foreach age cohort, 2 additional groups may be enrolled into Stage 1 for that vaccine
candidate/dose level:A 2-dose group, with the 2 doses administered 60 days apart rather than 21

A 1-dose group

In this stage, assuming 2 dose levels are selected following the initial dose escalation, up to
42 potential groups are foreseen; if all groups are fully enrolled, this corresponds to a total of
630 participants.

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A vaccine candidate/dose level that, in Stage 1, has an established dose level andimmunization schedule based on induction of an immune response in the sentinel evaluation,
including neutralizing antibodies, and is expected to be associated with protection against
COVID-19, can progress directly into Stage 3.
Vaccine candidate(s) that have preliminary evidence to support a dose and schedule and toshow that the candidate is safe and has evidence of vaccine-elicited antibody, but require
further safety and immunogenicity data to support progression to Stage 3, can progress toStage 2.
Since BNT162b1 and BNT162b3 are so similar, data from BNT162b1 may be used tosupport progression of BNT162b3 into either Stage 2 or Stage 3.

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4.1.2. Stage 2
On the basis of safety and/or immunogenicity data generated during the course of this study,
and/or the BioNTech study conducted in Germany (BNT162-01), 1 or more groups (vaccine
candidate/dose level) may be selected to proceed into Stage 2. Participants in this stage willbe 18 to 85 years of age, stratified as follows: 18 to 55 or 56 to 85 years. It is targeted toenroll approximately equal numbers of participants in the 2 age strata. Commencement ofeach age stratum will be dependent upon satisfactory safety and immunogenicity data fromthe 18- to 55-year and 65- to 85-year groups from Stage 1, respectively. It is therefore
possible that the 2 age strata may not start concurrently.
In each group selected for Stage 2, it is intended that 225 participants will be randomized in a
4:1 ratio to receive active vaccine (180 participants) or placebo (45 participants).
4.1.3. Stage 3
On the basis of safety and/or immunogenicity data generated during the course of this study,
and/or the BioNTech study conducted in Germany (BNT162-01), 1 or more group(s) may be
selected to proceed into Stage 3. Participants in this stage will be 18 to 85 years of age,stratified as follows: 18 to 55 years or 56 to 85 years. As in Stage 2, it is targeted to enroll
approximately equal numbers of participants in the 2 age strata and it is possible that the 2age strata may not start concurrently.
Stage 3 is event-driven. Under the assumption of a true VE rate of ≥60%, and using anefficacy criterion that requires the LL (of the alpha-adjusted CI for VE) to be >30%, a targetof 164 primary-endpoint cases of confirmed COVID-19 due to SARS-CoV-2 occurring atleast 7 days following the last dose of the primary series of the candidate vaccine will be
sufficient to provide 90% power to meet the primary objective. The total number ofparticipants enrolled in Stage 3 may vary depending on the incidence of COVID-19 at thetime of the enrollment, the number of candidate vaccines evaluated, the true underlying VE,
and a potential early stop for efficacy or futility.
Assuming a COVID-19 attack rate of 1.0% per year in the placebo group, an estimated 20%
nonevaluable rate, and 1:1 randomization, each vaccine candidate/dose level selected for
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Stage 3 is expected to comprise approximately 14,643 vaccine recipients per group. This is
the number of participants initially targeted for Stage 3 and may be adjusted based on advice
from DMC analyses of case accumulation and the percentage of participants who areseropositive at baseline. Dependent upon the evolution of the pandemic, it is possible that the
COVID-19 attack rate may be much higher, in which case accrual would be expected to be
more rapid, enabling the study’s primary endpoint to be evaluated much sooner.
For a vaccine candidate/dose level that progresses directly from Stage 1 to Stage 3, the first
360 participants enrolled (180 to active vaccine and 180 to placebo) will comprise the“Phase 2” portion. Safety data through 7 days after Dose 2 and immunogenicity data through21 days after Dose 1 from these 360 participants will be analyzed by the unblinded statisticalteam, reviewed by the DMC, and submitted to appropriate regulatory authorities for review.
Enrollment may continue during this period and these participants would be included in theefficacy evaluation in the “Phase 3” portion of the study.

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Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Stage 1 andStage 2 dosing arms that are not evaluated in Stage 3.
4.2. Scientific Rationale for Study Design
Additional surveillance for COVID-19 will be conducted as part of the study, given thepotential risk of disease enhancement. If a participant experiences symptoms, as detailed in
Section 8.13, a COVID-19 illness and subsequent convalescent visit will occur. As part ofthese visits, samples (nasal [midturbinate] swab and blood) will be taken for antigen andantibody assessment as well as recording of COVID-19–related clinical and laboratory
information (including local diagnosis).
Human reproductive safety data are not available for BNT162 RNA-based COVID-19
vaccines, but there is no suspicion of human teratogenicity based on the intended mechanismof action of the compound. Therefore, the use of a highly effective method of contraception
is required (see Appendix 4).
4.3. Justification for Dose
Because of the requirement for a rapid response to the newly emerged COVID-19 pandemic,
sufficient data are not currently available to experimentally validate the dose selection andinitial starting dose. Therefore, the original planned starting dose of 10 µg (for both
BNT162b1 and BNT162b2) in this study was based on nonclinical experience with the same
RNAs encoding other viral antigens (such as influenza and HIV antigens). The generalsafety and effectiveness of uRNA and modRNA platforms have been demonstrated inoncological clinical trials with different administration routes (NCT02410733,
NCT03871348). Doses of up to 400 µg total uRNA have been administered IV as RNA
lipoplex (RNA-LPX) and doses of up to 1000 µg total naked modRNA have been
administered intratumorally, both without signs of unpredictable overstimulation of theimmune system.
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Based on nonclinical data of the RNA components, with other liposomes or in conjunction
with the lipid nanoparticles as will be tested clinically in this study, it was expected that
doses in the 1- to 5-µg range would be immunogenic and induce neutralizing antibodies;
however, it was anticipated that 3- to 10-fold higher doses would likely be required to elicit astronger antibody response. Based on previous clinical and nonclinical experience, it was
expected that doses of up to 100 µg would be well tolerated.
Update as part of protocol amendment 2: preliminary experience in this study and the
BioNTech study conducted in Germany (BNT162-01) suggests that, for vaccine candidates
based on the modRNA platform, a dose level between 30 µg and 100 µg warrants
consideration. Therefore, a 50-µg dose level is formally included for BNT162b1 and
BNT162b2.

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Update as part of protocol amendment 3: as data have become available from this study andthe BNT162-01 study in Germany, it was decided:

To not study the BNT162a1 and BNT162c2 vaccine candidates at this time, so thesecandidates have been removed from the protocol; andThat lower dose levels of BNT162b1 and BNT162b2 warrant consideration. Therefore, a
20-µg dose level is formally included for both candidates.

Update as part of protocol amendment 4: the 50-µg dose level for BNT162b1 and BNT162b2
is removed and the 100-µg dose level for BNT162b2 is removed; similar dose levels of
BNT162b3 may be studied as for BNT162b1 and BNT162b2.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases ofthe study, including the last visit. Note that participants enrolled in Stages 1 and 2 in groups
that do not proceed to Stage 3 may be followed for fewer than 24 months (but no less than
6 months after the last vaccination).
The end of the study is defined as the date of last visit of the last participant in the study.
5. STUDY POPULATIONThis study can fulfill its objectives only if appropriate participants are enrolled. The
following eligibility criteria are designed to select participants for whom participation in the
study is considered appropriate. All relevant medical and nonmedical conditions should betaken into consideration when deciding whether a particular participant is suitable for thisprotocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also
known as protocol waivers or exemptions, is not permitted.

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5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male or female participants between the ages of 18 and 55 years, inclusive, 65 and85 years, inclusive, or 18 and 85 years, inclusive, at randomization (dependent uponstudy stage).


Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female(Section 10.4.2) participants.

Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, vaccination
plan, laboratory tests, lifestyle considerations, and other study procedures.

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3. Healthy participants who are determined by medical history, physical examination, andclinical judgment of the investigator to be eligible for inclusion in the study.
Note: Healthy participants with preexisting stable disease, defined as disease notrequiring significant change in therapy or hospitalization for worsening disease during
the 6 weeks before enrollment, can be included.
Informed Consent:
4. Capable of giving personal signed informed consent as described in Appendix 1, which
includes compliance with the requirements and restrictions listed in the ICD and in thisprotocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Other medical or psychiatric condition including recent (within the past year) or active
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study
participation or, in the investigator’s judgment, make the participant inappropriate for the
study.
2. Known infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or
hepatitis B virus (HBV).
3. History of severe adverse reaction associated with a vaccine and/or severe allergic
reaction (eg, anaphylaxis) to any component of the study intervention(s).
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4. Receipt of medications intended to prevent COVID-19.
5. Stages 1 and 2 only: Previous clinical or microbiological diagnosis of COVID-19.

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6. Sentinel participants in Stage 1 only: Individuals at high risk for severe COVID-19,
including those with any of the following risk factors:Hypertension

Diabetes mellitus

Chronic pulmonary diseaseAsthma

Current vaping or smoking

History of chronic smoking within the prior year

Chronic liver diseaseStage 3 or worse chronic kidney disease (glomerular filtration rate
<60 mL/min/1.73 m2)



Resident in a long-term facility

BMI >30 kg/m2

Anticipating the need for immunosuppressive treatment within the next 6 months

7. Sentinel participants in Stage 1 only: Individuals currently working in occupations withhigh risk of exposure to SARS-CoV-2 (eg, healthcare worker, emergency response
personnel).
8. Immunocompromised individuals with known or suspected immunodeficiency, as
determined by history and/or laboratory/physical examination.
9. Sentinel participants in Stage 1 only: Individuals with a history of autoimmune diseaseor an active autoimmune disease requiring therapeutic intervention, including but notlimited to: systemic or cutaneous lupus erythematosus, autoimmune arthritis/rheumatoid
arthritis, Guillain-Barré syndrome, multiple sclerosis, Sjögren’s syndrome, idiopathic
thrombocytopenia purpura, glomerulonephritis, autoimmune thyroiditis, giant cellarteritis (temporal arteritis), psoriasis, and insulin-dependent diabetes mellitus (type 1).
10. Bleeding diathesis or condition associated with prolonged bleeding that would, in theopinion of the investigator, contraindicate intramuscular injection.
11. Women who are pregnant or breastfeeding.
Prior/Concomitant Therapy:
12. Previous vaccination with any coronavirus vaccine.
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13. Individuals who receive treatment with immunosuppressive therapy, including cytotoxic
agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned
receipt throughout the study. If systemic corticosteroids have been administered shortterm (<14 days) for treatment of an acute illness, participants should not be enrolled into
the study until corticosteroid therapy has been discontinued for at least 28 days before
study intervention administration. Inhaled/nebulized (except for sentinel participants inStage 1 – see exclusion criterion 14), intra-articular, intrabursal, or topical (skin or eyes)corticosteroids are permitted.
14. Sentinel participants in Stage 1 only: Regular receipt of inhaled/nebulized
corticosteroids.
15. Receipt of blood/plasma products or immunoglobulin, from 60 days before study
intervention administration or planned receipt throughout the study.
Prior/Concurrent Clinical Study Experience:

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16. Participation in other studies involving study intervention within 28 days prior to study
entry and/or during study participation.
17. Previous participation in other studies involving study intervention containing lipid
nanoparticles.
Diagnostic Assessments:
18. Sentinel participants in Stage 1 only: Positive serological test for SARS-CoV-2 IgM
and/or IgG antibodies at the screening visit.
19. Sentinel participants in Stage 1 only: Any screening hematology and/or blood
chemistry laboratory value that meets the definition of a ≥ Grade 1 abnormality.
Note: With the exception of bilirubin, participants with any stable Grade 1 abnormalities(according to the toxicity grading scale) may be considered eligible at the discretion of
the investigator. (Note: A “stable” Grade 1 laboratory abnormality is defined as a reportof Grade 1 on an initial blood sample that remains ≤ Grade 1 upon repeat testing on asecond sample from the same participant.)
20. Sentinel participants in Stage 1 only: Positive test for HIV, hepatitis B surface antigen(HBsAg), hepatitis B core antibodies (HBc Abs), or hepatitis C virus antibodies(HCV Abs) at the screening visit.
21. Sentinel participants in Stage 1 only: SARS-CoV-2 NAAT-positive nasal swab within
24 hours before receipt of study intervention.

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Other Exclusions:
22. Investigator site staff or Pfizer employees directly involved in the conduct of the study,site staff otherwise supervised by the investigator, and their respective family members.
5.3. Lifestyle Considerations
5.3.1. Contraception

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)The investigator or his or her designee, in consultation with the participant, will confirm thatthe participant has selected an appropriate method of contraception for the individual
participant and his or her partner(s) from the permitted list of contraception methods(see Appendix 4, Section 10.4.4) and will confirm that the participant has been instructed inits consistent and correct use. At time points indicated in the SoA, the investigator ordesignee will inform the participant of the need to use highly effective contraception
consistently and correctly and document the conversation and the participant’s affirmation in
the participant’s chart (participants need to affirm their consistent and correct use of at least 1of the selected methods of contraception). In addition, the investigator or designee will
instruct the participant to call immediately if the selected contraception method is
discontinued or if pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but
are not subsequently randomly assigned to study intervention. A minimal set of screen
failure information is required to ensure transparent reporting of screen failure participants tomeet the CONSORT publishing requirements and to respond to queries from regulatory
authorities. Minimal information includes demography, screen failure details, eligibility
criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may berescreened under a different participant number.
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention
Administration
The following conditions are temporary or self-limiting and a participant may be vaccinatedonce the condition(s) has/have resolved and no other exclusion criteria are met.
1. Current febrile illness (body temperature ≥100.4°F [≥38°C]) or other acute illness within
48 hours before study intervention administration. This includes current symptoms that
could represent a potential COVID-19 illness:

New or increased cough;

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New or increased muscle pain;New loss of taste/smell;

Sore throat;

Diarrhea;Vomiting.

2. Receipt of any seasonal or pandemic influenza vaccine within 14 days, or any othernonstudy vaccine within 28 days, before study intervention administration.
3. Anticipated receipt of any seasonal or pandemic influenza vaccine within 14 days, or any
other nonstudy vaccine within 28 days, after study intervention administration.

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4. Receipt of short-term (<14 days) systemic corticosteroids. Study intervention
administration should be delayed until systemic corticosteroid use has been discontinued
for at least 28 days. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin oreyes) corticosteroids are permitted.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s),placebo, medical device(s), or study procedure(s) intended to be administered to a study
participant according to the study protocol.
The study may evaluate 2-dose (separated by 21 or 60 days) and single-dose schedules ofvarious different dose levels of 3 investigational RNA vaccine candidates for active
immunization against COVID-19 in 3 age groups (18 to 55 years of age, 65 to 85 years ofage, and 18 to 85 years of age [stratified as ≤55 or >55 years of age]).
These 3 investigational RNA vaccine candidates, with the addition of saline placebo, are the
3 potential study interventions that may be administered to a study participant:

BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 20 µg, 30 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 20 µg, 30 µg



BNT162b3 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding a membraneanchored RBD): 10 µg, 20 µg, 30 µgNormal saline (0.9% sodium chloride solution for injection)

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A list of all potential groups in the Stage 1 are shown in Table 1. Each of these groups may
or may not progress to the later stages of the study.
Table 1.

Potential Groups in Stage 1

GroupsN

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2-Dose Groups (Sentinel Cohorts)
b1-10-2-Y (Sentinel)
15[modRNA 10 µg (2 doses)]
b1-20-2-Y (Sentinel)
15[modRNA 20 µg (2 doses)]b1-30-2-Y (Sentinel)
15[modRNA 30 µg (2 doses)]b1-100-2-Y (Sentinel)
15[modRNA 100 µg(2 doses)]

Age
Group
(Years)18 to 55
18 to 55
18 to 55
18 to 55

b2-10-2-Y (Sentinel)[modRNA 10 µg (2 doses)]b2-20-2-Y (Sentinel)[modRNA 20 µg (2 doses)]b2-30-2-Y (Sentinel)[modRNA 30 µg (2 doses)]15

18 to 55

15

18 to 55

15

18 to 55

b3-10-2-Y (Sentinel)[modRNA 10 µg (2 doses)]b3-20-2-Y (Sentinel)[modRNA 20 µg (2 doses)]b3-30-2-Y (Sentinel)[modRNA 30 µg (2 doses)]15

18 to 55

15

18 to 55

15

18 to 55

b1-10-2-O (Sentinel)[modRNA 10 µg (2 doses)]
b1-20-2-O (Sentinel)[modRNA 20 µg (2 doses)]b1-30-2-O (Sentinel)[modRNA 30 µg (2 doses)]

15

65 to 8515

65 to 8515

65 to 85b2-10-2-O (Sentinel)[modRNA 10 µg (2 doses)]b2-20-2-O (Sentinel)[modRNA 20 µg (2 doses)]b2-30-2-O (Sentinel)[modRNA 30 µg (2 doses)]

15

65 to 8515

65 to 8515

65 to 85b3-10-2-O (Sentinel)[modRNA 10 µg (2 doses)]b3-20-2-O (Sentinel)[modRNA 20 µg (2 doses)]b3-30-2-O (Sentinel)[modRNA 30 µg (2 doses)]

15

65 to 8515

65 to 8515

65 to 85

Dose 1
Day 1
BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo

Dose 210 µg(n=12)(n=3)
20 µg (n=12)(n=3)
30 µg (n=12)(n=3)
100 µg (n=12)(n=3)

BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo

10 µg

BNT162b3
Placebo
BNT162b3
Placebo
BNT162b3
Placebo

10 µg

BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo

10 µg

BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo

10 µg

BNT162b3
Placebo
BNT162b3
Placebo
BNT162b3
Placebo

10 µg

20 µg
30 µg

20 µg
30 µg

20 µg
30 µg

20 µg
30 µg

20 µg
30 µg

Day 22
BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo(n=12)(n=3)
20 µg (n=12)(n=3)
30 µg (n=12)(n=3)
100 µg (n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo

10 µg(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

BNT162b3
Placebo
BNT162b3
Placebo
BNT162b3
Placebo

10 µg(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo

10 µg(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo

10 µg(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

BNT162b3
Placebo
BNT162b3
Placebo
BNT162b3
Placebo

10 µg

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10 µg

20 µg
30 µg

20 µg
30 µg

20 µg
30 µg

20 µg
30 µg

20 µg
30 µg

(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

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Table 1.

Potential Groups in Stage 1

Groups

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Single-Dose Groups
b1-x-1-Y[modRNA dose level(s)selected for Stage 2(1 dose)]b2-x-1-Y[modRNA dose level(s)selected for Stage 2(1 dose)]b3-x-1-Y[modRNA dose level(s)selected for Stage 2(1 dose)]b1-x-1-O[modRNA dose level(s)selected for Stage 2(1 dose)]b2-x-1-O[modRNA dose level(s)selected for Stage 2(1 dose)]b3-x-1-O[modRNA dose level(s)selected for Stage 2(1 dose)]

N

Age
Group
(Years)15

18 to 55

15

18 to 55

15

Dose 1
Day 1
BNT162b1
Placebo

Dose 2
Day 22
Placebo(n=15)(n=12)(n=3)

Placebo(n=15)

TBD(n=12)(n=3)

Placebo(n=15)

BNT162b1
Placebo

TBD(n=12)(n=3)

Placebo(n=15)

65 to 85

BNT162b2
Placebo

TBD(n=12)(n=3)

Placebo(n=15)

65 to 85

BNT162b3
Placebo

TBD(n=12)(n=3)

Placebo(n=15)

TBD(n=12)(n=3)

Day 61
BNT162b1
Placebo

TBD(n=12)(n=3)

BNT162b2
Placebo

TBD

18 to 55

BNT162b3
Placebo15

65 to 8515

15

2-Dose Groups (Longer Schedule)
b1-x-2L-Y
15[modRNA dose level(s)selected for Stage 2(2 doses)]b2-x-2L-Y
15[modRNA dose level(s)selected for Stage 2(2 doses)]b3-x-2L-Y
15[modRNA dose level(s)selected for Stage 2(2 doses)]

18 to 55

Day 1
BNT162b1
Placebo

TBD(n=12)(n=3)

18 to 55

BNT162b2
Placebo

TBD(n=12)(n=3)

BNT162b2
Placebo

TBD(n=12)(n=3)

18 to 55

BNT162b3
Placebo

TBD(n=12)(n=3)

BNT162b3
Placebo

TBD(n=12)(n=3)

b1-x-2L-O
15
65 to 85
BNT162b1
TBD(n=12)
BNT162b1 TBD[modRNA dose level(s)Placebo(n=3)
Placeboselected for Stage 2(2 doses)]b2-x-2L-O
15
65 to 85
BNT162b2
TBD(n=12)
BNT162b2 TBD[modRNA dose level(s)Placebo(n=3)
Placeboselected for Stage 2(2 doses)]b3-x-2L-O
15
65 to 85
BNT162b3
TBD(n=12)
BNT162b3 TBD[modRNA dose level(s)Placebo(n=3)
Placeboselected for Stage 2(2 doses)]Abbreviations: modRNA = nucleoside-modified messenger ribonucleic acid; TBD = to be determined.

(n=12)(n=3)

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6.1. Study Intervention(s) Administered
Intervention Name

BNT162b1 (BNT162
RNA-LNP vaccine
utilizing modRNA)

BNT162b2 (BNT162
RNA-LNP vaccine
utilizing modRNA)

BNT162b3 (BNT162
RNA-LNP vaccine
utilizing modRNA)Type
Dose Formulation

VaccinemodRNA

VaccinemodRNA

VaccinemodRNA

Saline placebo

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Placebo
Normal saline (0.9%sodium chloride
solution for injection)
Unit Dose Strength(s) 250 µg/0.5 mL
250 µg/0.5 mL
250 µg/0.5 mL
N/A
10-, 20-, 30-, 100-µg
10-, 20-, 30-µg
10-, 20-, 30-µg
N/A
Dosage Level(s)aRoute ofIntramuscular injection Intramuscular injection Intramuscular injection Intramuscular injection
Administration
Use
Experimental
Experimental
Experimental
Placebo
IMP or NIMP
IMP
IMP
IMP
IMP
Sourcing
Provided centrally by Provided centrally by Provided centrally by Provided centrally by
the sponsor
the sponsor
the sponsor
the sponsor
Packaging andStudy intervention will Study intervention will Study intervention will Study intervention willLabeling
be provided in a glass be provided in a glass be provided in a glass be provided in a glassvial as open-labelvial as open-labelvial as open-labelor plastic vial as opensupply. Each vial will supply. Each vial will supply. Each vial will label supply. Eachbe labeled as required be labeled as required be labeled as required vial will be labeled as
per country
per country
per country
required per country
requirement
requirement
requirement
requirementa.

Dependent upon safety and/or immunogenicity data generated during the course of this study, or the
BioNTech study conducted in Germany (BNT162-01), it is possible that groups may be started at the next
highest dose, groups may not be started, groups may be terminated early, and/or groups may be addedwith dose levels below the lowest stated dose or intermediate between the lowest and highest stated doses.

6.1.1. Administration
Participants will receive 1 dose of study intervention as randomized at each vaccination visit(Visits 1 and 4 for Stage 1 sentinel-cohort participants, Visits 1 and 2 for all otherparticipants) in accordance with the study’s SoA. The volume to be administered may varyby vaccine candidate and dose level; full details are described in the IP manual.
Study intervention should be administered intramuscularly into the deltoid muscle, preferablyof the nondominant arm, by an unblinded administrator.
Standard vaccination practices must be observed and vaccine must not be injected into bloodvessels. Appropriate medication and other supportive measures for management of an acute
hypersensitivity reaction should be available in accordance with local guidelines for standard
immunization practices.
Administration of study interventions should be performed by an appropriately qualified,
GCP-trained, and vaccine-experienced member of the study staff (eg, physician, nurse,
physician’s assistant, nurse practitioner, pharmacist, or medical assistant) as allowed by
local, state, and institutional guidance.
Study intervention administration details will be recorded on the CRF.
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6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study interventions received and any discrepancies arereported and resolved before use of the study intervention.

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2. Only participants enrolled in the study may receive study intervention and only
authorized site staff may supply or administer study intervention. All study interventions
must be stored in a secure, environmentally controlled, and monitored (manual or
automated recording) area in accordance with the labeled storage conditions with accesslimited to the investigator and authorized site staff. At a minimum, daily minimum andmaximum temperatures for all site storage locations must be documented and available
upon request. Data for nonworking days must indicate the minimum and maximum
temperatures since previously documented for all site storage locations upon return tobusiness.
3. Any excursions from the study intervention label storage conditions should be reported to
Pfizer upon discovery along with any actions taken. The site should actively pursue
options for returning the study intervention to the storage conditions described in thelabeling, as soon as possible. Once an excursion is identified, the study intervention must
be quarantined and not used until Pfizer provides permission to use the study
intervention. Specific details regarding the definition of an excursion and information thesite should report for each excursion will be provided to the site in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage conditions
stated on the label.
5. Study interventions should be stored in their original containers.
6. See the IP manual for storage conditions of the study intervention.
7. The investigator, institution, or the head of the medical institution (where applicable) is
responsible for study intervention accountability, reconciliation, and record maintenance(ie, receipt, reconciliation, and final disposition records), such as the IPAL orsponsor-approved equivalent. All study interventions will be accounted for using a study
intervention accountability form/record.
8. Further guidance and information for the final disposition of unused study interventions
are provided in the IP manual. All destruction must be adequately documented. If
destruction is authorized to take place at the investigator site, the investigator must ensurethat the materials are destroyed in compliance with applicable environmental regulations,institutional policy, and any special instructions provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of
discovery as described in the IP manual.

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6.2.1. Preparation and Dispensing
See the IP manual for instructions on how to prepare the study intervention foradministration. Study intervention should be prepared and dispensed by an appropriately
qualified and experienced member of the study staff (eg, physician, nurse, physician’s
assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as allowed by
local, state, and institutional guidance. A second staff member will verify the dispensing.
Study intervention and placebo will be prepared by qualified unblinded site personnel
according to the IP manual. The study intervention will be administered in such a way toensure the participants remain blinded.
6.3. Measures to Minimize Bias: Randomization and Blinding

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6.3.1. Allocation to Study Intervention
Allocation (randomization) of participants to vaccine groups will proceed through the use of
an IRT system (IWR). The site personnel (study coordinator or specified designee) will be
required to enter or select information including but not limited to the user’s ID andpassword, the protocol number, and the participant number. The site personnel will then be
provided with a vaccine assignment and randomization number. The IRT system will
provide a confirmation report containing the participant number, randomization number, andstudy intervention allocation assigned. The confirmation report must be stored in the site’s
files.
The study-specific IRT reference manual and IP manual will provide the contact informationand further details on the use of the IRT system.
6.3.2. Blinding of Site Personnel
In this observer blinded study, the study staff receiving, storing, dispensing, preparing, andadministering the study interventions will be unblinded. All other study and site personnel,
including the investigator, investigator staff, and participants, will be blinded to study
intervention assignments. In particular, the individuals who evaluate participant safety willbe blinded. Because the BNT162 RNA-based COVID-19 vaccine candidates and placebo
are different in physical appearance, the study intervention syringes will be administered in amanner that prevents the study participants from identifying the study intervention type basedon its appearance.
The responsibility of the unblinded dispenser and administrator must be assigned to anindividual or individuals who will not participate in the evaluation of any study participants.
Contact between the unblinded dispenser and study participants and unblinded administrator
and study participants should be kept to a minimum. The remaining site personnel must notknow study intervention assignments.

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6.3.3. Blinding of the Sponsor
To facilitate rapid review of data in real time, sponsor staff will be unblinded to study
intervention allocation for the participants in Stage 1 and in Stage 2. Sponsor staff will beblinded to study intervention allocation in Stage 3. All laboratory testing personnel
performing serology assays will remain blinded to study intervention assigned/received
throughout the study.
Those study team members who are involved in ensuring that protocol requirements forstudy intervention preparation, handling, allocation, and administration are fulfilled at the site
will be unblinded for the duration of the study (eg, unblinded study manager, unblindedclinical research associate). Unblinded clinician(s) who are not direct members of the study
team will review unblinded protocol deviations. All statistical analyses conducted on Stage 3
data while the study is ongoing will be performed by an unblinded statistical team.

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6.3.4. Breaking the Blind
The IRT will be programmed with blind-breaking instructions. In case of an emergency, theinvestigator has the sole responsibility for determining if unblinding of a participant’s study
intervention assignment is warranted. Participant safety must always be the firstconsideration in making such a determination. If the investigator decides that unblinding iswarranted, the investigator should make every effort to contact the sponsor prior to
unblinding a participant’s vaccine assignment unless this could delay further management of
the participant. If a participant’s vaccine assignment is unblinded, the sponsor must be
notified within 24 hours after breaking the blind. The date and reason that the blind was
broken must be recorded in the source documentation and CRF.
The study-specific IRT reference manual and IP manual will provide the contact informationand further details on the use of the IRT system.
6.4. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from theinvestigator or designee, under medical supervision. The date and time of each dose
administered in the clinic will be recorded in the source documents and recorded in the CRF.
The dose of study intervention and study participant identification will be confirmed at thetime of dosing by a member of the study site staff other than the person administering thestudy intervention.
6.5. Concomitant Therapy
The following concomitant medications and vaccinations will be recorded in the CRF:
All vaccinations received from 28 days prior to study enrollment until the 6-monthfollow-up visit (Visit 8 for Stage 1 sentinel cohorts, Visit 5 for Stage 1 nonsentinelcohorts and Stage 2 participants, and Visit 4 for Stage 3 participants).

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Prohibited medications listed in Section 6.5.1 will be recorded, to include start and stop
dates, name of the medication, dose, unit, route, and frequency.

In addition, for participants enrolled in the Stage 1 sentinel cohorts, all current
medication at baseline will be recorded, to include start date, name of the medication,dose, unit, route, and frequency.

6.5.1. Prohibited During the Study
Receipt of the following vaccines and medications during the time periods listed below may
exclude a participant from the per-protocol analysis from that point onwards, and may
require vaccinations to be discontinued in that participant; however, it is anticipated that theparticipant would not be withdrawn from the study (see Section 7). Medications should not
be withheld if required for a participant’s medical care.

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Unless considered medically necessary, no vaccines other than study intervention should be
administered within 28 days before and 28 days after each study vaccination. One exception
to this is that seasonal and pandemic influenza vaccine can be given at least 14 days after, orat least 14 days prior to, the administration of study intervention.
Receipt of chronic systemic treatment with known immunosuppressant medications, orradiotherapy, within 60 days before enrollment through conclusion of the study.
Receipt of systemic corticosteroids (≥20 mg/day of prednisone or equivalent) for ≥14 days is
prohibited from 28 days prior to enrollment to Visit 7 for Stage 1 sentinel cohorts, Visit 4 forStage 1 nonsentinel cohorts and Stage 2 participants, and Visit 3 for Stage 3 participants).
Receipt of inhaled/nebulized corticosteroids from 28 days prior to enrollment to Visit 7(1-month follow-up visit) for Stage 1 sentinel cohorts.
Receipt of blood/plasma products or immunoglobulins within 60 days before enrollment
through conclusion of the study.
Receipt of any other (nonstudy) coronavirus vaccine at any time prior to or during study
participation is prohibited.
Prophylactic antipyretics and other pain medication to prevent symptoms associated withstudy intervention administration are not permitted. However, if a participant is taking a
medication for another condition, even if it may have antipyretic or pain-relieving properties,
it should not be withheld prior to study vaccination.
6.5.2. Permitted During the Study
The use of antipyretics and other pain medication to treat symptoms associated with study
intervention administration or ongoing conditions is permitted.

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Medication other than that described as prohibited in Section 6.5.1 required for treatment ofpreexisting stable conditions is permitted.
Inhaled (except in Stage 1 sentinel cohorts – see Section 6.5.1), topical, or localized
injections of corticosteroids (eg, intra-articular or intrabursal administration) are permitted.
6.6. Dose Modification
This protocol allows some alteration of vaccine dose for individual participants and/or dosegroups from the currently outlined dosing schedule. For reasons of reactogenicity,
tolerability, or safety, the IRC may recommend to reduce the second dose of study
intervention and/or increase the interval between doses.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANTDISCONTINUATION/WITHDRAWAL
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7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study
intervention (definitive discontinuation). Reasons for definitive discontinuation of study
intervention may include the following: AEs; participant request; investigator request;
pregnancy; protocol deviation (including no longer meeting all the inclusion criteria, or
meeting 1 or more exclusion criteria).
Note that discontinuation of study intervention does not represent withdrawal from the study.
Per the study estimands, if study intervention is definitively discontinued, the participant willremain in the study to be evaluated for safety, immunogenicity, and efficacy. See the SoA
for data to be collected at the time of discontinuation of study intervention and follow-up for
any further evaluations that need to be completed.
In the event of discontinuation of study intervention, it must be documented on theappropriate CRF/in the medical records whether the participant is discontinuing further
receipt of study intervention or also from study procedures, posttreatment study follow-up,
and/or future collection of additional information.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request. Reasons fordiscontinuation from the study may include the following:

Refused further follow-up;

Lost to follow-up;



Death;
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Study terminated by sponsor;



AEs;



Participant request;

Investigator request;Protocol deviation.

If a participant does not return for a scheduled visit, every effort should be made to contact
the participant. All attempts to contact the participant and information received duringcontact attempts must be documented in the participant’s source document. In any
circumstance, every effort should be made to document participant outcome, if possible.
The investigator or his or her designee should capture the reason for withdrawal in the CRF
for all participants.

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If a participant withdraws from the study, he/she may request destruction of any remaining
samples taken and not tested, and the investigator must document any such requests in thesite study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1)
for disclosure of future information, no further evaluations should be performed and no
additional data should be collected. The sponsor may retain and continue to use any datacollected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not beviewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent
Participants who request to discontinue receipt of study intervention will remain in the study
and must continue to be followed for protocol-specified follow-up procedures. The only
exception to this is when a participant specifically withdraws consent for any further contact
with him or her or persons previously authorized by the participant to provide thisinformation. Participants should notify the investigator in writing of the decision towithdraw consent from future follow-up, whenever possible. The withdrawal of consent
should be explained in detail in the medical records by the investigator, as to whether thewithdrawal is only from further receipt of study intervention or also from study procedures
and/or posttreatment study follow-up, and entered on the appropriate CRF page. In the eventthat vital status (whether the participant is alive or dead) is being measured, publicly
available information should be used to determine vital status only as appropriately directedin accordance with local law.

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7.3. Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return forscheduled visits and is unable to be contacted by the study site.

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)The following actions must be taken if a participant fails to attend a required study visit:The site must attempt to contact the participant and reschedule the missed visit as soon as
possible and counsel the participant on the importance of maintaining the assigned visit
schedule and ascertain whether or not the participant wishes to and/or should continue inthe study;

Before a participant is deemed lost to follow-up, the investigator or designee must makeevery effort to regain contact with the participant (where possible, 3 telephone calls and,if necessary, a certified letter to the participant’s last known mailing address or local
equivalent methods). These contact attempts should be documented in the participant’s
medical record;Should the participant continue to be unreachable, he/she will be considered to havewithdrawn from the study.

8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed anddated ICD before performing any study-specific procedures.
The full date of birth will be collected to critically evaluate the immune response and safety
profile by age.
Study procedures and their timing are summarized in the SoA. Protocol waivers or
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence orawareness to determine whether the participant should continue or discontinue study
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential
participants meet all eligibility criteria. The investigator will maintain a screening log torecord details of all participants screened and to confirm eligibility or record reasons forscreening failure, as applicable.
Every effort should be made to ensure that protocol-required tests and procedures arecompleted as described. However, it is anticipated that from time to time there may becircumstances outside the control of the investigator that may make it unfeasible to perform
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the test. In these cases, the investigator must take all steps necessary to ensure the safety andwell-being of the participant. When a protocol-required test cannot be performed, theinvestigator will document the reason for the missed test and any corrective and preventive
actions that he or she has taken to ensure that required processes are adhered to as soon as
possible. The study team must be informed of these incidents in a timely manner.

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For samples being collected and shipped, detailed collection, processing, storage, andshipment instructions and contact information will be provided to the investigator site prior
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately
530 mL for participants in the Stage 1 sentinel cohorts; 350 mL for participants in the Stage 1
nonsentinel cohorts and Stage 2 participants; and 125 mL for Stage 3 participants.
Additionally, 50 mL of blood will be taken at an unplanned convalescent visit at any time aparticipant develops respiratory symptoms indicating a potential COVID-19 infection. Selectparticipants in the sentinel cohorts of Stage 1 will also be asked to provide an additional
blood sample of approximately 170 mL at either Visit 5, 6, or 7. These participants would
therefore have a total blood sampling volume of 700 mL during the 24-month study period.
Other additional blood samples may be taken for safety assessments at times specified by
Pfizer, provided the total volume taken during the study does not exceed 550 mL during any
period of 60 consecutive days.
8.1. Efficacy and/or Immunogenicity Assessments
Efficacy will be assessed throughout a participant’s involvement in the study throughsurveillance for potential cases of COVID-19. If, at any time, a participant develops acuterespiratory illness (see Section 8.13), for the purposes of the study he or she will beconsidered to potentially have COVID-19 illness.9 In this circumstance, the participant
should contact the site, an in-person or telehealth visit should occur, and assessments should
be conducted as specified in the SoA. The assessments will include a nasal (midturbinate)swab, which will be tested at a central laboratory using a reverse transcription–polymerase
chain reaction (RT-PCR) test (Cepheid; FDA approved under EUA), or other equivalent
nucleic acid amplification–based test (ie, NAAT), to detect SARS-CoV-2. In addition,clinical information and results from local standard-of-care tests (as detailed in Section 8.13)
will be assessed. A local NAAT result will be considered acceptable if it was obtained using:An FDA-cleared (including Emergency Use Authorization) assay; orAn assay that is not FDA cleared but was conducted in a laboratory that is currently
CLIA certified; orAn assay performed by a laboratory accredited according to the ISO 15189 standard by anational or regional accreditation body.

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Two definitions of SARS-CoV-2–related cases, and SARS-CoV-2–related severe cases, will
be considered (for both, the onset date of the case will be the date that symptoms were firstexperienced by the participant):

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Confirmed COVID-19: presence of at least 1 of the following symptoms and
SARS-CoV-2 NAAT positive at central laboratory or at a local testing facility (using an
acceptable test):Fever;

New or increased cough;

New or increased shortness of breath;Chills;

New or increased muscle pain;New loss of taste or smell;

Sore throat;

Diarrhea;Vomiting.

The second definition, which may be updated as more is learned about COVID-19, will
include the following additional symptoms defined by the CDC (listed athttps://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html):



Fatigue;Headache;

Nasal congestion or runny nose;Nausea.

Confirmed severe COVID-19: confirmed COVID-19 and presence of at least 1 of thefollowing:Clinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per minute,HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or PaO2/FiO2<300 mm Hg);

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Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation,mechanical ventilation, or ECMO);

Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiring vasopressors);

Significant acute renal, hepatic, or neurologic dysfunction*;Admission to an ICU;Death.

The DMC may recommend modification of the definition of severe disease according toemerging information.
* If a NAAT-confirmed case in Stage 3 may be considered severe, or not, solely on the basisof this criterion, the blinded data will be reviewed by 3 medically qualified Pfizer staff
members to assess whether the criterion is met; the majority opinion will prevail.

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In addition, a serological definition will be used for participants without clinical presentationof COVID-19:


Confirmed seroconversion to SARS-CoV-2 without confirmed COVID-19: positive
SARS-CoV-2 NVA-binding antibody result in a participant with a prior negative
SARS-CoV-2 NVA-binding antibody result

Serum samples will be obtained for immunogenicity testing at the visits specified in the SoA.
The following assays will be performed:

SARS-CoV-2 serum neutralization assay

SARS-CoV-2 anti-S1 IgG direct Luminex immunoassay

SARS-CoV-2 anti-RBD IgG direct Luminex immunoassay

Nonvaccine antigen (NVA) Ig direct Luminex immunoassay. The NVA will include a
SARS-CoV-2 target antigen that is not derived from the S glycoprotein, most likely anantigen derived from the SARS-CoV-2 nucleoprotein.

Note that all immunogenicity analyses will be based upon samples analyzed at the central
laboratory; the rapid test will only be performed at screening by all sites recruiting
participants in Stage 1 sentinel cohorts (see Section 8.11.1.1) to determine eligibility.
Serum obtained from the additional ~170-mL blood sample from select participants in thesentinel cohorts of Stage 1 at either Visit 5, 6, or 7 will be used for exploratory COVID-19
research, intended to establish a surrogate endpoint that is reasonably likely to predict clinicalbenefit.
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8.1.1. Biological Samples
Blood and nasal swab samples will be used only for scientific research. Each sample will belabeled with a code so that the laboratory personnel testing the samples will not know theparticipant’s identity. Samples that remain after performing assays outlined in the protocol
may be stored by Pfizer. Unless a time limitation is required by local regulations or ethicalrequirements, the samples will be stored for up to 15 years after the end of the study and thendestroyed. If allowed by the ICD, stored samples may be used for additional testing to better
understand the immune responses to the vaccine(s) under study in this protocol, to inform thedevelopment of other products, and/or for vaccine-related assay work supporting vaccine
programs. No testing of the participant’s DNA will be performed.
The participant may request that his or her samples, if still identifiable, be destroyed at any
time; however, any data already collected from those samples will still be used for thisresearch. The biological samples may be shared with other researchers as long asconfidentiality is maintained and no testing of the participant’s DNA is performed.

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8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinicallaboratory measurements may be obtained at any time during the study to assess any
perceived safety issues.
A clinical assessment, including medical history, will be performed on all participants at
his/her first visit to establish a baseline. Significant medical history and observations fromany physical examination, if performed, will be documented in the CRF.
AEs and SAEs are collected, recorded, and reported as defined in Section 8.3.
Acute reactions within the first 4 hours after administration of the study intervention (for the
first 5 participants vaccinated in each Stage 1 sentinel group), and within the first 30 minutes(for the remainder of participants), will be assessed and documented in the AE CRF.
The safety parameters also include reactogenicity e-diary reports of local reactions andsystemic events (including fever), and use of antipyretic medication that occur in the 7 days
after administration of the study intervention. These prospectively self-collected occurrencesof local reactions and systemic events are graded as described in Section 8.2.2.
8.2.1. Clinical Safety Laboratory Assessments (Sentinel-Cohort Participants Only)
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for
the timing and frequency. All protocol-required laboratory assessments, as defined inAppendix 2, must be conducted in accordance with the laboratory manual and the SoA.
Unscheduled clinical laboratory measurements may be obtained at any time during the study
to assess any perceived safety issues.
The investigator must review the laboratory report, document this review, and record any
clinically relevant changes occurring during the study in the AE section of the CRF. See
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Appendix 2 for the grading scale for assessment of clinically significant abnormal laboratory
findings. Clinically significant abnormal laboratory findings are those which are notassociated with the underlying disease, unless judged by the investigator to be more severe
than expected for the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during
participation in the study or within 28 days after the last dose of study intervention should be
repeated until the values return to normal or baseline or are no longer considered clinicallysignificant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 5 for suggested actions and follow-up assessments in the event of potential
drug-induced liver injury.

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8.2.2. Electronic Diary
Participants will be required to complete a reactogenicity e-diary through an application(see Section 8.14) installed on a provisioned device or on the participant’s own personal
device. All participants in Stages 1 and 2, and a subset of at least 6000 in Stage 3, will be
asked to monitor and record local reactions, systemic events, and antipyretic medication
usage for 7 days following administration of the study intervention. The reactogenicity
e-diary allows recording of these assessments only within a fixed time window, thus
providing the accurate representation of the participant’s experience at that time. Data on
local reactions and systemic events reported in the reactogenicity e-diary will be transferred
electronically to a third-party vendor, where they will be available for review by investigatorsand the Pfizer clinicians at all times via an internet-based portal.
At intervals agreed to by the vendor and Pfizer, these data will be transferred electronicallyinto Pfizer's database for analysis and reporting. These data do not need to be reported by theinvestigator in the CRF as AEs.
Investigators (or designee) will be required to review the reactogenicity e-diary data online atfrequent intervals as part of the ongoing safety review.
The investigator or designee must obtain stop dates from the participant for any ongoing
local reactions, systemic events, or use of antipyretic medication on the last day that thereactogenicity e-diary was completed. The stop dates should be documented in the source
documents and the information entered in the CRF.
8.2.2.1. Grading Scales
The grading scales used in this study to assess local reactions and systemic events as
described below are derived from the FDA Center for Biologics Evaluation and Research(CBER) guidelines on toxicity grading scales for healthy adult volunteers enrolled inpreventive vaccine clinical trials.8
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8.2.2.2. Local Reactions
During the reactogenicity e-diary reporting period, participants will be asked to assess
redness, swelling, and pain at the injection site and to record the symptoms in thereactogenicity e-diary. If a local reaction persists beyond the end of the reactogenicity
e-diary period following vaccination, the participant will be requested to report that
information. The investigator will enter this additional information in the CRF.

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Redness and swelling will be measured and recorded in measuring device units(range: 1 to 21) and then categorized during analysis as absent, mild, moderate, or severe
based on the grading scale in Table 2. Measuring device units can be converted tocentimeters according to the following formula: 1 measuring device unit = 0.5 cm. Pain at
the injection site will be assessed by the participant as absent, mild, moderate, or severe
according the grading scale in Table 2.
If a Grade 3 local reaction is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinicallyindicated. Only an investigator or medically qualified person is able to classify aparticipant’s local reaction as Grade 4. If a participant experiences a confirmed Grade 4 local
reaction, the investigator must immediately notify the sponsor and, if it is determined to berelated to the administration of the study intervention, further vaccinations will be
discontinued in that participant.
Table 2.

Local Reaction Grading Scale
Mild(Grade 1)

Moderate(Grade 2)

Pain at the
injection site

Does not interferewith activity

Interferes withactivity

Redness

2.0 cm to 5.0 cm(5 to 10 measuring
device units)
2.0 cm to 5.0 cm(5 to 10 measuring
device units)>5.0 cm to 10.0 cm(11 to 20 measuring
device units)>5.0 cm to 10.0 cm(11 to 20 measuring
device units)

Swelling

Severe(Grade 3)

Potentially Life
Threatening(Grade 4)
Prevents daily activity Emergency room visit
or hospitalization forsevere pain
>10 cmNecrosis or(≥21 measuringexfoliative dermatitis
device units)>10 cmNecrosis(≥21 measuring
device units)

8.2.2.3. Systemic Events
During the reactogenicity e-diary reporting period, participants will be asked to assess
vomiting, diarrhea, headache, fatigue, chills, new or worsened muscle pain, and new orworsened joint pain and to record the symptoms in the reactogenicity e-diary. The symptoms
will be assessed by the participant as absent, mild, moderate, or severe according to thegrading scale in Table 3.
If a Grade 3 systemic event is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinically
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indicated. Only an investigator or medically qualified person is able to classify aparticipant’s systemic event as Grade 4. If a participant experiences a confirmed Grade 4
systemic event, the investigator must immediately notify the sponsor and, if it is determined
to be related to the administration of the study intervention, further vaccinations will be
discontinued in that participant.
Table 3.

Systemic Event Grading Scale

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Mild(Grade 1)

Moderate(Grade 2)>2 times in
24 hours

Severe(Grade 3)

Vomiting

1-2 times in
24 hours

Requires IV
hydration

Diarrhea

2 to 3 loose stools 4 to 5 loose stools
in 24 hours
in 24 hours

6 or more loosestools in 24 hours

Headache

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Fatigue/tiredness

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Chills

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

New orworsened
muscle pain

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Does not interfere Some interference
New orwith activity
with activity
worsened
joint pain
Abbreviation: IV = intravenous.

Prevents daily
routine activity

Potentially Life
Threatening(Grade 4)
Emergency room visit or
hospitalization for
hypotensive shock
Emergency room visit or
hospitalization for severe
diarrhea
Emergency room visit or
hospitalization for severe
headache
Emergency room visit or
hospitalization for severe
fatigue
Emergency room visit or
hospitalization for severe
chillsEmergency room visit or
hospitalization for severe
new or worsened muscle
painEmergency room visit or
hospitalization for severe
new or worsened joint pain

8.2.2.4. Fever
In order to record information on fever, a thermometer will be given to participants with
instructions on how to measure oral temperature at home. Temperature will be collected in
the reactogenicity e-diary in the evening daily during the reactogenicity e-diary reporting
period. It will also be collected at any time during the reactogenicity e-diary data collection
periods when fever is suspected. Fever is defined as an oral temperature of ≥38.0°C(100.4°F). The highest temperature for each day will be recorded in the reactogenicity
e-diary. Temperature will be measured and recorded to 1 decimal place and then categorized
during analysis according to the scale shown in Table 4.
If a fever of ≥39.0°C (102.1°F) is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinicallyindicated. Only an investigator or medically qualified person is able to confirm a
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participant’s fever as >40.0°C (>104.0°F). If a participant experiences a confirmed fever>40.0°C (>104.0°F), the investigator must immediately notify the sponsor and, if it isdetermined to be related to the administration of the study intervention, further vaccinations
will be discontinued in that participant.
Table 4.

Scale for Fever≥38.0-38.4°C (100.4-101.1°F)>38.4-38.9°C (101.2-102.0°F)>38.9-40.0°C (102.1-104.0°F)>40.0°C (>104.0°F)

8.2.2.5. Antipyretic Medication
The use of antipyretic medication to treat symptoms associated with study intervention
administration will be recorded in the reactogenicity e-diary daily during the reporting period(Day 1 to Day 7).
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8.2.3. Stopping Rules
The following stopping rules are in place for all Stage 1 sentinel-cohort participants, basedon review of AE data and e-diary reactogenicity data. These data will be monitored on an
ongoing basis by the investigator (or medically qualified designee) and sponsor in order topromptly identify and flag any event that potentially contributes to a stopping rule.
The sponsor study team will be unblinded during the Stage 1, so will be able to assess
whether or not a stopping rule has been met on the basis of a participant’s individual study
intervention allocation.
In the event that sponsor personnel confirm that a stopping rule is met, the following actions
will commence:The IRC will review all appropriate data.

The stopping rule will PAUSE randomization and study intervention administration for
the impacted vaccine candidate all dose levels and age groups.



The DMC will review all appropriate data.

For all participants vaccinated, all other routine study conduct activities, including
ongoing data entry, reporting of AEs, participant reactogenicity e-diary completion,
blood sample collection, and participant follow-up, will continue during the pause.

A stopping rule is met if any of the following rules occur after administration of
investigational BNT162 vaccine; data from placebo recipients will not contribute to the

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stopping rules. Reactogenicity e-diary data confirmed by the investigator as being entered by
the participant in error will not contribute toward a stopping rule.
The BNT162b RNA platform will be evaluated for contribution to stopping rules overall;
vaccine candidate dose levels within the platform and age groups will contribute to stopping
rules together. However, it is possible that the recommendations may include halting or
continuing randomization with any of the BNT162 vaccine candidates.
Stopping Rule Criteria for Each BNT162 Vaccine Candidate:
1. If any participant vaccinated with the BNT162 candidate (at any dose level) develops an
SAE that is assessed by the investigator as possibly related, or for which there is noalternative, plausible, attributable cause.

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2. If any participant vaccinated with the BNT162 candidate (at any dose level) develops a
Grade 4 local reaction or systemic event after vaccination (see Section 8.2.2) that is
assessed as possibly related by the investigator, or for which there is no alternative,plausible, attributable cause.
3. If any participant vaccinated with the BNT162 candidate (at any dose level) develops afever >40.0°C (>104.0°F) for at least 1 daily measurement after vaccination(see Section 8.2.2.4) that is assessed as possibly related by the investigator, or for which
there is no alternative, plausible, attributable cause.
4. If any 2 participants vaccinated with the BNT162 candidate (at any dose level) report thesame or similar severe (Grade 3) AE (including laboratory abnormalities) after
vaccination, assessed as possibly related by the investigator, or for which there is noalternative, plausible, attributable cause.
5. If any participant dies or requires ICU admission due to SARS-CoV-2 infection; if thisstopping rule is met, all available clinical and preclinical safety and immunogenicity data
should be reviewed to evaluate for enhanced COVID-19 disease.
A separate stopping rule will apply in Stage 3 for enhanced COVID-19 disease. At the timeof each IA, the numbers of severe cases in the vaccine and placebo groups will be assessed.
If there are more severe cases in the vaccine group than in the placebo group, the DMC will
be advised to recommend that enrollment be stopped if the probability of the adverse split
being observed is <1%, assuming that severe cases are truly evenly split. Further details canbe found in Section 10.7. If enrollment is stopped, second doses will still be administered,and follow-up will continue. If the probability is ≥1% and <11%, the DMC will be advised torequest probability to be recalculated as each additional severe case is accrued.

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8.2.3.1. Randomization and Vaccination After a Stopping Rule Is Met
Once the IRC and DMC have reviewed the safety data and provided guidance, a notification
will be sent from the sponsor to the sites with guidance on how to proceed.
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19 Disease
As this is a sponsor open-label study during Stages 1 and 2, the sponsor will conduct
unblinded reviews of the data during the course of the study, including for the purpose ofsafety assessment.
Participants in all stages of the study will be surveilled for potential COVID-19 illness from
Visit 1 onwards (see Section 8.13). All NAAT-confirmed cases in Stages 1 and 2 will be
reviewed contemporaneously by the IRC and the DMC (see Section 9.6).

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)In Stage 3, the unblinded statistical team, including an unblinded medical monitor, will
review cases of severe COVID-19 as they are received, and will review AEs at least weekly
for additional potential cases of severe COVID-19. At any point the unblinded team may
discuss with the DMC chair whether the DMC should review cases for an adverse imbalanceof cases of COVID-19 and/or severe COVID-19 between the vaccine and placebo groups.
The purpose of these reviews will be to identify whether any features of each case appear
unusual, in particular greater severity, compared to available information at the time ofreview. Indicators of severity may include accelerated deterioration, need for hospitalization,need for ventilation, or death. Observed rates of these indicators will be compared with what
could be expected in a similar population to the study participants based upon available
information at the time of review. Since the DMC is able to review unblinded information, it
will also be able to compare cases in active vaccine and placebo recipients in Stage 3 (whensponsor staff will be blinded).
8.2.5. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA,
immediately before the administration of each vaccine dose. A negative pregnancy test result
will be required prior to the participant’s receiving the study intervention. Pregnancy tests
may also be repeated if requested by IRBs/ECs or if required by local regulations. In thecase of a positive confirmed pregnancy, the participant will be withdrawn fromadministration of study intervention but may remain in the study.

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8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or
the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, andrecording events that meet the definition of an AE or SAE and remain responsible to pursue
and obtain adequate information both to determine the outcome and to assess whether the
event meets the criteria for classification as an SAE or caused the participant to discontinue
the study intervention (see Section 7.1).
Each participant will be questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up
information in an expedited fashion.

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8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection
period”) for each participant begins from the time the participant provides informed consent,
which is obtained before the participant’s participation in the study (ie, before undergoing
any study-related procedure and/or receiving study intervention), through and including
Visit 7 for Stage 1 sentinel-cohort participants, Visit 4 for Stage 1 nonsentinel participants
and Stage 2 participants, and Visit 3 for Stage 3 participants. In addition, any AEs occurring
up to 48 hours after each subsequent blood draw must be recorded on the CRF.
SAEs will be collected from the time the participant provides informed consent toapproximately 6 months after the last dose of study intervention (Visit 8 for Stage 1
sentinel-cohort participants, Visit 5 for Stage 1 non–sentinel-cohort participants and Stage 2
participants, and Visit 4 for Stage 3 participants).
Follow-up by the investigator continues throughout and after the active collection period anduntil the AE or SAE or its sequelae resolve or stabilize at a level acceptable to theinvestigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervention
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE
reported using the Vaccines SAE Report Form.

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Investigators are not obligated to actively seek AEs or SAEs after the participant has
concluded study participation. However, if the investigator learns of any SAE, including adeath, at any time after a participant has completed the study, and he/she considers the event
to be reasonably related to the study intervention, the investigator must promptly report the
SAE to Pfizer using the Vaccines SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in
Section 8.3.1 are reported to Pfizer Safety on the Vaccines SAE Report Form immediately
upon awareness and under no circumstance should this exceed 24 hours, as indicated inAppendix 3. The investigator will submit any updated SAE data to the sponsor within
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF

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All nonserious AEs and SAEs occurring in a participant during the active collection period,
which begins after obtaining informed consent as described in Section 8.3.1, will be recordedon the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and theprocedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended andnonleading verbal questioning of the participant is the preferred method to inquire about
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow eachparticipant at subsequent visits/contacts. For each event, the investigator must pursue andobtain adequate information until resolution, stabilization, the event is otherwise explained,or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail toallow for a complete medical assessment of the case and independent determination of
possible causality. Any information relevant to the event, such as concomitant medications
and illnesses, must be provided. In the case of a participant death, a summary of available
autopsy findings must be submitted as soon as possible to Pfizer Safety.
Further information on follow-up procedures is given in Appendix 3.

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8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal
obligations and ethical responsibilities towards the safety of participants and the safety of astudy intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and otherregulatory agencies about the safety of a study intervention under clinical investigation. The
sponsor will comply with country-specific regulatory requirements relating to safety
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the
study and will notify the IRB/EC, if appropriate according to local requirements.

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8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding andoccupational exposure are reportable to Pfizer Safety within 24 hours of investigatorawareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if:A female participant is found to be pregnant while receiving or after discontinuing study
intervention.



A male participant who is receiving or has discontinued study intervention exposes afemale partner prior to or around the time of conception.



A female is found to be pregnant while being exposed or having been exposed to study
intervention due to environmental exposure. Below are examples of environmental
exposure during pregnancy:

A female family member or healthcare provider reports that she is pregnant after
having been exposed to the study intervention by inhalation or skin contact.

A male family member or healthcare provider who has been exposed to the study
intervention by inhalation or skin contact then exposes his female partner prior to or
around the time of conception.

The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s
awareness, irrespective of whether an SAE has occurred. The initial information submitted
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should include the anticipated date of delivery (see below for information related totermination of pregnancy).


If EDP occurs in a participant or a participant’s partner, the investigator must report thisinformation to Pfizer Safety on the Vaccines SAE Report Form and an EDP
Supplemental Form, regardless of whether an SAE has occurred. Details of thepregnancy will be collected after the start of study intervention and until 6 months after
the last dose of study intervention.



If EDP occurs in the setting of environmental exposure, the investigator must report
information to Pfizer Safety using the Vaccines SAE Report Form and EDP
Supplemental Form. Since the exposure information does not pertain to the participant
enrolled in the study, the information is not recorded on a CRF; however, a copy of thecompleted Vaccines SAE Report Form is maintained in the investigator site file.

Follow-up is conducted to obtain general information on the pregnancy and its outcome for
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as afollow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural
integrity of the neonate can be assessed at the time of birth. In the event of a termination, thereason(s) for termination should be specified and, if clinically possible, the structural
integrity of the terminated fetus should be assessed by gross visual inspection (unlesspreprocedure test findings are conclusive for a congenital anomaly and the findings arereported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meetsthe criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal
demise, neonatal death, or congenital anomaly), the investigator should follow the procedures
for reporting SAEs. Additional information about pregnancy outcomes that are reported to
Pfizer Safety as SAEs follows:

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard tocausality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs
when the investigator assesses the infant death as related or possibly related to exposure
to the study intervention.

Additional information regarding the EDP may be requested by the sponsor. Further
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on
preterm infants to identify developmental delays). In the case of paternal exposure, theinvestigator will provide the participant with the Pregnant Partner Release of Information
Form to deliver to his partner. The investigator must document in the source documents thatthe participant was given the Pregnant Partner Release of Information Form to provide to his
partner.
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8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if:A female participant is found to be breastfeeding while receiving or after discontinuing
study intervention.



A female is found to be breastfeeding while being exposed or having been exposed to
study intervention (ie, environmental exposure). An example of environmental exposure
during breastfeeding is a female family member or healthcare provider who reports that
she is breastfeeding after having been exposed to the study intervention by inhalation orskin contact.

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hoursof the investigator’s awareness, irrespective of whether an SAE has occurred. The
information must be reported using the Vaccines SAE Report Form. When exposure during
breastfeeding occurs in the setting of environmental exposure, the exposure information does
not pertain to the participant enrolled in the study, so the information is not recorded on a
CRF. However, a copy of the completed Vaccines SAE Report Form is maintained in theinvestigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specificallyapproved for use in breastfeeding women (eg, vitamins) is administered in accord withauthorized use. However, if the infant experiences an SAE associated with such a drug, theSAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with thestudy intervention, which may or may not lead to the occurrence of an AE. Such persons
may include healthcare providers, family members, and other roles that are involved in thetrial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of theinvestigator’s awareness, regardless of whether there is an associated SAE. The informationmust be reported using the Vaccines SAE Report Form. Since the information does not
pertain to a participant enrolled in the study, the information is not recorded on a CRF;
however, a copy of the completed Vaccines SAE Report Form is maintained in theinvestigator site file.
8.3.6. Cardiovascular and Death Events
Not applicable.
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs
or SAEs
Not applicable.
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8.3.8. Adverse Events of Special Interest
Not applicable.
8.3.8.1. Lack of Efficacy
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.
8.3.9. Medical Device Deficiencies
Not applicable.
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.

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Exposures to the study intervention under study may occur in clinical trial settings, such as
medication errors.
Safety Event

Recorded on the CRF

Reported on the Vaccines SAE Report
Form to Pfizer Safety Within 24 Hours
of Awareness

Medication errors

All (regardless of whether
associated with an AE)

Only if associated with an SAE

Medication errors include:Medication errors involving participant exposure to the study intervention;Potential medication errors or uses outside of what is foreseen in the protocol that do or
do not involve the study participant;The administration of expired study intervention;

The administration of an incorrect study intervention;

The administration of an incorrect dosage;The administration of study intervention that has undergone temperature excursion fromthe specified storage range, unless it is determined by the sponsor that the study
intervention under question is acceptable for use.

Such medication errors occurring to a study participant are to be captured on the medication
error page of the CRF, which is a specific version of the AE page.
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In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by theinvestigator, the medication error is recorded on the medication error page of the CRF and, if
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a Vaccines SAE
Report Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of study intervention greater than 1 dose of study intervention within
a 24-hour time period will be considered an overdose.
Pfizer does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:

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1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs.
3. Document the quantity of the excess dose as well as the duration of the overdose in the
CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7. Genetics
Genetics (specified analyses) are not evaluated in this study.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.9. Immunogenicity Assessments
Immunogenicity assessments are described in Section 8.1.
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8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are notevaluated in this study.
8.11. Study Procedures
8.11.1. Stage 1 Sentinel Cohorts
8.11.1.1. Screening: (0 to 28 Days Before Visit 1)
Before enrollment and before any study-related procedures are performed, voluntary, written
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.

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It is anticipated that the procedures below will be conducted in a stepwise manner; however,the visit can occur over more than 1 day.
Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance.

Obtain details of any medications currently taken.

Perform physical examination including vital signs (weight, height, body temperature,pulse rate, and seated blood pressure), evaluating any clinically significant abnormalities
within the following body systems: general appearance; skin; head, eyes, ears, nose, andthroat; heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph
nodes.



Collect a blood sample (approximately 20 mL) for potential future serological assessment
and to perform a rapid test for prior COVID-19 infection.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.

Collect a blood sample (approximately 10 mL) for HIV, HBsAg, HBc Ab, and HCV Ab
tests.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

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Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Record AEs as described in Section 8.3. AEs that occur prior to dosing should be notedon the Medical History CRF.



Ask the participant to contact the site staff or investigator immediately if any significant
illness or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

Complete the CRF.

8.11.1.2. Visit 1 – Vaccination 1: (Day 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Review screening laboratory results (hematology and chemistry, and HIV, HBsAg,
HBc Ab, and HCV Ab tests).

Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested(if possible at the site, otherwise at the central laboratory) within 24 hours and
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vaccination will proceed only if it is NAAT-negative for SARS-CoV-2 genomes.
The second will be sent to the central laboratory for potential later testing.
Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Obtain the participant’s randomization number and study intervention allocation using
the IRT system. Only an unblinded site staff member may obtain this information.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.



The first 5 participants vaccinated in each Stage 1 sentinel group must be observed byblinded site staff for any acute reactions for at least 4 hours after vaccination. For
participants enrolled thereafter, blinded site staff must observe the participant for at least
30 minutes after study intervention administration for any acute reactions. Record any
acute reactions (including time of onset) in the participant’s source documents and on the
AE page of the CRF, and on an SAE form as applicable.

Issue a measuring device to measure local reactions at the injection site and athermometer for recording daily temperatures and provide instructions on their use.



Explain the e-diary technologies available for this study (see Section 8.14), and assist theparticipant in downloading the study application onto the participant’s own device orissue a provisioned device if required. Provide instructions on e-diary completion andask the participant to complete the reactogenicity e-diary from Day 1 to Day 7, with
Day 1 being the day of vaccination and, if utilized, the COVID-19 illness e-diary (to becompleted if the participant is diagnosed with COVID-19 or has possible new orincreased symptoms, and when he/she receives a reminder, at least weekly).



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.
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Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1 to 3 Days After Visit 1)

Record AEs as described in Section 8.3.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

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Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to 8 Days After Visit 1)

Record AEs as described in Section 8.3.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.

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

Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.
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

Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary wascompleted and record stop dates in the CRF if required.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested (ifpossible at the site, otherwise at the central laboratory) within 24 hours and vaccination
will only proceed if it is NAAT-negative for SARS-CoV-2 genomes. The second will besent to the central laboratory for potential later testing.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met. If not, the participant should not receive further study intervention but willremain in the study to be evaluated for safety, immunogenicity, and efficacy(see Section 7.1).

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

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Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection
site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and ask the participant to complete thereactogenicity e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

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8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to 8 Days After Visit 4)

Record AEs as described in Section 8.3.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



If the participant (select participants only, details will be provided by the Sponsor)
consents, collect an additional 170 mL blood sample for exploratory COVID-19 research.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.
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Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

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8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to 16 Days After Visit 4)

Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary wascompleted and record stop dates in the CRF if required.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



If not collected at Visit 5, and the participant (select participants only, details will be
provided by the sponsor) consents, collect an additional 170-mL blood sample for
exploratory COVID-19 research.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

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

Ask the participant to contact the site staff or investigator immediately (this could be via
the COVID-19 illness e-diary) if he or she experiences any respiratory symptoms as
detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After Visit 4)

Record AEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



If not collected at Visit 5 or 6, and the participant (select participants only, details will be
provided by the sponsor) consents, collect an additional 170-mL blood sample for
exploratory COVID-19 research.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (154 to 168 Days After Visit 4)

Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.1.10. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 4)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.1.11. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 4)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect the participant’s e-diary or assist the participant to remove the study applicationfrom his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.2. Stage 1 Nonsentinel Cohorts and Stage 2 Cohorts

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8.11.2.1. Visit 1 – Vaccination 1: (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written,
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.
It is anticipated that the procedures below will be conducted in a stepwise manner.
Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance.



Perform physical examination including vital signs (weight, height, body temperature,pulse rate, and seated blood pressure), evaluating any clinically significant abnormalities
within the following body systems: general appearance; skin; head, eyes, ears, nose, andthroat; heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph
nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.
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

Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.



Record AEs as described in Section 8.3.

Obtain the participant’s randomization number and study intervention allocation using
the IRT system. Only an unblinded site staff member may obtain this information.

Collect a blood sample (approximately 25 mL) for immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Issue a measuring device to measure local reactions at the injection site and athermometer for recording daily temperatures and provide instructions on their use.



Explain the e-diary technologies available for this study (see Section 8.14), and assist theparticipant in downloading the study application onto the participant’s own device orissue a provisioned device if required. Provide instructions on e-diary completion andask the participant to complete the reactogenicity e-diary from Day 1 to Day 7, with
Day 1 being the day of vaccination and, if utilized, the COVID-19 illness e-diary (to becompleted if the participant is diagnosed with COVID-19 or has possible new orincreased symptoms, and when he/she receives a reminder, at least weekly).



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).
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

Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days or 56 to 70 Days After Visit 1)
The window for Visit 2 is dependent on the dosing schedule for the assigned group.
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary wascompleted and record stop dates in the CRF if required.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.
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Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met. If not, the participant should not receive further study intervention but willremain in the study to be evaluated for safety, immunogenicity, and efficacy(see Section 7.1).

Measure the participant’s body temperature.

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Collect a blood sample (approximately 25 mL) for immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection
site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and ask the participant to complete thereactogenicity e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.

Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.
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

Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

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8.11.2.3. Visit 3 – 2-Week Follow-up Visit: (12 to 16 Days After Visit 2)

Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary wascompleted and record stop dates in the CRF if required.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 25 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.
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8.11.2.4. Visit 4 – 1-Month Follow-up Visit: (28 to 35 Days After Visit 2)

Record AEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 25 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.11.2.5. Visit 5 – 6-Month Follow-up Visit: (154 to 168 Days After Visit 2)

Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect a blood sample (approximately 25 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.
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The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.2.6. Visit 6 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 2)Collect a blood sample (approximately 25 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.2.7. Visit 7 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 2)Collect a blood sample (approximately 25 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect the participant’s e-diary or assist the participant to remove the study applicationfrom his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.3. Stage 3 Cohort(s)8.11.3.1. Visit 1 – Vaccination 1: (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written,
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.

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It is anticipated that the procedures below will be conducted in a stepwise manner.
Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance.



Perform a clinical assessment. If the clinical assessment indicates that a physicalexamination is necessary to comprehensively evaluate the participant, perform a physicalexamination and record any findings in the source documents and, if clinicallysignificant, record on the medical history CRF.

Measure the participant’s height and weight.

Measure the participant’s body temperature.

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.



Record AEs as described in Section 8.3.

Obtain the participant’s randomization number and study intervention allocation number
using the IRT system. Only an unblinded site staff member may obtain this information.

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

Collect a blood sample (approximately 25 mL) for immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

For participants in the reactogenicity subset, issue a measuring device to measure local
reactions at the injection site and a thermometer for recording daily temperatures andprovide instructions on their use.

For participants not in the reactogenicity subset, issue a thermometer to monitor for fever(for COVID-19 disease surveillance) and provide instructions on its use.



Explain the e-diary technologies available for this study (see Section 8.14), and assist theparticipant in downloading the study application onto the participant’s own device orissue a provisioned device if required.



For participants in the reactogenicity subset, provide instructions on reactogenicity
e-diary completion and ask the participant to complete the reactogenicity e-diary fromDay 1 to Day 7, with Day 1 being the day of vaccination.

For all participants, provide instructions on COVID-19 illness e-diary completion andask the participant to complete the COVID-19 illness e-diary if he/she is diagnosed
with COVID-19 or has possible new or increased symptoms, and when he/she
receives a reminder, at least weekly. See Section 8.14 for further details.

If the participant is part of the reactogenicity subset, ask the participant to contact the site
staff or investigator immediately if he or she experiences any of the following from Day
1 to Day 7 after vaccination (where Day 1 is the day of vaccination) to determine if anunscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.
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

Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.

If the participant is part of the reactogenicity subset, the investigator or appropriately
qualified designee reviews the reactogenicity e-diary data online following vaccination toevaluate participant compliance and as part of the ongoing safety review. Daily review is
optimal during the active diary period.
8.11.3.2. Visit 2 – Vaccination 2: (19 to 23 Days or 56 to 70 Days After Visit 1)
The window for Visit 2 is dependent on the dosing schedule(s) selected for Stage 3.
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



If the participant is part of the reactogenicity subset, review the participant’s
reactogenicity e-diary data. Collect stop dates of any reactogenicity e-diary events
ongoing on the last day that the reactogenicity e-diary was completed and record stop
dates in the CRF if required.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met. If not, the participant should not receive further study intervention but will
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remain in the study to be evaluated for safety, immunogenicity, and efficacy(see Section 7.1).
Measure the participant’s body temperature.

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection
site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and, if the participant is part of thereactogenicity subset, ask the participant to complete the reactogenicity e-diary fromDay 1 to Day 7, with Day 1 being the day of vaccination.



If the participant is part of the reactogenicity subset, ask the participant to contact the site
staff or investigator immediately if he or she experiences any of the following fromDay 1 to Day 7 after vaccination (where Day 1 is the day of vaccination) to determine if
an unscheduled reactogenicity visit is required:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.

Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

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

Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.

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If the participant is part of the reactogenicity subset, the investigator or appropriately
qualified designee reviews the reactogenicity e-diary data online following vaccination toevaluate participant compliance and as part of the ongoing safety review. Daily review is
optimal during the active diary period.
8.11.3.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2): (28 to 35 Days After
Visit 2)


Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. If the participant is part of thereactogenicity subset, review the participant’s reactogenicity e-diary data. Collect stop
dates of any reactogenicity e-diary events ongoing on the last day that the reactogenicity
e-diary was completed and record stop dates in the CRF if required.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 25 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

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Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.3.4. Visit 4 – 6-Month Follow-up Visit: (154 to 168 Days After Visit 2)

Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.

Collect a blood sample (approximately 25 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.3.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.11.3.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 2)Collect a blood sample (approximately 25 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.3.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 2)Collect a blood sample (approximately 25 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect the participant’s e-diary or assist the participant to remove the study applicationfrom his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction
If a Grade 3 local reaction (Section 8.2.2.2), systemic event (Section 8.2.2.3), or fever(Section 8.2.2.4) is reported in the reactogenicity e-diary, a telephone contact should occur toascertain further details and determine whether a site visit is clinically indicated. If suspected
Grade 4 local reaction (Section 8.2.2.2), systemic event (Section 8.2.2.3), or fever(Section 8.2.2.4) is reported in the reactogenicity e-diary, a telephone contact or site visit
should occur to confirm whether the event meets the criteria for Grade 4.
A site visit must be scheduled as soon as possible to assess the participant unless any of thefollowing is true:The participant is unable to attend the unscheduled visit.

The local reaction/systemic event is no longer present at the time of the telephone
contact.



The participant recorded an incorrect value in the reactogenicity e-diary (confirmation ofa reactogenicity e-diary data entry error).



The PI or authorized designee determined it was not needed.

This telephone contact will be recorded in the participant’s source documentation and theCRF.
If the participant is unable to attend the unscheduled visit, or the PI or authorized designee
determined it was not needed, any ongoing local reactions/systemic events must be assessedat the next study visit.

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During the unscheduled visit, the reactions should be assessed by the investigator or a
medically qualified member of the study staff such as a study physician or a study nurse, asapplicable to the investigator’s local practice, who will:Measure body temperature (°F/°C).

Measure minimum and maximum diameters of redness (if present).

Measure minimum and maximum diameters of swelling (if present).



Assess injection site pain (if present) in accordance with the grades provided in
Section 8.2.2.2.

Assess systemic events (if present) in accordance with the grades provided in
Section 8.2.2.3.

Assess for other findings associated with the reaction and record on the AE page of the
CRF, if appropriate.

The investigator or an authorized designee will complete the unscheduled visit assessment
page of the CRF.
8.13. COVID-19 Disease Surveillance (All Participants)
If a participant experiences any of the following, he or she is instructed to contact the site
immediately and, if confirmed, participate in an in-person or telehealth visit as soon as
possible, optimally within 3 days of symptom onset. During the 7 days following eachvaccination, potential COVID-19 symptoms that overlap with solicited systemic events(ie, fever, chills, new or increased muscle pain, diarrhea, vomiting) should not trigger apotential COVID-19 illness visit unless, in the investigator’s opinion, the clinical picture ismore indicative of a possible COVID-19 illness than vaccine reactogenicity. Participants may
utilize a COVID-19 illness e-diary through an application (see Section 8.14) installed on aprovisioned device or on the participant’s own personal device to prompt him/her to reportany symptoms. Note that this does not substitute for a participant’s routine medical care.
Therefore, participants should be encouraged to seek care, if appropriate, from their usual
provider.


A diagnosis of COVID-19;



Fever;

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New or increased muscle pain;New loss of taste/smell;

Sore throat;

Diarrhea;Vomiting.

8.13.1. Potential COVID-19 Illness Visit: (Optimally Within 3 Days After Potential
COVID-19 Illness Onset)
This visit is expected to involve the sharing of healthcare information and services via
telecommunication technologies (eg, audio, video, video-conferencing software) remotely,
thus allowing the participant and investigator to communicate on aspects of clinical care.

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)As a participant’s COVID-19 illness may evolve over time, several contacts may be required
to obtain the following information:


Record AEs, as appropriate as described in Section 8.3.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Instruct the participant to self-collect a nasal (midturbinate) swab and ship for assessment
at the central laboratory. The result from this swab will be provided to the site once it isavailable, but this will not be in real time, and cannot be relied upon to direct clinicalcare. Therefore, the participant should be encouraged to seek care, if appropriate, fromhis or her usual provider.

Collect COVID-19–related standard-of-care clinical and laboratory information. This
includes, but is not limited to:Symptoms and signs, includingClinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per
minute, HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or
PaO2/FiO2 <300 mm Hg)



Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiringvasopressors)Significant acute renal, hepatic, or neurologic dysfunction

Respiratory failure (defined as needing high-flow oxygen, noninvasive
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Clinical diagnosis

Local laboratory COVID-19 test resultFull blood count

Blood chemistry, specifically creatinine, urea, liver function tests, and C-reactive
protein

Imaging results (eg, CT or MRI scan) to document neurologic dysfunction

Number and type of any healthcare contact; duration of hospitalization and ICU stay



Death



Schedule an appointment for the participant to return for the potential COVID-19
convalescent visit once he or she has recovered.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After Potential
COVID-19 Illness Visit)

Record AEs, as appropriate as described in Section 8.3.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Collect/update COVID-19–related clinical and laboratory information (detailed in
Section 8.13.1).

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.14. Communication and Use of Technology
In a study of this nature that requires illness events to be reported outside of scheduled study
visits, it is vital that communication between the study site and the participant is maintained
to ensure that endpoint events are not missed. This study will employ various methods,
tailored to the individual participant, to ensure that communication is maintained and study
information can be transmitted securely. Using appropriate technology, such as a study
application, a communication pathway between the participant and the study site staff will be
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established. The participant may be able to utilize his or her own devices to access thistechnology, or use a device provided by the sponsor. Traditional methods of telephone
communication will also be available. The technology solution may facilitate the following:Contact with the investigator, including the ability of the participant to report whether or
not he or she has experienced symptoms that could represent a potential COVID-19
illness (COVID-19 illness e-diary; see Section 8.13).

An alert in the event that the participant is hospitalized.



Visit reminders.



Messages of thanks and encouragement from the study team.



A platform for recording local reactions and systemic events (reactogenicity e-diary) –see Section 8.2.2.

If a participant is not actively completing either the reactogenicity or COVID-19 illness
e-diary, the investigator or designee is required to contact the participant to ascertain why
and also to obtain details of any missed events.
9. STATISTICAL CONSIDERATIONS
Methodology for summary and statistical analyses of the data collected in this study is
described here and further detailed in a statistical analysis plan (SAP), which will bemaintained by the sponsor. The SAP may modify what is outlined in the protocol whereappropriate; however, any major modifications of the primary endpoint definitions or theiranalyses will also be reflected in a protocol amendment.
9.1. Estimands and Statistical Hypotheses
9.1.1. Estimands
The estimand corresponding to each primary, secondary, and tertiary/exploratory objective is
described in the table in Section 3.
In the primary safety objective evaluations, missing reactogenicity e-diary data will not be
imputed. Missing AE dates will be imputed according to Pfizer safety rules. No othermissing information will be imputed in the safety analysis.
The estimands to evaluate the immunogenicity objectives are based on evaluable populations
for immunogenicity (Section 9.3). These estimands estimate the vaccine effect in the
hypothetical setting where participants follow the study schedules and protocol requirements
as directed. Missing antibody results will not be imputed. Immunogenicity results that are
below the LLOQ will be set to 0.5 × LLOQ in the analysis; this may be adjusted once
additional data on the assay characteristics become available.

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The estimands to evaluate the efficacy objectives are based on evaluable populations for
efficacy (Section 9.3). These estimands estimate the vaccine effect in the hypotheticalsetting where participants follow the study schedules and protocol requirements as directed.
In addition, VE will be analyzed by all-available efficacy population. Missing laboratory
results will not be imputed for the primary analysis, but missing data imputation for theefficacy endpoint may be performed as a sensitivity analysis.
9.1.2. Statistical Hypotheses

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Stage 3 of the study has 2 primary efficacy endpoints evaluating VE, which is defined as
VE = 100 × (1 – IRR). IRR is calculated as the ratio of first confirmed COVID-19 illness ratein the vaccine group to the corresponding illness rate in the placebo group. In Stage 3, theassessment of VE will be based on posterior probabilities of VE1 > 30% and VE2 > 30%.
VE1 represents VE for individual prophylactic BNT162 vaccines against confirmed
COVID-19 in participants without evidence of infection before vaccination, and VE2
represents VE for individual prophylactic BNT162 vaccines against confirmed COVID-19 in
all participants after vaccination.
For participants with multiple confirmed cases, only the first case will contribute to the VE
calculation for each hypothesis. VE1 and VE2 will be evaluated sequentially to control theoverall type I error to the desired level of 2.5%. VE is demonstrated if there is sufficientevidence (posterior probability) that either VE1 >30% or both VE1 and VE2 are >30%. The
assessment for the primary analysis will be based on posterior probability using a Bayesianmodel.
9.2. Sample Size Determination
The study sample size for the first 2 stages of the study is not based on any statistical
hypothesis testing. Stage 1 will comprise 15 participants (randomization ratio of 4:1 so that
12 receive active vaccine and 3 receive placebo) per group; up to 28 potential groups areforeseen; if all groups are fully enrolled, assuming 2 dose levels are selected following theinitial dose escalation, this corresponds to a total of 420 participants. Stage 2 will include 1
or more vaccine groups selected from Stage 1, and 225 participants will be randomized per
selected vaccine candidate in a 4:1 ratio to receive active vaccine (180 participants) orplacebo (45 participants).
For Stage 3, with assumptions of a true VE of 60% after the last dose of investigational
product, a total of approximately 164 first confirmed COVID-19 illness cases will provide
90% power to conclude true VE >30% with high probability, allowing early stopping for
efficacy at the IA. This would be achieved with 11,714 evaluable participants per group or
14,643 vaccine recipients randomized in a 1:1 ratio with placebo, for a total sample size of
29,286, based on the assumption of a 1.0% illness rate per year in the placebo group, and
20% of the participants being nonevaluable or having serological evidence of prior infection
with SARS-CoV-2, potentially making them immune to further infection. Dependent upon
the evolution of the pandemic, it is possible that the COVID-19 attack rate may be muchhigher, in which case accrual would be expected to be more rapid, enabling the study’s
primary endpoint to be evaluated much sooner. The total number of participants enrolled in
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Stage 3 may vary depending on the incidence of COVID-19 at the time of the enrollment, thenumber of candidate vaccines evaluated, the true underlying VE, and a potential early stopfor efficacy or futility.
For safety outcomes, Table 5 shows the probability of observing at least 1 AE for a given
true event rate of a particular AE, for various sample sizes. For example, if the true AE rate
is 10%, with 12 participants in a vaccine group, there is 72% probability of observing at least
1 AE.

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Table 5.

Probability of Observing at Least 1 AE by Assumed True Event Rates
With Different Sample Sizes

Assumed True
Event Rate of
an AE
0.01%
0.02%
0.04%
0.06%
0.08%
0.10%
0.15%
0.20%
0.25%
0.30%
0.35%
0.50%
1.00%
2.00%
3.00%
5.00%
7.00%
10.00%

N=12

N=45

N=180

N=3000N=6000N=9000N=15000

0.00
0.00
0.00
0.01
0.01
0.01
0.02
0.02
0.03
0.04
0.04
0.06
0.11
0.22
0.31
0.46
0.58
0.72

0.00
0.01
0.02
0.03
0.04
0.04
0.07
0.09
0.11
0.13
0.15
0.20
0.36
0.60
0.75
0.90
0.96
0.99

0.02
0.04
0.07
0.10
0.13
0.16
0.24
0.30
0.36
0.42
0.47
0.59
0.84
0.97
>0.99
>0.99
>0.99
>0.99

0.26
0.45
0.70
0.83
0.91
0.95
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

0.45
0.70
0.91
0.97
0.99
0.99
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

0.59
0.83
0.97
0.99
0.99
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

0.78
0.95
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

9.3. Analysis Sets
For purposes of analysis, the following populations are defined:
Population
Enrolled
Randomized
Dose 1 evaluable
immunogenicity

Description
All participants who have a signed ICD.
All participants who are assigned a randomization number in
the IWR system.
All eligible randomized participants who receive the vaccine
to which they are randomly assigned at the first dose, have atleast 1 valid and determinate immunogenicity result 21 days
after Dose 1, have blood collection within an appropriate
window after Dose 1, and have no other major protocol
deviations as determined by the clinician.

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Population
Dose 2 evaluable
immunogenicity

Dose 1 all-available
immunogenicity
Dose 2 all-available
immunogenicity

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Evaluable efficacy

All-available efficacy
SafetyDescription
All eligible randomized participants who receive 2 doses ofthe vaccine to which they are randomly assigned, within thepredefined window, have at least 1 valid and determinate
immunogenicity result after Dose 2, have blood collection
within an appropriate window after Dose 2, and have no othermajor protocol deviations as determined by the clinician.
All participants who receive at least 1 dose of the study
intervention with at least 1 valid and determinate
immunogenicity result after Dose 1 but before Dose 2.
All participants who receive at least 1 dose of the study
intervention with at least 1 valid and determinate
immunogenicity result after Dose 2.
All eligible randomized participants who receive all
vaccination(s) as randomized within the predefined window,
have the efficacy measurement after the last dose of study
intervention, and have no other major protocol deviations as
determined by the clinician. A major protocol deviation will
exclude a participant from the evaluable efficacy populationfrom the date that it occurs through the participant’s remaining
follow-up.
All eligible randomized participants who receive at least
1 vaccination and have the efficacy measurement at any timeafter Dose 1.
All randomized participants who receive at least 1 dose of thestudy intervention.

9.4. Statistical Analyses
The SAP will be developed and finalized before database lock for any of the planned
analyses in Section 9.5.1. It will describe the participant populations to be included in theanalyses and the procedures for accounting for missing, unused, and spurious data. Thissection provides a summary of the planned statistical analyses of the primary, secondary, andtertiary/exploratory endpoints.
9.4.1. Immunogenicity Analyses
The statistical analysis of immunogenicity results will be primarily based on the evaluable
immunogenicity populations as defined in Section 9.3.
An additional analysis will be performed based on the all-available populations if there is alarge enough difference in sample size between the all-available immunogenicity populationand the evaluable immunogenicity population. Participants will be summarized according to
the vaccine group to which they were randomized.

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Endpoint
Secondaryimmunogenicity

Statistical Analysis Methods
Geometric mean titers/concentrations (GMTs/GMCs) of
SARS-CoV-2 serum neutralizing titers and SARS-CoV-2 anti-S1
binding antibody and anti-RBD binding antibody

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2 anti-S1
binding antibody levels and anti-RBD binding antibody levels,
GMTs/GMCs and 2-sided 95% CIs will be provided for each
investigational product within each group before vaccination and ateach of the following time points:
Stage 1 sentinel cohorts: 7 and 21 days after Dose 1; 7 and
14 days and 1, 6, 12 and 24 months after Dose 2

Stage 1 nonsentinel cohorts and Stage 2 cohorts: 21 days after
Dose 1; 14 days and 1, 6, 12, and 24 months after Dose 2

Stage 3 cohort(s): 1, 6, 12, and 24 months after completion of
vaccination in participants with and without serological or
virological evidence of SARS-CoV-2 infection before
vaccination

Geometric means will be calculated as the mean of the assay results
after making the logarithm transformation and then exponentiating themean to express results on the original scale. Two-sided 95% CIs will
be obtained by taking natural log transforms of concentrations/titers,
calculating the 95% CI with reference to the t-distribution, and thenexponentiating the confidence limits.
GMFRs of SARS-CoV-2 serum neutralizing titers and
SARS-CoV-2 anti-S1 binding antibody and anti-RBD binding
antibody
For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2 anti-S1
binding antibody levels and anti-RBD binding antibody levels, the
GMFRs and 2-sided 95% CIs will be provided for each investigational
product within each group at each of the following time points:
Stage 1 sentinel cohorts: 7 and 21 days after Dose 1; 7 and
14 days and 1, 6, 12, and 24 months after Dose 2

Stage 1 nonsentinel cohorts and Stage 2 cohorts: 21 days after
Dose 1; 14 days and 1, 6, 12, and 24 months after Dose 2

Stage 3 cohort(s): 1, 6, 12, and 24 months after completion of
vaccination in participants with and without serological or

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Endpoint

Statistical Analysis Methods
virological evidence of SARS-CoV-2 infection before
vaccination
GMFRs will be limited to participants with nonmissing values prior to
the first dose and at the postvaccination time point. The GMFR will becalculated as the mean of the difference of logarithmically transformed
assay results (later time point – earlier time point) and exponentiating
the mean. The associated 2-sided CIs will be obtained by calculating
CIs using Student’s t-distribution for the mean difference of thelogarithmically transformed assay results and exponentiating theconfidence limits.

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Percentage of participants with ≥4-fold rise in SARS-CoV-2 serum
neutralizing titers and SARS-CoV-2 anti-S1 binding antibody andanti-RBD binding antibody
For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2 anti-S1
binding antibody levels and anti-RBD binding antibody levels,
percentages (and 2-sided 95% CIs) of participants with ≥4-fold rise
will be provided for each investigational product within each group ateach of the following time points:
Stage 1 sentinel cohorts: 7 and 21 days after Dose 1; 7 and
14 days and 1, 6, 12, and 24 months after Dose 2

Stage 1 nonsentinel cohorts and Stage 2 cohorts: 21 days after
Dose 1; 14 days and 1, 6, 12, and 24 months after Dose 2

The Clopper-Pearson method will be used to calculate the CIs.
GMR of SARS-CoV-2 serum neutralizing titer to SARS-CoV-2
anti-S1 binding antibody and SARS-CoV-2 anti-RBD binding
antibody
For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2 anti-S1
binding antibody levels and anti-RBD binding antibody levels, theGMRs and 2-sided 95% CIs will be provided for each investigational
product within each group at each of the following time points:
Stage 1 sentinel cohorts: 7 and 21 days after Dose 1; 7 and
14 days and 1, 6, 12, and 24 months after Dose 2

Stage 1 nonsentinel cohorts and Stage 2 cohorts: 21 days after
Dose 1; 14 days and 1, 6, 12, and 24 months after Dose 2

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Statistical Analysis Methods
GMRs will be limited to participants with nonmissing values for both
SARS-CoV-2 serum neutralizing titers and SARS-CoV-2 anti-S1
binding antibody/SARS-CoV-2 anti-RBD binding antibody at eachtime point. The GMR will be calculated as the mean of the differenceof logarithmically transformed assay results (eg, SARS-CoV-2 serum
neutralizing titers minus SARS-CoV-2 anti-S1 binding antibody foreach participant) and exponentiating the mean. Two-sided CIs will beobtained by calculating CIs using Student’s t-distribution for the meandifference of the logarithmically transformed assay results andexponentiating the confidence limits.

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Percentage of participants with antibody levels ≥ predefined
threshold(s) in participants with and without serological or
virological evidence of SARS-CoV-2 infection before vaccination
For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2 anti-S1
binding antibody levels and/or anti-RBD binding antibody levels,
percentages (and 2-sided 95% CIs) of participants with antibody levels≥ predefined thresholds will be provided for each investigational
product within each group at each of the following time points:
Stage 3 cohort(s): 1, 6, 12, and 24 months after completion of
vaccination in participants with and without serological or
virological evidence of SARS-CoV-2 infection before
vaccination

The Clopper-Pearson method will be used to calculate the CIs.
For all the immunogenicity endpoints, the analysis will be based on the
Dose 1 and Dose 2 evaluable immunogenicity populations. An
additional analysis will be performed based on the all-available
immunogenicity populations if there is a large enough difference insample size between the all-available immunogenicity populations andthe evaluable immunogenicity populations. Participants will besummarized according to the vaccine group to which they wererandomized. Missing serology data will not be imputed.
Exploratory
immunogenicity

For Stage 3 participants with and without confirmed COVID-19,
severe COVID-19, or SARS-CoV-2 infection without confirmed
COVID-19:
GMTs/GMCs of SARS-CoV-2 serum neutralizing titers,
SARS-CoV-2 anti-S1 binding antibody and anti-RBD binding
antibody, and SARS-CoV-2 NVA-specific binding antibody

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Statistical Analysis Methods
For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2 anti-S1
binding antibody levels and anti-RBD binding antibody levels,
GMTs/GMCs and 2-sided 95% CIs will be provided for each
investigational product within each group before vaccination and at 1,
6, 12, and 24 months after completion of vaccination.
Geometric means will be calculated as the mean of the assay results
after making the logarithm transformation and then exponentiating themean to express results on the original scale. Two-sided 95% CIs will
be obtained by taking natural log transforms of concentrations/titers,
calculating the 95% CI with reference to the t-distribution, and thenexponentiating the confidence limits.

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GMFRs of SARS-CoV-2 serum neutralizing titers, SARS-CoV-2
anti-S1 binding antibody and anti-RBD binding antibody, and
SARS-CoV-2 NVA-specific binding antibody
For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2 anti-S1
binding antibody levels and anti-RBD binding antibody levels, the
GMFRs and 2-sided 95% CIs will be provided for each investigational
product within each group at 1, 6, 12, and 24 months after completionof vaccination.
GMFRs will be limited to participants with nonmissing values prior to
the first dose and at the postvaccination time point. The GMFR will becalculated as the mean of the difference of logarithmically transformed
assay results (later time point – earlier time point) and exponentiating
the mean. The associated 2-sided CIs will be obtained by calculating
CIs using Student’s t-distribution for the mean difference of thelogarithmically transformed assay results and exponentiating theconfidence limits.
Percentage of participants with antibody levels ≥ predefined
threshold(s) for SARS-CoV-2 serological parameters at baseline
For SARS-CoV-2 serum neutralizing titers, SARS-CoV-2 anti-S1
binding antibody levels and/or anti-RBD binding antibody levels,
SARS-CoV-2 NVA-specific binding antibody, and SARS-CoV-2
detection by NAAT, percentages (and 2-sided 95% CIs) of participants
with antibody levels ≥ predefined threshold(s) will be provided foreach investigational product within each group at baseline and 1, 6, 12,
and 24 months after completion of vaccination.
The Clopper-Pearson method will be used to calculate the CIs.
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Statistical Analysis Methods
For all of the immunogenicity endpoints, the analysis will be based on
the Dose 1 and Dose 2 evaluable immunogenicity populations. An
additional analysis will be performed based on the all-available
immunogenicity populations if there is a large enough difference insample size between the all-available immunogenicity populations andthe evaluable immunogenicity populations. Participants will besummarized according to the vaccine group to which they wererandomized. Missing serology data will not be imputed.
RCDCs for immunogenicity results
Empirical RCDCs will be provided for SARS-CoV-2 serum
neutralizing titers, SARS-CoV-2 S1-specific binding antibody, andRBD-specific binding antibody after Dose 1 and after Dose 2.

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9.4.2. Efficacy Analyses
The statistical analysis of efficacy will be based on the evaluable efficacy population(primary analysis) and the all-available efficacy population as defined in Section 9.3.
Endpoint
Primary efficacy

Statistical Analysis Methods
Ratio of confirmed COVID-19 illness per 1000 person-years offollow-up in participants without evidence of infection before
vaccination for the active vaccine group to the placebo group
VE will be estimated by 100 × (1 – IRR), where IRR is the calculated
ratio of confirmed COVID-19 illness per 1000 person-years follow-up
in the active vaccine group to the corresponding illness rate in theplacebo group 7 days after the last dose. VE will be analyzed using abeta-binomial model.
After the above objective is met, the second primary endpoint will be
evaluated as below.
Ratio of confirmed COVID-19 illness per 1000 person-years offollow-up in participants with and without evidence of infection
before vaccination for the active vaccine group to the placebogroup
VE will be estimated by 100 × (1 – IRR), where IRR is the calculated
ratio of confirmed COVID-19 illness per 1000 person-years follow-up
in the active vaccine group to the corresponding illness rate in the

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Statistical Analysis Methods
placebo group after 7 days after the last dose. VE will be analyzed
using a beta-binomial model.
The efficacy analysis for the first primary objective evaluation will bebased on the participants without evidence of infection before
vaccination and included in the evaluable efficacy population and in
the all-available efficacy population.
The efficacy analysis for the second primary objective evaluation will
be based on all participants included in the evaluable efficacy
population and in the all-available efficacy population.
For the primary endpoint analysis, missing efficacy data will not be
imputed. A sensitivity analysis will be performed by imputing missing
values; details will be provided in the SAP.

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Secondary

Ratio of confirmed severe COVID-19 illness per 1000 person-years
of follow-up in participants without evidence of infection before
vaccination for the active vaccine group to the placebo group
Ratio of confirmed severe COVID-19 illness per 1000 person-years
of follow-up for the active vaccine group to the placebo group
These secondary efficacy objectives will be evaluated after the primaryobjectives are met. The analysis will be based on the evaluable efficacy
population and the all-available efficacy population. The analysis
methodology used for the primary efficacy endpoints will be applied
for the analysis of the secondary efficacy endpoints, with the samealpha-adjusted CI.
The following secondary efficacy endpoints will be evaluateddescriptively.
Ratio of confirmed COVID-19 illness (according to the
CDC-defined symptoms) per 1000 person-years of follow-up inparticipants without evidence of infection before vaccination for
the active vaccine group to the placebo group
Ratio of confirmed COVID-19 illness (according to the
CDC-defined symptoms) per 1000 person-years of follow-up inparticipants with and without evidence of infection before
vaccination for the active vaccine group to the placebo group
VE = 100 × (1 – IRR) will be estimated with confirmed COVID-19
illness according to the CDC-defined symptoms after 7 days after the
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Endpoint

Statistical Analysis Methods
last dose. The 2-sided 95% CI for VE will be derived using the
Clopper-Pearson method as described by Agresti.9
Missing efficacy data will not be imputed.

9.4.3. Safety Analyses

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Endpoint
Primary

Statistical Analysis Methods
Descriptive statistics will be provided for each reactogenicity endpoint
for each dose and vaccine group. Local reactions and systemic eventsfrom Day 1 through Day 7 after each vaccination will be presented byseverity cumulatively across severity levels. Descriptive summary
statistics will include counts and percentages of participants with theindicated endpoint and the associated Clopper-Pearson 95% CIs.
For Stage 1 sentinel cohorts, descriptive statistics will be provided forabnormal hematology and chemistry laboratory values at 1 and 7 days
after Dose 1 and 7 days after Dose 2, including grading shifts inhematology and chemistry laboratory assessments between baseline
and 1 and 7 days after Dose 1, and before Dose 2 and 7 days after
Dose 2. Descriptive summary statistics will include counts andpercentages of participants with the indicated endpoint and theassociated Clopper-Pearson 2-sided 95% CIs.
AEs will be categorized according to the Medical Dictionary forRegulatory Activities (MedDRA) terms. A 3-tier approach will be
used to summarize AEs. Under this approach AEs are classified into 1
of 3 tiers: (1) Tier 1 events are prespecified events of clinicalimportance and are identified in a list in the product’s safety review
plan; (2) Tier 2 events are those that are not Tier 1 but are considered“relatively common”; a MedDRA preferred term is defined as a Tier 2
event if there are at least 1% of participants in at least 1 vaccine groupreporting the event; and (3) Tier 3 events are those that are neither
Tier 1 nor Tier 2 events. For both Tier 1 and Tier 2 events, 2-sided
95% CIs for the difference between the vaccine and placebo groups inthe percentage of participants reporting the events based on the
Miettinen and Nurminen method10 will be provided. In addition, forTier 1 events, the asymptotic p-values will also be presented for thedifference between groups in the percentage of participants reporting
the events, based on the same test statistic and under the assumptionthat the test statistic is asymptotically normally distributed.

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Endpoint

Statistical Analysis Methods
Descriptive summary statistics (counts, percentages, and associatedClopper-Pearson 95% CIs) will be provided for any AE events foreach vaccine group.
SAEs will be categorized according to MedDRA terms. Counts,
percentages, and the associated Clopper-Pearson 95% CIs of SAEs
from Dose 1 to 6 months after last dose will be provided for eachvaccine group.

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)The safety analyses are based on the safety population. Participants
will be summarized by vaccine group according to the investigational
products they actually received. Missing reactogenicity e-diary data
will not be imputed; missing AE dates will be handled according to
the Pfizer safety rules.
SecondaryNot applicable (N/A)

Exploratory

N/A

9.4.4. Other Analyses
The ratios of (GMFR A to GMFR B) and (GMFR A to GMFR C) may be explored, where
GMFR A is the geometric mean of the ratio of the SARS-CoV-2 serum neutralizing titer at
the postvaccination time point to the corresponding titer at the prevaccination time point,
GFMR B is the geometric mean of the ratio of the SARS-CoV-2 S1-specific binding
antibody level at the postvaccination time point to the corresponding antibody level at theprevaccination time point, and GMFR C is the geometric mean of the ratio of the
SARS-CoV-2 RBD-specific binding antibody level at the postvaccination time point to thecorresponding antibody level at the prevaccination time point.
9.5. Interim Analyses
As this is a sponsor open-label study during Stages 1 and 2, the sponsor may conduct
unblinded reviews of the data during the course of the study for the purpose of safetyassessment, facilitating dose escalation decisions, and/or supporting clinical development.
During Stage 3, 4 IAs are planned and will be performed by an unblinded statistical teamafter accrual of 32, 62, 92, and 120 cases. At each IA:

VE for both primary objectives will be evaluated sequentially. Overwhelming efficacy
will be declared if the first primary study objective is met. The criteria for success at aninterim analysis are based on the posterior probability (ie, P[VE >30%|data]) at thecurrent number of cases. Overwhelming efficacy will be declared if the posterior
probability is higher than the success threshold. The success threshold for each interim
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analysis will be calibrated to protect overall type I error at 2.5%. Additional details about
the success threshold or boundary calculation at each interim analysis will be provided in
the SAP.
The study will stop for lack of benefit (futility) if the predicted probability of success at
the final analysis or study success is <5%. The posterior predictive POS will becalculated using a beta-binomial model. The futility assessment will be done for the firstprimary endpoint only and the futility boundary may be subject to change to reflectsubsequent program-related decisions by the sponsor.

Efficacy and futility boundaries will be applied in a nonbinding way.

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Bayesian approaches require specification of a prior distribution for the possible values of theunknown vaccine effect, thereby accounting for uncertainty in its value. A minimally
informative beta prior, beta (0.700102, 1), is proposed for θ = (1-VE)/(2-VE). The prior iscentered at θ = 0.4118 (VE=30%) which can be considered pessimistic. The prior allows
considerable uncertainty; the 95% interval for θ is (0.005, 0.964) and the corresponding 95%
interval for VE is (-26.2, 0.995).
Table 6 illustrates the boundary for efficacy and futility if IAs are performed after accrual of
32 62, 92, and 120 cases in participants without evidence of infection before vaccination.
Table 6.
AnalysisInterim Analysis Plan and Boundaries for Efficacy and Futility
Number of
Cases

Success Criteriaa

Futility Boundary

VE Point Estimate
VE Point Estimate(Case Split)(Case Split)
IA132
81.5% (5:27)
11.8% (15:17)
IA2
6270.8% (14:48)
27.8% (26:36)
IA3
92
62.7% (25:67)
35.7% (36:57)
IA4
120
57.1% (36:84)
N/A
Final
164
52.3% (53:111)
Abbreviations: IA = interim analysis; N/A = not applicable; VE = vaccine efficacy.
Note: Case split = vaccine : placebo.
a. Interim efficacy claim: P(VE >30%|data) > 0.9975; success at the final analysis: P(VE >30%|data)> 0.986.

Additional design operating characteristics (the boundary based on the number of cases
observed in the vaccine group; the probabilities for efficacy and futility given assumed
various VEs with a 1:1 randomization ratio) are listed in Table 7 and Table 8.

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Table 7.

Statistical Design Operating Characteristics: Probability of Success or
Failure for Interim Analyses

VaccineEfficacy(%)

Interim Analysis 1(Total Cases = 32)

30
50
60
70
80

Table 8.

Probabilityof Success(Cases in
VaccineGroup ≤5)
0.002
0.022
0.072
0.219
0.553

Probabilityof Success(Cases in
VaccineGroup ≤14)
0.002
0.034
0.132
0.335
0.370

Probabilityof Failure(Cases in
VaccineGroup ≥26)
0.231
0.027
0.011
0.010
<0.001

Interim Analysis 3(Total Cases = 92)
Probabilityof Success(Cases in
VaccineGroup ≤25)
0.003
0.089
0.263
0.325
0.077

Probabilityof Failure(Cases in
VaccineGroup ≥36)
0.217
0.033
0.010
<0.001<0.001

InterimAnalysis 4(Total Cases= 120)
Probability of
Success(CasesVaccineGroup ≤36)
0.005
0.138
0.253
0.117
<0.001

Statistical Design Operating Characteristics: Probability of Success for
Final Analysis and Overall

Vaccine Efficacy (%)

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Probabilityof Failure(Cases in
VaccineGroup ≥15)
0.315
0.044
0.021
0.020
<0.001

Interim Analysis 2(Total Cases = 62)

30
50
60
70
80

Final Analysis(Total Cases = 164)
Probability of Success (Cases in Vaccine
Group ≤53)
0.008
0.196
0.204
0.004
<0.001

Overall Probability of Success

0.020
0.479
0.924
>0.999>0.999If neither success nor futility has been declared after all IAs, the final analysis will be
performed and the first primary objective will have been met if there are 53 or fewer cases
observed in the vaccine group out of a total of 164 first confirmed cases from 7 days after
receipt of the last dose of investigational product onwards.
After the primary objectives are met, the secondary VE endpoints (confirmed severe
COVID-19 in participants without evidence of infection before vaccination and confirmed
severe COVID-19 in all participants) will be evaluated sequentially, by the same method
used for the primary VE endpoint evaluation. Success thresholds for secondary VE will beappropriately chosen to control overall Type I error at 2.5%. Further details will be provided
in the SAP. The remaining secondary VE endpoints will be evaluated descriptively to
calculate the observed VE with 95% CIs.

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9.5.1. Analysis Timing

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Statistical analyses will be carried out when the following data are available:Complete safety and immunogenicity analysis approximately 1 month after Dose 2 forStage 1.

Complete safety and immunogenicity analysis approximately 1 month after Dose 2 forStage 2.



Safety data through 7 days after Dose 2 and immunogenicity data through 21 days after
Dose 1 from the first 360 participants enrolled (180 to active vaccine and 180 to placebo)in Stage 3 for a vaccine candidate/dose level that progresses directly to Stage 3.

Safety and immunogenicity data through 1 month after Dose 2 from the first 6000
participants enrolled (3000 to active vaccine and 3000 to placebo) in Stage 3.



IAs for efficacy at 32, 62, 92, and 120 cases and futility at 32, 62, and 92 cases.

Complete safety and immunogenicity analysis approximately 6 months after Dose 2 for
all participants in Stage 3.

Complete efficacy and persistence-of-immunogenicity analysis after complete data are
available at the end of the study.

All analyses conducted on Stage 3 data while the study is ongoing will be performed by an
unblinded statistical team.
9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will use an IRC, a DMC, and a group of internal case reviewers. The IRC is
independent of the study team and includes only internal members. The DMC is independentof the study team and includes only external members. The IRC and DMC charters describe
the role of the IRC and DMC in more detail.
The responsibilities of the IRC will include:

Review of safety data to permit dose escalations in the 18- to 55-year age cohort



Review of safety data in the case of a stopping rule being met

Review of safety and/or immunogenicity data to:Allow groups of participants of 65 to 85 years of age to proceed

Select vaccine candidate(s)/dose level(s) and schedule(s) to proceed into Stage 2.
Data supporting the selection, including results for both binding antibody levels and
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serum neutralizing titers, and the ratio between them, will also be submitted to the
FDA for review


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Select vaccine candidate(s)/dose level(s) and schedule(s) to proceed into Stage 3.
Data supporting the selection, including results for both binding antibody levels andserum neutralizing titers, and the ratio between them, will also be submitted to the
FDA for review

Review of any available safety and/or immunogenicity data generated during the courseof this study, or the BioNTech study conducted in Germany, to determine:Whether any groups may not be started



Whether any groups may be terminated earlyWhether any groups may be added with dose levels below the lowest stated dose orintermediate between the lowest and highest stated doses

Contemporaneous review of all NAAT-confirmed COVID-19 illnesses in Stages 1 and 2

The DMC will be responsible for ongoing monitoring of the safety of participants in the
study according to the charter. This may include, but is not limited to:Contemporaneous review of related AEs up to 1 month after completion of thevaccination scheduleContemporaneous review of all SAEs up to 6 months after completion of the vaccination
schedule

Contemporaneous review of all NAAT-confirmed COVID-19 illnesses in Stages 1 and 2

At the time of the planned IAs, and ad hoc if requested by the unblinded team, review ofcases of COVID-19 for an adverse imbalance of cases of COVID-19 and/or severe
COVID-19 between the vaccine and placebo groups

The recommendations made by the DMC to alter the conduct of the study will be forwarded
to the appropriate Pfizer personnel for final decision. Pfizer will forward such decisions,which may include summaries of aggregate analyses of safety data, to regulatory authorities,
as appropriate.
If a NAAT-confirmed case in Stage 3 may be considered severe, or not, solely on the basis of“significant acute renal, hepatic, or neurologic dysfunction,” the blinded data will be
reviewed by 3 medically qualified Pfizer staff members to assess whether the criterion is met;
the majority opinion will prevail.

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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:Consensus ethical principles derived from international guidelines including the
Declaration of Helsinki and CIOMS International Ethical Guidelines;Applicable ICH GCP guidelines;Applicable laws and regulations, including applicable privacy laws.

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents(eg, advertisements) must be reviewed and approved by the sponsor and submitted to an
IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study is
initiated.
Any amendments to the protocol will require IRB/EC approval before implementation ofchanges made to the study design, except for changes necessary to eliminate an immediate
hazard to study participants.
The investigator will be responsible for the following:Providing written summaries of the status of the study to the IRB/EC annually or more
frequently in accordance with the requirements, policies, and procedures established by
the IRB/EC;



Notifying the IRB/EC of SAEs or other significant safety findings as required by IRB/EC
procedures;Providing oversight of the conduct of the study at the site and adherence to requirementsof 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014 for clinicalstudies (if applicable), and all other applicable local regulations.

10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicableregulatory authority in any area of the world, or if the investigator is aware of any new
information that might influence the evaluation of the benefits and risks of the study
intervention, Pfizer should be informed immediately.
In addition, the investigator will inform Pfizer immediately of any urgent safety measurestaken by the investigator to protect the study participants against any immediate hazard, andof any serious breaches of this protocol or of ICH GCP that the investigator becomes awareof.
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10.1.2. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to theparticipant and answer all questions regarding the study. The participant should be given
sufficient time and opportunity to ask questions and to decide whether or not to participate in
the trial.
Participants must be informed that their participation is voluntary. Participants will be
required to sign a statement of informed consent that meets the requirements of 21 CFR 50,
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/EC
or study center.
The investigator must ensure that each study participant is fully informed about the natureand objectives of the study, the sharing of data related to the study, and possible risks
associated with participation, including the risks associated with the processing of theparticipant’s personal data.

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)The participant must be informed that his/her personal study-related data will be used by thesponsor in accordance with local data protection law. The level of disclosure must also be
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical
Quality Assurance auditors or other authorized personnel appointed by the sponsor, byappropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or
her right to access and correct his or her personal data and to withdraw consent for theprocessing of his or her personal data.
The medical record must include a statement that written informed consent was obtained
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their
participation in the study.
A copy of the ICD(s) must be provided to the participant. Participants who are rescreened are
required to sign a new ICD.
Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate
section that addresses the use of samples for optional additional research. The optional
additional research does not require the collection of any further samples. The investigator
or authorized designee will explain to each participant the objectives of the additional
research. Participants will be told that they are free to refuse to participate and may
withdraw their consent at any time and for any reason during the storage period.

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10.1.3. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementationof organizational and technical measures to ensure protection of participant data.

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Participants’ personal data will be stored at the study site in encrypted electronic and/or paper
form and will be password protected or secured in a locked room to ensure that only
authorized study staff have access. The study site will implement appropriate technical andorganizational measures to ensure that the personal data can be recovered in the event ofdisaster. In the event of a potential personal data breach, the study site will be responsiblefor determining whether a personal data breach has in fact occurred and, if so, providing
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personaldata, participants will be assigned a single, participant-specific numerical code. Any
participant records or data sets that are transferred to the sponsor will contain the numericalcode; participant names will not be transferred. All other identifiable data transferred to thesponsor will be identified by this single, participant-specific code. The study site will
maintain a confidential list of participants who participated in the study, linking eachparticipant’s numerical code to his or her actual identity and medical record identification. In
case of data transfer, the sponsor will protect the confidentiality of participants’ personal dataconsistent with the clinical study agreement and applicable privacy laws.
10.1.4. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting theresults of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or
www.pfizer.com, and other public registries in accordance with applicable local
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, andcomplete manner and are reported regardless of the outcome of the study or the country inwhich the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional
studies (conducted in patients) that evaluate the safety and/or efficacy of a product,
regardless of the geographical location in which the study is conducted. These results are
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies inaccordance with the format and timelines set forth by EU requirements.

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www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used
to identify individual participants have been removed) on www.pfizer.com for
Pfizer-sponsored interventional studies at the same time the corresponding study results areposted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinicaldata to the EMA website. Clinical data, under Phase 1 of this policy, includes clinicaloverviews, clinical summaries, CSRs, and appendices containing the protocol and protocol
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of thispolicy, includes the publishing of individual participant data. Policy 0070 applies to newmarketing authorization applications submitted via the centralized procedure since
01 January 2015 and applications for line extensions and for new indications submitted via
the centralized procedure since 01 July 2015.

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Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposesof “bona-fide scientific research” that contributes to the scientific understanding of thedisease, target, or compound class. Pfizer will make available data from these trials
24 months after study completion. Patient-level data will be anonymized in accordance withapplicable privacy laws and regulations. CSRs will have personally identifiable information
redacted.
Data requests are considered from qualified researchers with the appropriate competencies toperform the proposed analyses. Research teams must include a biostatistician. Data will not
be provided to applicants with significant conflicts of interest, including individuals
requesting access for commercial/competitive or legal purposes.
10.1.5. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unlesstransmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is
responsible for verifying that data entries are accurate and correct by physically orelectronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports theinformation entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted
electronic and/or paper form and are password protected or secured in a locked room toprevent access by unauthorized third parties.

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The investigator must permit study-related monitoring, audits, IRB/EC review, andregulatory agency inspections and provide direct access to source data documents. This
verification may also occur after study completion. It is important that the investigator(s)and their relevant personnel are available during the monitoring visits and possible audits orinspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality
such as risk management and mitigation strategies and analytical risk-based monitoring),
methods, responsibilities, and requirements, including handling of noncompliance issues andmonitoring techniques (central, remote, or on-site monitoring), are provided in themonitoring plan.

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)The sponsor or designee is responsible for the data management of this study, including
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data enteredinto the CRF by authorized site personnel are accurate, complete, and verifiable from source
documents; that the safety and rights of participants are being protected; and that the study is
being conducted in accordance with the currently approved protocol and any other study
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must
be retained by the investigator for 15 years after study completion unless local regulations or
institutional policies require a longer retention period. No records may be destroyed during
the retention period without the written approval of the sponsor. No records may betransferred to another location or party without written notification to the sponsor. The
investigator must ensure that the records continue to be stored securely for as long as they are
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of suchdata are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory
inspection notification in relation to the study. Furthermore, the investigator will cooperatewith the sponsor or its agents to prepare the investigator site for the inspection and will allow
the sponsor or its agent, whenever feasible, to be present during the inspection. The
investigator site and investigator will promptly resolve any discrepancies that are identified
between the study data and the participant's medical records. The investigator will promptly
provide copies of the inspection findings to the sponsor or its agent. Before response
submission to the regulatory authorities, the investigator will provide the sponsor or its
agents with an opportunity to review and comment on responses to any such findings.

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10.1.6. Source Documents
Source documents provide evidence for the existence of the participant and substantiate theintegrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be
consistent with the source documents or the discrepancies must be explained. The
investigator may need to request previous medical records or transfer records, depending on
the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the study monitoring plan.
Description of the use of computerized system is documented in the Data Management Plan.
10.1.7. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment ofparticipants.

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)The first act of recruitment is the date of the first participant’s first visit and will be the study
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any
time for any reason at the sole discretion of the sponsor. Study sites will be closed uponstudy completion. A study site is considered closed when all required documents and study
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor
or designee if requested to do so by the responsible IRB/EC or if such termination is required
to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limitedto:

Failure of the investigator to comply with the protocol, the requirements of the IRB/EC
or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.

If the study is prematurely terminated or suspended, the sponsor shall promptly inform theinvestigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of
the reason for termination or suspension, as specified by the applicable regulatory
requirements. The investigator shall promptly inform the participant and should assure
appropriate participant therapy and/or follow-up.

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Study termination is also provided for in the clinical study agreement. If there is any conflict
between the contract and this protocol, the contract will control as to termination rights.
10.1.8. Sponsor’s Qualified Medical Personnel

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)The contact information for the sponsor's appropriately qualified medical personnel for the
study is documented in the study contact list located in the supporting study documentation.
To facilitate access to appropriately qualified medical personnel on study-related medical
questions or problems, participants are provided with a contact card at the time of informed
consent. The contact card contains, at a minimum, protocol and study intervention
identifiers, participant numbers, contact information for the investigator site, and contact
details for a contact center in the event that the investigator site staff cannot be reached toprovide advice on a medical question or problem originating from another healthcare
professional not involved in the participant’s participation in the study. The contact number
can also be used by investigator staff if they are seeking advice on medical questions or
problems; however, it should be used only in the event that the established communication
pathways between the investigator site and the study team are not available. It is therefore
intended to augment, but not replace, the established communication pathways between theinvestigator site and the study team for advice on medical questions or problems that may
arise during the study. The contact number is not intended for use by the participant directly,
and if a participant calls that number, he or she will be directed back to the investigator site.

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10.2. Appendix 2: Clinical Laboratory Tests

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)The following safety laboratory tests will be performed at times defined in the SoA section ofthis protocol. Additional laboratory results may be reported on these samples as a result of
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived
from calculated values. These additional tests would not require additional collection ofblood. Unscheduled clinical laboratory measurements may be obtained at any time during
the study to assess any perceived safety issues.
Hematology
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet countWBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)Basophils (Abs)
Lymphocytes (Abs)

Chemistry
BUN and creatinine
AST, ALT
Total bilirubin
Alkaline phosphatase

Other Urine pregnancy test (β-hCG)
At screening only: Hepatitis B core antibody
 Hepatitis B surface antigen
 Hepatitis C antibody
 Human immunodeficiency virus

Investigators must document their review of each laboratory safety report.
Clinically significant abnormal laboratory findings should be recorded in the AE CRF in
accordance with the following grading scale (Table 9).
Table 9.

Laboratory Abnormality Grading Scale

Hematology

Mild (Grade 1)

Hemoglobin
11.0 – 12.0
(Female) - g/dL
Hemoglobin
12.5 – 13.5
(Male) - g/dL
WBC increase 10,800 – 15,000
cells/mm3
WBC decrease 2,500 – 3,500
cells/mm3
Lymphocytes
750 – 1,000
decrease - cells/mm3
Neutrophils decrease 1,500 – 2,000- cells/mm3
Eosinophils 650 – 1500
cells/mm3
Platelets decreased - 125,000 – 140,000
cells/mm3

Moderate(Grade 2)

Severe (Grade 3)

9.5 – 10.9

8.0 – 9.4

Potentially Life
Threatening(Grade 4)<8.0

10.5 – 12.4

8.5 – 10.4

<8.5

15,001 – 20,000

20,001 – 25, 000>25,000

1,500 – 2,499

1,000 – 1,499<1,000500 – 749

250 – 499

<250

1,000 – 1,499

500 – 999

<500

1501 - 5000

>5000

Hypereosinophilic

100,000 – 124,000

25,000 – 99,000<25,000

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Table 9.

Laboratory Abnormality Grading Scale

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Chemistry

Mild (Grade 1)

Moderate(Grade 2)

Severe(Grade 3)

BUN - mg/dL
Creatinine – mg/dL

23 – 26
1.5 – 1.7

27 – 31
1.8 – 2.0> 31
2.1 – 2.5

Alkaline
phosphate –increase by factor
Liver function tests– ALT, AST
increase by factor
Bilirubin – whenaccompanied
by any increase inliver function test increase by factor
Bilirubin – whenliver function test is
normal - increase byfactor

1.1 – 2.0 x ULN

2.1 – 3.0 x ULN

3.1 – 10 x ULN

Potentially Life
Threatening(Grade 4)
Requires dialysis> 2.5 or requires
dialysis>10 x ULN

1.1 – 2.5 x ULN

2.6 – 5.0 x ULN

5.1 – 10 x ULN>10 x ULN

1.1 – 1.25 x ULN

1.26 – 1.5 x ULN

1.51 – 1.75 x ULN>1.75 x ULN

1.1 – 1.5 x ULN

1.6 – 2.0 x ULN

2.0 – 3.0 x ULN>3.0 x ULN

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen;
ULN = upper limit of normal; WBC = white blood cell.

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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition


An AE is any untoward medical occurrence in a patient or clinical study participant,temporally associated with the use of study intervention, whether or not consideredrelated to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including anabnormal laboratory finding), symptom, or disease (new or exacerbated) temporally
associated with the use of study intervention.

Events Meeting the AE Definition

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Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis)or other safety assessments (eg, ECG, radiological scans, vital sign measurements),
including those that worsen from baseline, considered clinically significant in the
medical and scientific judgment of the investigator Any abnormal laboratory test
results that meet any of the conditions below must be recorded as an AE:
Is associated with accompanying symptoms.



Requires additional diagnostic testing or medical/surgical intervention.



Leads to a change in study dosing (outside of any protocol-specified dose
adjustments) or discontinuation from the study, significant additional
concomitant drug treatment, or other therapy.



Exacerbation of a chronic or intermittent preexisting condition including either anincrease in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration eventhough it may have been present before the start of the study.



Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.



Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
intervention or a concomitant medication. Overdose per se will not be reported as
an AE/SAE unless it is an intentional overdose taken with possible suicidal/selfharming intent. Such overdoses should be reported regardless of sequelae.

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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safetyassessments which are associated with the underlying disease, unless judged by theinvestigator to be more severe than expected for the participant’s condition.



The disease/disorder being studied or expected progression, signs, or symptoms ofthe disease/disorder being studied, unless more severe than expected for theparticipant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).



Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present
or detected at the start of the study that do not worsen.

10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:a. Results in deathb. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which theparticipant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.
c. Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving
at least an overnight stay) at the hospital or emergency ward for observation and/or
treatment that would not have been appropriate in the physician’s office or outpatientsetting. Complications that occur during hospitalization are AEs. If a complication
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in
doubt as to whether “hospitalization” occurred or was necessary, the AE should beconsidered serious.
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Hospitalization for elective treatment of a preexisting condition that did not worsen frombaseline is not considered an AE.
d. Results in persistent disability/incapacity


The term disability means a substantial disruption of a person’s ability to conduct
normal life functions.

This definition is not intended to include experiences of relatively minor medicalsignificance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza,
and accidental trauma (eg, sprained ankle) which may interfere with or prevent
everyday life functions but do not constitute a substantial disruption.

e. Is a congenital anomaly/birth defect090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)

f. Other situations:Medical or scientific judgment should be exercised in deciding whether SAE
reporting is appropriate in other situations such as important medical events that
may not be immediately life-threatening or result in death or hospitalization but may
jeopardize the participant or may require medical or surgical intervention to prevent
one of the other outcomes listed in the above definition. These events should
usually be considered serious.



Examples of such events include invasive or malignant cancers, intensive treatment
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or
convulsions that do not result in hospitalization, or development of drug dependency
or drug abuse.

Suspected transmission via a Pfizer product of an infectious agent, pathogenic or
nonpathogenic, is considered serious. The event may be suspected from clinicalsymptoms or laboratory findings indicating an infection in a patient exposed to a
Pfizer product. The terms “suspected transmission” and “transmission” areconsidered synonymous. These cases are considered unexpected and handled asserious expedited cases by pharmacovigilance personnel. Such cases are also
considered for reporting as product defects, if appropriate.

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10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF andfor reporting serious adverse events on the Vaccines SAE Report Form to Pfizer Safety.
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious adverse
events (AEs); and (3) exposure to the study intervention under study during pregnancy orbreastfeeding, and occupational exposure.

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)It should be noted that the Vaccines SAE Report Form for reporting of SAE information is
not the same as the AE page of the CRF. When the same data are collected, the forms must
be completed in a consistent manner. AEs should be recorded using concise medical
terminology and the same AE term should be used on both the CRF and the Vaccines SAE
Report Form for reporting of SAE information.
Safety Event

Recorded on the CRF

SAE
Nonserious AE
Exposure to the study
intervention under study
during pregnancy orbreastfeeding, andoccupational exposure

All
All
All AEs/SAEs associatedwith exposure during
pregnancy or breastfeeding

Reported on the Vaccines
SAE Report Form to
Pfizer Safety Within 24
Hours of Awareness

All
None
All (and EDP supplemental
form for EDP)
Note: Include all SAEs
associated with exposure
Occupational exposure is not during pregnancy orbreastfeeding. Include allrecorded.
AEs/SAEs associated withoccupational exposure.

When an AE/SAE occurs, it is the responsibility of the investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostic
reports) related to the event.



The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s
medical records to Pfizer Safety in lieu of completion of the Vaccines SAE Report
Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases arerequested by Pfizer Safety. In this case, all participant identifiers, with the
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exception of the participant number, will be redacted on the copies of the medical
records before submission to Pfizer Safety.


The investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. Whenever possible, the diagnosis(not the individual signs/symptoms) will be documented as the AE/SAE.

Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during
the study and assign it to 1 of the following categories:

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)GRADE If required on the AE page of the CRF, the investigator will use theadjectives MILD, MODERATE, SEVERE, or LIFE-THREATENING todescribe the maximum intensity of the AE. For purposes of consistency,
these intensity grades are defined as follows:
1

MILD

Does not interfere with participant's usualfunction.

2

MODERATE

Interferes to some extent with participant's usualfunction.

3

SEVEREInterferes significantly with participant's usualfunction.

4

LIFE-THREATENING Life-threatening consequences; urgent
intervention indicated.

Assessment of Causality

The investigator is obligated to assess the relationship between study intervention
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence,
and/or arguments to suggest a causal relationship, rather than a relationship cannot
be ruled out.

The investigator will use clinical judgment to determine the relationship.



Alternative causes, such as underlying disease(s), concomitant therapy, and otherrisk factors, as well as the temporal relationship of the event to study intervention
administration, will be considered and investigated.

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The investigator will also consult the IB and/or product information, for marketed
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she
has reviewed the AE/SAE and has provided an assessment of causality.



There may be situations in which an SAE has occurred and the investigator has
minimal information to include in the initial report to the sponsor. However, it isvery important that the investigator always make an assessment of causality forevery event before the initial transmission of the SAE data to the sponsor.



The investigator may change his/her opinion of causality in light of follow-up
information and send an SAE follow-up report with the updated causality
assessment.



The causality assessment is one of the criteria used when determining regulatory
reporting requirements.



If the investigator does not know whether or not the study intervention caused theevent, then the event will be handled as “related to study intervention” for reporting
purposes, as defined by the sponsor. In addition, if the investigator determines thatan SAE is associated with study procedures, the investigator must record this causal
relationship in the source documents and CRF, and report such an assessment in the
dedicated section of the Vaccines SAE Report Form and in accordance with the
SAE reporting requirements.

Follow-up of AEs and SAEs


The investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by thesponsor to elucidate the nature and/or causality of the AE or SAE as fully as
possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other healthcare providers.



If a participant dies during participation in the study or during a recognizedfollow-up period, the investigator will provide Pfizer Safety with a copy of any
postmortem findings including histopathology.



New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours ofreceipt of the information.

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10.3.4. Reporting of SAEs

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SAE Reporting to Pfizer Safety via Vaccines SAE Report Form

Facsimile transmission of the Vaccines SAE Report Form is the preferred method totransmit this information to Pfizer Safety.



In circumstances when the facsimile is not working, notification by telephone isacceptable with a copy of the Vaccines SAE Report Form sent by overnight mail orcourier service.

Initial notification via telephone does not replace the need for the investigator tocomplete and sign the Vaccines SAE Report Form pages within the designatedreporting time frames.

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10.4. Appendix 4: Contraceptive Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during
the intervention period and for at least 28 days after the last dose of study intervention, whichcorresponds to the time needed to eliminate reproductive safety risk of the study
intervention(s):Refrain from donating sperm.

PLUS either:Be abstinent from heterosexual intercourse with a female of childbearing potential as
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) andagree to remain abstinent.

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)OR

Must agree to use a male condom when engaging in any activity that allows for passageof ejaculate to another person.



In addition to male condom use, a highly effective method of contraception may beconsidered in WOCBP partners of male participants (refer to the list of highly effective
methods below in Section 10.4.4).

10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using an acceptable contraceptive method as described below during
the intervention period (for a minimum of 28 days after the last dose of study
intervention). The investigator should evaluate the effectiveness of the contraceptive
method in relationship to the first dose of study intervention.

The investigator is responsible for review of medical history, menstrual history, and recent
sexual activity to decrease the risk for inclusion of a woman with an early undetected
pregnancy.

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10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot
be confirmed before the first dose of study intervention, additional evaluation should beconsidered.
Women in the following categories are not considered WOCBP:

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1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.

For individuals with permanent infertility due to an alternate medical cause other than theabove, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should beapplied to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s
review of the participant’s medical records, medical examination, or medical history
interview. The method of documentation should be recorded in the participant’s medical
record for the study.
2. Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause. In addition, ahigh FSH level in the postmenopausal range must be used to confirm apostmenopausal state in women under 60 years of age and not using hormonal
contraception or HRT.



Female on HRT and whose menopausal status is in doubt will be required to use
one of the nonestrogen hormonal highly effective contraception methods if theywish to continue their HRT during the study. Otherwise, they must discontinue
HRT to allow confirmation of postmenopausal status before study enrollment.

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10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations
regarding the use of contraceptive methods for those participating in clinical trials.
1. Implantable progestogen-only hormone contraception associated with inhibition ofovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner:

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Vasectomized partner is a highly effective contraceptive method provided that thepartner is the sole sexual partner of the woman of childbearing potential and theabsence of sperm has been confirmed. If not, an additional highly effective methodof contraception should be used. The spermatogenesis cycle is approximately
90 days.

6. Combined (estrogen- and progestogen-containing) hormonal contraception associatedwith inhibition of ovulation:


Oral;



Intravaginal;Transdermal;



Injectable.

7. Progestogen-only hormone contraception associated with inhibition of ovulation:


Oral;



Injectable.

8. Sexual abstinence:Sexual abstinence is considered a highly effective method only if defined as
refraining from heterosexual intercourse during the entire period of risk associatedwith the study intervention. The reliability of sexual abstinence needs to be evaluatedin relation to the duration of the study and the preferred and usual lifestyle of theparticipant.

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9. Progestogen-only oral hormonal contraception where inhibition of ovulation is not the
primary mode of action.
10. Male or female condom with or without spermicide.
11. Cervical cap, diaphragm, or sponge with spermicide.

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12. A combination of male condom with either cervical cap, diaphragm, or sponge with
spermicide (double-barrier methods).

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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations intransaminases) are termed “tolerators,” while those who show transient liver injury, but adapt
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of amore serious potential outcome. These participants fail to adapt and therefore are"susceptible" to progressive and serious liver injury, commonly referred to as DILI.
Participants who experience a transaminase elevation above 3 × ULN should be monitored
more frequently to determine if they are an “adaptor” or are “susceptible.”

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LFTs are not required as a routine safety monitoring procedure for all participants in thisstudy. However, should an investigator deem it necessary to assess LFTs because aparticipant presents with clinical signs/symptoms, such LFT results should be managed andfollowed as described below.
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will beelevated within the same laboratory sample). In rare instances, by the time TBili elevations
are detected, AST/ALT values might have decreased. This occurrence is still regarded as apotential DILI. Therefore, abnormal elevations in either AST OR ALT in addition to TBili
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law
criteria) cases and should always be considered important medical events, even before allother possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on theparticipant’s individual baseline values and underlying conditions. Participants who present
with the following laboratory abnormalities should be evaluated further as potential DILI
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:Participants with AST/ALT and TBili baseline values within the normal range who
subsequently present with AST OR ALT values >3 × ULN AND a TBili value >2 × ULN
with no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or notavailable.

For participants with baseline AST OR ALT OR TBili values above the ULN, thefollowing threshold values are used in the definition mentioned above, as needed,
depending on which values are above the ULN at baseline:Preexisting AST or ALT baseline values above the normal range: AST or ALT values>2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is smaller).

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Rises in AST/ALT and TBili separated by more than a few weeks should be assessedindividually based on clinical judgment; any case where uncertainty remains as to whether it
represents a potential Hy’s law case should be reviewed with the sponsor.

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)The participant should return to the investigator site and be evaluated as soon as possible,
preferably within 48 hours from awareness of the abnormal results. This evaluation should
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili for suspected cases ofHy’s law, additional laboratory tests should include albumin, CK, direct and indirect
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should
also be given to drawing a separate tube of clotted blood and an anticoagulated tube of bloodfor further testing, as needed, for further contemporaneous analyses at the time of therecognized initial abnormalities to determine etiology. A detailed history, including relevant
information, such as review of ethanol, acetaminophen/paracetamol (either by itself or as a
coformulated product in prescription or over-the-counter medications), recreational drug,
supplement (herbal) use and consumption, family history, sexual history, travel history,
history of contact with a jaundiced person, surgery, blood transfusion, history of liver orallergic disease, and potential occupational exposure to chemicals, should be collected.
Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary
tract) and collection of serum samples for acetaminophen/paracetamol drug and/or protein
adduct levels may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if noother reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law)cases are to be reported as SAEs, irrespective of availability of all the results of theinvestigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results ofreasonable investigations have been received and have excluded an alternative etiology.

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10.6. Appendix 6: Abbreviations

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)The following is a list of abbreviations that may be used in the protocol.
Abbreviation
2019-nCoV
Abs
AE
ALT
AST
-hCG
BMI
BUN
CBER
CDC
CFR
CI
CIOMS
CLIA
CONSORT
COVID-19
CRF
CRO
CSR
CT
DBP
DILI
DMC
DNA
DU
EC
ECMO
ECG
eCRF
e-diary
EDP
EMA
EU
EUA
EudraCT
FDA
FiO2
FSH
GCP

Term
novel coronavirus 2019absolute (in Appendix 2)
adverse event
alanine aminotransferase
aspartate aminotransferase
beta-human chorionic gonadotropin
body mass index
blood urea nitrogen
Center for Biologics Evaluation and ResearchCenters for Disease Control and Prevention (United States)
Code of Federal Regulations
confidence interval
Council for International Organizations of Medical Sciences
Clinical Laboratory Improvement Amendments
Consolidated Standards of Reporting Trials
coronavirus disease 2019case report form
contract research organization
clinical study reportcomputed tomography
diastolic blood pressuredrug-induced liver injury
data monitoring committee
deoxyribonucleic aciddosing unit
ethics committee
extracorporeal membrane oxygenationelectrocardiogram
electronic case report form
electronic diary
exposure during pregnancy
European Medicines Agency
European Union
emergency use application
European Clinical Trials Database
Food and Drug Administration
fraction of inspired oxygenfollicle-stimulating hormone
Good Clinical Practice

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Abbreviation
GGT
GMC
GMFR
GMR
GMT
HBc Ab
HBsAg
HBV
HCV
HCV Ab
HIPAA
HIV
HR
HRT
IA
IB
ICD
ICH
ICU
ID
Ig
IgG
IgM
IMP
IND
INR
IP manual
IPAL
IRB
IRC
IRR
IRT
ISO
IV
IWR
LFT
LL
LLOQ
LNP
LPX
MCH
MCHC

Term
gamma-glutamyl transferase
geometric mean concentrationgeometric mean fold risegeometric mean ratio
geometric mean titerhepatitis B core antibody
hepatitis B surface antigen
hepatitis B virus
hepatitis C virus
hepatitis C virus antibody
Health Insurance Portability and Accountability Act
human immunodeficiency virus
heart rate
hormone replacement therapy
interim analysis
investigator’s brochure
informed consent document
International Council for Harmonisation
intensive care unit
identification
immunoglobulin
immunoglobulin G
immunoglobulin M
investigational medicinal productinvestigational new druginternational normalized ratio
investigational product manual
Investigational Product Accountability Log
institutional review board
internal review committee
illness rate ratio
interactive response technology
International Organization for Standardization
intravenous(ly)interactive Web-based response
liver function test
lower limit
lower limit of quantitation
lipid nanoparticle
lipoplexmean corpuscular hemoglobinmean corpuscular hemoglobin concentration

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Abbreviation
MCV
MedDRAMERS
modRNA
MRI
N/A
NAAT
non-S
NVA
P2 S
PaO2
PCR
PI
POS
PPE
PT
RBC
RBD
RCDC
RNA
RR
RSV
RT-PCR
S1
SAE
SAP
saRNA
SARS
SARS-CoV-2
SBP
SoA
SOP
SpO2
SRSD
SUSAR
TBD
TBili
ULN
uRNA
US
vax

Term
mean corpuscular volume
Medical Dictionary for Regulatory Activities
Middle East respiratory syndrome
nucleoside-modified messenger ribonucleic acidmagnetic resonance imaging
not applicable
nucleic acid amplification test
nonspike protein
nonvaccine antigen
SARS-CoV-2 full-length, P2 mutant, “heads up,” prefusion spikeglycoprotein
partial pressure of oxygen, arterial
polymerase chain reaction
principal investigatorprobability of successpersonal protective equipment
prothrombin time
red blood cell
receptor-binding domain
reverse cumulative distribution curve
ribonucleic acidrespiratory rate
respiratory syncytial virus
reverse transcription–polymerase chain reaction
spike protein S1 subunit
serious adverse event
statistical analysis planself-amplifying messenger ribonucleic acidsevere acute respiratory syndrome
severe acute respiratory syndrome coronavirus 2
systolic blood pressureschedule of activities
standard operating procedureoxygen saturation as measured by pulse oximetry
single reference safety document
suspected unexpected serious adverse reaction
to be determinedtotal bilirubin
upper limit of normal
unmodified messenger ribonucleic acid
United States
vaccination

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Abbreviation
VE
WBC
WHO
WOCBP

Term
vaccine efficacy
white blood cell
World Health Organization
woman/women of childbearing potential

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10.7. Appendix 7: Stopping and Alert Rules for Enhanced COVID-19
At the time of the IAs at 32, 62, 92, and 120 cases, the number of severe COVID-19 cases inthe vaccine and placebo groups will be assessed. If there are more severe cases in thevaccine group than in the placebo group, the DMC will be advised to recommend thatenrollment be stopped if the probability of the adverse split being observed is <1%, assumingthat severe cases are truly evenly split (stopping rule, see Section 8.2.3). If the probability is≥1% and <11%, the DMC will be advised to request probability to be recalculated as each
additional severe case is accrued (alert rule). This is illustrated for severe cases, from 2 to20, in Table 10.

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)In Stage 3, the unblinded statistical team, including an unblinded medical monitor, will
review cases of severe COVID-19 as they are received, and will review AEs at least weekly
for additional potential cases of severe COVID-19. At any point the unblinded team may
discuss with the DMC chair whether the DMC should review cases for an adverse imbalanceof cases of COVID-19 and/or severe COVID-19 between the vaccine and placebo groups(see Section 8.2.4).
Table 10. For 2 to 20 Cases of Severe COVID-19, Probability of Observing This
Number or More of Severe Cases in the Vaccine Group at a Range ofTrue Adverse Ratios From 1:1 to 4:1
Severe Cases Split

Totalsevere
cases
True
ratio
2
3
4
5
6
6
7
7
8
8
9
9
9
10

Vaccine
(X)

2
3
4
5
5
6
6
7
7
8
7
8
9
8

Placebo

0
0
0
0
1
0
1
0
1
0
2
1
0
2

Probability ofObserving X
Severe Cases
in Vaccine
Group if Truly
Evenly Split;
STOPPING
RULE: <1%

Probability ofObserving X
or MoreSevere Cases
in Vaccine
Group if Truly
Evenly Split;
ALERT
RULE: <11%
True Split Ratio(Active:Placebo)

Probability of Observing X or
More Severe Cases in Vaccine
Group With Different True Split
RatiosTrue Split Ratio (Active:Placebo)

(1:1)

(1:1)

(2:1)

(3:1)

(4:1)

>1%
>1%
>1%
>1%
>1%
0.78%
>1%
0.39%
>1%
>1%
0.20%
>1%

6.25%
3.13%
10.94%
1.56%
6.25%
0.78%
3.52%
0.39%
8.98%
1.95%
0.20%
5.47%

19.79%
13.20%
35.18%
8.81%
26.40%
5.87%
19.56%
3.92%
37.80%
14.35%
2.61%
29.99%

31.64%
23.73%
53.39%
17.80%
44.49%
13.35%
36.71%
10.01%
60.07%
30.03%
7.51%
52.56%

40.96%
32.77%
65.54%
26.21%
57.67%
20.97%
50.33%
16.78%
73.82%
43.62%
13.42%
67.78%

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Table 10. For 2 to 20 Cases of Severe COVID-19, Probability of Observing This
Number or More of Severe Cases in the Vaccine Group at a Range ofTrue Adverse Ratios From 1:1 to 4:1

090177e1941f5ede\Approved\Approved On: 01-Jul-2020 13:44 (GMT)

Severe Cases Split

Totalsevere
cases
True
ratio
10
11
11
12
12
12
13
13
14
14
14
15
15
15
16
16
16
17
17
17
18
18
18
19
19
19
20
20
20

Vaccine
(X)

9
9
10
9
10
11
10
11
10
11
12
11
12
13
11
12
13
12
13
14
13
14
15
13
14
15
14
15
16

Placebo

1
2
1
3
2
1
3
2
4
3
2
4
3
2
5
4
3
5
4
3
5
4
3
6
5
4
6
5
4

Probability ofObserving X
Severe Cases
in Vaccine
Group if Truly
Evenly Split;
STOPPING
RULE: <1%

Probability ofObserving X
or MoreSevere Cases
in Vaccine
Group if Truly
Evenly Split;
ALERT
RULE: <11%
True Split Ratio(Active:Placebo)

Probability of Observing X or
More Severe Cases in Vaccine
Group With Different True Split
RatiosTrue Split Ratio (Active:Placebo)

(1:1)

(1:1)

(2:1)

(3:1)

(4:1)

0.98%
>1%
0.54%
>1%
>1%
0.29%
>1%
0.95%
>1%
>1%
0.56%
>1%
>1%
0.32%
>1%
>1%
0.85%
>1%
>1%
0.52%
>1%
>1%
0.31%
>1%
>1%
0.74%
>1%
>1%
0.46%

1.07%
3.27%
0.59%
7.30%
1.93%
0.32%
4.61%
1.12%
8.98%
2.87%
0.65%
5.92%
1.76%
0.37%
10.51%
3.84%
1.06%
7.17%
2.45%
0.64%
4.81%
1.54%
0.38%
8.35%
3.18%
0.96%
5.77%
2.07%
0.59%

10.44%
23.48%
7.55%
39.40%
18.18%
5.42%
32.33%
13.93%
47.66%
26.21%
10.58%
40.51%
21.00%
7.97%
54.81%
34.02%
16.66%
47.88%
28.24%
13.10%
41.34%
23.20%
10.22%
54.43%
35.30%
18.88%
48.06%
29.83%
15.22%

24.40%
45.52%
19.71%
64.88%
39.07%
15.84%
58.43%
33.26%
74.15%
52.13%
28.11%
68.65%
46.13%
23.61%
81.03%
63.02%
40.50%
76.53%
57.39%
35.30%
71.75%
51.87%
30.57%
82.51%
66.78%
46.54%
78.58%
61.72%
41.48%

37.58%
61.74%
32.21%
79.46%
55.83%
27.49%
74.73%
50.17%
87.02%
69.82%
44.81%
83.58%
64.82%
39.80%
91.83%
79.82%
59.81%
89.43%
75.82%
54.89%
86.71%
71.64%
50.10%
93.24%
83.69%
67.33%
91.33%
80.42%
62.96%

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11. REFERENCES
1

World Health Organization. WHO Director-General's opening remarks at the media
briefing on COVID-19. Available from: https://www.who.int/dg/speeches/detail/whodirector-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march2020. Published: 11 Mar 2020. Accessed: 01 Apr 2020.

2

World Health Organization. Coronavirus disease 2019 (COVID-19) situation report - 70.
In: Data as reported by national authorities by 10:00 CET 30 March 2020. Geneva,
Switzerland: World Health Organization; 2020.

3

Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19):
information for clinicians on investigational therapeutics for patients with COVID-19.
Available from: https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeuticoptions.html. Updated: 25 Apr 2020. Accessed: 26 Jun 2020.

4

Rauch S, Jasny E, Schmidt KE, et al. New vaccine technologies to combat outbreaksituations. Front Immunol 2018;9:1963.

5

Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics—developing a new class ofdrugs. Nat Rev Drug Discov 2014;13(10):759-80.

6

BioNTech RNA Pharmaceuticals GmbH. CorVAC/BNT162 Investigator’s Brochure.
Mainz, Germany: BioNTech RNA Pharmaceuticals GmbH; 25 Mar 2020.

7

Feldman RA, Fuhr R, Smolenov I, et al. mRNA vaccines against H10N8 and H7N9
influenza viruses of pandemic potential are immunogenic and well tolerated in healthy
adults in phase 1 randomized clinical trials. Vaccine. 2019;37(25):3326-34.

8

US Food and Drug Administration. Guidance for industry: toxicity grading scale forhealthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials.
Rockville, MD: Center for Biologics Evaluation and Research; September 2007.

9

Agresti A. Introduction: distributions and inference for categorical data. In: Agresti A,
ed. Categorical data analysis. 2nd ed. Hoboken, NJ: John Wiley & Sons; 2002:1-35.

10

Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med
1985;4(2):213-26.

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Document Approval Record
Document Name:

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Signed By:

Date(GMT)

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4Page 893

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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
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Protocol Amendment 3, 10 June 2020090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)A PHASE 1/2, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLIND,
DOSE-FINDING STUDY TO DESCRIBE THE SAFETY, TOLERABILITY,IMMUNOGENICITY, AND POTENTIAL EFFICACY OF SARS-COV-2 RNAVACCINE CANDIDATES AGAINST COVID-19 IN HEALTHY ADULTS

Study Sponsor:

BioNTechStudy Conducted By:

PfizerStudy Intervention Number:

PF-07302048

Study Intervention Name:

RNA-Based COVID-19 Vaccines

US IND Number:

19736

EudraCT Number:

N/A

Protocol Number:

C4591001

Phase:
1/2
Short Title: A Phase 1/2 Study to Describe the Safety, Tolerability, Immunogenicity, andPotential Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Adults

This document and accompanying materials contain confidential information belonging to Pfizer. Except asotherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold thisinformation in confidence and not copy or disclose it to others (except where required by applicable law) or
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer
must be promptly notified.

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Protocol Amendment Summary of Changes Table

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Document History
Document

Version Date

Summary and Rationale for Changes

Protocol amendment 3

10 June 2020

As data have become available from this study andthe BNT162-01 study in Germany, the following
decisions were made: Not to study the BNT162a1 and BNT162c2
vaccine candidates at this time. Therefore, thesecandidates have been removed from theprotocol.
 To study further lower dose levels of the
modRNA candidates. Therefore, a 20-µg doselevel is formally included for BNT162b1 and
BNT162b2.
 To permit individual and group dosing
alterations for the second dose of study
intervention.
Following regulatory feedback, the BNT162b3
vaccine candidate has been removed from theprotocol until further nonclinical data are available tosupport study in humans.
Given the rapidly evolving pandemic situation,
additional blood draws for exploratory COVID-19
research, intended to establish an immunologicalsurrogate of protection, will be taken from selectedparticipants who consent.
In order to increase flexibility enrolling participants,
an extended screening window (increased from 14 to
28 days) for sentinel participants in Stage 1 has been
added. This is considered acceptable since eligible
participants are expected to be either healthy or havestable medical conditions.
To increase the number of doses that can be obtained
from available vaccine vials, not all dose levels will
result in a dosing volume of 0.5 mL. Precise dosing
instructions will be provided in the IP manual.

Protocol amendment 2

27 May 2020

To facilitate the reporting of COVID-19 illness
diagnoses and potential symptoms to theinvestigator, participants may utilize a COVID-19
illness e-diary.
Given the urgent nature of the pandemic situation,
the following changes allow determination of theappropriate human dose level for both younger andolder adults to move speedily into the next phase ofclinical evaluation:

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

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Protocol amendment 1

13 May 2020

Added a new vaccine candidate, BNT162b3,
modRNA encoding a membrane-anchored RBD
 Added a 50-µg dose level for vaccine candidates
based on the modRNA platform (ie, BNT162b1,
BNT162b2, and BNT162b3)
 Modified the criteria required for the IRC todetermine dose escalation in the 18- to 55-year
age cohort and advancement to groups ofparticipants 65 to 85 years of age
In addition:
 Removed hemoglobin change-from-baseline
abnormalities from the laboratory abnormality
grading scale as abnormalities should be gradedbased upon absolute values
 Following regulatory feedback: Modified exclusion criteria and prohibitedinhaled/nebulized corticosteroids for sentinel
participants in Stage 1
 Clarified that the rapid test for prior COVID-19
infection for sentinel participants in Stage 1 will
be used only for screening purposes Removed time frames for stopping rules
 Stated that data supporting the selection of
vaccine candidate(s)/dose level(s) andschedule(s) for Stages 2 and 3 will be submitted
to the FDA for review

Following preliminary experience in the
BioNTech study conducted in Germany(BNT162-01):
Decreased the dose levels for BNT162a1 and
BNT162c2

Additionally: Clarified the roles of BioNTech and Pfizer
 Amended text so that the IRC decision toprogress group(s) into Stages 2 and 3 can bebased upon safety and immunogenicity data
after Dose 1 or 2
 Clarified safety data requirements to permit dose
escalation
 Amended text so that the progression toparticipants 65 to 85 years of age can be based
upon data from the same RNA platform Incorporated a protocol administrative change tocorrect the variant designation and the encoded
antigen to BNT162c2
 Clarified that the SARS-CoV-2 neutralizing
assay does not employ wild-type virus
 Clarified that the SARS-CoV-2 spike protein–binding antibody assay is specific for the S1subunitCONFIDENTIAL
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








090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)
Original protocol

15 April 2020

Clarified that efficacy against COVID-19 isbased upon illness (not infection) rate ratio
Incorporated a protocol administrative change tostate that the study placebo may be supplied in a
glass or plastic vial
Corrected a typographical error in Section 6.5.1
regarding the time frame for prior receipt ofblood/plasma products or immunoglobulins
Corrected a typographical error in Table 2
regarding the lower limit of diameter (cm) for
mild redness and swelling
Updated the °C fever scale in Table 4 to ensurethat all potential °F values are correctly assigned
Incorporated a protocol administrative change toclarify that a rapid test for prior COVID-19
infection will be performed for sentinel
participants in Stage 1, and a serum sample will
be drawn for potential future assessment
Clarified that, after screening, physicalexaminations in sentinel participants in Stage 1
will be directed
Clarified the descriptions of the populations foranalysis to align with the statistical analysis plan
Added a complete safety and immunogenicity
analysis approximately 6 months after Dose 2
for all participants in Stage 3
Amended text so that the stopping rules apply to
an RNA platform rather than a specific vaccine
candidate

N/A

This amendment incorporates all revisions to date, including amendments made at therequest of country health authorities and IRBs/ECs.

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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................10
1. PROTOCOL SUMMARY...................................................................................................121.1. Synopsis ..................................................................................................................121.2. Schema ....................................................................................................................17
1.3. Schedule of Activities .............................................................................................18
1.3.1. Stage 1 Sentinel Cohorts.............................................................................18
1.3.2. Stage 1 Nonsentinel Cohorts and Stage 2 Cohorts .....................................23
1.3.3. Stage 3 Cohort(s) ........................................................................................26
2. INTRODUCTION ...............................................................................................................28
2.1. Study Rationale .......................................................................................................28

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2.2. Background .............................................................................................................28
2.2.1. Clinical Overview.......................................................................................29
2.3. Benefit/Risk Assessment.........................................................................................29
2.3.1. Risk Assessment .........................................................................................30
2.3.2. Benefit Assessment.....................................................................................312.3.3. Overall Benefit/Risk Conclusion................................................................31
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................31
4. STUDY DESIGN.................................................................................................................33
4.1. Overall Design.........................................................................................................33
4.1.1. Stage 1 ........................................................................................................34
4.1.2. Stage 2 ........................................................................................................35
4.1.3. Stage 3 ........................................................................................................35
4.2. Scientific Rationale for Study Design .....................................................................35
4.3. Justification for Dose ..............................................................................................36
4.4. End of Study Definition ..........................................................................................36
5. STUDY POPULATION ......................................................................................................37
5.1. Inclusion Criteria.....................................................................................................37
5.2. Exclusion Criteria....................................................................................................38
5.3. Lifestyle Considerations..........................................................................................40
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5.3.1. Contraception..............................................................................................40
5.4. Screen Failures ........................................................................................................40
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study
Intervention Administration ......................................................................................41
6. STUDY INTERVENTION..................................................................................................41
6.1. Study Intervention(s) Administered ........................................................................44
6.1.1. Administration ............................................................................................44
6.2. Preparation/Handling/Storage/Accountability ........................................................45
6.2.1. Preparation and Dispensing ........................................................................46
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................46
6.3.1. Allocation to Study Intervention ................................................................46
6.3.2. Blinding of Site Personnel ..........................................................................46
6.3.3. Blinding of the Sponsor ..............................................................................47
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6.3.4. Breaking the Blind......................................................................................47
6.4. Study Intervention Compliance...............................................................................47
6.5. Concomitant Therapy..............................................................................................47
6.5.1. Prohibited During the Study .......................................................................48
6.5.2. Permitted During the Study ........................................................................48
6.6. Dose Modification...................................................................................................49
6.7. Intervention After the End of the Study ..................................................................49
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANTDISCONTINUATION/WITHDRAWAL...........................................................................49
7.1. Discontinuation of Study Intervention ....................................................................49
7.2. Participant Discontinuation/Withdrawal From the Study .......................................49
7.2.1. Withdrawal of Consent ...............................................................................50
7.3. Lost to Follow-up ....................................................................................................50
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................51
8.1. Efficacy and/or Immunogenicity Assessments .......................................................52
8.1.1. Biological Samples .....................................................................................53
8.2. Safety Assessments .................................................................................................54
8.2.1. Clinical Safety Laboratory Assessments (Sentinel-Cohort
Participants Only) ............................................................................................54
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8.2.2. Electronic Diary..........................................................................................55
8.2.2.1. Grading Scales...........................................................................55
8.2.2.2. Local Reactions .........................................................................55
8.2.2.3. Systemic Events ........................................................................56
8.2.2.4. Fever..........................................................................................57
8.2.2.5. Antipyretic Medication .............................................................58
8.2.3. Stopping Rules............................................................................................58
8.2.3.1. Randomization and Vaccination After a Stopping Rule Is
Met.....................................................................................................59
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19
Disease .............................................................................................................59
8.2.5. Pregnancy Testing ......................................................................................60
8.3. Adverse Events and Serious Adverse Events..........................................................60
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8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......60
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................61
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................61
8.3.2. Method of Detecting AEs and SAEs ..........................................................61
8.3.3. Follow-up of AEs and SAEs.......................................................................62
8.3.4. Regulatory Reporting Requirements for SAEs...........................................62
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational
Exposure ..........................................................................................................62
8.3.5.1. Exposure During Pregnancy......................................................63
8.3.5.2. Exposure During Breastfeeding ................................................64
8.3.5.3. Occupational Exposure .............................................................65
8.3.6. Medication Errors .......................................................................................65
8.4. Treatment of Overdose............................................................................................66
8.5. Pharmacokinetics ....................................................................................................66
8.6. Pharmacodynamics..................................................................................................66
8.7. Genetics ...................................................................................................................67
8.8. Biomarkers ..............................................................................................................67
8.9. Immunogenicity Assessments .................................................................................67
8.10. Health Economics .................................................................................................67
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8.11. Study Procedures...................................................................................................67
8.11.1. Stage 1 Sentinel Cohorts...........................................................................67
8.11.1.1. Screening: (0 to 28 Days Before Visit 1) ................................67
8.11.1.2. Visit 1 – Vaccination 1: (Day 1) .............................................68
8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1to 3 Days After Visit 1) .....................................................................71
8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to
8 Days After Visit 1) .........................................................................72
8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1) ...........73
8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to
8 Days After Visit 4) .........................................................................75
8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to
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8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After
Visit 4) ...............................................................................................77
8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (154 to 168 Days
After Visit 4)......................................................................................78
8.11.1.10. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 4)......................................................................................79
8.11.1.11. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 4)......................................................................................79
8.11.2. Stage 1 Nonsentinel Cohorts and Stage 2 Cohorts ...................................79
8.11.2.1. Visit 1 – Vaccination 1: (Day 1) .............................................79
8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days or 56 to 70 Days
After Visit 1)......................................................................................82
8.11.2.3. Visit 3 – 2-Week Follow-up Visit: (12 to 16 Days After
Visit 2) ...............................................................................................84
8.11.2.4. Visit 4 – 1-Month Follow-up Visit: (28 to 35 Days After
Visit 2) ...............................................................................................84
8.11.2.5. Visit 5 – 6-Month Follow-up Visit: (154 to 168 Days
After Visit 2)......................................................................................85
8.11.2.6. Visit 6 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 2)......................................................................................85
8.11.2.7. Visit 7 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 2)......................................................................................86
8.11.3. Stage 3 Cohort(s) ......................................................................................86
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8.11.3.1. Visit 1 – Vaccination 1: (Day 1) .............................................86
8.11.3.2. Visit 2 – Vaccination 2: (19 to 23 Days or 56 to 70 Days
After Visit 1)......................................................................................89
8.11.3.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2):(28 to 35 Days After Visit 2).............................................................90
8.11.3.4. Visit 4 – 6-Month Safety Telephone Contact: (154 to
168 Days After Visit 2) .....................................................................91
8.11.3.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 2)......................................................................................92
8.11.3.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 2)......................................................................................92
8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction ........................92
8.13. COVID-19 Disease Surveillance (All Participants)..............................................94

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8.13.1. Potential COVID-19 Illness Telehealth Visit: (Optimally Within 3
Days After Potential COVID-19 Illness Onset)...............................................94
8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After
Potential COVID-19 Illness Visit)..................................................................95
8.14. Communication and Use of Technology...............................................................96
9. STATISTICAL CONSIDERATIONS ................................................................................96
9.1. Estimands and Statistical Hypotheses .....................................................................96
9.1.1. Estimands....................................................................................................96
9.1.2. Statistical Hypotheses.................................................................................97
9.2. Sample Size Determination.....................................................................................97
9.3. Analysis Sets ...........................................................................................................98
9.4. Statistical Analyses .................................................................................................99
9.4.1. Immunogenicity Analyses ..........................................................................99
9.4.2. Efficacy Analyses .....................................................................................102
9.4.3. Safety Analyses ........................................................................................103
9.4.4. Other Analyses..........................................................................................104
9.5. Interim Analyses ...................................................................................................105
9.5.1. Analysis Timing........................................................................................105
9.6. Data Monitoring Committee or Other Independent Oversight Committee...........105
10. SUPPORTING DOCUMENTATION AND OPERATIONALCONSIDERATIONS ........................................................................................................107
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10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .............107
10.1.1. Regulatory and Ethical Considerations ..................................................107
10.1.1.1. Reporting of Safety Issues and Serious Breaches of theProtocol or ICH GCP.......................................................................107
10.1.2. Informed Consent Process ......................................................................108
10.1.3. Data Protection .......................................................................................109
10.1.4. Dissemination of Clinical Study Data ....................................................109
10.1.5. Data Quality Assurance ..........................................................................110
10.1.6. Source Documents ..................................................................................112
10.1.7. Study and Site Start and Closure ............................................................112
10.1.8. Sponsor’s Qualified Medical Personnel .................................................113
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................114

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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting ....................................................................116
10.3.1. Definition of AE .....................................................................................116
10.3.2. Definition of SAE ...................................................................................117
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.....................119
10.3.4. Reporting of SAEs..................................................................................122
10.4. Appendix 4: Contraceptive Guidance .................................................................123
10.4.1. Male Participant Reproductive Inclusion Criteria ..................................123
10.4.2. Female Participant Reproductive Inclusion Criteria...............................123
10.4.3. Woman of Childbearing Potential ..........................................................124
10.4.4. Contraception Methods...........................................................................125
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ......127
10.6. Appendix 6: Abbreviations .................................................................................129
11. REFERENCES ................................................................................................................132
LIST OF TABLES
Table 1.

Potential Groups in Stage 1 ......................................................................42

Table 2.

Local Reaction Grading Scale ..................................................................56

Table 3.

Systemic Event Grading Scale..................................................................57

Table 4.

Scale for Fever..........................................................................................58
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Protocol Amendment 3, 10 June 2020

Table 5.

Probability of Observing at Least 1 AE by Assumed True Event
Rates With Different Sample Sizes ..........................................................98

Table 6.

Laboratory Abnormality Grading Scale .................................................114

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1. PROTOCOL SUMMARY
1.1. Synopsis
Short Title: A Phase 1/2 Study to Describe the Safety, Tolerability, Immunogenicity, andPotential Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Adults
Rationale

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A pneumonia of unknown cause detected in Wuhan, China, was first reported in
December 2019. On 08 January 2020, the pathogen causing this outbreak was identified as anovel coronavirus 2019. The outbreak was declared a Public Health Emergency ofInternational Concern on 30 January 2020. On 12 February 2020, the virus was officiallynamed as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the WHO
officially named the disease caused by SARS-CoV-2 as coronavirus disease 2019
(COVID-19). On 11 March 2020, the WHO upgraded the status of the COVID-19 outbreakfrom epidemic to pandemic, which is now spreading globally at high speed.
There are currently no vaccines to prevent infection with SARS-CoV-2 or antiviral drugs totreat COVID-19. Given the rapid transmission of COVID-19 and incidence of disease in the
United States and elsewhere, the rapid development of an effective vaccine is of utmost
importance.
BioNTech has developed RNA-based vaccine candidates using a platform approach thatenables the rapid development of vaccines against emerging viral diseases, including
SARS-CoV-2. Each vaccine candidate is based on a platform of nucleoside-modified
messenger RNA (modRNA, BNT162b). Each vaccine candidate expresses 1 of 2 antigens:the SARS-CoV-2 full-length, P2 mutant, “heads up,” prefusion spike glycoprotein (P2 S)(version 9), or a trimerized SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD)(version 5). The 2 SARS-CoV-2 vaccine candidates that may be tested in this study are
therefore:
BNT162b1 (variant RBP020.3): a modRNA encoding the RBD;
BNT162b2 (variant RBP020.2): a modRNA encoding P2 S.
All candidates are formulated in the same lipid nanoparticle (LNP) composition. This study
is intended to investigate the safety, immunogenicity, and potential efficacy of these2 prophylactic BNT162 vaccines against COVID-19.

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It is expected that the various candidate vaccines may not all be available from the start ofthe study, in which case they will be rolled into the study in a consecutive fashion as they are
released. A Phase 1/2 study of the same vaccine candidates (BNT162-01), conducted inGermany by BioNTech in adults 18 to 55 years of age, is planned to start in April 2020.
Study C4591001 is designed to complement and expand upon the German study and confirm
the optimal vaccine candidate(s), dose level(s), number of doses, and schedule ofadministration.

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Objectives, Estimands, and Endpoints
Objectives

Estimands

Endpoints

Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Primary:
In participants receiving at least 1 doseof study intervention and having safety
data reported after any vaccination, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each doseAdverse events (AEs) from
Dose 1 to 1 month after the lastdose
 Serious AEs (SAEs) from Dose 1
to 6 months after the last doseIn addition, in sentinel cohorts from
Stage 1, the percentage of participantswith:
Abnormal hematology andchemistry laboratory values 1 and7 days after Dose 1; and 7 days
after Dose 2
Grading shifts in hematology andchemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2
Secondary:In participants complying with the key
protocol criteria (evaluableparticipants) at the following time
points after receipt of study
intervention:

Primary:
Local reactions (pain at the
injection site, redness, andswelling)

Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs

Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Hematology and chemistry laboratory
parameters detailed in Section 10.2

Secondary:Stage 1 Sentinel Cohorts: 7 and21 days after Dose 1; 7 and 14 days and1, 6, 12, and 24 months after Dose 2
Stage 1 Nonsentinel Cohorts andStage 2 Cohorts: 21 days after Dose 1;
14 days and 1, 6, 12, and 24 months
after Dose 2
Stage 3 Cohort(s): 1, 12, and24 months after Dose 2

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Objectives

Estimands










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Endpoints

Geometric mean titers (GMTs) at SARS-CoV-2 serum neutralizing titers
each time point
Geometric mean fold rise (GMFR)
from before vaccination to eachsubsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
SARS-CoV-2 S1-specific binding
Geometric mean concentrations
antibody levels and RBD-specific(GMCs) at each time point
GMFR from before vaccination to binding antibody levels
each subsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
SARS-CoV-2 serum neutralizing
Geometric mean ratio (GMR),
titersestimated by the ratio of thegeometric mean of SARS-CoV-2 
SARS-CoV-2 S1-specific binding
serum neutralizing titers to theantibody levels
geometric mean of SARS-CoV-2– 
SARS-CoV-2 RBD-specificspecific binding antibody levels at
binding antibody levels
each time point

To evaluate the efficacy of prophylactic In participants complying with the key
BNT162 vaccines against confirmed
protocol criteria (evaluable
COVID-19
participants) following receipt of thelast dose of study intervention:
100 × (1 – illness rate ratio) [ratio ofactive vaccine to placebo]
Tertiary/Exploratory:
Tertiary/Exploratory:
To describe the relationship between
SARS-CoV-2 serological parametersand:
NAAT-confirmed COVID-19

Symptomatic SARS-CoV-2
infection
Asymptomatic SARS-CoV-2
infection

COVID-19 incidence per 1000 personyears of follow-up

Tertiary/Exploratory:
Nonvaccine antigen SARS-CoV-2
antibody levels

Overall Design
This is a Phase 1/2, randomized, placebo-controlled, observer-blind, dose-finding, andvaccine candidate–selection study in healthy adults.
The study will evaluate the safety, tolerability, immunogenicity, and potential efficacy of 2
different SARS-CoV-2 RNA vaccine candidates against COVID-19:


As a 2-dose (separated by 21 or 60 days) or single-dose schedule

At various different dose levels
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In 3 age groups (18 to 55 years of age, 65 to 85 years of age, and 18 to 85 years of age[stratified as ≤55 or >55 years of age])

Dependent upon safety and/or immunogenicity data generated during the course of thisstudy, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
may be started at the next highest dose, groups may not be started, groups may be terminatedearly, and/or groups may be added with dose levels below the lowest stated dose orintermediate between the lowest and highest stated doses.
The study consists of 3 stages. Stage 1: to identify preferred vaccine candidate(s), doselevel(s), number of doses, and schedule of administration (with the first 15 participants ateach dose level of each vaccine candidate comprising a sentinel cohort); Stage 2: an
expanded-cohort stage; and Stage 3: a final candidate/dose large-scale stage. These stages,
and the progression between them, are detailed in the schema (Section 1.2).

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Number of Participants
Each group in Stage 1 will comprise 15 participants (12 receiving active vaccine and3 receiving placebo). In this stage, assuming 2 dose levels are selected following the initial
dose escalation, up to 28 potential groups are foreseen; if all groups are fully enrolled, thiscorresponds to a total of 420 participants.
Each group in Stage 2 will comprise 225 participants (180 receiving active vaccine and
45 receiving placebo). The total number of participants to be enrolled in this stage depends
on the number of groups to be pursued.
The vaccine candidate/dose level selected for Stage 3 will comprise 3000 participants. An
equal number of participants will receive placebo, ie, randomized in a 1:1 ratio.
Intervention Groups and Duration
The study may evaluate single-dose and 2-dose (separated by 21 or 60 days) schedules ofvarious different dose levels of 2 investigational RNA vaccine candidates for active
immunization against COVID-19 in 3 age groups (18 to 55 years of age, 65 to 85 years ofage, and 18 to 85 years of age [stratified as ≤55 or >55 years of age]):

BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 20 µg, 30 µg, 50 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 20 µg, 30 µg, 50 µg, 100 µg

Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Stage 1 andStage 2 dosing arms that are not evaluated in Stage 3.

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Data Monitoring Committee or Other Independent Oversight Committee
The study will utilize an IRC, an internal Pfizer committee that will review data to allow
dose escalation or changes to continuation of specific groups.
An external data monitoring committee (DMC) will be formed and will review cumulative
unblinded data throughout the study.
Statistical Methods
The study sample size for the first 2 stages of the study is not based on any statistical
hypothesis testing. For the third stage, with assumptions of a true vaccine efficacy (VE) of
70%, 53 cases of COVID-19 will provide 90% power to conclude true VE >20%.
This would be achieved with 3000 participants per group, based on the assumption of a 1.7%
incidence rate in the placebo group, and 20% of the participants being nonevaluable.

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)The primary safety objective will be evaluated by descriptive summary statistics for local
reactions, systemic events, abnormal hematology and chemistry laboratory parameters(sentinel cohorts only), and AEs and SAEs, for each vaccine group. A 3-tier approach will
be used to summarize AEs.
The secondary immunogenicity objectives will be evaluated descriptively by GMT, GMC,
GMFR, percentage of participants with ≥4-fold rise, and GMC ratio, and the associated 95%
confidence intervals (CIs), for SARS-CoV-2 serum neutralizing titers, SARS-CoV-2
S1-specific binding antibody levels, and RBD-specific binding antibody levels at the various
time points.
For the secondary efficacy objective, VE is defined as VE = 100 × (1 – IRR), where IRR is
the illness rate ratio, the calculated ratio of COVID-19 incidence in the active vaccine groupto the incidence in the placebo group. The null hypothesis (VE ≤ 20%) will be rejected if thelower bound of the 95% CI for VE is >20%; no interim analysis of VE is planned.

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1.2. SchemaStage 1

(4:1 randomization active:placebo)
For each vaccine candidate

Age: 18-55 y
Low-dose-level 2-dose group (n=15):
SENTINEL

Age: 65-85 y

IRC (safety

IRC (safety)

after Dose 1)

Low-dose-level 2-dose group (n=15):
SENTINEL

Mid-dose-level 2-dose group (n=15):
SENTINEL
IRC (safety

IRC (safety)

Mid-dose-level 2-dose group (n=15):
SENTINEL

after Dose 1)

High-dose-level 2-dose group (n=15):
SENTINEL
IRC (safety
after Dose 1)

High-dose-level 2-dose group (n=15):
SENTINEL

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IRC choice of group(s) for Stages 2 & 3(safety & immunogenicity after Dose 1 or 2)
Dose level(s) selected for Stage 2: 2dose (60 days apart) group(s) (n=15)

Dose level(s) selected for Stage 2: 2dose (60 days apart) group(s) (n=15)&
Dose level(s) selected for Stage 2: 1dose group(s) (n=15)&
Dose level(s) selected for Stage 2: 1dose group(s) (n=15)(4:1 randomization active:placebo)

Stage 2Age: 18-85(Stratified 18-55 or 56-85)
Group for each selected vaccine
candidate/dose level(n=180 per active group)

IRC ongoing review ofsafety & immunogenicity data
Stage 3

(1:1 randomization active:placebo)

Age: 18-85(Stratified 18-55 or 56-85)
Selected vaccine candidate/dose level(n=3000 per group)
Abbreviation: IRC = internal review committee.

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Protocol C4591001
Protocol Amendment 3, 10 June 2020

1.3. Schedule of Activities

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with theprotocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations orassessments required to protect the well-being of the participant.
1.3.1. Stage 1 Sentinel Cohorts
An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 10 (24-month follow-up visit) that COVID-19 is suspected.
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit Telehealth
Visit
Visit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

X

X

X

X

X

Obtain informed consent

X

Assign participant number

X

Obtain demography andmedical history data

X

Obtain details of medications
currently taken

X

Perform physical examination

X

2

3

4

5

6

7

8

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset

X

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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Protocol Amendment 3, 10 June 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit Telehealth
Visit
Visit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

Measure vital signs(including body temperature)

X

X

X

X

X

X

Collect blood sample forhematology and chemistrylaboratory testsa~10 mL~10 mL~10 mL~10 mL~10 mL

Collect screening blood
sample for HIV, HBsAg,
HBc Ab, and HCV Ab tests~10 mL

Serological test for prior
COVID-19 infection~20 mL

Perform urine pregnancy test
(if appropriate)X

Obtain nasal (midturbinate)swab(s)b

2

3

4

X

X

X

X

Collect nonstudy vaccine
information

X

X

Confirm eligibility

X

X

Collect prohibited medication
use

X

X

Review temporary delay
criteria

X

X

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset
X

X
X

X

X

X

X

X

X
X

Review hematology andchemistry results

X

5

X

X

X

X

X

X

X

X

X

X

X

X

X

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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Protocol Amendment 3, 10 June 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

4

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit Telehealth
Visit
Visit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

Confirm use of contraceptives(if appropriate)

X

X

X

X

X

X

~50 mL~50 mL

Obtain randomization number
and study intervention
allocation

X

Collect blood sample for
immunogenicity assessment~50 mL

Administer study intervention

X

X

Assess acute reactions for atleast 30 minutes after study
intervention administrationc

X

X

Explain participant
communication methods(including for e-diarycompletion), assist theparticipant with downloading
the app, or issue provisioned
device, if required

X

Provide thermometer andmeasuring device

X

5

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset
X

X~50 mL ~50 mL ~50 mL ~50 mL+++
optionald optionald optionald~170 mL ~170 mL ~170 mL~50 mL~50 mL~50 mLX

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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Protocol Amendment 3, 10 June 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit Telehealth
Visit
Visit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 46 to 8Days
After
Visit 1

4

5

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset

Review reactogenicity e-diarydata (daily review is optimal
during the active diary period)
Review ongoingreactogenicity e-diary
symptoms and obtain stopdatesCollect AEs and SAEs as
appropriate

X

X

X

X

X

X

X

X

X

X

X

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X

X

X

X

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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Protocol Amendment 3, 10 June 2020
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit Telehealth
Visit
Visit

Visit Window (Days)

0 to 28
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 46 to 8Days
After
Visit 1

4

5

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset

Collect e-diary or assist theparticipant to delete
application

X

Collection of COVID-19–
related clinical and laboratory
information (including local
diagnosis)

X

X

Abbreviations: e-diary = electronic diary; HBc Ab = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HCV Ab = hepatitis C virus antibody;
HIV = human immunodeficiency virus; NAAT = nucleic acid amplification test; vax = vaccination.

a.
b.
c.
d.

Hematology: hemoglobin, complete blood count with differential, and platelets. Blood chemistry: alanine aminotransferase (ALT), aspartate
aminotransferase (AST), alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), and creatinine.
Two swabs will be taken at Visits 1 and 4. One will be tested (if possible at the site, otherwise at the central laboratory) within 24 hours and vaccination will
only proceed if it is NAAT-negative for SARS-CoV-2 genomes. The second will be sent to the central laboratory for potential later testing.
The first 5 participants in in each sentinel group will be observed at the site for at least 4 hours after study intervention administration. Further vaccination
will commence no sooner than 24 hours after the fifth participant received his or her vaccination.
An optional blood draw of ~170 mL will be taken at 1 of the visits (from selected participants who consent) for exploratory COVID-19 research.

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1.3.2. Stage 1 Nonsentinel Cohorts and Stage 2 Cohorts
An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 7 (24-month follow-up visit) that COVID-19 is suspected.

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)

Visit Number
Visit Description

Visit Window (Days)

1

2

3

4

5

6

7

Unplanned

Unplanned

2-WeekFollow-up
Visit

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
COVID-19
Illness
Telehealth
Visit

Potential
COVID-19
ConvalescentVisit

19 to 23 Days 12 to 16 Days 28 to 35 Days
After Visit 1 After Visit 2 After Visit 2
or56 to 70 Days
After Visit 1a

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19 Illness Visit
Illness Onset

X

X

Vaccination 1 Vaccination 2

Day 1

Obtain informed consent

X

Assign participant number

X

Obtain demography and medical
history data

X

Perform physical examination

X

Measure vital signs

X

Perform urine pregnancy test
(if appropriate)

X

X

Collect nonstudy vaccine information

X

X

X

X

X

X

X

X

X

X

X

Collect prohibited medication use
Confirm eligibility

X

X

Measure temperature (body)

X

X

Review temporary delay criteria

X

X

Confirm use of contraceptives(if appropriate)

X

X

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X

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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Protocol Amendment 3, 10 June 2020
Visit Number

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Visit Description

Visit Window (Days)

Obtain randomization number andstudy intervention allocation
Collect blood sample for
immunogenicity assessment

1

2

3

4

5

6

7

Unplanned

Unplanned

2-WeekFollow-up
Visit

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
COVID-19
Illness
Telehealth
Visit

Potential
COVID-19
ConvalescentVisit

19 to 23 Days 12 to 16 Days 28 to 35 Days
After Visit 1 After Visit 2 After Visit 2
or56 to 70 Days
After Visit 1a

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19 Illness Visit
Illness Onset~25 mL~25 mL~25 mL

Vaccination 1 Vaccination 2

Day 1

X
~25 mL~25 mL

Obtain nasal (midturbinate) swab

X

X

Administer study intervention

X

X

Assess acute reactions for at least 30
minutes after study intervention
administration

X

X

Explain participant communication
methods (including for e-diarycompletion), assist the participant withdownloading the app, or issue
provisioned device, if required

X

Provide participant with thermometerand measuring deviceX~25 mL~25 mL~50 mL
X

X

Review reactogenicity e-diary data
(daily review is optimal during theactive diary period)
Review ongoing reactogenicity e-diary
symptoms and obtain stop dates
Collect AEs and SAEs as appropriate

X

X

X

X

X

X

X

X

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X

X

X

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Protocol Amendment 3, 10 June 2020
Visit Number

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Visit Description

Visit Window (Days)

1

2

3

4

5

6

7

Unplanned

Unplanned

2-WeekFollow-up
Visit

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
COVID-19
Illness
Telehealth
Visit

Potential
COVID-19
ConvalescentVisit

19 to 23 Days 12 to 16 Days 28 to 35 Days
After Visit 1 After Visit 2 After Visit 2
or56 to 70 Days
After Visit 1a

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19 Illness Visit
Illness Onset

Vaccination 1 Vaccination 2

Day 1

Collect e-diary or assist the participant
to delete application

X

Collection of COVID-19–related
clinical and laboratory information(including local diagnosis)

X

X

Abbreviation: e-diary = electronic diary.
a. The window for Visit 2 is dependent on the dosing schedule for the assigned group.

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1.3.3. Stage 3 Cohort(s)An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 6 (24-month follow-up visit) that COVID-19 is suspected.

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)

Visit Number
Visit Description

Visit Window (Days)

1

2

3

4

5

6

Unplanned

Unplanned

1-MonthFollow-up
Visit

6-Month
SafetyTelephoneContact

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
COVID-19
Illness
Telehealth
Visit

Potential
COVID-19
ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2
or56 to 70 Days
After Visit 1a

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

X

X~25 mL~25 mL

Vaccination 1 Vaccination 2

Day 1

Obtain informed consent

X

Assign participant number

X

Obtain demography and medical history data

X

Perform physical examination

X

Measure vital signs

X

Perform urine pregnancy test (if appropriate)

X

X

Collect nonstudy vaccine information

X

X

X

X

X

X

X

Collect prohibited medication use
Confirm eligibility

X

X

Measure temperature (body)

X

X

Review temporary delay criteria

X

X

Confirm use of contraceptives (if appropriate)

X

X

Obtain randomization number and study
intervention allocation

X

Collect blood sample for immunogenicity
assessment~25 mL

Obtain nasal (midturbinate) swab

X

X

X

X

~25 mLX~50 mLX

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Protocol Amendment 3, 10 June 2020
Visit Number

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Visit Description

2

3

4

5

6

Unplanned

Unplanned

1-MonthFollow-up
Visit

6-Month
SafetyTelephoneContact

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
COVID-19
Illness
Telehealth
Visit

Potential
COVID-19
ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2
or56 to 70 Days
After Visit 1a

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

X

X

X

Vaccination 1 Vaccination 2

Visit Window (Days)

Day 1

Administer study intervention

X

X

Assess acute reactions for at least 30 minutes after
study intervention administration

X

X

Explain participant communication methods(including for e-diary completion), assist theparticipant with downloading the app, or issue
provisioned device, if required

X

Provide participant with thermometer andmeasuring device

X

X

Review reactogenicity e-diary data (daily review is
optimal during the active diary period)
Review ongoing reactogenicity e-diary symptoms
and obtain stop dates
Collect AEs and SAEs as appropriate

X

X

X

X

X

Collect e-diary or assist the participant to delete
application

X

X

X

X

X

Telephone contact

X

Collection of COVID-19–related clinical andlaboratory information (including local diagnosis)
Abbreviation: e-diary = electronic diary.
a. The window for Visit 2 is dependent on the dosing schedule(s) selected for the Stage 3.

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2. INTRODUCTION
The BNT162 RNA-based COVID-19 vaccines are currently being investigated forprevention of COVID-19 in healthy adults.
2.1. Study Rationale
The purpose of the study is to rapidly describe the safety, tolerability, immunogenicity, andpotential efficacy of 2 BNT162 RNA-based COVID-19 vaccine candidates against
COVID-19 in healthy adults. There are currently no vaccines to prevent infection with
SARS-CoV-2 or antiviral drugs to treat COVID-19. Given the global crisis of COVID-19
and fast expansion of the disease in the United States and elsewhere, the rapid developmentof an effective vaccine is of utmost importance.

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2.2. Background
In December 2019, a pneumonia outbreak of unknown cause occurred in Wuhan, China.
In January 2020, it became clear that a novel coronavirus (2019-nCoV) was the underlying
cause. Later in January, the genetic sequence of the 2019-nCoV became available to theWorld Health Organization (WHO) and public (MN908947.3), and the virus was categorized
in the Betacoronavirus subfamily. By sequence analysis, the phylogenetic tree revealed acloser relationship to severe acute respiratory syndrome (SARS) virus isolates than to anothercoronavirus infecting humans, the Middle East respiratory syndrome (MERS) virus.
SARS-CoV-2 infections and the resulting disease, COVID-19, have spread globally,affecting a growing number of countries.
On 11 March 2020, the WHO characterized the COVID-19 outbreak as a pandemic.1
The WHO Situation Update Report dated 30 March 2020 noted 693,224 confirmed caseswith 33,106 deaths globally, including 142,081 confirmed cases with 2457 deaths in theAmericas.2 The United States currently has the most reported cases globally. At the time ofthis communication, the number of confirmed cases continues to rise globally. There are
currently no vaccines or effective antiviral drugs to treat SARS-CoV-2 infections or the
disease it causes, COVID-19.3
A prophylactic, RNA-based SARS-CoV-2 vaccine provides one of the most flexible andfastest approaches available to immunize against the emerging virus.4,5The development of an RNA-based vaccine encoding a viral antigen, which is then expressedby the vaccine recipient as a protein capable of eliciting protective immune responses,
provides significant advantages over more traditional vaccine approaches. Unlike live
attenuated vaccines, RNA vaccines do not carry the risks associated with infection and may
be given to people who cannot be administered live virus (eg, pregnant women andimmunocompromised persons). RNA-based vaccines are manufactured via a cell-free invitro transcription process, which allows an easy and rapid production and the prospect of
producing high numbers of vaccination doses within a shorter time period than achieved with

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traditional vaccine approaches. This capability is pivotal to enable the most effective
response in outbreak scenarios.
Two SARS-CoV-2–RNA lipid nanoparticle (RNA-LNP) vaccines based on a platform of
nucleoside-modified messenger RNA (modRNA, BNT162b) will be evaluated in this study.
Each vaccine candidate expresses 1 of 2 antigens: the SARS-CoV-2 full-length, P2 mutant,“heads up,” prefusion spike glycoprotein (P2 S) (version 9), or a trimerized SARS-CoV-2
spike glycoprotein-receptor binding domain (RBD) (version 5). The 2 SARS-CoV-2 vaccine
candidates that may be tested in this study are therefore:

BNT162b1 (variant RBP020.3): nucleoside-modified messenger RNA (modRNA) withblunted innate immune sensor–activating capacity and augmented expression encoding
the RBD.



BNT162b2 (variant RBP020.2): nucleoside-modified messenger RNA (modRNA) as
above, but encoding P2 S.

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)

2.2.1. Clinical Overview
BNT162 vaccines have not been administered to humans before and thus there are no
previous clinical data with these specific vaccines. However, given clinical data from othersimilarly formulated uRNA liposomal vaccines from BioNTech in oncology trials6 andrecent published results from clinical trials using modRNA influenza vaccines by Moderna,7
the BNT162 vaccines are expected to have a favorable safety profile with mild, localized,
and transient effects.
2.3. Benefit/Risk Assessment
There is an ongoing global pandemic of COVID-19 with no preventative or therapeutic
options available. While there are currently no data available from clinical trials on the useof BNT162 vaccines in humans, available nonclinical data with these vaccines, and data from
nonclinical studies and clinical trials with the same or related RNA components, or antigens,support a favorable risk/benefit profile. Anticipated AEs after vaccination are expected to be
manageable using routine symptom-driven standard of care as determined by theinvestigators and, as a result, the profile of these vaccine candidates support initiation of thisPhase 1/2 clinical study.
More detailed information about the known and expected benefits and risks and reasonably
expected AEs of BNT162 RNA-based COVID-19 vaccines may be found in theinvestigator’s brochure (IB), which is the SRSD for this study.

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2.3.1. Risk Assessment
Potential Risk of ClinicalSignificance

Summary of Data/Rationale for Risk

Mitigation Strategy

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Study Intervention: BNT162 RNA-Based COVID-19 Vaccine
Potential for local reactions (injection These are common adverse reactions seensite redness, injection site swelling, with other vaccines, as noted in the FDA
and injection site pain) and systemic Center for Biologics Evaluation andResearch (CBER) guidelines on toxicity
events (fever, fatigue, headache,
grading scales for healthy adult volunteers
chills, vomiting, diarrhea, muscle
pain, and joint pain) following
enrolled in preventive vaccine clinicalvaccination.
trials.8

The study design includes the use of sentinel cohorts and dose escalation toclosely monitor and limit the rate of enrollment to ensure participant safety.
The study employs the use of a reactogenicity e-diary to monitor local
reactions and systemic events in real time. Stopping rules are also in place
for sentinel cohorts. The first 5 sentinel-cohort participants in each groupwill be observed for 4 hours after vaccination to assess any immediate AEs.

Unknown AEs and laboratory
abnormalities with a novel vaccine.

The study design includes the use of sentinel cohorts and dose escalation toThis study is one of the first 2 parallelrunning clinical studies with the BNT162 closely monitor and limit the rate of enrollment to ensure participant safety.
vaccine candidates and as such there are no An IRC and DMC will also review safety data throughout the study.
Stopping rules are also in place for sentinel cohorts. The first 5 sentinelclinical data available for this vaccine.
cohort participants in each group will be observed for 4 hours after
vaccination to assess any immediate AEs.

Potential for COVID-19 diseaseenhancement.

Disease enhancement has been seen
following vaccination with respiratorysyncytial virus (RSV), feline coronavirus,
and Dengue virus vaccines.

The study excludes participants with likely previous or current COVID-19.
All participants are followed for SARS-CoV-2 antigen-specific antibody
and SARS-CoV-2 serum neutralizing titers, and COVID-19 illness,
including markers of severity.

Study Procedures
Participants will be required to attend Without appropriate social distancing andhealthcare facilities during the global PPE, there is a potential for increased
exposure to SARS-CoV-2.
SARS-CoV-2 pandemic.
Venipuncture will be performed
during the study.

There is the risk of bleeding, bruising,hematoma formation, and infection at the
venipuncture site.

Pfizer will work with sites to ensure an appropriate COVID-19 prevention
strategy.
Only appropriately qualified personnel would obtain the blood draw.

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2.3.2. Benefit Assessment
Benefits to individual participants may include:Receipt of a potentially efficacious COVID-19 vaccine during a global pandemicAccess to COVID-19 diagnostic and antibody testingContributing to research to help others in a time of global pandemic

2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in thisstudy, the potential risks identified in association with BNT162 RNA-based COVID-19
vaccine are justified by the anticipated benefits that may be afforded to healthy participants.

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3. OBJECTIVES, ESTIMANDS, AND ENDPOINTSObjectives

Estimands

Endpoints

Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Primary:
In participants receiving at least 1 doseof study intervention and having safety
data reported after any vaccination, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each doseAdverse events (AEs) from
Dose 1 to 1 month after the lastdose
 Serious AEs (SAEs) from Dose 1
to 6 months after the last doseIn addition, in sentinel cohorts from
Stage 1, the percentage of participantswith:
Abnormal hematology andchemistry laboratory values 1 and7 days after Dose 1; and 7 days
after Dose 2
Grading shifts in hematology andchemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2

Primary:
Local reactions (pain at the
injection site, redness, andswelling)

Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs

Hematology and chemistry laboratory
parameters detailed in Section 10.2

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Objectives

Estimands

Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Secondary:In participants complying with the key
protocol criteria (evaluableparticipants) at the following time
points after receipt of study
intervention:

Endpoints
Secondary:Stage 1 Sentinel Cohorts: 7 and21 days after Dose 1; 7 and 14 days and1, 6, 12, and 24 months after Dose 2
Stage 1 Nonsentinel Cohorts andStage 2 Cohorts: 21 days after Dose 1;
14 days and 1, 6, 12, and 24 months
after Dose 2
Stage 3 Cohort(s): 1, 12, and24 months after Dose 2
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







Geometric mean titers (GMTs) at SARS-CoV-2 serum neutralizing titers
each time point
Geometric mean fold rise (GMFR)
from before vaccination to eachsubsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
SARS-CoV-2 S1-specific binding
Geometric mean concentrations
antibody levels and RBD-specific(GMCs) at each time point
GMFR from prior to first dose of binding antibody levels
study intervention to eachsubsequent time point
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
SARS-CoV-2 serum neutralizing
Geometric mean ratio (GMR),
titersestimated by the ratio of thegeometric mean of SARS-CoV-2

SARS-CoV-2 S1-specific binding
serum neutralizing titers to theantibody levels
geometric mean of SARS-CoV-2–
specific binding antibody levels at each time point

To evaluate the efficacy of prophylactic In participants complying with the key
BNT162 vaccines against confirmed
protocol criteria (evaluable
COVID-19
participants) following receipt of thelast dose of study intervention:
100 × (1 – illness rate ratio)[ratio of active vaccine to placebo]

SARS-CoV-2 RBD-specificbinding antibody levels

COVID-19 incidence per 1000 personyears of follow-up

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Objectives
Tertiary/Exploratory:
To describe the relationship between
SARS-CoV-2 serological parametersand:
NAAT-confirmed COVID-19

Symptomatic SARS-CoV-2
infection
Asymptomatic SARS-CoV-2
infection

Estimands
Tertiary/Exploratory:

Endpoints
Tertiary/Exploratory:
Nonvaccine antigen SARS-CoV-2
antibody levels

4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1/2, randomized, placebo-controlled, observer-blind, dose-finding, andvaccine candidate–selection study in healthy adults.

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)The study will evaluate the safety, tolerability, immunogenicity, and potential efficacy of 2
different SARS-CoV-2 RNA vaccine candidates against COVID-19:


As a 2-dose (separated by 21 or 60 days) or single-dose schedule

At various different dose levels

In 3 age groups (18 to 55 years of age, 65 to 85 years of age, and 18 to 85 years of age[stratified as ≤55 or >55 years of age])

Dependent upon safety and/or immunogenicity data generated during the course of thisstudy, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
may be started at the next highest dose, groups may not be started, groups may be terminatedearly, and/or groups may be added with dose levels below the lowest stated dose orintermediate between the lowest and highest stated doses.
The study consists of 3 stages. Stage 1: to identify preferred vaccine candidate(s), doselevel(s), number of doses, and schedule of administration (with the first 15 participants ateach dose level of each vaccine candidate comprising a sentinel cohort); Stage 2: an
expanded-cohort stage; and Stage 3; a final candidate/dose large-scale stage. These stages,
and the progression between them, are detailed in the schema (Section 1.2).
The study is observer-blinded, as the physical appearance of the investigational vaccine
candidates and the placebo may differ. The participant, investigator, study coordinator, andother site staff will be blinded. At the study site, only the dispenser(s)/administrator(s) are
unblinded.
To facilitate rapid review of data in real time, sponsor staff will be unblinded to vaccine
allocation for the participants in Stage 1 and Stage 2.

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4.1.1. Stage 1
Each group (vaccine candidate/dose level/age group/number of doses) will comprise
15 participants; 12 participants will be randomized to receive active vaccine and 3 to receive
placebo. On Day 22, those in 2-dose groups will receive the same vaccine they received on
Day 1; for those in single-dose groups, all will receive placebo. Full details of all potential
groups in Stage 1 may be found in Table 1.

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)For each vaccine candidate/dose level/age group, the 15 participants randomized into each2-dose group will comprise a sentinel cohort, to which the following apply:Additional safety assessments (see Section 8.2)

Controlled enrollment:No more than 5 participants (4 active, 1 placebo) can be vaccinated on the first day

The first 5 participants must be observed by blinded site staff for at least 4 hours after
vaccination for any acute reactions

Vaccination of the remaining participants will commence no sooner than 24 hours
after the fifth participant received his or her vaccination

Application of stopping rules

IRC review of safety data to determine escalation to the next dose level in the 18- to
55-year age cohort:Escalation between dose levels will be based on IRC review of at least 7-day
post–Dose 1 safety data in this study and/or the BioNTech study conducted inGermany (BNT162-01)

Note that, since both candidates are based upon the same RNA platform, dose
escalation for the second candidate studied may be based upon the safety profile ofthe first candidate studied being deemed acceptable at the same, or a higher, doselevel by the IRC

Groups of participants 65 to 85 years of age will not be started until safety data for the RNA
platform have been deemed acceptable at the same, or a higher, dose level in the 18- to
55-year age cohort by the IRC.
Once the IRC has selected a vaccine candidate/dose level to proceed into Stage 2, for eachage cohort, 2 additional groups will be enrolled into Stage 1 for that vaccine candidate/doselevel:
A 2-dose group, with the 2 doses administered 60 days apart rather than 21
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

A 1-dose group

In this stage, assuming 2 dose levels are selected following the initial dose escalation, up to
28 potential groups are foreseen; if all groups are fully enrolled, this corresponds to a total of
420 participants.
4.1.2. Stage 2
On the basis of safety and/or immunogenicity data generated during the course of this study,
and/or the BioNTech study conducted in Germany (BNT162-01), 1 or more groups (vaccine
candidate/dose level) may be selected to proceed into Stage 2. Participants in this stage willbe 18 to 85 years of age, stratified equally: 18 to 55 or 56 to 85 years. Commencement ofeach age stratum will be dependent upon satisfactory safety and immunogenicity data fromthe 18- to 55-year and 65- to 85-year groups from Stage 1, respectively. It is therefore
possible that the 2 age strata may not start concurrently.
In each group selected for Stage 2, it is intended that 225 participants will be randomized in a
4:1 ratio to receive active vaccine (180 participants) or placebo (45 participants).

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4.1.3. Stage 3
On the basis of safety and/or immunogenicity data generated during the course of this study,
and/or the BioNTech study conducted in Germany (BNT162-01), 1 group may be selected toproceed into Stage 3. Participants in this stage will be 18 to 85 years of age, stratified
equally: 18 to 55 years or 56 to 85 years. As in Stage 2, it is possible that the 2 age strata
may not start concurrently.
The vaccine candidate/dose level selected for Stage 3 will comprise 3000 participants. An
equal number of participants will receive placebo, ie, randomized in a 1:1 ratio.
Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Stage 1 andStage 2 dosing arms that are not evaluated in Stage 3.
4.2. Scientific Rationale for Study Design
Additional surveillance for COVID-19 will be conducted as part of the study, given thepotential risk of disease enhancement. If a participant experiences respiratory symptoms, asdetailed in Section 8.13, a COVID-19 illness and subsequent convalescent visit will occur.
As part of these visits, samples (nasal [midturbinate] swab and blood) will be taken for
antigen and antibody assessment as well as recording of COVID-19–related clinical andlaboratory information (including local diagnosis).
Human reproductive safety data are not available for BNT162 RNA-based COVID-19
vaccines, but there is no suspicion of human teratogenicity based on the intended mechanismof action of the compound. Therefore, the use of a highly effective method of contraception
is required (see Appendix 4).
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4.3. Justification for Dose
Because of the requirement for a rapid response to the newly emerged COVID-19 pandemic,
sufficient data are not currently available to experimentally validate the dose selection andinitial starting dose. Therefore, the original planned starting dose of 10 µg (for both
BNT162b1 and BNT162b2) in this study was based on nonclinical experience with the same
RNAs encoding other viral antigens (such as influenza and HIV antigens). The generalsafety and effectiveness of uRNA and modRNA platforms have been demonstrated inoncological clinical trials with different administration routes (NCT02410733,
NCT03871348). Doses of up to 400 µg total uRNA have been administered IV as RNA
lipoplex (RNA-LPX) and doses of up to 1000 µg total naked modRNA have been
administered intratumorally, both without signs of unpredictable overstimulation of theimmune system.

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Based on nonclinical data of the RNA components, with other liposomes or in conjunction
with the lipid nanoparticles as will be tested clinically in this study, it was expected that
doses in the 1- to 5-µg range would be immunogenic and induce neutralizing antibodies;
however, it was anticipated that 3- to 10-fold higher doses would likely be required to elicit astronger antibody response. Based on previous clinical and nonclinical experience, it was
expected that doses of up to 100 µg would be well tolerated.
Update as part of protocol amendment 2: preliminary experience in this study and the
BioNTech study conducted in Germany (BNT162-01) suggests that, for vaccine candidates
based on the modRNA platform, a dose level between 30 µg and 100 µg warrants
consideration. Therefore, a 50-µg dose level is formally included for BNT162b1 and
BNT162b2.
Update as part of protocol amendment 3: as data have become available from this study andthe BNT162-01 study in Germany, it was decided:

To not study the BNT162a1 and BNT162c2 vaccine candidates at this time, so thesecandidates have been removed from the protocol; andThat lower dose levels of BNT162b1 and BNT162b2 warrant consideration. Therefore, a
20-µg dose level is formally included for both candidates.

Taken together, the planned starting doses in this study in healthy participants are considered
to be safe, but still sufficient to induce an antiviral immune response.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases ofthe study, including the last visit. Note that participants enrolled in Stages 1 and 2 in groups
that do not proceed to Stage 3 may be followed for fewer than 24 months (but no less than
6 months after the last vaccination).
The end of the study is defined as the date of last visit of the last participant in the study.
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5. STUDY POPULATIONThis study can fulfill its objectives only if appropriate participants are enrolled. The
following eligibility criteria are designed to select participants for whom participation in the
study is considered appropriate. All relevant medical and nonmedical conditions should betaken into consideration when deciding whether a particular participant is suitable for thisprotocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:

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1. Male or female participants between the ages of 18 and 55 years, inclusive, 65 and85 years, inclusive, or 18 and 85 years, inclusive, at randomization (dependent uponstudy stage).


Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female(Section 10.4.2) participants.

Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, vaccination
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Healthy participants who are determined by medical history, physical examination, andclinical judgment of the investigator to be eligible for inclusion in the study.
Note: Healthy participants with preexisting stable disease, defined as disease notrequiring significant change in therapy or hospitalization for worsening disease during
the 6 weeks before enrollment, can be included.
Informed Consent:
4. Capable of giving personal signed informed consent as described in Appendix 1, which
includes compliance with the requirements and restrictions listed in the ICD and in thisprotocol.

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5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Other medical or psychiatric condition including recent (within the past year) or active
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study
participation or, in the investigator’s judgment, make the participant inappropriate for the
study.
2. Known infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or
hepatitis B virus (HBV).
3. History of severe adverse reaction associated with a vaccine and/or severe allergic
reaction (eg, anaphylaxis) to any component of the study intervention(s).
4. Receipt of medications intended to prevent COVID-19.

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5. Stages 1 and 2 only: Previous clinical or microbiological diagnosis of COVID-19.
6. Sentinel participants in Stage 1 only: Individuals at high risk for severe COVID-19,
including those with any of the following risk factors:Hypertension

Diabetes mellitus

Chronic pulmonary diseaseAsthma

Current vaping or smoking

History of chronic smoking within the prior year

Chronic liver diseaseStage 3 or worse chronic kidney disease (glomerular filtration rate <60
mL/min/1.73 m2)



Resident in a long-term facility

BMI >30 kg/m2

Anticipating the need for immunosuppressive treatment within the next 6 months

7. Sentinel participants in Stage 1 only: Individuals currently working in occupations withhigh risk of exposure to SARS-CoV-2 (eg, healthcare worker, emergency response
personnel).

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8. Immunocompromised individuals with known or suspected immunodeficiency, as
determined by history and/or laboratory/physical examination.
9. Individuals with a history of autoimmune disease or an active autoimmune diseaserequiring therapeutic intervention, including but not limited to: systemic or cutaneous
lupus erythematosus, autoimmune arthritis/rheumatoid arthritis, Guillain-Barré
syndrome, multiple sclerosis, Sjögren’s syndrome, idiopathic thrombocytopenia purpura,glomerulonephritis, autoimmune thyroiditis, giant cell arteritis (temporal arteritis),
psoriasis, and insulin-dependent diabetes mellitus (type 1).
10. Bleeding diathesis or condition associated with prolonged bleeding that would, in theopinion of the investigator, contraindicate intramuscular injection.
11. Women who are pregnant or breastfeeding.
Prior/Concomitant Therapy:

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12. Previous vaccination with any coronavirus vaccine.
13. Individuals who receive treatment with immunosuppressive therapy, including cytotoxic
agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned
receipt throughout the study. If systemic corticosteroids have been administered shortterm (<14 days) for treatment of an acute illness, participants should not be enrolled into
the study until corticosteroid therapy has been discontinued for at least 28 days before
study intervention administration. Inhaled/nebulized (except for sentinel participants inStage 1 – see exclusion criterion 14), intra-articular, intrabursal, or topical (skin or eyes)corticosteroids are permitted.
14. Sentinel participants in Stage 1 only: Regular receipt of inhaled/nebulized
corticosteroids.
15. Receipt of blood/plasma products or immunoglobulin, from 60 days before study
intervention administration or planned receipt throughout the study.
Prior/Concurrent Clinical Study Experience:
16. Participation in other studies involving study intervention within 28 days prior to study
entry and/or during study participation.
17. Previous participation in other studies involving study intervention containing lipid
nanoparticles.
Diagnostic Assessments:
18. Sentinel participants in Stage 1 only: Positive serological test for SARS-CoV-2 IgM
and/or IgG antibodies at the screening visit.
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19. Sentinel participants in Stage 1 only: Any screening hematology and/or blood
chemistry laboratory value that meets the definition of a ≥ Grade 1 abnormality.
Note: With the exception of bilirubin, participants with any stable Grade 1 abnormalities(according to the toxicity grading scale) may be considered eligible at the discretion of
the investigator. (Note: A “stable” Grade 1 laboratory abnormality is defined as a reportof Grade 1 on an initial blood sample that remains ≤ Grade 1 upon repeat testing on asecond sample from the same participant.)
20. Sentinel participants in Stage 1 only: Positive test for HIV, hepatitis B surface antigen(HBsAg), hepatitis B core antibodies (HBc Abs), or hepatitis C virus antibodies(HCV Abs) at the screening visit.
21. Sentinel participants in Stage 1 only: SARS-CoV-2 NAAT-positive nasal swab within
24 hours before receipt of study intervention.
Other Exclusions:

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22. Investigator site staff or Pfizer employees directly involved in the conduct of the study,site staff otherwise supervised by the investigator, and their respective family members.
5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm thatthe participant has selected an appropriate method of contraception for the individual
participant and his or her partner(s) from the permitted list of contraception methods(see Appendix 4, Section 10.4.4) and will confirm that the participant has been instructed inits consistent and correct use. At time points indicated in the SoA, the investigator ordesignee will inform the participant of the need to use highly effective contraception
consistently and correctly and document the conversation and the participant’s affirmation in
the participant’s chart (participants need to affirm their consistent and correct use of at least 1of the selected methods of contraception). In addition, the investigator or designee will
instruct the participant to call immediately if the selected contraception method is
discontinued or if pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but
are not subsequently randomly assigned to study intervention. A minimal set of screen
failure information is required to ensure transparent reporting of screen failure participants tomeet the CONSORT publishing requirements and to respond to queries from regulatory
authorities. Minimal information includes demography, screen failure details, eligibility
criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may berescreened under a different participant number.
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5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention
Administration
The following conditions are temporary or self-limiting and a participant may be vaccinatedonce the condition(s) has/have resolved and no other exclusion criteria are met.

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1. Current febrile illness (body temperature ≥100.4°F [≥38°C]) or other acute illness within
48 hours before study intervention administration. This includes current symptoms that
could represent a potential COVID-19 illness:

New or increased cough;

New or increased shortness of breath;New or increased sore throat;

New or increased wheezing;New or increased sputum production;New or increased nasal congestion;New or increased nasal discharge;



Loss of taste/smell.

2. Receipt of any seasonal or pandemic influenza vaccine within 14 days, or any othernonstudy vaccine within 28 days, before study intervention administration.
3. Anticipated receipt of any seasonal or pandemic influenza vaccine within 14 days, or any
other nonstudy vaccine within 28 days, after study intervention administration.
4. Receipt of short-term (<14 days) systemic corticosteroids. Study intervention
administration should be delayed until systemic corticosteroid use has been discontinued
for at least 28 days. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin oreyes) corticosteroids are permitted.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s),placebo, medical device(s), or study procedure(s) intended to be administered to a study
participant according to the study protocol.
The study may evaluate 2-dose (separated by 21 or 60 days) and single-dose schedules ofvarious different dose levels of 2 investigational RNA vaccine candidates for active
immunization against COVID-19 in 3 age groups (18 to 55 years of age, 65 to 85 years ofage, and 18 to 85 years of age [stratified as ≤55 or >55 years of age]).
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These 2 investigational RNA vaccine candidates, with the addition of saline placebo, are the
3 potential study interventions that may be administered to a study participant:

BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 20 µg, 30 µg, 50 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 20 µg, 30 µg, 50 µg, 100 µg

Normal saline (0.9% sodium chloride solution for injection)

A list of all potential groups in the Stage 1 are shown in Table 1. Each of these groups may
or may not progress to the later stages of the study.
Table 1.

Potential Groups in Stage 1

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2-Dose Groups (Sentinel Cohorts)
b1-10-2-Y (Sentinel)
15[modRNA 10 µg (2 doses)]
b1-20-2-Y (Sentinel)
15[modRNA 20 µg (2 doses)]b1-30-2-Y (Sentinel)
15[modRNA 30 µg (2 doses)]
b1-50-2-Y (Sentinel)
15[modRNA 50 µg (2 doses)]b1-100-2-Y (Sentinel)
15[modRNA 100 µg(2 doses)]

Age
Group
(Years)18 to 55
18 to 55
18 to 55
18 to 55
18 to 55

b2-10-2-Y (Sentinel)[modRNA 10 µg (2 doses)]b2-20-2-Y (Sentinel)[modRNA 20 µg (2 doses)]b2-30-2-Y (Sentinel)[modRNA 30 µg (2 doses)]b2-50-2-Y (Sentinel)[modRNA 50 µg (2 doses)]b2-100-2-Y (Sentinel)[modRNA 100 µg(2 doses)]15

18 to 55

15

18 to 55

15

18 to 55

15

18 to 55

15

18 to 55

b1-10-2-O (Sentinel)[modRNA 10 µg (2 doses)]
b1-20-2-O (Sentinel)[modRNA 20 µg (2 doses)]b1-30-2-O (Sentinel)[modRNA 30 µg (2 doses)]
b1-50-2-O (Sentinel)[modRNA 50 µg (2 doses)]b1-100-2-O (Sentinel)

15

65 to 8515

65 to 8515

65 to 8515

65 to 8515

65 to 85

Dose 1
Day 1
BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo

10 µg(n=12)(n=3)
20 µg (n=12)(n=3)
30 µg (n=12)(n=3)
50 µg (n=12)(n=3)
100 µg (n=12)(n=3)

Dose 2
Day 22
BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo

10 µg(n=12)(n=3)
20 µg (n=12)(n=3)
30 µg (n=12)(n=3)
50 µg (n=12)(n=3)
100 µg (n=12)(n=3)

BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo

10 µg(n=12)(n=3)
20 µg (n=12)(n=3)
30 µg (n=12)(n=3)
50 µg (n=12)(n=3)
100 µg (n=12)(n=3)

BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo

10 µg

BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo

10 µg

BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo

10 µg(n=12)(n=3)
20 µg (n=12)(n=3)
30 µg (n=12)(n=3)
50 µg (n=12)(n=3)
100 µg (n=12)(n=3)

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20 µg (n=12)(n=3)
30 µg (n=12)(n=3)
50 µg (n=12)(n=3)
100 µg (n=12)(n=3)(n=12)(n=3)
20 µg (n=12)(n=3)
30 µg (n=12)(n=3)
50 µg (n=12)(n=3)
100 µg (n=12)(n=3)

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Table 1.

Potential Groups in Stage 1

Groups

N

Age
Group
(Years)15

65 to 8515

65 to 8515

65 to 8515

65 to 8515

65 to 8515

18 to 55

15

18 to 55

15

15

Dose 1

Dose 2[modRNA 100 µg(2 doses)]

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b2-10-2-O (Sentinel)[modRNA 10 µg (2 doses)]b2-20-2-O (Sentinel)[modRNA 20 µg (2 doses)]b2-30-2-O (Sentinel)[modRNA 30 µg (2 doses)]b2-50-2-O (Sentinel)[modRNA 50 µg (2 doses)]b2-100-2-O (Sentinel)[modRNA 100 µg(2 doses)]
Single-Dose Groups
b1-x-1-Y[modRNA dose level(s)selected for Stage 2(1 dose)]b2-x-1-Y[modRNA dose level(s)selected for Stage 2(1 dose)]b1-x-1-O[modRNA dose level(s)selected for Stage 2(1 dose)]b2-x-1-O[modRNA dose level(s)selected for Stage 2(1 dose)]

2-Dose Groups (Longer Schedule)
b1-x-2L-Y
15[modRNA dose level(s)selected for Stage 2(2 doses)]b2-x-2L-Y
15[modRNA dose level(s)selected for Stage 2(2 doses)](n=12)(n=3)
20 µg (n=12)(n=3)
30 µg (n=12)(n=3)
50 µg (n=12)(n=3)
100 µg (n=12)(n=3)

BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo

TBD(n=12)(n=3)

Day 22
Placebo(n=15)

BNT162b2
Placebo

TBD(n=12)(n=3)

Placebo(n=15)

65 to 85

BNT162b1
Placebo

TBD(n=12)(n=3)

Placebo(n=15)

65 to 85

BNT162b2
Placebo

TBD(n=12)(n=3)

Placebo(n=15)

TBD(n=12)(n=3)

Day 61
BNT162b1
Placebo

TBD(n=12)(n=3)

BNT162b2
Placebo18 to 55

BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
Day 1
BNT162b1
Placebo

Day 1
BNT162b1
Placebo

10 µg

10 µg

(n=12)(n=3)
20 µg (n=12)(n=3)
30 µg (n=12)(n=3)
50 µg (n=12)(n=3)
100 µg (n=12)
(n=3)

TBD

(n=12)(n=3)

TBD(n=12)(n=3)

b1-x-2L-O
15
65 to 85
BNT162b1
TBD(n=12)
BNT162b1 TBD[modRNA dose level(s)Placebo(n=3)
Placeboselected for Stage 2(2 doses)]b2-x-2L-O
15
65 to 85
BNT162b2
TBD(n=12)
BNT162b2 TBD[modRNA dose level(s)Placebo(n=3)
Placeboselected for Stage 2(2 doses)]Abbreviations: modRNA = nucleoside-modified messenger ribonucleic acid; TBD = to be determined.

(n=12)(n=3)

18 to 55

BNT162b2
Placebo

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6.1. Study Intervention(s) Administered
Intervention Name

BNT162b1 (BNT162 RNALNP vaccine utilizing
modRNA)

BNT162b2 (BNT162 RNALNP vaccine utilizing
modRNA)

Saline placebo

Type
Dose Formulation

VaccinemodRNA

VaccinemodRNA

Unit Dose Strength(s)Dosage Level(s)aRoute of
AdministrationUse
IMP or NIMP
Sourcing

250 µg/0.5 mL
10-, 20-,30-, 50-, 100-µg
Intramuscular injection

250 µg/0.5 mL
10-, 20-,30-, 50-, 100-µg
Intramuscular injection

Placebo
Normal saline (0.9% sodium
chloride solution for injection)
N/A
N/A
Intramuscular injection

Experimental
IMP
Provided centrally by thesponsorStudy intervention will be
provided in a glass vial as
open-label supply. Each vial
will be labeled as required per
country requirement

Experimental
IMP
Provided centrally by thesponsorStudy intervention will be
provided in a glass vial as
open-label supply. Each vial
will be labeled as required per
country requirement

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Packaging andLabelinga.

PlaceboIMP
Provided centrally by thesponsorStudy intervention will be
provided in a glass or plastic
vial as open-label supply.
Each vial will be labeled as
required per country
requirement

Dependent upon safety and/or immunogenicity data generated during the course of this study, or the
BioNTech study conducted in Germany (BNT162-01), it is possible that groups may be started at the next
highest dose, groups may not be started, groups may be terminated early, and/or groups may be addedwith dose levels below the lowest stated dose or intermediate between the lowest and highest stateddoses.

6.1.1. Administration
Participants will receive 1 dose of study intervention as randomized at each vaccination visit(Visits 1 and 4 for Stage 1 sentinel-cohort participants, Visits 1 and 2 for all otherparticipants) in accordance with the study’s SoA. The volume to be administered may varyby vaccine candidate and dose level; full details are described in the IP manual.
Study intervention should be administered intramuscularly into the deltoid muscle, preferablyof the nondominant arm, by an unblinded administrator.
Standard vaccination practices must be observed and vaccine must not be injected into bloodvessels. Appropriate medication and other supportive measures for management of an acute
hypersensitivity reaction should be available in accordance with local guidelines for standard
immunization practices.
Administration of study interventions should be performed by an appropriately qualified,
GCP-trained, and vaccine-experienced member of the study staff (eg, physician, nurse,
physician’s assistant, nurse practitioner, pharmacist, or medical assistant) as allowed by
local, state, and institutional guidance.
Study intervention administration details will be recorded on the CRF.
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6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study interventions received and any discrepancies arereported and resolved before use of the study intervention.

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2. Only participants enrolled in the study may receive study intervention and only
authorized site staff may supply or administer study intervention. All study interventions
must be stored in a secure, environmentally controlled, and monitored (manual or
automated recording) area in accordance with the labeled storage conditions with accesslimited to the investigator and authorized site staff. At a minimum, daily minimum andmaximum temperatures for all site storage locations must be documented and available
upon request. Data for nonworking days must indicate the minimum and maximum
temperatures since previously documented for all site storage locations upon return tobusiness.
3. Any excursions from the study intervention label storage conditions should be reported to
Pfizer upon discovery along with any actions taken. The site should actively pursue
options for returning the study intervention to the storage conditions described in thelabeling, as soon as possible. Once an excursion is identified, the study intervention must
be quarantined and not used until Pfizer provides permission to use the study
intervention. Specific details regarding the definition of an excursion and information thesite should report for each excursion will be provided to the site in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage conditions
stated on the label.
5. Study interventions should be stored in their original containers.
6. See the IP manual for storage conditions of the study intervention.
7. The investigator, institution, or the head of the medical institution (where applicable) is
responsible for study intervention accountability, reconciliation, and record maintenance(ie, receipt, reconciliation, and final disposition records), such as the IPAL orsponsor-approved equivalent. All study interventions will be accounted for using a study
intervention accountability form/record.
8. Further guidance and information for the final disposition of unused study interventions
are provided in the IP manual. All destruction must be adequately documented. If
destruction is authorized to take place at the investigator site, the investigator must ensurethat the materials are destroyed in compliance with applicable environmental regulations,institutional policy, and any special instructions provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of
discovery as described in the IP manual.

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6.2.1. Preparation and Dispensing
See the IP manual for instructions on how to prepare the study intervention foradministration. Study intervention should be prepared and dispensed by an appropriately
qualified and experienced member of the study staff (eg, physician, nurse, physician’s
assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as allowed by
local, state, and institutional guidance. A second staff member will verify the dispensing.
Study intervention and placebo will be prepared by qualified unblinded site personnel
according to the IP manual. The study intervention will be administered in such a way toensure the participants remain blinded.
6.3. Measures to Minimize Bias: Randomization and Blinding

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6.3.1. Allocation to Study Intervention
Allocation (randomization) of participants to vaccine groups will proceed through the use of
an IRT system (IWR). The site personnel (study coordinator or specified designee) will be
required to enter or select information including but not limited to the user’s ID andpassword, the protocol number, and the participant number. The site personnel will then be
provided with a vaccine assignment and randomization number. The IRT system will
provide a confirmation report containing the participant number, randomization number, andstudy intervention allocation assigned. The confirmation report must be stored in the site’s
files.
The study-specific IRT reference manual and IP manual will provide the contact informationand further details on the use of the IRT system.
6.3.2. Blinding of Site Personnel
In this observer blinded study, the study staff receiving, storing, dispensing, preparing, andadministering the study interventions will be unblinded. All other study and site personnel,
including the investigator, investigator staff, and participants, will be blinded to study
intervention assignments. In particular, the individuals who evaluate participant safety willbe blinded. Because the BNT162 RNA-based COVID-19 vaccine candidates and placebo
are different in physical appearance, the study intervention syringes will be administered in amanner that prevents the study participants from identifying the study intervention type basedon its appearance.
The responsibility of the unblinded dispenser and administrator must be assigned to anindividual or individuals who will not participate in the evaluation of any study participants.
Contact between the unblinded dispenser and study participants and unblinded administrator
and study participants should be kept to a minimum. The remaining site personnel must notknow study intervention assignments.

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6.3.3. Blinding of the Sponsor
To facilitate rapid review of data in real time, sponsor staff will be unblinded to study
intervention allocation for the participants in Stage 1 and in Stage 2. Sponsor staff will beblinded to study intervention allocation in Stage 3. All laboratory testing personnel
performing serology assays will remain blinded to study intervention assigned/received
throughout the study.
Those study team members who are involved in ensuring that protocol requirements forstudy intervention preparation, handling, allocation, and administration are fulfilled at the site
will be unblinded for the duration of the study (eg, unblinded study manager, unblindedclinical research associate). Unblinded clinician(s) who are not direct members of the study
team will review unblinded protocol deviations.

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6.3.4. Breaking the Blind
The IRT will be programmed with blind-breaking instructions. In case of an emergency, theinvestigator has the sole responsibility for determining if unblinding of a participant’s study
intervention assignment is warranted. Participant safety must always be the firstconsideration in making such a determination. If the investigator decides that unblinding iswarranted, the investigator should make every effort to contact the sponsor prior to
unblinding a participant’s vaccine assignment unless this could delay further management of
the participant. If a participant’s vaccine assignment is unblinded, the sponsor must be
notified within 24 hours after breaking the blind. The date and reason that the blind was
broken must be recorded in the source documentation and CRF.
The study-specific IRT reference manual and IP manual will provide the contact informationand further details on the use of the IRT system.
6.4. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from theinvestigator or designee, under medical supervision. The date and time of each dose
administered in the clinic will be recorded in the source documents and recorded in the CRF.
The dose of study intervention and study participant identification will be confirmed at thetime of dosing by a member of the study site staff other than the person administering thestudy intervention.
6.5. Concomitant Therapy
The following concomitant medications and vaccinations will be recorded in the CRF:
All vaccinations received from 28 days prior to study enrollment until the 6-monthfollow-up visit (Visit 8 for Stage 1 sentinel cohorts, Visit 5 for Stage 1 nonsentinelcohorts and Stage 2 participants, and Visit 4 for Stage 3 participants).

Prohibited medications listed in Section 6.5.1 will be recorded, to include start and stop
dates, name of the medication, dose, unit, route, and frequency.
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In addition, for participants enrolled in the Stage 1 sentinel cohorts, all current
medication at baseline will be recorded, to include start date, name of the medication,dose, unit, route, and frequency.

6.5.1. Prohibited During the Study
Receipt of the following vaccines and medications during the time periods listed below may
exclude a participant from the per-protocol analysis, and may require vaccinations to bediscontinued in that participant; however, it is anticipated that the participant would not be
withdrawn from the study (see Section 7). Medications should not be withheld if required fora participant’s medical care.
Unless considered medically necessary, no vaccines other than study intervention should be
administered within 28 days before and 28 days after each study vaccination. One exception
to this is that seasonal and pandemic influenza vaccine can be given at least 14 days after, orat least 14 days prior to, the administration of study intervention.

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Receipt of chronic systemic treatment with known immunosuppressant medications, orradiotherapy, within 60 days before enrollment through conclusion of the study.
Receipt of systemic corticosteroids (≥20 mg/day of prednisone or equivalent) for ≥14 days is
prohibited from 28 days prior to enrollment to Visit 7 for Stage 1 sentinel cohorts, Visit 4 forStage 1 nonsentinel cohorts and Stage 2 participants, and Visit 3 for Stage 3 participants).
Receipt of inhaled/nebulized corticosteroids from 28 days prior to enrollment to Visit 7(1-month follow-up visit) for Stage 1 sentinel cohorts.
Receipt of blood/plasma products or immunoglobulins within 60 days before enrollment
through conclusion of the study.
Receipt of any other (nonstudy) coronavirus vaccine at any time prior to or during study
participation is prohibited.
Prophylactic antipyretics and other pain medication to prevent symptoms associated withstudy intervention administration are not permitted. However, if a participant is taking a
medication for another condition, even if it may have antipyretic or pain-relieving properties,
it should not be withheld prior to study vaccination.
6.5.2. Permitted During the Study
The use of antipyretics and other pain medication to treat symptoms associated with study
intervention administration or ongoing conditions is permitted.
Medication other than that described as prohibited in Section 6.5.1 required for treatment ofpreexisting stable conditions is permitted.

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Inhaled (except in Stage 1 sentinel cohorts – see Section 6.5.1), topical, or localized
injections of corticosteroids (eg, intra-articular or intrabursal administration) are permitted.
6.6. Dose Modification
This protocol allows some alteration of vaccine dose for individual participants and/or dosegroups from the currently outlined dosing schedule. For reasons of reactogenicity,
tolerability, or safety, the IRC may recommend to reduce the second dose of study
intervention and/or increase the interval between doses.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANTDISCONTINUATION/WITHDRAWAL

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7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study
intervention (definitive discontinuation). Reasons for definitive discontinuation of study
intervention may include the following: AEs; participant request; investigator request;
pregnancy; protocol deviation (including no longer meeting all the inclusion criteria, or
meeting 1 or more exclusion criteria).
Note that discontinuation of study intervention does not represent withdrawal from the study.
Per the study estimands, if study intervention is definitively discontinued, the participant willremain in the study to be evaluated for safety, immunogenicity, and potential efficacy. See
the SoA for data to be collected at the time of discontinuation of study intervention andfollow-up for any further evaluations that need to be completed.
In the event of discontinuation of study intervention, it must be documented on theappropriate CRF/in the medical records whether the participant is discontinuing further
receipt of study intervention or also from study procedures, posttreatment study follow-up,
and/or future collection of additional information.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request. Reasons fordiscontinuation from the study may include the following:

Refused further follow-up;

Lost to follow-up;



Death;



Study terminated by sponsor;



AEs;
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Investigator request;Protocol deviation.

If a participant does not return for a scheduled visit, every effort should be made to contact
the participant. All attempts to contact the participant and information received duringcontact attempts must be documented in the participant’s source document. In any
circumstance, every effort should be made to document participant outcome, if possible.
The investigator or his or her designee should capture the reason for withdrawal in the CRF
for all participants.

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If a participant withdraws from the study, he/she may request destruction of any remaining
samples taken and not tested, and the investigator must document any such requests in thesite study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1)
for disclosure of future information, no further evaluations should be performed and no
additional data should be collected. The sponsor may retain and continue to use any datacollected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not beviewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent
Participants who request to discontinue receipt of study intervention will remain in the study
and must continue to be followed for protocol-specified follow-up procedures. The only
exception to this is when a participant specifically withdraws consent for any further contact
with him or her or persons previously authorized by the participant to provide thisinformation. Participants should notify the investigator in writing of the decision towithdraw consent from future follow-up, whenever possible. The withdrawal of consent
should be explained in detail in the medical records by the investigator, as to whether thewithdrawal is only from further receipt of study intervention or also from study procedures
and/or posttreatment study follow-up, and entered on the appropriate CRF page. In the eventthat vital status (whether the participant is alive or dead) is being measured, publicly
available information should be used to determine vital status only as appropriately directedin accordance with local law.
7.3. Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return forscheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to attend a required study visit:

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The site must attempt to contact the participant and reschedule the missed visit as soon as
possible and counsel the participant on the importance of maintaining the assigned visit
schedule and ascertain whether or not the participant wishes to and/or should continue inthe study;

Before a participant is deemed lost to follow-up, the investigator or designee must makeevery effort to regain contact with the participant (where possible, 3 telephone calls and,if necessary, a certified letter to the participant’s last known mailing address or local
equivalent methods). These contact attempts should be documented in the participant’s
medical record;Should the participant continue to be unreachable, he/she will be considered to havewithdrawn from the study.

8. STUDY ASSESSMENTS AND PROCEDURES

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)The investigator (or an appropriate delegate at the investigator site) must obtain a signed anddated ICD before performing any study-specific procedures.
The full date of birth will be collected to critically evaluate the immune response and safety
profile by age.
Study procedures and their timing are summarized in the SoA. Protocol waivers or
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence orawareness to determine whether the participant should continue or discontinue study
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential
participants meet all eligibility criteria. The investigator will maintain a screening log torecord details of all participants screened and to confirm eligibility or record reasons forscreening failure, as applicable.
Every effort should be made to ensure that protocol-required tests and procedures arecompleted as described. However, it is anticipated that from time to time there may becircumstances outside the control of the investigator that may make it unfeasible to performthe test. In these cases, the investigator must take all steps necessary to ensure the safety andwell-being of the participant. When a protocol-required test cannot be performed, theinvestigator will document the reason for the missed test and any corrective and preventive
actions that he or she has taken to ensure that required processes are adhered to as soon as
possible. The study team must be informed of these incidents in a timely manner.

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For samples being collected and shipped, detailed collection, processing, storage, andshipment instructions and contact information will be provided to the investigator site prior
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately
530 mL for participants in the Stage 1 sentinel cohorts; 350 mL for participants in the Stage 1
nonsentinel cohorts and Stage 2 participants; and 200 mL for Stage 3 participants.
Additionally, 50 mL of blood will be taken at an unplanned convalescent visit at any time aparticipant develops respiratory symptoms indicating a potential COVID-19 infection. Selectparticipants in the sentinel cohorts of Stage 1 will also be asked to provide an additional
blood sample of approximately 170 mL at either Visit 5, 6, or 7. These participants would
therefore have a total blood sampling volume of 700 mL during the 24-month study period.
Other additional blood samples may be taken for safety assessments at times specified by
Pfizer, provided the total volume taken during the study does not exceed 550 mL during any
period of 60 consecutive days.

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8.1. Efficacy and/or Immunogenicity Assessments
Efficacy will be assessed throughout a participant’s involvement in the study throughsurveillance for potential cases of COVID-19. If, at any time, a participant develops acuterespiratory illness (see Section 8.13), for the purposes of the study he or she will beconsidered to potentially have COVID-19 illness.9 In this circumstance, the participant
should contact the site, a telehealth visit should occur, and assessments should be conducted
as specified in the SoA. The assessments will include a nasal (midturbinate) swab, which
will be tested at a central laboratory using a reverse transcription–polymerase chain reaction(RT-PCR) test (Cepheid; FDA approved under EUA), or other equivalent nucleic acidamplification–based test (ie, NAAT), to detect SARS-CoV-2. In addition, clinicalinformation and results from local standard-of-care tests (as detailed in Section 8.13) will beassessed. Four definitions of potential SARS-CoV-2–related cases will be considered:Centrally confirmed COVID-19: presence of at least 1 symptom described in
Section 8.13 and SARS-CoV-2 NAAT positive at central laboratory

Locally confirmed COVID-19: presence of at least 1 symptom described in Section 8.13
and investigator-confirmed SARS-CoV-2 NAAT positive at a local testing facilityCentrally confirmed symptomatic seroconversion to SARS-CoV-2 (exploratory):presence of at least 1 symptom described in Section 8.13 and a positive nonvaccine
antigen SARS-CoV-2 antibody result in a participant whose most recent prior nonvaccine
antigen SARS-CoV-2 antibody result was negativeCentrally confirmed asymptomatic seroconversion to SARS-CoV-2 (exploratory):
positive nonvaccine antigen SARS-CoV-2 antibody result in a participant with a priornonvaccine antigen SARS-CoV-2 antibody result was negative

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Serum samples will be obtained for immunogenicity testing at the visits specified in the SoA.
The following assays will be performed:

SARS-CoV-2 serum neutralization assay

SARS-CoV-2 S1-specific IgG direct Luminex immunoassay

SARS-CoV-2 RBD-specific IgG direct Luminex immunoassay

Nonvaccine antigen (NVA) Ig direct Luminex immunoassay. The NVA will include a
SARS-CoV-2 target antigen that is not derived from the S glycoprotein, most likely anantigen derived from the SARS-CoV-2 nucleoprotein.

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Note that all immunogenicity analyses will be based upon samples analyzed at the central
laboratory; the rapid test will only be performed at screening by all sites recruiting
participants in Stage 1 sentinel cohorts (see Section 8.11.1.1) to determine eligibility.
Serum obtained from the additional ~170-mL blood sample from select participants in thesentinel cohorts of Stage 1 at either Visit 5, 6, or 7 will be used for exploratory COVID-19
research, intended to establish a surrogate endpoint that is reasonably likely to predict clinicalbenefit.
8.1.1. Biological Samples
Blood and nasal swab samples will be used only for scientific research. Each sample will belabeled with a code so that the laboratory personnel testing the samples will not know theparticipant’s identity. Samples that remain after performing assays outlined in the protocol
may be stored by Pfizer. Unless a time limitation is required by local regulations or ethicalrequirements, the samples will be stored for up to 15 years after the end of the study and thendestroyed. If allowed by the ICD, stored samples may be used for additional testing to better
understand the immune responses to the vaccine(s) under study in this protocol, to inform thedevelopment of other products, and/or for vaccine-related assay work supporting vaccine
programs. No testing of the participant’s DNA will be performed.
The participant may request that his or her samples, if still identifiable, be destroyed at any
time; however, any data already collected from those samples will still be used for thisresearch. The biological samples may be shared with other researchers as long asconfidentiality is maintained and no testing of the participant’s DNA is performed.

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8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinicallaboratory measurements may be obtained at any time during the study to assess any
perceived safety issues.
A clinical assessment, including medical history, will be performed on all participants at
his/her first visit to establish a baseline. Significant medical history and observations fromany physical examination, if performed, will be documented in the CRF.
AEs and SAEs are collected, recorded, and reported as defined in Section 8.3.
Acute reactions within the first 4 hours after administration of the study intervention (for the
first 5 participants vaccinated in each Stage 1 sentinel group), and within the first 30 minutes(for the remainder of participants), will be assessed and documented in the AE CRF.

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)The safety parameters also include reactogenicity e-diary reports of local reactions andsystemic events (including fever), and use of antipyretic medication that occur in the 7 days
after administration of the study intervention. These prospectively self-collected occurrencesof local reactions and systemic events are graded as described in Section 8.2.2.
8.2.1. Clinical Safety Laboratory Assessments (Sentinel-Cohort Participants Only)
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for
the timing and frequency. All protocol-required laboratory assessments, as defined inAppendix 2, must be conducted in accordance with the laboratory manual and the SoA.
Unscheduled clinical laboratory measurements may be obtained at any time during the study
to assess any perceived safety issues.
The investigator must review the laboratory report, document this review, and record any
clinically relevant changes occurring during the study in the AE section of the CRF. See
Appendix 2 for the grading scale for assessment of clinically significant abnormal laboratory
findings. Clinically significant abnormal laboratory findings are those which are notassociated with the underlying disease, unless judged by the investigator to be more severe
than expected for the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during
participation in the study or within 28 days after the last dose of study intervention should be
repeated until the values return to normal or baseline or are no longer considered clinicallysignificant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 5 for suggested actions and follow-up assessments in the event of potential
drug-induced liver injury.

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8.2.2. Electronic Diary
Participants will be required to complete a reactogenicity e-diary through an application(see Section 8.14) installed on a provisioned device or on the participant’s own personal
device. The participant will be asked to monitor and record local reactions, systemic events,
and antipyretic medication usage for 7 days following administration of the study
intervention. The reactogenicity e-diary allows recording of these assessments only within afixed time window, thus providing the accurate representation of the participant’s experienceat that time. Data on local reactions and systemic events reported in the reactogenicity
e-diary will be transferred electronically to a third-party vendor, where they will be available
for review by investigators and the Pfizer clinicians at all times via an internet-based portal.
At intervals agreed to by the vendor and Pfizer, these data will be transferred electronicallyinto Pfizer's database for analysis and reporting. These data do not need to be reported by theinvestigator in the CRF as AEs.

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Investigators (or designee) will be required to review the reactogenicity e-diary data online atfrequent intervals as part of the ongoing safety review.
The investigator or designee must obtain stop dates from the participant for any ongoing
local reactions, systemic events, or use of antipyretic medication on the last day that thereactogenicity e-diary was completed. The stop dates should be documented in the source
documents and the information entered in the CRF.
8.2.2.1. Grading Scales
The grading scales used in this study to assess local reactions and systemic events as
described below are derived from the FDA Center for Biologics Evaluation and Research(CBER) guidelines on toxicity grading scales for healthy adult volunteers enrolled inpreventive vaccine clinical trials.8
8.2.2.2. Local Reactions
During the reactogenicity e-diary reporting period, participants will be asked to assess
redness, swelling, and pain at the injection site and to record the symptoms in thereactogenicity e-diary. If a local reaction persists beyond the end of the reactogenicity
e-diary period following vaccination, the participant will be requested to report that
information. The investigator will enter this additional information in the CRF.
Redness and swelling will be measured and recorded in measuring device units(range: 1 to 21) and then categorized during analysis as absent, mild, moderate, or severe
based on the grading scale in Table 2. Measuring device units can be converted tocentimeters according to the following formula: 1 measuring device unit = 0.5 cm. Pain at
the injection site will be assessed by the participant as absent, mild, moderate, or severe
according the grading scale in Table 2.

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If a Grade 3 local reaction is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinicallyindicated. Only an investigator or medically qualified person is able to classify aparticipant’s local reaction as Grade 4. If a participant experiences a confirmed Grade 4 local
reaction, the investigator must immediately notify the sponsor and, if it is determined to berelated to the administration of the study intervention, further vaccinations will be
discontinued in that participant.
Table 2.

Local Reaction Grading Scale
Mild(Grade 1)

Pain at the
injection site

Does not interferewith activity

Interferes withactivity

Redness

2.0 cm to 5.0 cm(5 to 10 measuring
device units)
2.0 cm to 5.0 cm(5 to 10 measuring
device units)>5.0 cm to 10.0 cm(11 to 20 measuring
device units)>5.0 cm to 10.0 cm(11 to 20 measuring
device units)

Swelling

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Moderate(Grade 2)

Severe(Grade 3)

Potentially Life
Threatening(Grade 4)
Prevents daily activity Emergency room visit
or hospitalization forsevere pain
>10 cmNecrosis or(≥21 measuringexfoliative dermatitis
device units)>10 cmNecrosis(≥21 measuring
device units)

8.2.2.3. Systemic Events
During the reactogenicity e-diary reporting period, participants will be asked to assess
vomiting, diarrhea, headache, fatigue, chills, new or worsened muscle pain, and new orworsened joint pain and to record the symptoms in the reactogenicity e-diary. The symptoms
will be assessed by the participant as absent, mild, moderate, or severe according to thegrading scale in Table 3.
If a Grade 3 systemic event is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinicallyindicated. Only an investigator or medically qualified person is able to classify aparticipant’s systemic event as Grade 4. If a participant experiences a confirmed Grade 4
systemic event, the investigator must immediately notify the sponsor and, if it is determined
to be related to the administration of the study intervention, further vaccinations will be
discontinued in that participant.

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Table 3.

Systemic Event Grading Scale

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Mild(Grade 1)

Moderate(Grade 2)>2 times in
24 hours

Severe(Grade 3)

Vomiting

1-2 times in
24 hours

Requires IV
hydration

Diarrhea

2 to 3 loose stools 4 to 5 loose stools
in 24 hours
in 24 hours

6 or more loosestools in 24 hours

Headache

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Fatigue/tiredness

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Chills

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

New orworsened
muscle pain

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Does not interfere Some interference
New orwith activity
with activity
worsened
joint pain
Abbreviation: IV = intravenous.

Prevents daily
routine activity

Potentially Life
Threatening(Grade 4)
Emergency room visit or
hospitalization for
hypotensive shock
Emergency room visit or
hospitalization for severe
diarrhea
Emergency room visit or
hospitalization for severe
headache
Emergency room visit or
hospitalization for severe
fatigue
Emergency room visit or
hospitalization for severe
chillsEmergency room visit or
hospitalization for severe
new or worsened muscle
painEmergency room visit or
hospitalization for severe
new or worsened joint pain

8.2.2.4. Fever
In order to record information on fever, a thermometer will be given to participants with
instructions on how to measure oral temperature at home. Temperature will be collected in
the reactogenicity e-diary in the evening daily during the reactogenicity e-diary reporting
period. It will also be collected at any time during the reactogenicity e-diary data collection
periods when fever is suspected. Fever is defined as an oral temperature of ≥38.0°C(100.4°F). The highest temperature for each day will be recorded in the reactogenicity
e-diary. Temperature will be measured and recorded to 1 decimal place and then categorized
during analysis according to the scale shown in Table 4.
If a fever of ≥39.0°C (102.1°F) is reported in the reactogenicity e-diary, a telephone contact
should occur to ascertain further details and determine whether a site visit is clinicallyindicated. Only an investigator or medically qualified person is able to confirm aparticipant’s fever as >40.0°C (>104.0°F). If a participant experiences a confirmed fever>40.0°C (>104.0°F), the investigator must immediately notify the sponsor and, if it isdetermined to be related to the administration of the study intervention, further vaccinations
will be discontinued in that participant.

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Table 4.

Scale for Fever≥38.0-38.4°C (100.4-101.1°F)>38.4-38.9°C (101.2-102.0°F)>38.9-40.0°C (102.1-104.0°F)>40.0°C (>104.0°F)

8.2.2.5. Antipyretic Medication
The use of antipyretic medication to treat symptoms associated with study intervention
administration will be recorded in the reactogenicity e-diary daily during the reporting period(Day 1 to Day 7).
8.2.3. Stopping Rules

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)The following stopping rules are in place for all Stage 1 sentinel-cohort participants, basedon review of AE data and e-diary reactogenicity data. These data will be monitored on an
ongoing basis by the investigator (or medically qualified designee) and sponsor in order topromptly identify and flag any event that potentially contributes to a stopping rule.
The sponsor study team will be unblinded during the Stage 1, so will be able to assess
whether or not a stopping rule has been met on the basis of a participant’s individual study
intervention allocation.
In the event that sponsor personnel confirm that a stopping rule is met, the following actions
will commence:The IRC will review all appropriate data.

The stopping rule will PAUSE randomization and study intervention administration for
the impacted vaccine candidate all dose levels and age groups.



The DMC will review all appropriate data.

For all participants vaccinated, all other routine study conduct activities, including
ongoing data entry, reporting of AEs, participant reactogenicity e-diary completion,
blood sample collection, and participant follow-up, will continue during the pause.

A stopping rule is met if any of the following rules occur after administration of
investigational BNT162 vaccine; data from placebo recipients will not contribute to thestopping rules. Reactogenicity e-diary data confirmed by the investigator as being entered by
the participant in error will not contribute toward a stopping rule.

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The BNT162b RNA platform will be evaluated for contribution to stopping rules overall;
vaccine candidate dose levels within the platform and age groups will contribute to stopping
rules together. However, it is possible that the recommendations may include halting or
continuing randomization with any of the BNT162 vaccine candidates.
Stopping Rule Criteria for Each BNT162 Vaccine Candidate:
1. If any participant vaccinated with the BNT162 candidate (at any dose level) develops an
SAE that is assessed by the investigator as possibly related, or for which there is noalternative, plausible, attributable cause.

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2. If any participant vaccinated with the BNT162 candidate (at any dose level) develops a
Grade 4 local reaction or systemic event after vaccination (see Section 8.2.2) that is
assessed as possibly related by the investigator, or for which there is no alternative,plausible, attributable cause.
3. If any participant vaccinated with the BNT162 candidate (at any dose level) develops afever >40.0°C (>104.0°F) for at least 1 daily measurement after vaccination(see Section 8.2.2.4) that is assessed as possibly related by the investigator, or for which
there is no alternative, plausible, attributable cause.
4. If any 2 participants vaccinated with the BNT162 candidate (at any dose level) report thesame or similar severe (Grade 3) AE (including laboratory abnormalities) after
vaccination, assessed as possibly related by the investigator, or for which there is noalternative, plausible, attributable cause.
5. If any participant dies or requires ICU admission due to SARS-CoV-2 infection; if thisstopping rule is met, all available clinical and preclinical safety and immunogenicity data
should be reviewed to evaluate for enhanced COVID-19 disease.
8.2.3.1. Randomization and Vaccination After a Stopping Rule Is Met
Once the IRC and DMC have reviewed the safety data and provided guidance, a notification
will be sent from the sponsor to the sites with guidance on how to proceed.
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19 Disease
As this is a sponsor open-label study during Stages 1 and 2, the sponsor will conduct
unblinded reviews of the data during the course of the study, including for the purpose ofsafety assessment.
Participants in all stages of the study will be surveilled for potential COVID-19 illness from
Visit 1 onwards (see Section 8.13). All NAAT-confirmed cases will be reviewed
contemporaneously by the IRC and the DMC (see Section 9.6). In addition, instances ofsymptomatic and asymptomatic seroconversion to SARS-CoV-2 (see Section 8.1) will be
reviewed.

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The purpose of these reviews will be to identify whether any features of each case appear
unusual, in particular greater severity, compared to available information at the time ofreview. Indicators of severity may include accelerated deterioration, need for hospitalization,need for ventilation, or death. Observed rates of these indicators will be compared with what
could be expected in a similar population to the study participants based upon available
information at the time of review. Since the DMC is able to review unblinded information, it
will also be able to compare cases in active vaccine and placebo recipients in Stage 3 (whensponsor staff will be blinded).
8.2.5. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA,
immediately before the administration of each vaccine dose. A negative pregnancy test result
will be required prior to the participant’s receiving the study intervention. Pregnancy tests
may also be repeated if requested by IRBs/ECs or if required by local regulations. In thecase of a positive confirmed pregnancy, the participant will be withdrawn fromadministration of study intervention but may remain in the study.
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8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or
the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, andrecording events that meet the definition of an AE or SAE and remain responsible to pursue
and obtain adequate information both to determine the outcome and to assess whether the
event meets the criteria for classification as an SAE or caused the participant to discontinue
the study intervention (see Section 7.1).
Each participant will be questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection
period”) for each participant begins from the time the participant provides informed consent,
which is obtained before the participant’s participation in the study (ie, before undergoing
any study-related procedure and/or receiving study intervention), through and including
Visit 7 for Stage 1 sentinel-cohort participants, Visit 4 for Stage 1 nonsentinel participants
and Stage 2 participants, and Visit 3 for Stage 3 participants. In addition, any AEs occurring
up to 48 hours after each subsequent blood draw must be recorded on the CRF.

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SAEs will be collected from the time the participant provides informed consent toapproximately 6 months after the last dose of study intervention (Visit 8 for Stage 1
sentinel-cohort participants, Visit 5 for Stage 1 non–sentinel-cohort participants and Stage 2
participants, and Visit 4 for Stage 3 participants).
Follow-up by the investigator continues throughout and after the active collection period anduntil the AE or SAE or its sequelae resolve or stabilize at a level acceptable to theinvestigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of
future information, the active collection period ends when consent is withdrawn.

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If a participant definitively discontinues or temporarily discontinues study intervention
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE
reported using the Vaccines SAE Report Form.
Investigators are not obligated to actively seek AEs or SAEs after the participant has
concluded study participation. However, if the investigator learns of any SAE, including adeath, at any time after a participant has completed the study, and he/she considers the event
to be reasonably related to the study intervention, the investigator must promptly report the
SAE to Pfizer using the Vaccines SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in
Section 8.3.1 are reported to Pfizer Safety on the Vaccines SAE Report Form immediately
upon awareness and under no circumstance should this exceed 24 hours, as indicated inAppendix 3. The investigator will submit any updated SAE data to the sponsor within
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period as
described in Section 8.3.1 are recorded on the CRF. AEs and SAEs that begin after obtaining
informed consent but before the start of study intervention will be recorded on the Medical
History/Current Medical Conditions section of the CRF, not the AE section. AEs and SAEs
that begin after the start of study intervention are recorded on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and theprocedures for completing and transmitting SAE reports are provided in Appendix 3.
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Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended andnonleading verbal questioning of the participant is the preferred method to inquire about
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow eachparticipant at subsequent visits/contacts. For each event, the investigator must pursue andobtain adequate information until resolution, stabilization, the event is otherwise explained,or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail toallow for a complete medical assessment of the case and independent determination of
possible causality. Any information relevant to the event, such as concomitant medications
and illnesses, must be provided. In the case of a participant death, a summary of available
autopsy findings must be submitted as soon as possible to Pfizer Safety.
Further information on follow-up procedures is given in Appendix 3.

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8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal
obligations and ethical responsibilities towards the safety of participants and the safety of astudy intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and otherregulatory agencies about the safety of a study intervention under clinical investigation. The
sponsor will comply with country-specific regulatory requirements relating to safety
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding andoccupational exposure are reportable to Pfizer Safety within 24 hours of investigatorawareness.

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8.3.5.1. Exposure During Pregnancy

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)An EDP occurs if:A female participant is found to be pregnant while receiving or after discontinuing study
intervention.



A male participant who is receiving or has discontinued study intervention exposes afemale partner prior to or around the time of conception.



A female is found to be pregnant while being exposed or having been exposed to study
intervention due to environmental exposure. Below are examples of environmental
exposure during pregnancy:

A female family member or healthcare provider reports that she is pregnant after
having been exposed to the study intervention by inhalation or skin contact.

A male family member or healthcare provider who has been exposed to the study
intervention by inhalation or skin contact then exposes his female partner prior to or
around the time of conception.

The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s
awareness, irrespective of whether an SAE has occurred. The initial information submitted
should include the anticipated date of delivery (see below for information related totermination of pregnancy).


If EDP occurs in a participant or a participant’s partner, the investigator must report thisinformation to Pfizer Safety on the Vaccines SAE Report Form and an EDP
Supplemental Form, regardless of whether an SAE has occurred. Details of thepregnancy will be collected after the start of study intervention and until 6 months after
the last dose of study intervention.



If EDP occurs in the setting of environmental exposure, the investigator must report
information to Pfizer Safety using the Vaccines SAE Report Form and EDP
Supplemental Form. Since the exposure information does not pertain to the participant
enrolled in the study, the information is not recorded on a CRF; however, a copy of thecompleted Vaccines SAE Report Form is maintained in the investigator site file.

Follow-up is conducted to obtain general information on the pregnancy and its outcome for
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as afollow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural
integrity of the neonate can be assessed at the time of birth. In the event of a termination, thereason(s) for termination should be specified and, if clinically possible, the structural
integrity of the terminated fetus should be assessed by gross visual inspection (unless

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preprocedure test findings are conclusive for a congenital anomaly and the findings arereported).

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Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meetsthe criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal
demise, neonatal death, or congenital anomaly), the investigator should follow the procedures
for reporting SAEs. Additional information about pregnancy outcomes that are reported to
Pfizer Safety as SAEs follows:

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard tocausality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs
when the investigator assesses the infant death as related or possibly related to exposure
to the study intervention.

Additional information regarding the EDP may be requested by the sponsor. Further
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on
preterm infants to identify developmental delays). In the case of paternal exposure, theinvestigator will provide the participant with the Pregnant Partner Release of Information
Form to deliver to his partner. The investigator must document in the source documents thatthe participant was given the Pregnant Partner Release of Information Form to provide to his
partner.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if:A female participant is found to be breastfeeding while receiving or after discontinuing
study intervention.



A female is found to be breastfeeding while being exposed or having been exposed to
study intervention (ie, environmental exposure). An example of environmental exposure
during breastfeeding is a female family member or healthcare provider who reports that
she is breastfeeding after having been exposed to the study intervention by inhalation orskin contact.

The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hoursof the investigator’s awareness, irrespective of whether an SAE has occurred. The
information must be reported using the Vaccines SAE Report Form. When exposure during
breastfeeding occurs in the setting of environmental exposure, the exposure information does
not pertain to the participant enrolled in the study, so the information is not recorded on a
CRF. However, a copy of the completed Vaccines SAE Report Form is maintained in theinvestigator site file.

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An exposure during breastfeeding report is not created when a Pfizer drug specificallyapproved for use in breastfeeding women (eg, vitamins) is administered in accord withauthorized use. However, if the infant experiences an SAE associated with such a drug, theSAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with thestudy intervention, which may or may not lead to the occurrence of an AE. Such persons
may include healthcare providers, family members, and other roles that are involved in thetrial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of theinvestigator’s awareness, regardless of whether there is an associated SAE. The informationmust be reported using the Vaccines SAE Report Form. Since the information does not
pertain to a participant enrolled in the study, the information is not recorded on a CRF;
however, a copy of the completed Vaccines SAE Report Form is maintained in theinvestigator site file.

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8.3.6. Medication Errors
Medication errors may result from the administration or consumption of the study
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as
medication errors.
Safety Event

Recorded on the CRF

Reported on the Vaccines SAE Report
Form to Pfizer Safety Within 24 Hours
of Awareness

Medication errors

All (regardless of whether
associated with an AE)

Only if associated with an SAE

Medication errors include:Medication errors involving participant exposure to the study intervention;Potential medication errors or uses outside of what is foreseen in the protocol that do or
do not involve the study participant;The administration of expired study intervention;

The administration of an incorrect study intervention;

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The administration of an incorrect dosage;The administration of study intervention that has undergone temperature excursion fromthe specified storage range, unless it is determined by the sponsor that the study
intervention under question is acceptable for use.

Such medication errors occurring to a study participant are to be captured on the medication
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by theinvestigator, the medication error is recorded on the medication error page of the CRF and, if
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a Vaccines SAE
Report Form only when associated with an SAE.
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8.4. Treatment of Overdose
For this study, any dose of study intervention greater than 1 dose of study intervention within
a 24-hour time period will be considered an overdose.
Pfizer does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the medical monitor immediately.
2. Closely monitor the participant for any AEs/SAEs.
3. Document the quantity of the excess dose as well as the duration of the overdose in the
CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.

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8.7. Genetics
Genetics (specified analyses) are not evaluated in this study.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.9. Immunogenicity Assessments
Immunogenicity assessments are described in Section 8.1.
8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are notevaluated in this study.
8.11. Study Procedures
8.11.1. Stage 1 Sentinel Cohorts

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8.11.1.1. Screening: (0 to 28 Days Before Visit 1)
Before enrollment and before any study-related procedures are performed, voluntary, written
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.
It is anticipated that the procedures below will be conducted in a stepwise manner; however,the visit can occur over more than 1 day.
Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance.

Obtain details of any medications currently taken.

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Perform physical examination including vital signs (weight, height, body temperature,pulse rate, and seated blood pressure), evaluating any clinically significant abnormalities
within the following body systems: general appearance; skin; head, eyes, ears, nose, andthroat; heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph
nodes.



Collect a blood sample (approximately 20 mL) for potential future serological assessment
and to perform a rapid test for prior COVID-19 infection.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.

Collect a blood sample (approximately 10 mL) for HIV, HBsAg, HBc Ab, and HCV Ab
tests.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Record AEs as described in Section 8.3. AEs that occur prior to dosing should be notedon the Medical History CRF.



Ask the participant to contact the site staff or investigator immediately if any significant
illness or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

Complete the CRF.

8.11.1.2. Visit 1 – Vaccination 1: (Day 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.
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

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Review screening laboratory results (hematology and chemistry, and HIV, HBsAg,
HBc Ab, and HCV Ab tests).

Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested(if possible at the site, otherwise at the central laboratory) within 24 hours andvaccination will proceed only if it is NAAT-negative for SARS-CoV-2 genomes.
The second will be sent to the central laboratory for potential later testing.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Obtain the participant’s randomization number and study intervention allocation using
the IRT system. Either blinded site staff or unblinded site staff member may obtain thisinformation.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.



The first 5 participants vaccinated in each Stage 1 sentinel group must be observed byblinded site staff for any acute reactions for at least 4 hours after vaccination. For
participants enrolled thereafter, blinded site staff must observe the participant for at least
30 minutes after study intervention administration for any acute reactions. Record any
acute reactions (including time of onset) in the participant’s source documents and on the
AE page of the CRF, and on an SAE form as applicable.

Issue a measuring device to measure local reactions at the injection site and athermometer for recording daily temperatures and provide instructions on their use.
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Explain the e-diary technologies available for this study (see Section 8.14), and assist theparticipant in downloading the study application onto the participant’s own device orissue a provisioned device if required. Provide instructions on e-diary completion andask the participant to complete the reactogenicity e-diary from Day 1 to Day 7, with
Day 1 being the day of vaccination and, if utilized, the COVID-19 illness e-diary (to becompleted if the participant is diagnosed with COVID-19 or has possible new orincreased symptoms, and when he/she receives a reminder, at least weekly).



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

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8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1 to 3 Days After Visit 1)

Record AEs as described in Section 8.3.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.

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The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

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8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to 8 Days After Visit 1)

Record AEs as described in Section 8.3.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.

Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.
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

Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

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8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary wascompleted and record stop dates in the CRF if required.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

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Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested (ifpossible at the site, otherwise at the central laboratory) within 24 hours and vaccination
will only proceed if it is NAAT-negative for SARS-CoV-2 genomes. The second will besent to the central laboratory for potential later testing.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met. If not, the participant should not receive further study intervention but willremain in the study to be evaluated for safety, immunogenicity, and potential efficacy(see Section 7.1).

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection
site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and ask the participant to complete thereactogenicity e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.
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

Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to 8 Days After Visit 4)

Record AEs as described in Section 8.3.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

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If the participant (select participants only, details will be provided by the Sponsor)
consents, collect an additional 170 mL blood sample for exploratory COVID-19 research.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to 16 Days After Visit 4)

Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary wascompleted and record stop dates in the CRF if required.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

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

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



If not collected at Visit 5, and the participant (select participants only, details will be
provided by the sponsor) consents, collect an additional 170-mL blood sample for
exploratory COVID-19 research.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately (this could be via
the COVID-19 illness e-diary) if he or she experiences any respiratory symptoms as
detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After Visit 4)

Record AEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

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If not collected at Visit 5 or 6, and the participant (select participants only, details will be
provided by the sponsor) consents, collect an additional 170-mL blood sample for
exploratory COVID-19 research.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (154 to 168 Days After Visit 4)

Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.1.10. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 4)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.1.11. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 4)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect the participant’s e-diary or assist the participant to remove the study applicationfrom his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.2. Stage 1 Nonsentinel Cohorts and Stage 2 Cohorts
8.11.2.1. Visit 1 – Vaccination 1: (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written,
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.

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It is anticipated that the procedures below will be conducted in a stepwise manner.
Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance.



Perform physical examination including vital signs (weight, height, body temperature,pulse rate, and seated blood pressure), evaluating any clinically significant abnormalities
within the following body systems: general appearance; skin; head, eyes, ears, nose, andthroat; heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph
nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.



Record AEs as described in Section 8.3.

Obtain the participant’s randomization number and study intervention allocation using
the IRT system. Either blinded site staff or unblinded site staff member may obtain thisinformation.

Collect a blood sample (approximately 25 mL) for immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.
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Issue a measuring device to measure local reactions at the injection site and athermometer for recording daily temperatures and provide instructions on their use.



Explain the e-diary technologies available for this study (see Section 8.14), and assist theparticipant in downloading the study application onto the participant’s own device orissue a provisioned device if required. Provide instructions on e-diary completion andask the participant to complete the reactogenicity e-diary from Day 1 to Day 7, with
Day 1 being the day of vaccination and, if utilized, the COVID-19 illness e-diary (to becompleted if the participant is diagnosed with COVID-19 or has possible new orincreased symptoms, and when he/she receives a reminder, at least weekly).



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

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8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days or 56 to 70 Days After Visit 1)
The window for Visit 2 is dependent on the dosing schedule for the assigned group.

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It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary wascompleted and record stop dates in the CRF if required.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met. If not, the participant should not receive further study intervention but willremain in the study to be evaluated for safety, immunogenicity, and potential efficacy(see Section 7.1).

Measure the participant’s body temperature.

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Collect a blood sample (approximately 25 mL) for immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

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Ensure the participant has a measuring device to measure local reactions at the injection
site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and ask the participant to complete thereactogenicity e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the reactogenicity e-diarydata online following vaccination to evaluate participant compliance and as part of theongoing safety review. Daily review is optimal during the active diary period.

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8.11.2.3. Visit 3 – 2-Week Follow-up Visit: (12 to 16 Days After Visit 2)

Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary wascompleted and record stop dates in the CRF if required.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 25 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.11.2.4. Visit 4 – 1-Month Follow-up Visit: (28 to 35 Days After Visit 2)

Record AEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 25 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

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

Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.2.5. Visit 5 – 6-Month Follow-up Visit: (154 to 168 Days After Visit 2)

Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect a blood sample (approximately 25 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.2.6. Visit 6 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 2)Collect a blood sample (approximately 25 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.
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Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.2.7. Visit 7 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 2)Collect a blood sample (approximately 25 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect the participant’s e-diary or assist the participant to remove the study applicationfrom his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.3. Stage 3 Cohort(s)8.11.3.1. Visit 1 – Vaccination 1: (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written,
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.
It is anticipated that the procedures below will be conducted in a stepwise manner.
Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance.

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Perform physical examination including vital signs (weight, height, body temperature,pulse rate, and seated blood pressure), evaluating any clinically significant abnormalities
within the following body systems: general appearance; skin; head, eyes, ears, nose, andthroat; heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph
nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.



Record AEs as described in Section 8.3.

Obtain the participant’s randomization number and study intervention allocation number
using the IRT system. Either blinded site staff or unblinded site staff member may obtain
this information.

Collect a blood sample (approximately 25 mL) for immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Issue a measuring device to measure local reactions at the injection site and athermometer for recording daily temperatures and provide instructions on their use.



Explain the e-diary technologies available for this study (see Section 8.14), and assist theparticipant in downloading the study application onto the participant’s own device orissue a provisioned device if required. Provide instructions on e-diary completion and ask
the participant to complete the reactogenicity e-diary from Day 1 to Day 7, with Day 1
being the day of vaccination and, if utilized, the COVID-19 illness e-diary (to be
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completed if the participant is diagnosed with COVID-19 or has possible new orincreased symptoms, and when he/she receives a reminder, at least weekly).

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Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.

The investigator or appropriately qualified designee reviews the reactogenicity e-diary data
online following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

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8.11.3.2. Visit 2 – Vaccination 2: (19 to 23 Days or 56 to 70 Days After Visit 1)
The window for Visit 2 is dependent on the dosing schedule(s) selected for Stage 3.

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It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary wascompleted and record stop dates in the CRF if required.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met. If not, the participant should not receive further study intervention but willremain in the study to be evaluated for safety, immunogenicity, and potential efficacy(see Section 7.1).

Measure the participant’s body temperature.

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection
site and a thermometer for recording daily temperatures.
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Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and ask the participant to complete thereactogenicity e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.

The investigator or appropriately qualified designee reviews the reactogenicity e-diary data
online following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.
8.11.3.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2): (28 to 35 Days After
Visit 2)


Record AEs as described in Section 8.3.



Review the participant’s reactogenicity e-diary data. Collect stop dates of any
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary wascompleted and record stop dates in the CRF if required.

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

Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 25 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.11.3.4. Visit 4 – 6-Month Safety Telephone Contact: (154 to 168 Days After Visit 2)Contact the participant by telephone in order to obtain the following information.



Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.3.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.3.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 2)Collect a blood sample (approximately 25 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator (this could be via the
COVID-19 illness e-diary) immediately if he or she experiences any respiratory
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.3.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 2)Collect a blood sample (approximately 25 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect the participant’s e-diary or assist the participant to remove the study applicationfrom his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction
If a Grade 3 local reaction (Section 8.2.2.2), systemic event (Section 8.2.2.3), or fever(Section 8.2.2.4) is reported in the reactogenicity e-diary, a telephone contact should occur toascertain further details and determine whether a site visit is clinically indicated. If suspected
Grade 4 local reaction (Section 8.2.2.2), systemic event (Section 8.2.2.3), or fever(Section 8.2.2.4) is reported in the reactogenicity e-diary, a telephone contact or site visit
should occur to confirm whether the event meets the criteria for Grade 4.

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A site visit must be scheduled as soon as possible to assess the participant unless any of thefollowing is true:The participant is unable to attend the unscheduled visit.

The local reaction/systemic event is no longer present at the time of the telephone
contact.



The participant recorded an incorrect value in the reactogenicity e-diary (confirmation ofa reactogenicity e-diary data entry error).



The PI or authorized designee determined it was not needed.

This telephone contact will be recorded in the participant’s source documentation and theCRF.

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If the participant is unable to attend the unscheduled visit, or the PI or authorized designee
determined it was not needed, any ongoing local reactions/systemic events must be assessedat the next study visit.
During the unscheduled visit, the reactions should be assessed by the investigator or a
medically qualified member of the study staff such as a study physician or a study nurse, asapplicable to the investigator’s local practice, who will:Measure body temperature (°F/°C).

Measure minimum and maximum diameters of redness (if present).

Measure minimum and maximum diameters of swelling (if present).



Assess injection site pain (if present) in accordance with the grades provided in
Section 8.2.2.2.

Assess systemic events (if present) in accordance with the grades provided in
Section 8.2.2.3.

Assess for other findings associated with the reaction and record on the AE page of the
CRF, if appropriate.

The investigator or an authorized designee will complete the unscheduled visit assessment
page of the CRF.

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8.13. COVID-19 Disease Surveillance (All Participants)

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If a participant experiences any of the following, he or she is instructed to contact the site
immediately, and if confirmed, participate in a telehealth visit as soon as possible, optimallywithin 3 days of symptom onset. Participants may utilize a COVID-19 illness e-diarythrough an application (see Section 8.14) installed on a provisioned device or on theparticipant’s own personal device to prompt him/her to report any symptoms. Note that thisdoes not substitute for a participant’s routine medical care. Therefore participants should be
encouraged to seek care, if appropriate, from their usual provider.


A diagnosis of COVID-19;



Fever;

New or increased cough;

New or increased shortness of breath;New or increased sore throat;

New or increased wheezing;New or increased sputum production;New or increased nasal congestion;New or increased nasal discharge;



Loss of taste/smell.

8.13.1. Potential COVID-19 Illness Telehealth Visit: (Optimally Within 3 Days After
Potential COVID-19 Illness Onset)
This telehealth visit is expected to involve the sharing of healthcare information and services
via telecommunication technologies (eg, audio, video, video-conferencing software)remotely, thus allowing the participant and investigator to communicate on aspects of clinicalcare.
As a participant’s COVID-19 illness may evolve over time, several telehealth contacts may
be required to obtain the following information:


Record AEs, as appropriate as described in Section 8.3.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

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

Instruct the participant to self-collect a nasal (midturbinate) swab and ship for assessment
at the central laboratory. The result from this swab will be provided to the site once it isavailable, but this will not be in real time, and cannot be relied upon to direct clinicalcare. Therefore, the participant should be encouraged to seek care, if appropriate, fromhis or her usual provider.

Collect COVID-19–related standard-of-care clinical and laboratory information. This
includes, but is not limited to:Symptoms

Clinical diagnosis

Local laboratory COVID-19 test resultFull blood countC-reactive protein

Number and type of any healthcare contact; duration of hospitalization and intensive
care unit stay

Need for oxygen therapy



Need for ventilation



Schedule an appointment for the participant to return for the potential COVID-19
convalescent visit once he or she has recovered.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After Potential
COVID-19 Illness Visit)

Record AEs, as appropriate as described in Section 8.3.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Collect/update COVID-19–related clinical and laboratory information (detailed in
Section 8.13.1).

Complete the source documents.
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The investigator or an authorized designee completes the CRFs.

8.14. Communication and Use of Technology

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In a study of this nature that requires illness events to be reported outside of scheduled study
visits, it is vital that communication between the study site and the participant is maintained
to ensure that endpoint events are not missed. This study will employ various methods,
tailored to the individual participant, to ensure that communication is maintained and study
information can be transmitted securely. Using appropriate technology, such as a study
application, a communication pathway between the participant and the study site staff will beestablished. The participant may be able to utilize his or her own devices to access thistechnology, or use a device provided by the sponsor. Traditional methods of telephone
communication will also be available. The technology solution may facilitate the following:Contact with the investigator, including the ability of the participant to report whether or
not he or she has experienced symptoms that could represent a potential COVID-19
illness (see Section 8.13).

An alert in the event that the participant is hospitalized.



Visit reminders.



Messages of thanks and encouragement from the study team.



A platform for recording local reactions and systemic events (reactogenicity e-diary) –see Section 8.2.2.

9. STATISTICAL CONSIDERATIONS
Methodology for summary and statistical analyses of the data collected in this study is
described here and further detailed in a statistical analysis plan (SAP), which will bemaintained by the sponsor. The SAP may modify what is outlined in the protocol whereappropriate; however, any major modifications of the primary endpoint definitions or theiranalyses will also be reflected in a protocol amendment.
9.1. Estimands and Statistical Hypotheses
9.1.1. Estimands
The estimand corresponding to each primary, secondary, and tertiary/exploratory objective is
described in the table in Section 3.
In the primary safety objective evaluations, missing reactogenicity e-diary data will not be
imputed. Missing AE dates will be imputed according to Pfizer safety rules. No othermissing information will be imputed in the safety analysis.

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The estimands to evaluate the immunogenicity objectives are based on evaluable populations
for immunogenicity (Section 9.3). These estimands estimate the vaccine effect in the
hypothetical setting where participants follow the study schedules and protocol requirements
as directed. Missing antibody results will not be imputed. Immunogenicity results that are
below the LLOQ will be set to 0.5 × LLOQ in the analysis; this may be adjusted once
additional data on the assay characteristics become available.
The estimands to evaluate the efficacy objectives are based on evaluable populations for
efficacy (Section 9.3). These estimands estimate the vaccine effect in the hypotheticalsetting where participants follow the study schedules and protocol requirements as directed.
Missing laboratory results will not be imputed for the primary analysis, but missing data
imputation for the efficacy endpoint may be performed as a sensitivity analysis.
9.1.2. Statistical Hypotheses

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)At the end of Stage 3, the vaccine efficacy (VE) will be evaluated. VE is defined as
VE = 100 × (1 – IRR), where IRR is the illness rate ratio, the calculated ratio of the
COVID-19 illness rate in the active vaccine group to the incidence rate in the placebo group.
The efficacy hypothesis is:
H0: VE ≤20% vs Ha: VE >20%
where H0 and Ha represent null hypothesis and alternative hypothesis. For participants withmultiple illnesses, only the first COVID-19 confirmed case will contribute to the VE
calculation in the hypothesis test.
The efficacy will be demonstrated if the null hypothesis VE ≤20% is rejected at the 0.025
significance level, that is, when the lower limit of the 2-sided 95% CI for VE is >20%, which
is derived using the Clopper-Pearson method as described by Agresti.99.2. Sample Size Determination
The study sample size for the first 2 stages of the study is not based on any statistical
hypothesis testing. Stage 1 will comprise 15 participants (randomization ratio of 4:1 so that
12 receive active vaccine and 3 receive placebo) per group; up to 28 potential groups areforeseen; if all groups are fully enrolled, assuming 2 dose levels are selected following theinitial dose escalation, this corresponds to a total of 420 participants. Stage 2 will include 1
or more vaccine groups selected from Stage 1, and 225 participants will be randomized per
selected vaccine candidate in a 4:1 ratio to receive active vaccine (180 participants) orplacebo (45 participants).
For Stage 3, for the selected vaccine candidate/dose level, with assumptions of a true vaccine
efficacy (VE) of 70%, 53 cases of COVID-19 will provide 90% power to conclude true
VE >20%. This would be achieved with 3000 participants per group (1:1 randomization
ratio), based on the assumption of a 1.7% incidence rate in the placebo group, and 20% of theparticipants being nonevaluable.

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For safety outcomes, Table 5 shows the probability of observing at least 1 AE for a given
true event rate of a particular AE, for various sample sizes. For example, if the true AE rate
is 10%, with 12 participants in a vaccine group, there is 72% probability of observing at least
1 AE.
Table 5.

Probability of Observing at Least 1 AE by Assumed True Event Rates
With Different Sample Sizes

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Assumed True Event
Rate of an AE
0.10%
0.50%
1.00%
2.00%
3.00%
5.00%
7.00%
10.00%

N=12

N=45

N=180

N=3000

0.01
0.06
0.11
0.22
0.31
0.46
0.58
0.72

0.04
0.20
0.36
0.60
0.75
0.90
0.96
0.99

0.16
0.59
0.84
0.97
>0.99
>0.99
>0.99
>0.99

0.95
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

9.3. Analysis Sets
For purposes of analysis, the following populations are defined:
Population
Enrolled
Randomized
Dose 1 evaluable
immunogenicity

Dose 2 evaluable
immunogenicity

Dose 1 all-available
immunogenicity
Dose 2 all-available
immunogenicity

Description
All participants who have a signed ICD.
All participants who are assigned a randomization number in
the IWR system.
All eligible randomized participants who receive the vaccine
to which they are randomly assigned at the first dose, have atleast 1 valid and determinate immunogenicity result 21 days
after Dose 1, have blood collection within an appropriate
window after Dose 1, and have no other major protocol
deviations as determined by the clinician.
All eligible randomized participants who receive 2 doses ofthe vaccine to which they are randomly assigned, within thepredefined window, have at least 1 valid and determinate
immunogenicity result after Dose 2, have blood collection
within an appropriate window after Dose 2, and have no othermajor protocol deviations as determined by the clinician.
All participants who receive at least 1 dose of the study
intervention with at least 1 valid and determinate
immunogenicity result after Dose 1 but before Dose 2.
All participants who receive at least 1 dose of the study
intervention with at least 1 valid and determinate
immunogenicity result after Dose 2.

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Population
Evaluable efficacy

All-available efficacy
SafetyDescription
All eligible randomized participants who receive
vaccination(s) as randomized within the predefined window,
have the efficacy measurement after the last dose of study
intervention, and have no other major protocol deviations as
determined by the clinician.
All eligible randomized participants who receive at least
1 vaccination and have the efficacy measurement at any timeafter Dose 1.
All randomized participants who receive at least 1 dose of thestudy intervention.

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9.4. Statistical Analyses
The SAP will be developed and finalized before database lock for any of the planned
analyses in Section 9.5.1. It will describe the participant populations to be included in theanalyses and the procedures for accounting for missing, unused, and spurious data. Thissection provides a summary of the planned statistical analyses of the primary, secondary, andtertiary/exploratory endpoints.
9.4.1. Immunogenicity Analyses
The statistical analysis of immunogenicity results will be primarily based on the evaluable
immunogenicity populations as defined in Section 9.3.
An additional analysis will be performed based on the all-available populations if there is alarge enough difference in sample size between the all-available immunogenicity populationand the evaluable immunogenicity population. Participants will be summarized according to
the vaccine group to which they were randomized.

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Endpoint
Secondaryimmunogenicity

Statistical Analysis Methods
Geometric mean titers/concentrations (GMTs/GMCs) of
SARS-CoV-2 serum neutralizing titers and SARS-CoV-2
S1-specific binding antibody and RBD-specific binding antibody

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2
S1-specific binding antibody levels and RBD-specific binding antibody
levels, GMTs/GMCs and 2-sided 95% CIs will be provided for each
investigational product (active/placebo) within each group before
vaccination and at each of the following time points:
Stage 1 sentinel cohorts: 7 and 21 days after Dose 1; 7 and
14 days and 1, 6, 12 and 24 months after Dose 2

Stage 1 nonsentinel cohorts and Stage 2 cohorts: 21 days after
Dose 1; 14 days and 1, 6, 12, and 24 months after Dose 2

Stage 3 cohort(s): 1, 12, and 24 months after Dose 2

Geometric means and the associated 2-sided CIs will be derived by
calculating means and CIs on the natural log scale based on thet-distribution, and then exponentiating the results.
GMFRs of SARS-CoV-2 serum neutralizing titers and
SARS-CoV-2 S1-specific binding antibody and RBD-specificbinding antibody
For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2
S1-specific antibody levels and RBD-specific binding antibody levels,
the GMFRs and 2-sided 95% CIs will be provided for each
investigational product within each group at each of the following time
points:Stage 1 sentinel cohorts: 7 and 21 days after Dose 1; 7 and
14 days and 1, 6, 12, and 24 months after Dose 2

Stage 1 nonsentinel cohorts and Stage 2 cohorts: 21 days after
Dose 1; 14 days and 1, 6, 12, and 24 months after Dose 2

Stage 3 cohort(s): 1, 12, and 24 months after Dose 2

GMFRs will be limited to participants with nonmissing values prior to
the first dose and at the postvaccination time point. The GMFR will becalculated as the mean of the difference of logarithmically transformed
assay results (later time point – earlier time point) and transformed
back to the original scale. Two-sided CIs will be obtained by
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Endpoint

Statistical Analysis Methods
calculating CIs using Student’s t-distribution for the mean difference ofthe logarithmically transformed assay results and transforming thelimits back to the original scale.
Percentage of participants with ≥4-fold rise in SARS-CoV-2 serum
neutralizing titers and SARS-CoV-2 S1-specific binding antibody
and RBD-specific binding antibody

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2
S1-specific antibody levels and RBD-specific binding antibody levels,
percentages (and 2-sided 95% CIs) of participants with ≥4-fold rise
will be provided for each investigational product within each group ateach of the following time points:
Stage 1 sentinel cohorts: 7 and 21 days after Dose 1; 7 and
14 days and 1, 6, 12, and 24 months after Dose 2

Stage 1 nonsentinel cohorts and Stage 2 cohorts: 21 days after
Dose 1; 14 days and 1, 6, 12, and 24 months after Dose 2

Stage 3 cohort(s): 1, 12, and 24 months after Dose 2

The Clopper-Pearson method will be used to calculate the CIs.
GMR of SARS-CoV-2 serum neutralizing titer to SARS-CoV-2
S1-specific antibody and SARS-CoV-2 RBD-specific binding
antibody
For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2
S1-specific binding antibody levels and RBD-specific binding antibody
levels, the GMRs and 2-sided 95% CIs will be provided for each
investigational product within each group at each of the following time
points:Stage 1 sentinel cohorts: 7 and 21 days after Dose 1; 7 and
14 days and 1, 6, 12, and 24 months after Dose 2

Stage 1 nonsentinel cohorts and Stage 2 cohorts: 21 days after
Dose 1; 14 days and 1, 6, 12, and 24 months after Dose 2

Stage 3 Cohort(s): 1, 12, and 24 months after Dose 2

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Endpoint

Statistical Analysis Methods
GMRs will be limited to participants with nonmissing values for both
SARS-CoV-2 serum neutralizing titers and SARS-CoV-2 S1-specificantibody/SARS-CoV-2 RBD-specific binding antibody at each time
point. The GMR will be calculated as the mean of the difference oflogarithmically transformed assay results (eg, SARS-CoV-2 serum
neutralizing titers minus SARS-CoV-2 S1-specific antibody for eachparticipant) and transformed back to the original scale. Two-sided CIs
will be obtained by calculating CIs using Student’s t-distribution forthe mean difference of the logarithmically transformed assay results
and transforming the limits back to the original scale.
The same analysis methods will be applied to the immunogenicity
endpoints in Stages 2 and 3. For all the immunogenicity endpoints, theanalysis will be based on the Dose 1 and Dose 2 evaluable
immunogenicity populations. An additional analysis will be performed
based on the all-available immunogenicity populations if there is alarge enough difference in sample size between the all-available
immunogenicity populations and the evaluable immunogenicity
populations. Participants will be summarized according to the vaccine
group to which they were randomized. Missing serology data will not
be imputed.

Tertiary/
exploratory
immunogenicity

Correlation of an RT-PCR–confirmed COVID-19 infection andseropositivity/seroconversion measured by nonvaccine antigen
SARS-CoV-2 antibody
If sufficient data are collected, percentages (and 2-sided 95% CIs) ofparticipants with confirmed COVID-19 and nonvaccine antigen
SARS-CoV-2 antibody levels after Dose 1 and after Dose 2 will be
provided.
RCDCs for immunogenicity results
Empirical RCDCs will be provided for SARS-CoV-2 serum
neutralizing titers, SARS-CoV-2 S1-specific antibody, andRBD-specific binding antibody after Dose 1 and after Dose 2.

9.4.2. Efficacy Analyses
The statistical analysis of efficacy will be based on the evaluable efficacy population(primary analysis) and the all-available efficacy population as defined in Section 9.3.

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Endpoint
Statistical Analysis Methods
Secondary efficacy Ratio of COVID-19 incidence per 1000 person-years of follow-up
for the active vaccine group to the placebo group
Vaccine efficacy will be estimated by 100 × (1 – IRR), where IRR is
the illness rate ratio, the calculated ratio of COVID-19 infection
incidence per 1000 person-years follow-up in the active vaccine groupto the corresponding incidence in the placebo group after 2 doses. The
2-sided 95% CI for VE will be derived using the Clopper-Pearson
method.

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)The analysis will be based on the evaluable efficacy population and the
all-available efficacy population. For the primary analysis, missing
efficacy data will not be imputed. A sensitivity analysis may be
performed by imputing missing values; details will be provided in the
SAP.

9.4.3. Safety Analyses
Endpoint
PrimaryStatistical Analysis Methods
Descriptive statistics will be provided for each reactogenicity
endpoint for each dose and vaccine group. Local reactions andsystemic events from Day 1 through Day 7 after each vaccination
will be presented by severity cumulatively across severity levels.
Descriptive summary statistics will include counts and percentagesof participants with the indicated endpoint and the associatedClopper-Pearson 95% CIs.

For Stage 1 sentinel cohorts, descriptive statistics will be provided
for abnormal hematology and chemistry laboratory values at 1 and7 days after Dose 1 and 7 days after Dose 2, including grading
shifts in hematology and chemistry laboratory assessments
between baseline and 1 and 7 days after Dose 1, and before Dose 2
and 7 days after Dose 2. Descriptive summary statistics will
include counts and percentages of participants with the indicatedendpoint and the associated Clopper-Pearson 2-sided 95% CIs.



AEs will be categorized according to the Medical Dictionary forRegulatory Activities (MedDRA) terms. A 3-tier approach will be
used to summarize AEs. Under this approach AEs are classified
into 1 of 3 tiers: (1) Tier 1 events are prespecified events ofclinical importance and are identified in a list in the product’s
safety review plan; (2) Tier 2 events are those that are not Tier 1
but are considered “relatively common”; a MedDRA preferred

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Endpoint

Statistical Analysis Methods
term is defined as a Tier 2 event if there are at least 1% ofparticipants in at least 1 vaccine group reporting the event; and (3)Tier 3 events are those that are neither Tier 1 nor Tier 2 events.
For both Tier 1 and Tier 2 events, 2-sided 95% CIs for thedifference between the vaccine and placebo groups in thepercentage of participants reporting the events based on the
Miettinen and Nurminen method10 will be provided. In addition,
for Tier 1 events, the asymptotic p-values will also be presented
for the difference between groups in the percentage of participants
reporting the events, based on the same test statistic and under theassumption that the test statistic is asymptotically normally
distributed.

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)Descriptive summary statistics (counts, percentages, andassociated Clopper-Pearson 95% CIs) will be provided for any
AE events for each vaccine group.



SAEs will be categorized according to MedDRA terms. Counts,
percentages, and the associated Clopper-Pearson 95% CIs of SAEs
from Dose 1 to 6 months after last dose will be provided for eachvaccine group.

The safety analyses are based on the safety population.
Participants will be summarized by vaccine group according to theinvestigational products they actually received. Missing
reactogenicity e-diary data will not be imputed; missing AE dates
will be handled according to the Pfizer safety rules.

Secondary

Not applicable (N/A)

Exploratory

N/A

9.4.4. Other Analyses
The ratios of (GMFR A to GMFR B) and (GMFR A to GMFR C) may be explored, where
GMFR A is the geometric mean of the ratio of the SARS-CoV-2 serum neutralizing titer at
the postvaccination time point to the corresponding titer at the prevaccination time point,
GFMR B is the geometric mean of the ratio of the SARS-CoV-2 S1-specific binding
antibody level at the postvaccination time point to the corresponding antibody level at theprevaccination time point, and GMFR C is the geometric mean of the ratio of the
SARS-CoV-2 RBD-specific binding antibody level at the postvaccination time point to thecorresponding antibody level at the prevaccination time point.

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9.5. Interim Analyses
No formal interim analysis is planned in this study. As this is a sponsor open-label study
during Stages 1 and 2, the sponsor may conduct unblinded reviews of the data during thecourse of the study for the purpose of safety assessment, facilitating dose escalation
decisions, and/or supporting clinical development.
9.5.1. Analysis Timing

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Statistical analyses will be carried out when the following data are available:Complete safety and immunogenicity analysis approximately 3 weeks after Dose 2 forStage 1.

Complete safety and immunogenicity analysis approximately 3 weeks after Dose 2 forStage 2.

Complete safety and immunogenicity analysis approximately 6 months after Dose 2 for
all participants in Stage 3.

Complete efficacy and persistence-of-immunogenicity analysis after complete data are
available at the end of the study.

9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will use an IRC and a DMC. The IRC is independent of the study team andincludes only internal members. The DMC is independent of the study team and includes
only external members. The IRC and DMC charters describe the role of the IRC and DMC
in more detail.
The responsibilities of the IRC will include:

Review of safety data to permit dose escalations in the 18- to 55-year age cohort



Review of safety data in the case of a stopping rule being met

Review of safety and/or immunogenicity data to:Allow groups of participants of 65 to 85 years of age to proceed

Select vaccine candidate(s)/dose level(s) and schedule(s) to proceed into Stage 2.
Data supporting the selection, including results for both binding antibody levels andserum neutralizing titers, and the ratio between them, will also be submitted to the
FDA for review

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





Select vaccine candidate(s)/dose level(s) and schedule(s) to proceed into Stage 3.
Data supporting the selection, including results for both binding antibody levels andserum neutralizing titers, and the ratio between them, will also be submitted to the
FDA for review

Review of any available safety and/or immunogenicity data generated during the courseof this study, or the BioNTech study conducted in Germany, to determine:Whether any groups may not be started



Whether any groups may be terminated earlyWhether any groups may be added with dose levels below the lowest stated dose orintermediate between the lowest and highest stated doses

Contemporaneous review of all NAAT-confirmed COVID-19 illnesses

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)The DMC will be responsible for ongoing monitoring of the safety of participants in the
study according to the charter. This may include, but is not limited to:Contemporaneous review of related AEs up to 1 month after completion of thevaccination scheduleContemporaneous review of all SAEs up to 6 months after completion of the vaccination
schedule

Contemporaneous review of all NAAT-confirmed COVID-19 illnesses

The recommendations made by the DMC to alter the conduct of the study will be forwarded
to the appropriate Pfizer personnel for final decision. Pfizer will forward such decisions,which may include summaries of aggregate analyses of safety data, to regulatory authorities,
as appropriate.

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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:Consensus ethical principles derived from international guidelines including the
Declaration of Helsinki and CIOMS International Ethical Guidelines;Applicable ICH GCP guidelines;Applicable laws and regulations, including applicable privacy laws.

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents(eg, advertisements) must be reviewed and approved by the sponsor and submitted to an
IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study is
initiated.
Any amendments to the protocol will require IRB/EC approval before implementation ofchanges made to the study design, except for changes necessary to eliminate an immediate
hazard to study participants.
The investigator will be responsible for the following:Providing written summaries of the status of the study to the IRB/EC annually or more
frequently in accordance with the requirements, policies, and procedures established by
the IRB/EC;



Notifying the IRB/EC of SAEs or other significant safety findings as required by IRB/EC
procedures;Providing oversight of the conduct of the study at the site and adherence to requirementsof 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014 for clinicalstudies (if applicable), and all other applicable local regulations.

10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicableregulatory authority in any area of the world, or if the investigator is aware of any new
information that might influence the evaluation of the benefits and risks of the study
intervention, Pfizer should be informed immediately.
In addition, the investigator will inform Pfizer immediately of any urgent safety measurestaken by the investigator to protect the study participants against any immediate hazard, andof any serious breaches of this protocol or of ICH GCP that the investigator becomes awareof.
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10.1.2. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to theparticipant and answer all questions regarding the study. The participant should be given
sufficient time and opportunity to ask questions and to decide whether or not to participate in
the trial.
Participants must be informed that their participation is voluntary. Participants will be
required to sign a statement of informed consent that meets the requirements of 21 CFR 50,
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/EC
or study center.
The investigator must ensure that each study participant is fully informed about the natureand objectives of the study, the sharing of data related to the study, and possible risks
associated with participation, including the risks associated with the processing of theparticipant’s personal data.

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)The participant must be informed that his/her personal study-related data will be used by thesponsor in accordance with local data protection law. The level of disclosure must also be
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical
Quality Assurance auditors or other authorized personnel appointed by the sponsor, byappropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or
her right to access and correct his or her personal data and to withdraw consent for theprocessing of his or her personal data.
The medical record must include a statement that written informed consent was obtained
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their
participation in the study.
A copy of the ICD(s) must be provided to the participant. Participants who are rescreened are
required to sign a new ICD.
Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate
section that addresses the use of samples for optional additional research. The optional
additional research does not require the collection of any further samples. The investigator
or authorized designee will explain to each participant the objectives of the additional
research. Participants will be told that they are free to refuse to participate and may
withdraw their consent at any time and for any reason during the storage period.

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10.1.3. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementationof organizational and technical measures to ensure protection of participant data.

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Participants’ personal data will be stored at the study site in encrypted electronic and/or paper
form and will be password protected or secured in a locked room to ensure that only
authorized study staff have access. The study site will implement appropriate technical andorganizational measures to ensure that the personal data can be recovered in the event ofdisaster. In the event of a potential personal data breach, the study site will be responsiblefor determining whether a personal data breach has in fact occurred and, if so, providing
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personaldata, participants will be assigned a single, participant-specific numerical code. Any
participant records or data sets that are transferred to the sponsor will contain the numericalcode; participant names will not be transferred. All other identifiable data transferred to thesponsor will be identified by this single, participant-specific code. The study site will
maintain a confidential list of participants who participated in the study, linking eachparticipant’s numerical code to his or her actual identity and medical record identification. In
case of data transfer, the sponsor will protect the confidentiality of participants’ personal dataconsistent with the clinical study agreement and applicable privacy laws.
10.1.4. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting theresults of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or
www.pfizer.com, and other public registries in accordance with applicable local
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, andcomplete manner and are reported regardless of the outcome of the study or the country inwhich the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional
studies (conducted in patients) that evaluate the safety and/or efficacy of a product,
regardless of the geographical location in which the study is conducted. These results are
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies inaccordance with the format and timelines set forth by EU requirements.

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www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used
to identify individual participants have been removed) on www.pfizer.com for
Pfizer-sponsored interventional studies at the same time the corresponding study results areposted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinicaldata to the EMA website. Clinical data, under Phase 1 of this policy, includes clinicaloverviews, clinical summaries, CSRs, and appendices containing the protocol and protocol
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of thispolicy, includes the publishing of individual participant data. Policy 0070 applies to newmarketing authorization applications submitted via the centralized procedure since
01 January 2015 and applications for line extensions and for new indications submitted via
the centralized procedure since 01 July 2015.

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Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposesof “bona-fide scientific research” that contributes to the scientific understanding of thedisease, target, or compound class. Pfizer will make available data from these trials
24 months after study completion. Patient-level data will be anonymized in accordance withapplicable privacy laws and regulations. CSRs will have personally identifiable information
redacted.
Data requests are considered from qualified researchers with the appropriate competencies toperform the proposed analyses. Research teams must include a biostatistician. Data will not
be provided to applicants with significant conflicts of interest, including individuals
requesting access for commercial/competitive or legal purposes.
10.1.5. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unlesstransmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is
responsible for verifying that data entries are accurate and correct by physically orelectronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports theinformation entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted
electronic and/or paper form and are password protected or secured in a locked room toprevent access by unauthorized third parties.

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The investigator must permit study-related monitoring, audits, IRB/EC review, andregulatory agency inspections and provide direct access to source data documents. This
verification may also occur after study completion. It is important that the investigator(s)and their relevant personnel are available during the monitoring visits and possible audits orinspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality
such as risk management and mitigation strategies and analytical risk-based monitoring),
methods, responsibilities, and requirements, including handling of noncompliance issues andmonitoring techniques (central, remote, or on-site monitoring), are provided in themonitoring plan.

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)The sponsor or designee is responsible for the data management of this study, including
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data enteredinto the CRF by authorized site personnel are accurate, complete, and verifiable from source
documents; that the safety and rights of participants are being protected; and that the study is
being conducted in accordance with the currently approved protocol and any other study
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must
be retained by the investigator for 15 years after study completion unless local regulations or
institutional policies require a longer retention period. No records may be destroyed during
the retention period without the written approval of the sponsor. No records may betransferred to another location or party without written notification to the sponsor. The
investigator must ensure that the records continue to be stored securely for as long as they are
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of suchdata are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory
inspection notification in relation to the study. Furthermore, the investigator will cooperatewith the sponsor or its agents to prepare the investigator site for the inspection and will allow
the sponsor or its agent, whenever feasible, to be present during the inspection. The
investigator site and investigator will promptly resolve any discrepancies that are identified
between the study data and the participant's medical records. The investigator will promptly
provide copies of the inspection findings to the sponsor or its agent. Before response
submission to the regulatory authorities, the investigator will provide the sponsor or its
agents with an opportunity to review and comment on responses to any such findings.

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10.1.6. Source Documents
Source documents provide evidence for the existence of the participant and substantiate theintegrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be
consistent with the source documents or the discrepancies must be explained. The
investigator may need to request previous medical records or transfer records, depending on
the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the study monitoring plan.
Description of the use of computerized system is documented in the Data Management Plan.
10.1.7. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment ofparticipants.

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)The first act of recruitment is the date of the first participant’s first visit and will be the study
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any
time for any reason at the sole discretion of the sponsor. Study sites will be closed uponstudy completion. A study site is considered closed when all required documents and study
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor
or designee if requested to do so by the responsible IRB/EC or if such termination is required
to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limitedto:

Failure of the investigator to comply with the protocol, the requirements of the IRB/EC
or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.

If the study is prematurely terminated or suspended, the sponsor shall promptly inform theinvestigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of
the reason for termination or suspension, as specified by the applicable regulatory
requirements. The investigator shall promptly inform the participant and should assure
appropriate participant therapy and/or follow-up.

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Study termination is also provided for in the clinical study agreement. If there is any conflict
between the contract and this protocol, the contract will control as to termination rights.
10.1.8. Sponsor’s Qualified Medical Personnel

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)The contact information for the sponsor's appropriately qualified medical personnel for the
study is documented in the study contact list located in the supporting study documentation.
To facilitate access to appropriately qualified medical personnel on study-related medical
questions or problems, participants are provided with a contact card at the time of informed
consent. The contact card contains, at a minimum, protocol and study intervention
identifiers, participant numbers, contact information for the investigator site, and contact
details for a contact center in the event that the investigator site staff cannot be reached toprovide advice on a medical question or problem originating from another healthcare
professional not involved in the participant’s participation in the study. The contact number
can also be used by investigator staff if they are seeking advice on medical questions or
problems; however, it should be used only in the event that the established communication
pathways between the investigator site and the study team are not available. It is therefore
intended to augment, but not replace, the established communication pathways between theinvestigator site and the study team for advice on medical questions or problems that may
arise during the study. The contact number is not intended for use by the participant directly,
and if a participant calls that number, he or she will be directed back to the investigator site.

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10.2. Appendix 2: Clinical Laboratory Tests

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)The following safety laboratory tests will be performed at times defined in the SoA section ofthis protocol. Additional laboratory results may be reported on these samples as a result of
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived
from calculated values. These additional tests would not require additional collection ofblood. Unscheduled clinical laboratory measurements may be obtained at any time during
the study to assess any perceived safety issues.
Hematology
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet countWBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)Basophils (Abs)
Lymphocytes (Abs)

Chemistry
BUN and creatinine
AST, ALT
Total bilirubin
Alkaline phosphatase

Other Urine pregnancy test (β-hCG)
At screening only: Hepatitis B core antibody
 Hepatitis B surface antigen
 Hepatitis C antibody
 Human immunodeficiency virus

Investigators must document their review of each laboratory safety report.
Clinically significant abnormal laboratory findings should be recorded in the AE CRF in
accordance with the following grading scale (Table 6).
Table 6.
Hematology

Laboratory Abnormality Grading Scale
Mild (Grade 1)

Moderate(Grade 2)

Severe (Grade 3)

Hemoglobin
11.0 – 12.0
(Female) - g/dL
Hemoglobin
12.5 – 13.5
(Male) - g/dL
WBC increase 10,800 – 15,000
cells/mm3
WBC decrease 2,500 – 3,500
cells/mm3
Lymphocytes
750 – 1,000
decrease - cells/mm3
Neutrophils decrease 1,500 – 2,000- cells/mm3

9.5 – 10.9

8.0 – 9.4

Potentially Life
Threatening(Grade 4)<8.0

10.5 – 12.4

8.5 – 10.4

<8.5

15,001 – 20,000

20,001 – 25, 000>25,000

1,500 – 2,499

1,000 – 1,499<1,000500 – 749

250 – 499

<250

1,000 – 1,499

500 – 999

<500

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Table 6.

Laboratory Abnormality Grading Scale

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Hematology

Mild (Grade 1)

Moderate(Grade 2)

Severe (Grade 3)

Eosinophils 650 – 1500
cells/mm3
Platelets decreased - 125,000 – 140,000
cells/mm3
Chemistry
Mild (Grade 1)

1501 - 5000

>5000

Potentially Life
Threatening(Grade 4)Hypereosinophilic

100,000 – 124,000

25,000 – 99,000<25,000

Moderate(Grade 2)

Severe(Grade 3)

BUN - mg/dL
Creatinine – mg/dL

23 – 26
1.5 – 1.7

27 – 31
1.8 – 2.0> 31
2.1 – 2.5

Alkaline
phosphate –increase by factor
Liver function tests– ALT, AST
increase by factor
Bilirubin – whenaccompanied
by any increase inliver function test increase by factor
Bilirubin – whenliver function test is
normal - increase byfactor

1.1 – 2.0 x ULN

2.1 – 3.0 x ULN

3.1 – 10 x ULN

Potentially Life
Threatening(Grade 4)
Requires dialysis> 2.5 or requires
dialysis>10 x ULN

1.1 – 2.5 x ULN

2.6 – 5.0 x ULN

5.1 – 10 x ULN>10 x ULN

1.1 – 1.25 x ULN

1.26 – 1.5 x ULN

1.51 – 1.75 x ULN>1.75 x ULN

1.1 – 1.5 x ULN

1.6 – 2.0 x ULN

2.0 – 3.0 x ULN>3.0 x ULN

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen;
ULN = upper limit of normal; WBC = white blood cell.

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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition


An AE is any untoward medical occurrence in a patient or clinical study participant,temporally associated with the use of study intervention, whether or not consideredrelated to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including anabnormal laboratory finding), symptom, or disease (new or exacerbated) temporally
associated with the use of study intervention.

Events Meeting the AE Definition

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Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis)or other safety assessments (eg, ECG, radiological scans, vital sign measurements),
including those that worsen from baseline, considered clinically significant in the
medical and scientific judgment of the investigator Any abnormal laboratory test
results that meet any of the conditions below must be recorded as an AE:
Is associated with accompanying symptoms.



Requires additional diagnostic testing or medical/surgical intervention.



Leads to a change in study dosing (outside of any protocol-specified dose
adjustments) or discontinuation from the study, significant additional
concomitant drug treatment, or other therapy.



Exacerbation of a chronic or intermittent preexisting condition including either anincrease in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration eventhough it may have been present before the start of the study.



Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.



Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
intervention or a concomitant medication. Overdose per se will not be reported as
an AE/SAE unless it is an intentional overdose taken with possible suicidal/selfharming intent. Such overdoses should be reported regardless of sequelae.

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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safetyassessments which are associated with the underlying disease, unless judged by theinvestigator to be more severe than expected for the participant’s condition.



The disease/disorder being studied or expected progression, signs, or symptoms ofthe disease/disorder being studied, unless more severe than expected for theparticipant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).



Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present
or detected at the start of the study that do not worsen.

10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:a. Results in deathb. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which theparticipant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.

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In general, hospitalization signifies that the participant has been detained (usually involving
at least an overnight stay) at the hospital or emergency ward for observation and/or
treatment that would not have been appropriate in the physician’s office or outpatientsetting. Complications that occur during hospitalization are AEs. If a complication
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in
doubt as to whether “hospitalization” occurred or was necessary, the AE should beconsidered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen frombaseline is not considered an AE.

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)d. Results in persistent disability/incapacity


The term disability means a substantial disruption of a person’s ability to conduct
normal life functions.

This definition is not intended to include experiences of relatively minor medicalsignificance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza,
and accidental trauma (eg, sprained ankle) which may interfere with or prevent
everyday life functions but do not constitute a substantial disruption.

e. Is a congenital anomaly/birth defectf. Other situations:Medical or scientific judgment should be exercised in deciding whether SAE
reporting is appropriate in other situations such as important medical events that
may not be immediately life-threatening or result in death or hospitalization but may
jeopardize the participant or may require medical or surgical intervention to prevent
one of the other outcomes listed in the above definition. These events should
usually be considered serious.



Examples of such events include invasive or malignant cancers, intensive treatment
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or
convulsions that do not result in hospitalization, or development of drug dependency
or drug abuse.

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10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF andfor reporting serious adverse events on the Vaccines SAE Report Form to Pfizer Safety.
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious adverse
events (AEs); and (3) exposure to the study intervention under study during pregnancy orbreastfeeding, and occupational exposure.

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)It should be noted that the Vaccines SAE Report Form for reporting of SAE information is
not the same as the AE page of the CRF. When the same data are collected, the forms must
be completed in a consistent manner. AEs should be recorded using concise medical
terminology and the same AE term should be used on both the CRF and the Vaccines SAE
Report Form for reporting of SAE information.
Safety Event

Recorded on the CRF

Reported on the Vaccines
SAE Report Form to
Pfizer Safety Within 24
Hours of Awareness

SAE
Nonserious AE
Exposure to the study
intervention under study
during pregnancy orbreastfeeding, andoccupational exposure

All
All
None

All
None
All (and EDP supplemental
form for EDP)When an AE/SAE occurs, it is the responsibility of the investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostic
reports) related to the event.



The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s
medical records to Pfizer Safety in lieu of completion of the Vaccines SAE Report
Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases arerequested by Pfizer Safety. In this case, all participant identifiers, with the
exception of the participant number, will be redacted on the copies of the medical
records before submission to Pfizer Safety.
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The investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. Whenever possible, the diagnosis(not the individual signs/symptoms) will be documented as the AE/SAE.

Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during
the study and assign it to 1 of the following categories:

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)GRADE If required on the AE page of the CRF, the investigator will use theadjectives MILD, MODERATE, SEVERE, or LIFE-THREATENING todescribe the maximum intensity of the AE. For purposes of consistency,
these intensity grades are defined as follows:
1

MILD

Does not interfere with participant's usualfunction.

2

MODERATE

Interferes to some extent with participant's usualfunction.

3

SEVEREInterferes significantly with participant's usualfunction.

4

LIFE-THREATENING Life-threatening consequences; urgent
intervention indicated.

Assessment of Causality

The investigator is obligated to assess the relationship between study intervention
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence,
and/or arguments to suggest a causal relationship, rather than a relationship cannot
be ruled out.

The investigator will use clinical judgment to determine the relationship.



Alternative causes, such as underlying disease(s), concomitant therapy, and otherrisk factors, as well as the temporal relationship of the event to study intervention
administration, will be considered and investigated.



The investigator will also consult the IB and/or product information, for marketed
products, in his/her assessment.

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has reviewed the AE/SAE and has provided an assessment of causality.



There may be situations in which an SAE has occurred and the investigator has
minimal information to include in the initial report to the sponsor. However, it isvery important that the investigator always make an assessment of causality forevery event before the initial transmission of the SAE data to the sponsor.



The investigator may change his/her opinion of causality in light of follow-up
information and send an SAE follow-up report with the updated causality
assessment.



The causality assessment is one of the criteria used when determining regulatory
reporting requirements.



If the investigator does not know whether or not the study intervention caused theevent, then the event will be handled as “related to study intervention” for reporting
purposes, as defined by the sponsor. In addition, if the investigator determines thatan SAE is associated with study procedures, the investigator must record this causal
relationship in the source documents and CRF, and report such an assessment in the
dedicated section of the Vaccines SAE Report Form and in accordance with the
SAE reporting requirements.

Follow-up of AEs and SAEs


The investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by thesponsor to elucidate the nature and/or causality of the AE or SAE as fully as
possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other healthcare providers.



If a participant dies during participation in the study or during a recognizedfollow-up period, the investigator will provide Pfizer Safety with a copy of any
postmortem findings including histopathology.



New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours ofreceipt of the information.

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10.3.4. Reporting of SAEs

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SAE Reporting to Pfizer Safety via Vaccines SAE Report Form

Facsimile transmission of the Vaccines SAE Report Form is the preferred method totransmit this information to Pfizer Safety.



In circumstances when the facsimile is not working, notification by telephone isacceptable with a copy of the Vaccines SAE Report Form sent by overnight mail orcourier service.

Initial notification via telephone does not replace the need for the investigator tocomplete and sign the Vaccines SAE Report Form pages within the designatedreporting time frames.

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10.4. Appendix 4: Contraceptive Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during
the intervention period and for at least 28 days after the last dose of study intervention, whichcorresponds to the time needed to eliminate reproductive safety risk of the study
intervention(s):Refrain from donating sperm.

PLUS either:Be abstinent from heterosexual intercourse with a female of childbearing potential as
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) andagree to remain abstinent.

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)OR

Must agree to use a male condom when engaging in any activity that allows for passageof ejaculate to another person.



In addition to male condom use, a highly effective method of contraception may beconsidered in WOCBP partners of male participants (refer to the list of highly effective
methods below in Section 10.4.4).

10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using an acceptable contraceptive method as described below during
the intervention period (for a minimum of 28 days after the last dose of study
intervention). The investigator should evaluate the effectiveness of the contraceptive
method in relationship to the first dose of study intervention.

The investigator is responsible for review of medical history, menstrual history, and recent
sexual activity to decrease the risk for inclusion of a woman with an early undetected
pregnancy.

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10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot
be confirmed before the first dose of study intervention, additional evaluation should beconsidered.
Women in the following categories are not considered WOCBP:

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1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.

For individuals with permanent infertility due to an alternate medical cause other than theabove, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should beapplied to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s
review of the participant’s medical records, medical examination, or medical history
interview. The method of documentation should be recorded in the participant’s medical
record for the study.
2. Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause. In addition, ahigh FSH level in the postmenopausal range must be used to confirm apostmenopausal state in women under 60 years of age and not using hormonal
contraception or HRT.



Female on HRT and whose menopausal status is in doubt will be required to use
one of the nonestrogen hormonal highly effective contraception methods if theywish to continue their HRT during the study. Otherwise, they must discontinue
HRT to allow confirmation of postmenopausal status before study enrollment.

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10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations
regarding the use of contraceptive methods for those participating in clinical trials.
1. Implantable progestogen-only hormone contraception associated with inhibition ofovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner:

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Vasectomized partner is a highly effective contraceptive method provided that thepartner is the sole sexual partner of the woman of childbearing potential and theabsence of sperm has been confirmed. If not, an additional highly effective methodof contraception should be used. The spermatogenesis cycle is approximately
90 days.

6. Combined (estrogen- and progestogen-containing) hormonal contraception associatedwith inhibition of ovulation:


Oral;



Intravaginal;Transdermal;



Injectable.

7. Progestogen-only hormone contraception associated with inhibition of ovulation:


Oral;



Injectable.

8. Sexual abstinence:Sexual abstinence is considered a highly effective method only if defined as
refraining from heterosexual intercourse during the entire period of risk associatedwith the study intervention. The reliability of sexual abstinence needs to be evaluatedin relation to the duration of the study and the preferred and usual lifestyle of theparticipant.

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9. Progestogen-only oral hormonal contraception where inhibition of ovulation is not the
primary mode of action.
10. Male or female condom with or without spermicide.
11. Cervical cap, diaphragm, or sponge with spermicide.

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12. A combination of male condom with either cervical cap, diaphragm, or sponge with
spermicide (double-barrier methods).

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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations intransaminases) are termed “tolerators,” while those who show transient liver injury, but adapt
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of amore serious potential outcome. These participants fail to adapt and therefore are"susceptible" to progressive and serious liver injury, commonly referred to as DILI.
Participants who experience a transaminase elevation above 3 × ULN should be monitored
more frequently to determine if they are an “adaptor” or are “susceptible.”

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LFTs are not required as a routine safety monitoring procedure for all participants in thisstudy. However, should an investigator deem it necessary to assess LFTs because aparticipant presents with clinical signs/symptoms, such LFT results should be managed andfollowed as described below.
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will beelevated within the same laboratory sample). In rare instances, by the time TBili elevations
are detected, AST/ALT values might have decreased. This occurrence is still regarded as apotential DILI. Therefore, abnormal elevations in either AST OR ALT in addition to TBili
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law
criteria) cases and should always be considered important medical events, even before allother possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on theparticipant’s individual baseline values and underlying conditions. Participants who present
with the following laboratory abnormalities should be evaluated further as potential DILI
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:Participants with AST/ALT and TBili baseline values within the normal range who
subsequently present with AST OR ALT values >3 × ULN AND a TBili value >2 × ULN
with no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or notavailable.

For participants with baseline AST OR ALT OR TBili values above the ULN, thefollowing threshold values are used in the definition mentioned above, as needed,
depending on which values are above the ULN at baseline:Preexisting AST or ALT baseline values above the normal range: AST or ALT values>2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is smaller).

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Rises in AST/ALT and TBili separated by more than a few weeks should be assessedindividually based on clinical judgment; any case where uncertainty remains as to whether it
represents a potential Hy’s law case should be reviewed with the sponsor.

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)The participant should return to the investigator site and be evaluated as soon as possible,
preferably within 48 hours from awareness of the abnormal results. This evaluation should
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili for suspected cases ofHy’s law, additional laboratory tests should include albumin, CK, direct and indirect
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should
also be given to drawing a separate tube of clotted blood and an anticoagulated tube of bloodfor further testing, as needed, for further contemporaneous analyses at the time of therecognized initial abnormalities to determine etiology. A detailed history, including relevant
information, such as review of ethanol, acetaminophen/paracetamol (either by itself or as a
coformulated product in prescription or over-the-counter medications), recreational drug,
supplement (herbal) use and consumption, family history, sexual history, travel history,
history of contact with a jaundiced person, surgery, blood transfusion, history of liver orallergic disease, and potential occupational exposure to chemicals, should be collected.
Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary
tract) and collection of serum samples for acetaminophen/paracetamol drug and/or protein
adduct levels may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if noother reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law)cases are to be reported as SAEs, irrespective of availability of all the results of theinvestigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results ofreasonable investigations have been received and have excluded an alternative etiology.

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10.6. Appendix 6: Abbreviations

090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)The following is a list of abbreviations that may be used in the protocol.
Abbreviation
2019-nCoV
Abs
AE
ALT
AST
-hCG
BMI
BUN
CBER
CFR
CI
CIOMS
CONSORT
COVID-19
CRF
CRO
CSR
CT
DILI
DMC
DNA
DU
EC
ECG
eCRF
e-diary
EDP
EMA
EU
EUA
EudraCT
FDA
FSH
GCP
GGT
GMC
GMFR
GMR
GMT

Term
novel coronavirus 2019absolute (in Appendix 2)
adverse event
alanine aminotransferase
aspartate aminotransferase
beta-human chorionic gonadotropin
body mass index
blood urea nitrogen
Center for Biologics Evaluation and Research
Code of Federal Regulations
confidence interval
Council for International Organizations of Medical Sciences
Consolidated Standards of Reporting Trials
coronavirus disease 2019case report form
contract research organization
clinical study reportclinical trial
drug-induced liver injury
data monitoring committee
deoxyribonucleic aciddosing unit
ethics committee
electrocardiogram
electronic case report form
electronic diary
exposure during pregnancy
European Medicines Agency
European Union
emergency use application
European Clinical Trials Database
Food and Drug Administration
follicle-stimulating hormone
Good Clinical Practice
gamma-glutamyl transferase
geometric mean concentrationgeometric mean fold risegeometric mean ratio
geometric mean titer

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Abbreviation
HBc Ab
HBsAg
HBV
HCV
HCV Ab
HIPAA
HIV
HRT
IB
ICD
ICH
ICU
ID
Ig
IgG
IgM
IMP
IND
INR
IP manual
IPAL
IRB
IRC
IRR
IRT
IV
IWR
LFT
LLOQ
LNP
LPX
MCH
MCHC
MCV
MedDRAMERS
modRNA
N/A
NAAT
NVA
P2 S

Term
hepatitis B core antibody
hepatitis B surface antigen
hepatitis B virus
hepatitis C virus
hepatitis C virus antibody
Health Insurance Portability and Accountability Act
human immunodeficiency virus
hormone replacement therapy
investigator’s brochure
informed consent document
International Council for Harmonisation
intensive care unit
identification
immunoglobulin
immunoglobulin G
immunoglobulin M
investigational medicinal productinvestigational new druginternational normalized ratio
investigational product manual
Investigational Product Accountability Log
institutional review board
internal review committee
illness rate ratio
interactive response technology
intravenous(ly)interactive Web-based response
liver function test
lower limit of quantitation
lipid nanoparticle
lipoplexmean corpuscular hemoglobinmean corpuscular hemoglobin concentration
mean corpuscular volume
Medical Dictionary for Regulatory Activities
Middle East respiratory syndrome
nucleoside-modified messenger ribonucleic acidnot applicable
nucleic acid amplification test
nonvaccine antigen
SARS-CoV-2 full-length, P2 mutant, “heads up,” prefusion spikeglycoprotein

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Abbreviation
PCR
PI
PPE
PT
RBC
RBD
RCDC
RNA
RSV
RT-PCR
S1
SAE
SAP
saRNA
SARS
SARS-CoV-2
SoA
SOP
SRSD
SUSAR
TBD
TBili
ULN
uRNA
US
vax
VE
WBC
WHO
WOCBP

Term
polymerase chain reaction
principal investigatorpersonal protective equipment
prothrombin time
red blood cell
receptor-binding domain
reverse cumulative distribution curve
ribonucleic acidrespiratory syncytial virus
reverse transcription–polymerase chain reaction
spike protein S1 subunit
serious adverse event
statistical analysis planself-amplifying messenger ribonucleic acidsevere acute respiratory syndrome
severe acute respiratory syndrome coronavirus 2schedule of activities
standard operating procedure
single reference safety document
suspected unexpected serious adverse reaction
to be determinedtotal bilirubin
upper limit of normal
unmodified messenger ribonucleic acid
United States
vaccination
vaccine efficacy
white blood cell
World Health Organization
woman/women of childbearing potential

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Protocol Amendment 3, 10 June 2020090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)

11. REFERENCES
1

World Health Organization. WHO Director-General's opening remarks at the media
briefing on COVID-19. Available from: https://www.who.int/dg/speeches/detail/whodirector-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march2020. Published: 11 Mar 2020. Accessed: 01 Apr 2020.

2

World Health Organization. Coronavirus disease 2019 (COVID-19) situation report - 70.
In: Data as reported by national authorities by 10:00 CET 30 March 2020. Geneva,
Switzerland: World Health Organization; 2020.

3

Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19):
therapeutic options. Available from: https://www.cdc.gov/coronavirus/2019ncov/hcp/therapeutic-options.html. Accessed: 12 Apr 2020.

4

Rauch S, Jasny E, Schmidt KE, et al. New vaccine technologies to combat outbreaksituations. Front Immunol 2018;9:1963.

5

Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics—developing a new class ofdrugs. Nat Rev Drug Discov 2014;13(10):759-80.

6

BioNTech RNA Pharmaceuticals GmbH. CorVAC/BNT162 Investigator’s Brochure.
Mainz, Germany: BioNTech RNA Pharmaceuticals GmbH; 25 Mar 2020.

7

Feldman RA, Fuhr R, Smolenov I, et al. mRNA vaccines against H10N8 and H7N9
influenza viruses of pandemic potential are immunogenic and well tolerated in healthy
adults in phase 1 randomized clinical trials. Vaccine. 2019;37(25):3326-34.

8

US Food and Drug Administration. Guidance for industry: toxicity grading scale forhealthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials.
Rockville, MD: Center for Biologics Evaluation and Research; September 2007.

9

Agresti A. Introduction: distributions and inference for categorical data. In: Agresti A,
ed. Categorical data analysis. 2nd ed. Hoboken, NJ: John Wiley & Sons; 2002:1-35.

10

Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med
1985;4(2):213-26.

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Document Approval Record
Document Name:

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090177e193b65c72\Approved\Approved On: 11-Jun-2020 13:54 (GMT)

Signed By:

Date(GMT)

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Page 1026

FDA-CBER-2021-5683-0015079

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Protocol Amendment 2, 27 May 2020090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)A PHASE 1/2, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLIND,
DOSE-FINDING STUDY TO DESCRIBE THE SAFETY, TOLERABILITY,IMMUNOGENICITY, AND POTENTIAL EFFICACY OF SARS-COV-2 RNAVACCINE CANDIDATES AGAINST COVID-19 IN HEALTHY ADULTS

Study Sponsor:

BioNTechStudy Conducted By:

PfizerStudy Intervention Number:

PF-07302048

Study Intervention Name:

RNA-Based COVID-19 Vaccines

US IND Number:

19736

EudraCT Number:

N/A

Protocol Number:

C4591001

Phase:
1/2
Short Title: A Phase 1/2 Study to Describe the Safety, Tolerability, Immunogenicity, andPotential Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Adults

This document and accompanying materials contain confidential information belonging to Pfizer. Except asotherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold thisinformation in confidence and not copy or disclose it to others (except where required by applicable law) or
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer
must be promptly notified.

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Protocol Amendment 2, 27 May 2020

Protocol Amendment Summary of Changes Table

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Document History
Document

Version Date

Summary and Rationale for Changes

Protocolamendment 2

27 May 2020

Protocolamendment 1

13 May 2020

Given the urgent nature of the pandemic
situation, the following changes allow
determination of the appropriate humandose level for both younger and older adults
to move speedily into the next phase ofclinical evaluation:
 Added a new vaccine candidate,
BNT162b3, modRNA encoding amembrane-anchored RBD
 Added a 50-µg dose level for vaccine
candidates based on the modRNA
platform (ie, BNT162b1, BNT162b2,
and BNT162b3)
 Modified the criteria required for the IRC
to determine dose escalation in the 18- to
55-year age cohort and advancement togroups of participants 65 to 85 years ofage
In addition:
 Removed hemoglobin change-frombaseline abnormalities from thelaboratory abnormality grading scale asabnormalities should be graded based
upon absolute values
Following regulatory feedback: Modified exclusion criteria andprohibited inhaled/nebulized
corticosteroids for sentinel participants inStage 1
 Clarified that the rapid test for prior
COVID-19 infection for sentinel
participants in Stage 1 will be used only
for screening purposes Removed time frames for stopping rules
 Stated that data supporting the selectionof vaccine candidate(s)/dose level(s) andschedule(s) for Stages 2 and 3 will be
submitted to the FDA for review

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Following preliminary experience in the
BioNTech study conducted in Germany(BNT162-01):
 Decreased the dose levels for BNT162a1
and BNT162c2
Additionally: Clarified the roles of BioNTech andPfizer Amended text so that the IRC decision toprogress group(s) into Stages 2 and 3 canbe based upon safety andimmunogenicity data after Dose 1 or 2
 Clarified safety data requirements topermit dose escalation
 Amended text so that the progression toparticipants 65 to 85 years of age can bebased upon data from the same RNA
platform Incorporated a protocol administrativechange to correct the variant designationand the encoded antigen to BNT162c2
 Clarified that the SARS-CoV-2
neutralizing assay does not employ wildtype virus
 Clarified that the SARS-CoV-2 spike
protein–binding antibody assay is
specific for the S1 subunit
 Clarified that efficacy against COVID-19
is based upon illness (not infection) rate
ratio
 Incorporated a protocol administrativechange to state that the study placebo
may be supplied in a glass or plastic vial Corrected a typographical error in
Section 6.5.1 regarding the time framefor prior receipt of blood/plasma
products or immunoglobulins
 Corrected a typographical error in Table
2 regarding the lower limit of diameter(cm) for mild redness and swelling Updated the °C fever scale in Table 4 toensure that all potential °F values arecorrectly assigned
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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
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Protocol Amendment 2, 27 May 2020

Original protocol

15 April 2020

 Incorporated a protocol administrativechange to clarify that a rapid test forprior COVID-19 infection will be
performed for sentinel participants inStage 1, and a serum sample will bedrawn for potential future assessment
 Clarified that, after screening, physicalexaminations in sentinel participants inStage 1 will be directed Clarified the descriptions of the
populations for analysis to align with thestatistical analysis plan
 Added a complete safety andimmunogenicity analysis approximately
6 months after Dose 2 for all participantsin Stage 3
 Amended text so that the stopping rules
apply to an RNA platform rather than aspecific vaccine candidate
N/A

This amendment incorporates all revisions to date, including amendments made at therequest of country health authorities and IRBs/ECs.

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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................10
1. PROTOCOL SUMMARY...................................................................................................121.1. Synopsis ..................................................................................................................121.2. Schema ....................................................................................................................17
1.3. Schedule of Activities .............................................................................................18
1.3.1. Stage 1 Sentinel Cohorts.............................................................................18
1.3.2. Stage 1 Nonsentinel Cohorts and Stage 2 Cohorts .....................................22
1.3.3. Stage 3 Cohort(s) ........................................................................................24
2. INTRODUCTION ...............................................................................................................26
2.1. Study Rationale .......................................................................................................26

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2.2. Background .............................................................................................................26
2.2.1. Clinical Overview.......................................................................................27
2.3. Benefit/Risk Assessment.........................................................................................27
2.3.1. Risk Assessment .........................................................................................29
2.3.2. Benefit Assessment.....................................................................................30
2.3.3. Overall Benefit/Risk Conclusion................................................................30
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................30
4. STUDY DESIGN.................................................................................................................32
4.1. Overall Design.........................................................................................................32
4.1.1. Stage 1 ........................................................................................................33
4.1.2. Stage 2 ........................................................................................................34
4.1.3. Stage 3 ........................................................................................................34
4.2. Scientific Rationale for Study Design .....................................................................34
4.3. Justification for Dose ..............................................................................................35
4.4. End of Study Definition ..........................................................................................35
5. STUDY POPULATION ......................................................................................................36
5.1. Inclusion Criteria.....................................................................................................36
5.2. Exclusion Criteria....................................................................................................37
5.3. Lifestyle Considerations..........................................................................................39
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5.3.1. Contraception..............................................................................................39
5.4. Screen Failures ........................................................................................................39
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study
Intervention Administration ......................................................................................40
6. STUDY INTERVENTION..................................................................................................40
6.1. Study Intervention(s) Administered ........................................................................45
6.1.1. Administration ............................................................................................46
6.2. Preparation/Handling/Storage/Accountability ........................................................46
6.2.1. Preparation and Dispensing ........................................................................47
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................47
6.3.1. Allocation to Study Intervention ................................................................47
6.3.2. Blinding of Site Personnel ..........................................................................48
6.3.3. Blinding of the Sponsor ..............................................................................48
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6.3.4. Breaking the Blind......................................................................................48
6.4. Study Intervention Compliance...............................................................................49
6.5. Concomitant Therapy..............................................................................................49
6.5.1. Prohibited During the Study .......................................................................49
6.5.2. Permitted During the Study ........................................................................50
6.6. Dose Modification...................................................................................................50
6.7. Intervention After the End of the Study ..................................................................50
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANTDISCONTINUATION/WITHDRAWAL...........................................................................50
7.1. Discontinuation of Study Intervention ....................................................................50
7.2. Participant Discontinuation/Withdrawal From the Study .......................................51
7.2.1. Withdrawal of Consent ...............................................................................51
7.3. Lost to Follow-up ....................................................................................................52
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................52
8.1. Efficacy and/or Immunogenicity Assessments .......................................................53
8.1.1. Biological Samples .....................................................................................54
8.2. Safety Assessments .................................................................................................55
8.2.1. Clinical Safety Laboratory Assessments (Sentinel-Cohort
Participants Only) ............................................................................................55
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8.2.2. Electronic Diary..........................................................................................56
8.2.2.1. Grading Scales...........................................................................56
8.2.2.2. Local Reactions .........................................................................56
8.2.2.3. Systemic Events ........................................................................57
8.2.2.4. Fever..........................................................................................58
8.2.2.5. Antipyretic Medication .............................................................59
8.2.3. Stopping Rules............................................................................................59
8.2.3.1. Randomization and Vaccination After a Stopping Rule Is
Met.....................................................................................................60
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19
Disease .............................................................................................................60
8.2.5. Pregnancy Testing ......................................................................................61
8.3. Adverse Events and Serious Adverse Events..........................................................61
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8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......61
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................62
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................62
8.3.2. Method of Detecting AEs and SAEs ..........................................................62
8.3.3. Follow-up of AEs and SAEs.......................................................................63
8.3.4. Regulatory Reporting Requirements for SAEs...........................................63
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational
Exposure ..........................................................................................................63
8.3.5.1. Exposure During Pregnancy......................................................64
8.3.5.2. Exposure During Breastfeeding ................................................65
8.3.5.3. Occupational Exposure .............................................................66
8.3.6. Medication Errors .......................................................................................66
8.4. Treatment of Overdose............................................................................................67
8.5. Pharmacokinetics ....................................................................................................67
8.6. Pharmacodynamics..................................................................................................67
8.7. Genetics ...................................................................................................................68
8.8. Biomarkers ..............................................................................................................68
8.9. Immunogenicity Assessments .................................................................................68
8.10. Health Economics .................................................................................................68
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8.11. Study Procedures...................................................................................................68
8.11.1. Stage 1 Sentinel Cohorts...........................................................................68
8.11.1.1. Screening: (0 to 14 Days Before Visit 1) ................................68
8.11.1.2. Visit 1 – Vaccination 1: (Day 1) .............................................69
8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1to 3 Days After Visit 1) .....................................................................71
8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to
8 Days After Visit 1) .........................................................................73
8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1) ...........74
8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to
8 Days After Visit 4) .........................................................................76
8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to
16 Days After Visit 4) .......................................................................77090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)

8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After
Visit 4) ...............................................................................................78
8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (154 to 168 Days
After Visit 4)......................................................................................79
8.11.1.10. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 4)......................................................................................79
8.11.1.11. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 4)......................................................................................80
8.11.2. Stage 1 Nonsentinel Cohorts and Stage 2 Cohorts ...................................80
8.11.2.1. Visit 1 – Vaccination 1: (Day 1) .............................................80
8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days or 56 to 70 Days
After Visit 1)......................................................................................82
8.11.2.3. Visit 3 – 2-Week Follow-up Visit: (12 to 16 Days After
Visit 2) ...............................................................................................84
8.11.2.4. Visit 4 – 1-Month Follow-up Visit: (28 to 35 Days After
Visit 2) ...............................................................................................85
8.11.2.5. Visit 5 – 6-Month Follow-up Visit: (154 to 168 Days
After Visit 2)......................................................................................85
8.11.2.6. Visit 6 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 2)......................................................................................86
8.11.2.7. Visit 7 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 2)......................................................................................86
8.11.3. Stage 3 Cohort(s) ......................................................................................86
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8.11.3.1. Visit 1 – Vaccination 1: (Day 1) .............................................86
8.11.3.2. Visit 2 – Vaccination 2: (19 to 23 Days or 56 to 70 Days
After Visit 1)......................................................................................89
8.11.3.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2):(28 to 35 Days After Visit 2).............................................................90
8.11.3.4. Visit 4 – 6-Month Safety Telephone Contact: (154 to
168 Days After Visit 2) .....................................................................91
8.11.3.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 2)......................................................................................92
8.11.3.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 2)......................................................................................92
8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction ........................92
8.13. COVID-19 Disease Surveillance (All Participants)..............................................93090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)

8.13.1. Potential COVID-19 Illness Telehealth Visit: (Optimally Within 3
Days After Potential COVID-19 Illness Onset)...............................................94
8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After
Potential COVID-19 Illness Visit)..................................................................95
9. STATISTICAL CONSIDERATIONS ................................................................................95
9.1. Estimands and Statistical Hypotheses .....................................................................96
9.1.1. Estimands....................................................................................................96
9.1.2. Statistical Hypotheses.................................................................................96
9.2. Sample Size Determination.....................................................................................96
9.3. Analysis Sets ...........................................................................................................97
9.4. Statistical Analyses .................................................................................................98
9.4.1. Immunogenicity Analyses ..........................................................................98
9.4.2. Efficacy Analyses .....................................................................................101
9.4.3. Safety Analyses ........................................................................................102
9.4.4. Other Analyses..........................................................................................103
9.5. Interim Analyses ...................................................................................................104
9.5.1. Analysis Timing........................................................................................104
9.6. Data Monitoring Committee or Other Independent Oversight Committee...........104
10. SUPPORTING DOCUMENTATION AND OPERATIONALCONSIDERATIONS ........................................................................................................106
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .............106
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10.1.1. Regulatory and Ethical Considerations ..................................................106
10.1.1.1. Reporting of Safety Issues and Serious Breaches of theProtocol or ICH GCP.......................................................................106
10.1.2. Informed Consent Process ......................................................................107
10.1.3. Data Protection .......................................................................................108
10.1.4. Dissemination of Clinical Study Data ....................................................108
10.1.5. Data Quality Assurance ..........................................................................109
10.1.6. Source Documents ..................................................................................111
10.1.7. Study and Site Start and Closure ............................................................111
10.1.8. Sponsor’s Qualified Medical Personnel .................................................112
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................113
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting ....................................................................115
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10.3.1. Definition of AE .....................................................................................115
10.3.2. Definition of SAE ...................................................................................116
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.....................118
10.3.4. Reporting of SAEs..................................................................................121
10.4. Appendix 4: Contraceptive Guidance .................................................................122
10.4.1. Male Participant Reproductive Inclusion Criteria ..................................122
10.4.2. Female Participant Reproductive Inclusion Criteria...............................122
10.4.3. Woman of Childbearing Potential ..........................................................123
10.4.4. Contraception Methods...........................................................................124
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ......126
10.6. Appendix 6: Abbreviations .................................................................................128
11. REFERENCES ................................................................................................................131
LIST OF TABLES
Table 1.

Potential Groups in Stage 1 ......................................................................41

Table 2.

Local Reaction Grading Scale ..................................................................57

Table 3.

Systemic Event Grading Scale..................................................................58

Table 4.

Scale for Fever..........................................................................................59

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Table 5.

Probability of Observing at Least 1 AE by Assumed True Event
Rates With Different Sample Sizes ..........................................................97

Table 6.

Laboratory Abnormality Grading Scale .................................................113

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1. PROTOCOL SUMMARY
1.1. Synopsis
Short Title: A Phase 1/2 Study to Describe the Safety, Tolerability, Immunogenicity, andPotential Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Adults
Rationale

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)

A pneumonia of unknown cause detected in Wuhan, China, was first reported in
December 2019. On 08 January 2020, the pathogen causing this outbreak was identified as anovel coronavirus 2019. The outbreak was declared a Public Health Emergency ofInternational Concern on 30 January 2020. On 12 February 2020, the virus was officiallynamed as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the WHO
officially named the disease caused by SARS-CoV-2 as coronavirus disease 2019
(COVID-19). On 11 March 2020, the WHO upgraded the status of the COVID-19 outbreakfrom epidemic to pandemic, which is now spreading globally at high speed.
There are currently no vaccines to prevent infection with SARS-CoV-2 or antiviral drugs totreat COVID-19. Given the rapid transmission of COVID-19 and incidence of disease in the
United States and elsewhere, the rapid development of an effective vaccine is of utmost
importance.
BioNTech has developed RNA-based vaccine candidates using a platform approach thatenables the rapid development of vaccines against emerging viral diseases, including
SARS-CoV-2. Each vaccine candidate is based on 1 of 3 RNA platforms: unmodified
messenger RNA (uRNA, BNT162a), nucleoside-modified messenger RNA (modRNA,
BNT162b), or self-amplifying messenger RNA (saRNA, BNT162c). Each vaccine candidate
expresses 1 of 3 antigens: the SARS-CoV-2 full-length, P2 mutant, “heads up,” prefusion
spike glycoprotein (P2 S) (version 9), a trimerized SARS-CoV-2 spike glycoprotein receptorbinding domain (RBD) (version 5) or a membrane-anchored RBD. The 5 SARS-CoV-2
vaccine candidates that may be tested in this study are therefore:
BNT162a1 (variant RBL063.3): a uRNA encoding the RBD;
BNT162b1 (variant RBP020.3): a modRNA encoding the RBD;
BNT162b2 (variant RBP020.2): a modRNA encoding P2 S;
BNT162b3: a modRNA encoding a membrane-anchored RBD;
BNT162c2 (variant RBS004.2): an saRNA encoding the P2 S.
All candidates are formulated in the same lipid nanoparticle (LNP) composition. This study
is intended to investigate the safety, immunogenicity, and potential efficacy of these
5 prophylactic BNT162 vaccines against COVID-19.

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It is expected that the various candidate vaccines may not all be available from the start ofthe study, in which case they will be rolled into the study in a consecutive fashion as they are
released. A Phase 1/2 study of the same vaccine candidates (BNT162-01), conducted inGermany by BioNTech in adults 18 to 55 years of age, is planned to start in April 2020.
Study C4591001 is designed to complement and expand upon the German study and confirm
the optimal vaccine candidate(s) (BNT162a1, BNT162b1, BNT162b2, BNT162b3, or
BNT162c2), dose level(s), number of doses, and schedule of administration.

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Objectives, Estimands, and Endpoints
Objectives

Estimands

Endpoints

Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Primary:
In participants receiving at least 1 doseof study intervention and having safety
data reported after any vaccination, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each doseAdverse events (AEs) from
Dose 1 to 1 month after the lastdose
 Serious AEs (SAEs) from Dose 1
to 6 months after the last doseIn addition, in sentinel cohorts from
Stage 1, the percentage of participantswith:
Abnormal hematology andchemistry laboratory values 1 and7 days after Dose 1; and 7 days
after Dose 2
Grading shifts in hematology andchemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2
Secondary:In participants complying with the key
protocol criteria (evaluableparticipants) at the following time
points after receipt of study
intervention:

Primary:
Local reactions (pain at the
injection site, redness, andswelling)

Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs

Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Hematology and chemistry laboratory
parameters detailed in Section 10.2

Secondary:Stage 1 Sentinel Cohorts: 7 and21 days after Dose 1; 7 and 14 days and1, 6, 12, and 24 months after Dose 2
Stage 1 Nonsentinel Cohorts andStage 2 Cohorts: 21 days after Dose 1;
14 days and 1, 6, 12, and 24 months
after Dose 2
Stage 3 Cohort(s): 1, 12, and24 months after Dose 2

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Objectives

Estimands










090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)

Endpoints

Geometric mean titers (GMTs) at SARS-CoV-2 serum neutralizing titers
each time point
Geometric mean fold rise (GMFR)
from before vaccination to eachsubsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
SARS-CoV-2 S1-specific binding
Geometric mean concentrations
antibody levels and RBD-specific(GMCs) at each time point
GMFR from before vaccination to binding antibody levels
each subsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
SARS-CoV-2 serum neutralizing
Geometric mean ratio (GMR),
titersestimated by the ratio of thegeometric mean of SARS-CoV-2 
SARS-CoV-2 S1-specific binding
serum neutralizing titers to theantibody levels
geometric mean of SARS-CoV-2– 
SARS-CoV-2 RBD-specificspecific binding antibody levels at
binding antibody levels
each time point

To evaluate the efficacy of prophylactic In participants complying with the key
BNT162 vaccines against confirmed
protocol criteria (evaluable
COVID-19
participants) following receipt of thelast dose of study intervention:
100 × (1 – illness rate ratio) [ratio ofactive vaccine to placebo]
Tertiary/Exploratory:
Tertiary/Exploratory:
To describe the relationship between
SARS-CoV-2 serological parametersand:
NAAT-confirmed COVID-19

Symptomatic SARS-CoV-2
infection
Asymptomatic SARS-CoV-2
infection

COVID-19 incidence per 1000 personyears of follow-up

Tertiary/Exploratory:
Nonvaccine antigen SARS-CoV-2
antibody levels

Overall Design
This is a Phase 1/2, randomized, placebo-controlled, observer-blind, dose-finding, andvaccine candidate–selection study in healthy adults.
The study will evaluate the safety, tolerability, immunogenicity, and potential efficacy of up
to 5 different SARS-CoV-2 RNA vaccine candidates against COVID-19:


As a 2-dose (separated by 21 or 60 days) or single-dose schedule

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

At various different dose levels

In 3 age groups (18 to 55 years of age, 65 to 85 years of age, and 18 to 85 years of age[stratified as ≤55 or >55 years of age])

Dependent upon safety and/or immunogenicity data generated during the course of thisstudy, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
may be started at the next highest dose, groups may not be started, groups may be terminatedearly, and/or groups may be added with dose levels below the lowest stated dose orintermediate between the lowest and highest stated doses.
The study consists of 3 stages. Stage 1: to identify preferred vaccine candidate(s), doselevel(s), number of doses, and schedule of administration (with the first 15 participants ateach dose level of each vaccine candidate comprising a sentinel cohort); Stage 2: an
expanded-cohort stage; and Stage 3: a final candidate/dose large-scale stage. These stages,
and the progression between them, are detailed in the schema (Section 1.2).

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Number of Participants
Each group in Stage 1 will comprise 15 participants (12 receiving active vaccine and3 receiving placebo). In this stage, assuming 2 dose levels are selected following the initial
dose escalation, up to 56 potential groups are foreseen; if all groups are fully enrolled, thiscorresponds to a total of 840 participants.
Each group in Stage 2 will comprise 225 participants (180 receiving active vaccine and
45 receiving placebo). The total number of participants to be enrolled in this stage depends
on the number of groups to be pursued.
The vaccine candidate/dose level selected for Stage 3 will comprise 3000 participants. An
equal number of participants will receive placebo, ie, randomized in a 1:1 ratio.
Intervention Groups and Duration
The study may evaluate single-dose and 2-dose (separated by 21 or 60 days) schedules ofvarious different dose levels of up to 5 investigational RNA vaccine candidates for active
immunization against COVID-19 in 3 age groups (18 to 55 years of age, 65 to 85 years ofage, and 18 to 85 years of age [stratified as ≤55 or >55 years of age]):

BNT162a1 (RNA-LNP vaccine utilizing uRNA and encoding the RBD): 0.1 µg, 0.3 µg,
1 µg

BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 30 µg, 50 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 30 µg, 50 µg, 100 µg
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

BNT162b3 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding a membraneanchored RBD): 10 µg, 30 µg, 50 µg, 100 µg



BNT162c2 (BNT162 RNA-LNP vaccine utilizing saRNA and encoding the RBD):
0.1 µg, 0.3 µg, 1 µg

Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Stage 1 andStage 2 dosing arms that are not evaluated in Stage 3.
Data Monitoring Committee or Other Independent Oversight Committee
The study will utilize an IRC, an internal Pfizer committee that will review data to allow
dose escalation or changes to continuation of specific groups.
An external data monitoring committee (DMC) will be formed and will review cumulative
unblinded data throughout the study.

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Statistical Methods
The study sample size for the first 2 stages of the study is not based on any statistical
hypothesis testing. For the third stage, with assumptions of a true vaccine efficacy (VE) of
70%, 53 cases of COVID-19 will provide 90% power to conclude true VE >20%.
This would be achieved with 3000 participants per group, based on the assumption of a 1.7%
incidence rate in the placebo group, and 20% of the participants being nonevaluable.
The primary safety objective will be evaluated by descriptive summary statistics for local
reactions, systemic events, abnormal hematology and chemistry laboratory parameters(sentinel cohorts only), and AEs and SAEs, for each vaccine group. A 3-tier approach will
be used to summarize AEs.
The secondary immunogenicity objectives will be evaluated descriptively by GMT, GMC,
GMFR, percentage of participants with ≥4-fold rise, and GMC ratio, and the associated 95%
confidence intervals (CIs), for SARS-CoV-2 serum neutralizing titers, SARS-CoV-2
S1-specific binding antibody levels, and RBD-specific binding antibody levels at the various
time points.
For the secondary efficacy objective, VE is defined as VE = 100 × (1 – IRR), where IRR is
the illness rate ratio, the calculated ratio of COVID-19 incidence in the active vaccine groupto the incidence in the placebo group. The null hypothesis (VE ≤ 20%) will be rejected if thelower bound of the 95% CI for VE is >20%; no interim analysis of VE is planned.

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1.2. SchemaStage 1

(4:1 randomization active:placebo)
For each vaccine candidate

Age: 18-55 y
Low-dose-level 2-dose group (n=15):
SENTINEL

Age: 65-85 y

IRC (safety

IRC (safety)

after Dose 1)

Low-dose-level 2-dose group (n=15):
SENTINEL

Mid-dose-level 2-dose group (n=15):
SENTINEL
IRC (safety

IRC (safety)

Mid-dose-level 2-dose group (n=15):
SENTINEL

after Dose 1)

High-dose-level 2-dose group (n=15):
SENTINEL
IRC (safety
after Dose 1)

High-dose-level 2-dose group (n=15):
SENTINEL

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IRC choice of group(s) for Stages 2 & 3(safety & immunogenicity after Dose 1 or 2)
Dose level(s) selected for Stage 2: 2dose (60 days apart) group(s) (n=15)

Dose level(s) selected for Stage 2: 2dose (60 days apart) group(s) (n=15)&
Dose level(s) selected for Stage 2: 1dose group(s) (n=15)&
Dose level(s) selected for Stage 2: 1dose group(s) (n=15)(4:1 randomization active:placebo)

Stage 2Age: 18-85(Stratified 18-55 or 56-85)
Group for each selected vaccine
candidate/dose level(n=180 per active group)

IRC ongoing review ofsafety & immunogenicity data
Stage 3

(1:1 randomization active:placebo)

Age: 18-85(Stratified 18-55 or 56-85)
Selected vaccine candidate/dose level(n=3000 per group)
Abbreviation: IRC = internal review committee.

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1.3. Schedule of Activities

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with theprotocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations orassessments required to protect the well-being of the participant.
1.3.1. Stage 1 Sentinel Cohorts
An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 10 (24-month follow-up visit) that COVID-19 is suspected.
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit Telehealth
Visit
Visit

Visit Window (Days)

0 to 14
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

X

X

X

X

X

Obtain informed consent

X

Assign participant number

X

Obtain demography andmedical history data

X

Obtain details of medications
currently taken

X

Perform physical examination

X

2

3

4

5

6

7

8

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset

X

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Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit Telehealth
Visit
Visit

Visit Window (Days)

0 to 14
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

Measure vital signs(including body temperature)

X

X

X

X

X

X

Collect blood sample forhematology and chemistrylaboratory testsa~10 mL~10 mL~10 mL~10 mL~10 mL

Collect screening blood
sample for HIV, HBsAg,
HBc Ab, and HCV Ab tests~10 mL

Serological test for prior
COVID-19 infection~20 mL

Perform urine pregnancy test
(if appropriate)X

Obtain nasal (midturbinate)swab(s)b

2

3

4

X

X

X

X

Collect nonstudy vaccine
information

X

X

Confirm eligibility

X

X

Collect prohibited medicationuse
Review hematology andchemistry results

X

Review temporary delay
criteria

X

X

X

X

X

X
X

5

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset
X

X
X

X

X

X

X

X

X

X

X

X

X

X

X
X

X

X

X

X

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Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

4

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit Telehealth
Visit
Visit

Visit Window (Days)

0 to 14
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

Confirm use of contraceptives(if appropriate)

X

X

X

X

X

X

X

X

~50 mL~50 mL~50 mL~50 mL~50 mL~50 mL~50 mL~50 mL

X

X

X

X

Obtain randomization number
and study intervention
allocation

X

Collect blood sample for
immunogenicity assessment~50 mL

Administer study intervention

X

X

Assess acute reactions for atleast 30 minutes after study
intervention administrationc

X

X

Provide participant with 7day e-diary, thermometer, andmeasuring device

X

X

5

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset~50 mL

Review e-diary data (daily
review is optimal during theactive diary period)
Review ongoing e-diary
symptoms and obtain stopdatesCollect AEs and SAEs as
appropriate

X

X

X

X

X

X

X

X

X

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Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit Telehealth
Visit
Visit

Visit Window (Days)

0 to 14
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 46 to 8Days
After
Visit 1

4

5

Collect e-diary or assist theparticipant to delete
application

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset
X

Collection of COVID-19–
related clinical and laboratory
information (including local
diagnosis)

X

X

Abbreviations: e-diary = electronic diary; HBc Ab = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HCV Ab = hepatitis C virus antibody; HIV = humanimmunodeficiency virus; NAAT = nucleic acid amplification test; vax = vaccination.
a. Hematology: hemoglobin, complete blood count with differential, and platelets. Blood chemistry: alanine aminotransferase (ALT), aspartate aminotransferase (AST),
alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), and creatinine.
b. Two swabs will be taken at Visits 1 and 4. One will be tested (if possible at the site, otherwise at the central laboratory) within 24 hours and vaccination will only proceed if
it is NAAT-negative for SARS-CoV-2 genomes. The second will be sent to the central laboratory for potential later testing.
c. The first 5 participants in in each sentinel group will be observed at the site for at least 4 hours after study intervention administration. Further vaccination will commence nosooner than 24 hours after the fifth participant received his or her vaccination.

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1.3.2. Stage 1 Nonsentinel Cohorts and Stage 2 Cohorts
An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 7 (24-month follow-up visit) that COVID-19 is suspected.

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)

Visit Number
Visit Description

Visit Window (Days)

1

2

3

4

5

6

7

Unplanned

Unplanned

2-WeekFollow-up
Visit

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
COVID-19
Illness
Telehealth
Visit

Potential
COVID-19
ConvalescentVisit

19 to 23 Days 12 to 16 Days 28 to 35 Days
After Visit 1 After Visit 2 After Visit 2
or56 to 70 Days
After Visit 1a

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19 Illness Visit
Illness Onset

X

X

Vaccination 1 Vaccination 2

Day 1

Obtain informed consent

X

Assign participant number

X

Obtain demography and medical
history data

X

Perform physical examination

X

Measure vital signs

X

Perform urine pregnancy test
(if appropriate)

X

X

Collect nonstudy vaccine information

X

X

X

X

X

X

X

X

X

X

X

Collect prohibited medication use
Confirm eligibility

X

X

Measure temperature (body)

X

X

Review temporary delay criteria

X

X

Confirm use of contraceptives(if appropriate)

X

X

Obtain randomization number andstudy intervention allocation

X

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Visit Number

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Visit Description

Visit Window (Days)

Collect blood sample for
immunogenicity assessment

1

2

3

4

5

6

7

Unplanned

Unplanned

2-WeekFollow-up
Visit

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
COVID-19
Illness
Telehealth
Visit

Potential
COVID-19
ConvalescentVisit

19 to 23 Days 12 to 16 Days 28 to 35 Days
After Visit 1 After Visit 2 After Visit 2
or56 to 70 Days
After Visit 1a

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19 Illness Visit
Illness Onset~50 mL~50 mL~50 mL

Vaccination 1 Vaccination 2

Day 1~50 mL~50 mL

Obtain nasal (midturbinate) swab

X

X

Administer study intervention

X

X

Assess acute reactions for at least 30
minutes after study intervention
administration

X

X

Provide participant with 7-day e-diary,
thermometer, and measuring device

XX~50 mL~50 mL~50 mL
X

Review e-diary data (daily review is
optimal during the active diary period)
Review ongoing e-diary symptoms andobtain stop dates
Collect AEs and SAEs as appropriate
Collect e-diary or assist the participant
to delete application

X

X

X

X

X

X

X

X

X

X

X

X

X

X

Collection of COVID-19–related
clinical and laboratory information(including local diagnosis)
Abbreviation: e-diary = electronic diary.
a. The window for Visit 2 is dependent on the dosing schedule for the assigned group.

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1.3.3. Stage 3 Cohort(s)An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 6 (24-month follow-up visit) that COVID-19 is suspected.

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Visit Number
Visit Description

Visit Window (Days)

1

2

3

4

5

6

Unplanned

Unplanned

1-MonthFollow-up
Visit

6-Month
SafetyTelephoneContact

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
COVID-19
Illness
Telehealth
Visit

Potential
COVID-19
ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2
or56 to 70 Days
After Visit 1a

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

X

X~50 mL~50 mL

Vaccination 1 Vaccination 2

Day 1

Obtain informed consent

X

Assign participant number

X

Obtain demography and medical history data

X

Perform physical examination

X

Measure vital signs

X

Perform urine pregnancy test (if appropriate)

X

X

Collect nonstudy vaccine information

X

X

X

X

X

X

X

Collect prohibited medication use
Confirm eligibility

X

X

Measure temperature (body)

X

X

Review temporary delay criteria

X

X

Confirm use of contraceptives (if appropriate)

X

X

Obtain randomization number and study
intervention allocation

X

Collect blood sample for immunogenicity
assessment~50 mL

Obtain nasal (midturbinate) swab

X

X

X

X

~50 mLX~50 mLX

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Visit Number

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Visit Description

2

3

4

5

6

Unplanned

Unplanned

1-MonthFollow-up
Visit

6-Month
SafetyTelephoneContact

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
COVID-19
Illness
Telehealth
Visit

Potential
COVID-19
ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2
or56 to 70 Days
After Visit 1a

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

X

X

X

Vaccination 1 Vaccination 2

Visit Window (Days)

Day 1

Administer study intervention

X

X

Assess acute reactions for at least 30 minutes after
study intervention administration

X

X

Provide participant with 7-day e-diary,
thermometer, and measuring device

X

X

Review e-diary data (daily review is optimal during
the active diary period)
Review ongoing e-diary symptoms and obtain stopdatesCollect AEs and SAEs as appropriate

X

Collect e-diary or assist the participant to delete
application

X

X

X

X

X

X

X

X

X

Telephone contact

X

Collection of COVID-19–related clinical andlaboratory information (including local diagnosis)
Abbreviation: e-diary = electronic diary.
a. The window for Visit 2 is dependent on the dosing schedule(s) selected for the Stage 3.

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2. INTRODUCTION
The BNT162 RNA-based COVID-19 vaccines are currently being investigated forprevention of COVID-19 in healthy adults.
2.1. Study Rationale
The purpose of the study is to rapidly describe the safety, tolerability, immunogenicity, andpotential efficacy of up to 5 BNT162 RNA-based COVID-19 vaccine candidates against
COVID-19 in healthy adults. There are currently no vaccines to prevent infection with
SARS-CoV-2 or antiviral drugs to treat COVID-19. Given the global crisis of COVID-19
and fast expansion of the disease in the United States and elsewhere, the rapid developmentof an effective vaccine is of utmost importance.

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2.2. Background
In December 2019, a pneumonia outbreak of unknown cause occurred in Wuhan, China.
In January 2020, it became clear that a novel coronavirus (2019-nCoV) was the underlying
cause. Later in January, the genetic sequence of the 2019-nCoV became available to theWorld Health Organization (WHO) and public (MN908947.3), and the virus was categorized
in the Betacoronavirus subfamily. By sequence analysis, the phylogenetic tree revealed acloser relationship to severe acute respiratory syndrome (SARS) virus isolates than to anothercoronavirus infecting humans, the Middle East respiratory syndrome (MERS) virus.
SARS-CoV-2 infections and the resulting disease, COVID-19, have spread globally,affecting a growing number of countries.
On 11 March 2020, the WHO characterized the COVID-19 outbreak as a pandemic.1
The WHO Situation Update Report dated 30 March 2020 noted 693,224 confirmed caseswith 33,106 deaths globally, including 142,081 confirmed cases with 2457 deaths in theAmericas.2 The United States currently has the most reported cases globally. At the time ofthis communication, the number of confirmed cases continues to rise globally. There are
currently no vaccines or effective antiviral drugs to treat SARS-CoV-2 infections or the
disease it causes, COVID-19.3
A prophylactic, RNA-based SARS-CoV-2 vaccine provides one of the most flexible andfastest approaches available to immunize against the emerging virus.4,5The development of an RNA-based vaccine encoding a viral antigen, which is then expressedby the vaccine recipient as a protein capable of eliciting protective immune responses,
provides significant advantages over more traditional vaccine approaches. Unlike live
attenuated vaccines, RNA vaccines do not carry the risks associated with infection and may
be given to people who cannot be administered live virus (eg, pregnant women andimmunocompromised persons). RNA-based vaccines are manufactured via a cell-free invitro transcription process, which allows an easy and rapid production and the prospect of
producing high numbers of vaccination doses within a shorter time period than achieved with

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traditional vaccine approaches. This capability is pivotal to enable the most effective
response in outbreak scenarios.

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Five SARS-CoV-2–RNA lipid nanoparticle (RNA-LNP) vaccines utilizing different RNA
formats may be evaluated in this study. Each vaccine candidate is based on 1 of 3 RNA
platforms: unmodified messenger RNA (uRNA, BNT162a), nucleoside-modified messenger
RNA (modRNA, BNT162b), or self-amplifying messenger RNA (saRNA, BNT162c). Eachvaccine candidate expresses 1 of 3 antigens: the SARS-CoV-2 full-length, P2 mutant, “heads
up,” prefusion spike glycoprotein (P2 S) (version 9), a trimerized SARS-CoV-2 spikeglycoprotein receptor binding domain (RBD) (version 5), or a membrane-anchored RBD.
The 5 SARS-CoV-2 vaccine candidates that may be tested in this study are therefore:

BNT162a1 (variant RBL063.3): uridine-containing unmodified messenger RNA (uRNA)
with high intrinsic adjuvanticity, encoding the RBD.



BNT162b1 (variant RBP020.3): nucleoside-modified messenger RNA (modRNA) withblunted innate immune sensor–activating capacity and augmented expression encoding
the RBD.



BNT162b2 (variant RBP020.2): nucleoside-modified messenger RNA (modRNA) as
above but encoding P2 S.



BNT162b3: nucleoside-modified messenger RNA (modRNA) as above but encoding amembrane-anchored RBD.



BNT162c2 (variant RBS004.2): self-amplifying messenger RNA (saRNA) encoding theP2 S, in which higher amounts of protein per injected RNA template can be produced.

2.2.1. Clinical Overview
BNT162 vaccines have not been administered to humans before and thus there are no
previous clinical data with these specific vaccines. However, given clinical data from othersimilarly formulated uRNA liposomal vaccines from BioNTech in oncology trials6 andrecent published results from clinical trials using modRNA influenza vaccines by Moderna,7
the BNT162 vaccines are expected to have a favorable safety profile with mild, localized,
and transient effects.
2.3. Benefit/Risk Assessment
There is an ongoing global pandemic of COVID-19 with no preventative or therapeutic
options available. While there are currently no data available from clinical trials on the useof BNT162 vaccines in humans, available nonclinical data with these vaccines, and data from
nonclinical studies and clinical trials with the same or related RNA components, or antigens,support a favorable risk/benefit profile. Anticipated AEs after vaccination are expected to be
manageable using routine symptom-driven standard of care as determined by theinvestigators and, as a result, the profile of these vaccine candidates support initiation of thisPhase 1/2 clinical study.
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More detailed information about the known and expected benefits and risks and reasonably
expected AEs of BNT162 RNA-based COVID-19 vaccines may be found in theinvestigator’s brochure (IB), which is the SRSD for this study.

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2.3.1. Risk Assessment
Potential Risk of ClinicalSignificance

Summary of Data/Rationale for Risk

Mitigation Strategy

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Study Intervention: BNT162 RNA-Based COVID-19 Vaccine
Potential for local reactions (injection These are common adverse reactions seensite redness, injection site swelling, with other vaccines, as noted in the FDA
and injection site pain) and systemic Center for Biologics Evaluation andResearch (CBER) guidelines on toxicity
events (fever, fatigue, headache,
grading scales for healthy adult volunteers
chills, vomiting, diarrhea, muscle
pain, and joint pain) following
enrolled in preventive vaccine clinicalvaccination.
trials.8

The study design includes the use of sentinel cohorts and dose escalation toclosely monitor and limit the rate of enrollment to ensure participant safety.
The study employs the use of an e-diary to monitor local reactions andsystemic events in real time. Stopping rules are also in place for sentinelcohorts. The first 5 sentinel-cohort participants in each group will beobserved for 4 hours after vaccination to assess any immediate AEs.

Unknown AEs and laboratory
abnormalities with a novel vaccine.

The study design includes the use of sentinel cohorts and dose escalation toThis study is one of the first 2 parallelrunning clinical studies with the BNT162 closely monitor and limit the rate of enrollment to ensure participant safety.
vaccine candidates and as such there are no An IRC and DMC will also review safety data throughout the study.
Stopping rules are also in place for sentinel cohorts. The first 5 sentinel
clinical data available for this vaccine.
cohort participants in each group will be observed for 4 hours after
vaccination to assess any immediate AEs.

Potential for COVID-19 diseaseenhancement.

Disease enhancement has been seen
following vaccination with respiratorysyncytial virus (RSV), feline coronavirus,
and Dengue virus vaccines.

The study excludes participants with likely previous or current COVID-19.
All participants are followed for SARS-CoV-2 antigen-specific antibody
and SARS-CoV-2 serum neutralizing titers, and COVID-19 illness,
including markers of severity.

Study Procedures
Participants will be required to attend Without appropriate social distancing andhealthcare facilities during the global PPE, there is a potential for increased
exposure to SARS-CoV-2.
SARS-CoV-2 pandemic.
Venipuncture will be performed
during the study.

There is the risk of bleeding, bruising,hematoma formation, and infection at the
venipuncture site.

Pfizer will work with sites to ensure an appropriate COVID-19 prevention
strategy.
Only appropriately qualified personnel would obtain the blood draw.

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2.3.2. Benefit Assessment
Benefits to individual participants may include:Receipt of a potentially efficacious COVID-19 vaccine during a global pandemicAccess to COVID-19 diagnostic and antibody testingContributing to research to help others in a time of global pandemic

2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in thisstudy, the potential risks identified in association with BNT162 RNA-based COVID-19
vaccine are justified by the anticipated benefits that may be afforded to healthy participants.

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3. OBJECTIVES, ESTIMANDS, AND ENDPOINTSObjectives

Estimands

Endpoints

Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Primary:
In participants receiving at least 1 doseof study intervention and having safety
data reported after any vaccination, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each doseAdverse events (AEs) from
Dose 1 to 1 month after the lastdose
 Serious AEs (SAEs) from Dose 1
to 6 months after the last doseIn addition, in sentinel cohorts from
Stage 1, the percentage of participantswith:
Abnormal hematology andchemistry laboratory values 1 and7 days after Dose 1; and 7 days
after Dose 2
Grading shifts in hematology andchemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2

Primary:
Local reactions (pain at the
injection site, redness, andswelling)

Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs

Hematology and chemistry laboratory
parameters detailed in Section 10.2

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Objectives

Estimands

Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Secondary:In participants complying with the key
protocol criteria (evaluableparticipants) at the following time
points after receipt of study
intervention:

Endpoints
Secondary:Stage 1 Sentinel Cohorts: 7 and21 days after Dose 1; 7 and 14 days and1, 6, 12, and 24 months after Dose 2
Stage 1 Nonsentinel Cohorts andStage 2 Cohorts: 21 days after Dose 1;
14 days and 1, 6, 12, and 24 months
after Dose 2
Stage 3 Cohort(s): 1, 12, and24 months after Dose 2
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







Geometric mean titers (GMTs) at SARS-CoV-2 serum neutralizing titers
each time point
Geometric mean fold rise (GMFR)
from before vaccination to eachsubsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
SARS-CoV-2 S1-specific binding
Geometric mean concentrations
antibody levels and RBD-specific(GMCs) at each time point
GMFR from prior to first dose of binding antibody levels
study intervention to eachsubsequent time point
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
SARS-CoV-2 serum neutralizing
Geometric mean ratio (GMR),
titersestimated by the ratio of thegeometric mean of SARS-CoV-2

SARS-CoV-2 S1-specific binding
serum neutralizing titers to theantibody levels
geometric mean of SARS-CoV-2–
specific binding antibody levels at each time point

To evaluate the efficacy of prophylactic In participants complying with the key
BNT162 vaccines against confirmed
protocol criteria (evaluable
COVID-19
participants) following receipt of thelast dose of study intervention:
100 × (1 – illness rate ratio)[ratio of active vaccine to placebo]

SARS-CoV-2 RBD-specificbinding antibody levels

COVID-19 incidence per 1000 personyears of follow-up

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Objectives
Tertiary/Exploratory:
To describe the relationship between
SARS-CoV-2 serological parametersand:
NAAT-confirmed COVID-19

Symptomatic SARS-CoV-2
infection
Asymptomatic SARS-CoV-2
infection

Estimands
Tertiary/Exploratory:

Endpoints
Tertiary/Exploratory:
Nonvaccine antigen SARS-CoV-2
antibody levels

4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1/2, randomized, placebo-controlled, observer-blind, dose-finding, andvaccine candidate–selection study in healthy adults.

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)The study will evaluate the safety, tolerability, immunogenicity, and potential efficacy of up
to 5 different SARS-CoV-2 RNA vaccine candidates against COVID-19:


As a 2-dose (separated by 21 or 60 days) or single-dose schedule

At various different dose levels

In 3 age groups (18 to 55 years of age, 65 to 85 years of age, and 18 to 85 years of age[stratified as ≤55 or >55 years of age])

Dependent upon safety and/or immunogenicity data generated during the course of thisstudy, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
may be started at the next highest dose, groups may not be started, groups may be terminatedearly, and/or groups may be added with dose levels below the lowest stated dose orintermediate between the lowest and highest stated doses.
The study consists of 3 stages. Stage 1: to identify preferred vaccine candidate(s), doselevel(s), number of doses, and schedule of administration (with the first 15 participants ateach dose level of each vaccine candidate comprising a sentinel cohort); Stage 2: an
expanded-cohort stage; and Stage 3; a final candidate/dose large-scale stage. These stages,
and the progression between them, are detailed in the schema (Section 1.2).
The study is observer-blinded, as the physical appearance of the investigational vaccine
candidates and the placebo may differ. The participant, investigator, study coordinator, andother site staff will be blinded. At the study site, only the dispenser(s)/administrator(s) are
unblinded.
To facilitate rapid review of data in real time, sponsor staff will be unblinded to vaccine
allocation for the participants in Stage 1 and Stage 2.

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4.1.1. Stage 1
Each group (vaccine candidate/dose level/age group/number of doses) will comprise
15 participants; 12 participants will be randomized to receive active vaccine and 3 to receive
placebo. On Day 22, those in 2-dose groups will receive the same vaccine they received on
Day 1; for those in single-dose groups, all will receive placebo. Full details of all potential
groups in Stage 1 may be found in Table 1.

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)For each vaccine candidate/dose level/age group, the 15 participants randomized into each 2dose group will comprise a sentinel cohort, to which the following apply:Additional safety assessments (see Section 8.2)

Controlled enrollment:No more than 5 participants (4 active, 1 placebo) can be vaccinated on the first day

The first 5 participants must be observed by blinded site staff for at least 4 hours after
vaccination for any acute reactions

Vaccination of the remaining participants will commence no sooner than 24 hours
after the fifth participant received his or her vaccination

Application of stopping rules

IRC review of safety data to determine escalation to the next dose level in the 18- to 55year age cohort:Escalation between dose levels will be based on IRC review of at least 7-day post–
Dose 1 safety data in this study and/or the BioNTech study conducted in Germany(BNT162-01)

Note that, for candidates based upon the same RNA platform (eg, BNT162b1,
BNT162b2, and BNT162b3), dose escalation for the second and subsequentcandidates studied may be based upon the safety profile of the first candidate studied
being deemed acceptable at the same, or a higher, dose level by the IRC

Groups of participants 65 to 85 years of age will not be started until safety data for the same
RNA platform have been deemed acceptable at the same, or a higher, dose level in the 18- to
55-year age cohort by the IRC.
Once the IRC has selected a vaccine candidate/dose level to proceed into Stage 2, for eachage cohort, 2 additional groups will be enrolled into Stage 1 for that vaccine candidate/doselevel:
A 2-dose group, with the 2 doses administered 60 days apart rather than 21
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

A 1-dose group

In this stage, assuming 2 dose levels are selected following the initial dose escalation, up to
56 potential groups are foreseen; if all groups are fully enrolled, this corresponds to a total of
840 participants.
4.1.2. Stage 2
On the basis of safety and/or immunogenicity data generated during the course of this study,
and/or the BioNTech study conducted in Germany (BNT162-01), 1 or more groups (vaccine
candidate/dose level) may be selected to proceed into Stage 2. Participants in this stage willbe 18 to 85 years of age, stratified equally: 18 to 55 or 56 to 85 years. Commencement ofeach age stratum will be dependent upon satisfactory safety and immunogenicity data fromthe 18- to 55-year and 65- to 85-year groups from Stage 1, respectively. It is therefore
possible that the 2 age strata may not start concurrently.
In each group selected for Stage 2, it is intended that 225 participants will be randomized in a
4:1 ratio to receive active vaccine (180 participants) or placebo (45 participants).

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4.1.3. Stage 3
On the basis of safety and/or immunogenicity data generated during the course of this study,
and/or the BioNTech study conducted in Germany (BNT162-01), 1 group may be selected toproceed into Stage 3. Participants in this stage will be 18 to 85 years of age, stratified
equally: 18 to 55 years or 56 to 85 years. As in Stage 2, it is possible that the 2 age strata may
not start concurrently.
The vaccine candidate/dose level selected for Stage 3 will comprise 3000 participants. An
equal number of participants will receive placebo, ie, randomized in a 1:1 ratio.
Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Stage 1 andStage 2 dosing arms that are not evaluated in Stage 3.
4.2. Scientific Rationale for Study Design
Additional surveillance for COVID-19 will be conducted as part of the study, given thepotential risk of disease enhancement. If a participant experiences respiratory symptoms, asdetailed in Section 8.13, a COVID-19 illness and subsequent convalescent visit will occur.
As part of these visits, samples (nasal [midturbinate] swab and blood) will be taken for
antigen and antibody assessment as well as recording of COVID-19–related clinical andlaboratory information (including local diagnosis).
Human reproductive safety data are not available for BNT162 RNA-based COVID-19
vaccines, but there is no suspicion of human teratogenicity based on the intended mechanismof action of the compound. Therefore, the use of a highly effective method of contraception
is required (see Appendix 4).
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4.3. Justification for Dose
Because of the requirement for a rapid response to the newly emerged COVID-19 pandemic,
sufficient data are not currently available to experimentally validate the dose selection andinitial starting dose. Therefore, the original planned starting doses of 3 µg (for BNT162a1
and BNT162c2) and 10 µg (for BNT162b1 and BNT162b2) in this study were based on
nonclinical experience with the same RNAs encoding other viral antigens (such as influenza
and HIV antigens). The general safety and effectiveness of uRNA and modRNA platforms
have been demonstrated in oncological clinical trials with different administration routes(NCT02410733, NCT03871348). Doses of up to 400 µg total uRNA have been administered
IV as RNA lipoplex (RNA-LPX) and doses of up to 1000 µg total naked modRNA have been
administered intratumorally, both without signs of unpredictable overstimulation of theimmune system.

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Based on nonclinical data of the RNA components (uRNA, modRNA, saRNA), with otherliposomes or in conjunction with the lipid nanoparticles as will be tested clinically in thisstudy, it was expected that doses in the 1- to 5-µg range would be immunogenic and induce
neutralizing antibodies; however, it was anticipated that 3- to 10-fold higher doses would
likely be required to elicit a stronger antibody response. Based on previous clinical andnonclinical experience, it was expected that doses of up to 100 µg would be well tolerated.
Update as part of protocol amendment 1: preliminary experience in the BioNTech study
conducted in Germany (BNT162-01), following vaccination of 6 participants with 3 µg of
BNT162a1, demonstrated an undesirable level of systemic reactogenicity. Therefore,
potential dose levels for BNT162a1 and BNT162c2 (which are both based upon unmodifiedRNA) dependent upon further data from the BNT162-01 study, are each reduced 30-fold to
0.1 µg, 0.3 µg, and 1 µg.
Update as part of protocol amendment 2: preliminary experience in this study and the
BioNTech study conducted in Germany (BNT162-01) suggests that, for vaccine candidates
based on the modRNA platform, a dose level between 30 µg and 100 µg warrants
consideration. Therefore, a 50-µg dose level is formally included for BNT162b1,
BNT162b2, and BNT162b3.
Taken together, the planned starting doses in this study in healthy participants are considered
to be safe, but still sufficient to induce an antiviral immune response.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases ofthe study, including the last visit. Note that participants enrolled in Stages 1 and 2 in groups
that do not proceed to Stage 3 may be followed for fewer than 24 months (but no less than
6 months after the last vaccination).
The end of the study is defined as the date of last visit of the last participant in the study.

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5. STUDY POPULATIONThis study can fulfill its objectives only if appropriate participants are enrolled. The
following eligibility criteria are designed to select participants for whom participation in the
study is considered appropriate. All relevant medical and nonmedical conditions should betaken into consideration when deciding whether a particular participant is suitable for thisprotocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:

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1. Male or female participants between the ages of 18 and 55 years, inclusive, 65 and85 years, inclusive, or 18 and 85 years, inclusive, at randomization (dependent uponstudy stage).


Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female(Section 10.4.2) participants.

Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, vaccination
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Healthy participants who are determined by medical history, physical examination, andclinical judgment of the investigator to be eligible for inclusion in the study.
Note: Healthy participants with preexisting stable disease, defined as disease notrequiring significant change in therapy or hospitalization for worsening disease during
the 6 weeks before enrollment, can be included.
Informed Consent:
4. Capable of giving personal signed informed consent as described in Appendix 1, which
includes compliance with the requirements and restrictions listed in the ICD and in thisprotocol.

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5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Other medical or psychiatric condition including recent (within the past year) or active
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study
participation or, in the investigator’s judgment, make the participant inappropriate for the
study.
2. Known infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or
hepatitis B virus (HBV).
3. History of severe adverse reaction associated with a vaccine and/or severe allergic
reaction (eg, anaphylaxis) to any component of the study intervention(s).
4. Receipt of medications intended to prevent COVID-19.

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5. Stages 1 and 2 only: Previous clinical or microbiological diagnosis of COVID-19.
6. Sentinel participants in Stage 1 only: Individuals at high risk for severe COVID-19,
including those with any of the following risk factors:Hypertension

Diabetes mellitus

Chronic pulmonary diseaseAsthma

Current vaping or smoking

History of chronic smoking within the prior year

Chronic liver diseaseStage 3 or worse chronic kidney disease (glomerular filtration rate <60
mL/min/1.73 m2)



Resident in a long-term facility

BMI >30 kg/m2

Anticipating the need for immunosuppressive treatment within the next 6 months

7. Sentinel participants in Stage 1 only: Individuals currently working in occupations withhigh risk of exposure to SARS-CoV-2 (eg, healthcare worker, emergency response
personnel).

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8. Immunocompromised individuals with known or suspected immunodeficiency, as
determined by history and/or laboratory/physical examination.
9. Individuals with a history of autoimmune disease or an active autoimmune diseaserequiring therapeutic intervention, including but not limited to: systemic or cutaneous
lupus erythematosus, autoimmune arthritis/rheumatoid arthritis, Guillain-Barré
syndrome, multiple sclerosis, Sjögren’s syndrome, idiopathic thrombocytopenia purpura,glomerulonephritis, autoimmune thyroiditis, giant cell arteritis (temporal arteritis),
psoriasis, and insulin-dependent diabetes mellitus (type 1).
10. Bleeding diathesis or condition associated with prolonged bleeding that would, in theopinion of the investigator, contraindicate intramuscular injection.
11. Women who are pregnant or breastfeeding.
Prior/Concomitant Therapy:

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12. Previous vaccination with any coronavirus vaccine.
13. Individuals who receive treatment with immunosuppressive therapy, including cytotoxic
agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned
receipt throughout the study. If systemic corticosteroids have been administered shortterm (<14 days) for treatment of an acute illness, participants should not be enrolled into
the study until corticosteroid therapy has been discontinued for at least 28 days before
study intervention administration. Inhaled/nebulized (except for sentinel participants inStage 1 – see exclusion criterion 14), intra-articular, intrabursal, or topical (skin or eyes)corticosteroids are permitted.
14. Sentinel participants in Stage 1 only: Regular receipt of inhaled/nebulized
corticosteroids.
15. Receipt of blood/plasma products or immunoglobulin, from 60 days before study
intervention administration or planned receipt throughout the study.
Prior/Concurrent Clinical Study Experience:
16. Participation in other studies involving study intervention within 28 days prior to study
entry and/or during study participation.
17. Previous participation in other studies involving study intervention containing lipid
nanoparticles.
Diagnostic Assessments:
18. Sentinel participants in Stage 1 only: Positive serological test for SARS-CoV-2 IgM
and/or IgG antibodies at the screening visit.
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19. Sentinel participants in Stage 1 only: Any screening hematology and/or blood
chemistry laboratory value that meets the definition of a ≥ Grade 1 abnormality.
Note: With the exception of bilirubin, participants with any stable Grade 1 abnormalities(according to the toxicity grading scale) may be considered eligible at the discretion of
the investigator. (Note: A “stable” Grade 1 laboratory abnormality is defined as a reportof Grade 1 on an initial blood sample that remains ≤ Grade 1 upon repeat testing on asecond sample from the same participant.)
20. Sentinel participants in Stage 1 only: Positive test for HIV, hepatitis B surface antigen(HBsAg), hepatitis B core antibodies (HBc Abs), or hepatitis C virus antibodies(HCV Abs) at the screening visit.
21. Sentinel participants in Stage 1 only: SARS-CoV-2 NAAT-positive nasal swab within
24 hours before receipt of study intervention.
Other Exclusions:

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22. Investigator site staff or Pfizer employees directly involved in the conduct of the study,site staff otherwise supervised by the investigator, and their respective family members.
5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm thatthe participant has selected an appropriate method of contraception for the individual
participant and his or her partner(s) from the permitted list of contraception methods(see Appendix 4, Section 10.4.4) and will confirm that the participant has been instructed inits consistent and correct use. At time points indicated in the SoA, the investigator ordesignee will inform the participant of the need to use highly effective contraception
consistently and correctly and document the conversation and the participant’s affirmation in
the participant’s chart (participants need to affirm their consistent and correct use of at least 1of the selected methods of contraception). In addition, the investigator or designee will
instruct the participant to call immediately if the selected contraception method is
discontinued or if pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but
are not subsequently randomly assigned to study intervention. A minimal set of screen
failure information is required to ensure transparent reporting of screen failure participants tomeet the CONSORT publishing requirements and to respond to queries from regulatory
authorities. Minimal information includes demography, screen failure details, eligibility
criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may berescreened under a different participant number.
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5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention
Administration
The following conditions are temporary or self-limiting and a participant may be vaccinatedonce the condition(s) has/have resolved and no other exclusion criteria are met.

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1. Current febrile illness (body temperature ≥100.4°F [≥38°C]) or other acute illness within
48 hours before study intervention administration. This includes current symptoms that
could represent a potential COVID-19 illness:

New or increased cough;

New or increased shortness of breath;New or increased sore throat;

New or increased wheezing;New or increased sputum production;New or increased nasal congestion;New or increased nasal discharge;



Loss of taste/smell.

2. Receipt of any seasonal or pandemic influenza vaccine within 14 days, or any othernonstudy vaccine within 28 days, before study intervention administration.
3. Anticipated receipt of any seasonal or pandemic influenza vaccine within 14 days, or any
other nonstudy vaccine within 28 days, after study intervention administration.
4. Receipt of short-term (<14 days) systemic corticosteroids. Study intervention
administration should be delayed until systemic corticosteroid use has been discontinued
for at least 28 days. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin oreyes) corticosteroids are permitted.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s),placebo, medical device(s), or study procedure(s) intended to be administered to a study
participant according to the study protocol.
The study may evaluate 2-dose (separated by 21 or 60 days) and single-dose schedules ofvarious different dose levels of up to 5 investigational RNA vaccine candidates for active
immunization against COVID-19 in 3 age groups (18 to 55 years of age, 65 to 85 years ofage, and 18 to 85 years of age [stratified as ≤55 or >55 years of age]). These 5
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investigational RNA vaccine candidates, with the addition of saline placebo, are the 6potential study interventions that may be administered to a study participant:

BNT162a1 (RNA-LNP vaccine utilizing uRNA and encoding the RBD): 0.1 µg, 0.3 µg,
1 µg

BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 30 µg, 50 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 30 µg, 50 µg, 100 µg



BNT162b3 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding a membraneanchored RBD): 10 µg, 30 µg, 50 µg, 100 µg



BNT162c2 (BNT162 RNA-LNP vaccine utilizing saRNA and encoding the RBD):
0.1 µg, 0.3 µg, 1 µg

Normal saline (0.9% sodium chloride solution for injection)

A list of all potential groups in the Stage 1 are shown in Table 1. Each of these groups may
or may not progress to the later stages of the study.
Table 1.

Potential Groups in Stage 1

GroupsN

2-Dose Groups (Sentinel Cohorts)
a-0.1-2-Y (Sentinel)
15[uRNA 0.1 µg (2 doses)]a-0.3-2-Y (Sentinel)
15[uRNA 0.3 µg (2 doses)]a-1-2-Y (Sentinel)
15[uRNA 1 µg (2 doses)]

Age
Group
(Years)18 to 55
18 to 55
18 to 55

b1-10-2-Y (Sentinel)[modRNA 10 µg (2 doses)]b1-30-2-Y (Sentinel)[modRNA 30 µg (2 doses)]
b1-50-2-Y (Sentinel)[modRNA 50 µg (2 doses)]b1-100-2-Y (Sentinel)[modRNA 100 µg(2 doses)]15

18 to 55

15

18 to 55

15

18 to 55

15

18 to 55

b2-10-2-Y (Sentinel)[modRNA 10 µg (2 doses)]b2-30-2-Y (Sentinel)[modRNA 30 µg (2 doses)]b2-50-2-Y (Sentinel)[modRNA 50 µg (2 doses)]15

18 to 55

15

18 to 55

15

18 to 55

Dose 1
Day 1
BNT162a1
Placebo
BNT162a1
Placebo
BNT162a1
Placebo

0.1 µg0.3 µg
1 µg

Dose 2(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

Day 22
BNT162a1
Placebo
BNT162a1
Placebo
BNT162a1
Placebo

0.1 µg0.3 µg
1 µg

BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo

10 µg(n=12)(n=3)
30 µg (n=12)(n=3)
50 µg (n=12)(n=3)
100 µg (n=12)(n=3)

BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo

10 µg

BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo

10 µg

BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo

10 µg

30 µg
50 µg

(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

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30 µg (n=12)(n=3)
50 µg (n=12)(n=3)
100 µg (n=12)
(n=3)

30 µg
50 µg

(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

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Table 1.

Potential Groups in Stage 1

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)GroupsNb2-100-2-Y (Sentinel)[modRNA 100 µg(2 doses)]

15

Age
Group
(Years)18 to 55

b3-10-2-Y (Sentinel)[modRNA 10 µg (2 doses)]b3-30-2-Y (Sentinel)[modRNA 30 µg (2 doses)]b3-50-2-Y (Sentinel)[modRNA 50 µg (2 doses)]b3-100-2-Y (Sentinel)[modRNA 100 µg(2 doses)]15

18 to 55

15

18 to 55

15

18 to 55

15

18 to 55

c-0.1-2-Y (Sentinel)[saRNA 0.1 µg (2 doses)]c-0.3-2-Y (Sentinel)[saRNA 0.3 µg (2 doses)]c-1-2-Y (Sentinel)[saRNA 1 µg (2 doses)]15

18 to 55

15

18 to 55

15

18 to 55

15

65 to 8515

65 to 8515

65 to 85b1-10-2-O (Sentinel)[modRNA 10 µg (2 doses)]b1-30-2-O (Sentinel)[modRNA 30 µg (2 doses)]
b1-50-2-O (Sentinel)[modRNA 50 µg (2 doses)]b1-100-2-O (Sentinel)[modRNA 100 µg(2 doses)]

15

65 to 8515

65 to 8515

65 to 8515

65 to 85b2-10-2-O (Sentinel)[modRNA 10 µg (2 doses)]b2-30-2-O (Sentinel)[modRNA 30 µg (2 doses)]b2-50-2-O (Sentinel)[modRNA 50 µg (2 doses)]b2-100-2-O (Sentinel)[modRNA 100 µg(2 doses)]

15

65 to 8515

65 to 8515

65 to 8515

65 to 85b3-10-2-O (Sentinel)[modRNA 10 µg (2 doses)]b3-30-2-O (Sentinel)[modRNA 30 µg (2 doses)]

15

65 to 8515

65 to 85a-0.1-2-O (Sentinel)[uRNA 0.1 µg (2 doses)]a-0.3-2-O (Sentinel)[uRNA 0.3 µg (2 doses)]a-1-2-O (Sentinel)[uRNA 1 µg (2 doses)]

Dose 1

Dose 2

BNT162b2
Placebo

100 µg (n=12)(n=3)

BNT162b2
Placebo

100 µg (n=12)(n=3)

BNT162b3
Placebo
BNT162b3
Placebo
BNT162b3
Placebo
BNT162b3
Placebo

10 µg(n=12)(n=3)
30 µg (n=12)(n=3)
50 µg (n=12)(n=3)
100 µg (n=12)(n=3)

BNT162b3
Placebo
BNT162b3
Placebo
BNT162b3
Placebo
BNT162b3
Placebo

10 µg

BNT162c2
Placebo
BNT162c2
Placebo
BNT162c2
Placebo

0.1 µg(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

BNT162c2
Placebo
BNT162c2
Placebo
BNT162c2
Placebo

0.1 µg

BNT162a1
Placebo
BNT162a1
Placebo
BNT162a1
Placebo

0.1 µg(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

BNT162a1
Placebo
BNT162a1
Placebo
BNT162a1
Placebo

0.1 µg

BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo

10 µg(n=12)(n=3)
30 µg (n=12)(n=3)
50 µg (n=12)(n=3)
100 µg (n=12)(n=3)

BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo

10 µg

BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo

10 µg(n=12)(n=3)
30 µg (n=12)(n=3)
50 µg (n=12)(n=3)
100 µg (n=12)(n=3)

BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo

10 µg

BNT162b3
Placebo
BNT162b3
Placebo

10 µg

BNT162b3
Placebo
BNT162b3
Placebo

10 µg

0.3 µg1 µg

0.3 µg1 µg

30 µg(n=12)(n=3)(n=12)(n=3)

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30 µg (n=12)(n=3)
50 µg (n=12)(n=3)
100 µg (n=12)(n=3)

0.3 µg1 µg

0.3 µg1 µg(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)
30 µg (n=12)(n=3)
50 µg (n=12)(n=3)
100 µg (n=12)(n=3)(n=12)(n=3)
30 µg (n=12)(n=3)
50 µg (n=12)(n=3)
100 µg (n=12)
(n=3)

30 µg

(n=12)(n=3)(n=12)(n=3)

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Table 1.

Potential Groups in Stage 1

GroupsNb3-50-2-O (Sentinel)[modRNA 50 µg (2 doses)]b3-100-2-O (Sentinel)[modRNA 100 µg(2 doses)]

15

Age
Group
(Years)65 to 8515

65 to 85c-0.1-2-O (Sentinel)[saRNA 0.1 µg (2 doses)]c-0.3-2-O (Sentinel)[saRNA 0.3 µg (2 doses)]c-1-2-O (Sentinel)[saRNA 1 µg (2 doses)]

15

65 to 8515

65 to 8515

65 to 8515

18 to 55

15

18 to 55

15

Single-Dose Groups
a-x-1-Y[uRNA dose level(s)selected for Stage 2(1 dose)]b1-x-1-Y[modRNA dose level(s)selected for Stage 2(1 dose)]b2-x-1-Y[modRNA dose level(s)selected for Stage 2(1 dose)]b3-x-1-Y[modRNA dose level(s)selected for Stage 2(1 dose)]c-x-1-Y[saRNA dose level(s)selected for Stage 2(1 dose)]a-x-1-O[uRNA dose level(s)selected for Stage 2(1 dose)]b1-x-1-O[modRNA dose level(s)selected for Stage 2(1 dose)]b2-x-1-O[modRNA dose level(s)selected for Stage 2(1 dose)]b3-x-1-O[modRNA dose level(s)selected for Stage 2(1 dose)]

Dose 1

Dose 2

BNT162b3
Placebo
BNT162b3
Placebo50 µg(n=12)(n=3)
100 µg (n=12)(n=3)

BNT162b3
Placebo
BNT162b3
Placebo

50 µg

BNT162c2
Placebo
BNT162c2
Placebo
BNT162c2
Placebo

0.1 µg

BNT162c2
Placebo
BNT162c2
Placebo
BNT162c2
Placebo

0.1 µg

Day 1
BNT162a1
Placebo

0.3 µg1 µg(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)
100 µg (n=12)(n=3)

0.3 µg1 µg(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

Day 22
Placebo(n=15)(n=12)(n=3)

Placebo(n=15)

TBD(n=12)(n=3)

Placebo(n=15)

BNT162b3
Placebo

TBD(n=12)(n=3)

Placebo(n=15)

18 to 55

BNT162c2
Placebo

TBD(n=12)(n=3)

Placebo(n=15)

15

65 to 85

BNT162a1
Placebo

TBD(n=12)(n=3)

Placebo(n=15)

15

65 to 85

BNT162b1
Placebo

TBD(n=12)(n=3)

Placebo(n=15)

15

65 to 85

BNT162b2
Placebo

TBD(n=12)(n=3)

Placebo(n=15)

15

65 to 85

BNT162b3
Placebo

TBD(n=12)(n=3)

Placebo(n=15)

TBD(n=12)(n=3)

BNT162b1
Placebo

TBD

18 to 55

BNT162b2
Placebo15

18 to 55

15

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Table 1.

Potential Groups in Stage 1

GroupsN

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c-x-1-O[saRNA dose level(s)selected for Stage 2(1 dose)]15

2-Dose Groups (Longer Schedule)
a-x-2L-Y
15[uRNA dose level(s)selected for Stage 2(2 doses)]b1-x-2L-Y
15[modRNA dose level(s)selected for Stage 2(2 doses)]b2-x-2L-Y
15[modRNA dose level(s)selected for Stage 2(2 doses)]b3-x-2L-Y
15[modRNA dose level(s)selected for Stage 2(2 doses)]c-x-2L-Y
15[saRNA dose level(s)selected for Stage 2(2 doses)]

Age
Group
(Years)65 to 85

18 to 55

Dose 1
BNT162c2
Placebo

Day 1
BNT162a1
Placebo

Dose 2TBD(n=12)(n=3)

Placebo

TBD(n=12)(n=3)

Day 61
BNT162a1
Placebo(n=15)

TBD(n=12)(n=3)

18 to 55

BNT162b1
Placebo

TBD(n=12)(n=3)

BNT162b1
Placebo

TBD(n=12)(n=3)

18 to 55

BNT162b2
Placebo

TBD(n=12)(n=3)

BNT162b2
Placebo

TBD(n=12)(n=3)

18 to 55

BNT162b3
Placebo

TBD(n=12)(n=3)

BNT162b3
Placebo

TBD(n=12)(n=3)

18 to 55

BNT162c2
Placebo

TBD(n=12)(n=3)

BNT162c2
Placebo

TBD(n=12)(n=3)

a-x-2L-O
15
65 to 85
BNT162a1
TBD(n=12)
BNT162a1 TBD(n=12)[uRNA dose level(s)Placebo(n=3)
Placebo(n=3)
selected for Stage 2(2 doses)]b1-x-2L-O
15
65 to 85
BNT162b1
TBD(n=12)
BNT162b1 TBD(n=12)[modRNA dose level(s)Placebo(n=3)
Placebo(n=3)
selected for Stage 2(2 doses)]b2-x-2L-O
15
65 to 85
BNT162b2
TBD(n=12)
BNT162b2 TBD(n=12)[modRNA dose level(s)Placebo(n=3)
Placebo(n=3)
selected for Stage 2(2 doses)]b3-x-2L-O
15
65 to 85
BNT162b3
TBD(n=12)
BNT162b3 TBD(n=12)[modRNA dose level(s)Placebo(n=3)
Placebo(n=3)
selected for Stage 2(2 doses)]c-x-2L-O
15
65 to 85
BNT162c2
TBD(n=12)
BNT162c2 TBD(n=12)[saRNA dose level(s)Placebo(n=3)
Placebo(n=3)
selected for Stage 2(2 doses)]Abbreviations: modRNA = nucleoside-modified messenger ribonucleic acid; saRNA = self-amplifying messenger
ribonucleic acid; TBD = to be determined; uRNA = unmodified messenger ribonucleic acid.

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6.1. Study Intervention(s) Administered
Intervention Name

BNT162a1(BNT 162 RNA-LNP
vaccine utilizinguRNA)

BNT162b1 (BNT162
RNA-LNP vaccine
utilizing modRNA)

BNT162b2 (BNT162
RNA-LNP vaccine
utilizing modRNA)

BNT162b3 (BNT162
RNA-LNP vaccine
utilizing modRNA)

BNT162c2 (BNT162
RNA-LNP vaccine
utilizing saRNA

Type
Dose Formulation

VaccineuRNA

VaccinemodRNA

VaccinemodRNA

VaccinemodRNA

VaccinesaRNAExperimental
IMP
Provided centrally by
the sponsor
Study intervention will
be provided in a glassvial as open-label
supply.
Each vial will belabeled as required per
country requirement

Experimental
IMP
Provided centrally by
the sponsor
Study intervention will
be provided in a glassvial as open-label
supply. Each vial will
be labeled as required
per country
requirement

Experimental
IMP
Provided centrally by
the sponsor
Study intervention will
be provided in a glassvial as open-label
supply. Each vial will
be labeled as required
per country
requirement

Experimental
IMP
Provided centrally by
the sponsor
Study intervention will
be provided in a glassvial as open-label
supply. Each vial will
be labeled as required
per country
requirement

Experimental
IMP
Provided centrally by
the sponsor
Study intervention will
be provided in a glassvial as open-label
supply. Each vial will
be labeled as required
per country
requirement

Unit Dose Strength(s)Dosage Level(s)aRoute of
AdministrationUse
IMP or NIMP
Sourcing
Packaging andLabeling

Saline placebo

Placebo
Normal saline (0.9%sodium chloride
solution for injection)
250 µg/0.5 mL
250 µg/0.5 mL
250 µg/0.5 mL
250 µg/0.5 mL
250 µg/0.5 mL
N/A
0.1-, 0.3-, 1-µg
10-, 30-, 50-, 100-µg
10-, 30-, 50-, 100-µg
10-, 30-, 50-, 100-µg
0.1-, 0.3-, 1-µg
N/A
Intramuscular injection Intramuscular injection Intramuscular injection Intramuscular injection Intramuscular injection Intramuscular injection
PlaceboIMP
Provided centrally by
the sponsor
Study intervention will
be provided in a glassor plastic vial as openlabel supply. Each vial
will be labeled as
required per country
requirementa. Dependent upon safety and/or immunogenicity data generated during the course of this study, or the BioNTech study conducted in Germany (BNT162-01),
it is possible that groups may be started at the next highest dose, groups may not be started, groups may be terminated early, and/or groups may be addedwith dose levels below the lowest stated dose or intermediate between the lowest and highest stated doses.

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6.1.1. Administration
Participants will receive 1 dose (0.5 mL) of study intervention as randomized at eachvaccination visit (Visits 1 and 4 for Stage 1 sentinel cohort participants, Visits 1 and 2 for allother participants) in accordance with the study’s SoA.
Study intervention should be administered intramuscularly into the deltoid muscle, preferablyof the nondominant arm, by an unblinded administrator.
Standard vaccination practices must be observed and vaccine must not be injected into bloodvessels. Appropriate medication and other supportive measures for management of an acute
hypersensitivity reaction should be available in accordance with local guidelines for standard
immunization practices.
Administration of study interventions should be performed by an appropriately qualified,
GCP-trained, and vaccine-experienced member of the study staff (eg, physician, nurse,
physician’s assistant, nurse practitioner, pharmacist, or medical assistant) as allowed by
local, state, and institutional guidance.

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Study intervention administration details will be recorded on the CRF.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study interventions received and any discrepancies arereported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only
authorized site staff may supply or administer study intervention. All study interventions
must be stored in a secure, environmentally controlled, and monitored (manual or
automated recording) area in accordance with the labeled storage conditions with accesslimited to the investigator and authorized site staff. At a minimum, daily minimum andmaximum temperatures for all site storage locations must be documented and available
upon request. Data for nonworking days must indicate the minimum and maximum
temperatures since previously documented for all site storage locations upon return tobusiness.
3. Any excursions from the study intervention label storage conditions should be reported to
Pfizer upon discovery along with any actions taken. The site should actively pursue
options for returning the study intervention to the storage conditions described in thelabeling, as soon as possible. Once an excursion is identified, the study intervention must
be quarantined and not used until Pfizer provides permission to use the study
intervention. Specific details regarding the definition of an excursion and information thesite should report for each excursion will be provided to the site in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage conditions
stated on the label.
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5. Study interventions should be stored in their original containers.
6. See the IP manual for storage conditions of the study intervention.
7. The investigator, institution, or the head of the medical institution (where applicable) is
responsible for study intervention accountability, reconciliation, and record maintenance(ie, receipt, reconciliation, and final disposition records), such as the IPAL or sponsorapproved equivalent. All study interventions will be accounted for using a study
intervention accountability form/record.
8. Further guidance and information for the final disposition of unused study interventions
are provided in the IP manual. All destruction must be adequately documented. If
destruction is authorized to take place at the investigator site, the investigator must ensurethat the materials are destroyed in compliance with applicable environmental regulations,institutional policy, and any special instructions provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of
discovery as described in the IP manual.
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6.2.1. Preparation and Dispensing
See the IP manual for instructions on how to prepare the study intervention foradministration. Study intervention should be prepared and dispensed by an appropriately
qualified and experienced member of the study staff (eg, physician, nurse, physician’s
assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as allowed by
local, state, and institutional guidance. A second staff member will verify the dispensing.
Study intervention and placebo will be prepared by qualified unblinded site personnel
according to the IP manual. The study intervention will be administered in such a way toensure the participants remain blinded.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
Allocation (randomization) of participants to vaccine groups will proceed through the use of
an IRT system (IWR). The site personnel (study coordinator or specified designee) will be
required to enter or select information including but not limited to the user’s ID andpassword, the protocol number, and the participant number. The site personnel will then be
provided with a vaccine assignment and randomization number. The IRT system will
provide a confirmation report containing the participant number, randomization number, andstudy intervention allocation assigned. The confirmation report must be stored in the site’s
files.
The study-specific IRT reference manual and IP manual will provide the contact informationand further details on the use of the IRT system.
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6.3.2. Blinding of Site Personnel
In this observer blinded study, the study staff receiving, storing, dispensing, preparing, andadministering the study interventions will be unblinded. All other study and site personnel,
including the investigator, investigator staff, and participants, will be blinded to study
intervention assignments. In particular, the individuals who evaluate participant safety willbe blinded. Because the BNT162 RNA-based COVID-19 vaccine candidates and placebo
are different in physical appearance, the study intervention syringes will be administered in amanner that prevents the study participants from identifying the study intervention type basedon its appearance.
The responsibility of the unblinded dispenser and administrator must be assigned to anindividual or individuals who will not participate in the evaluation of any study participants.
Contact between the unblinded dispenser and study participants and unblinded administrator
and study participants should be kept to a minimum. The remaining site personnel must notknow study intervention assignments.

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6.3.3. Blinding of the Sponsor
To facilitate rapid review of data in real time, sponsor staff will be unblinded to study
intervention allocation for the participants in Stage 1 and in Stage 2. Sponsor staff will beblinded to study intervention allocation in Stage 3. All laboratory testing personnel
performing serology assays will remain blinded to study intervention assigned/received
throughout the study.
Those study team members who are involved in ensuring that protocol requirements forstudy intervention preparation, handling, allocation, and administration are fulfilled at the site
will be unblinded for the duration of the study (eg, unblinded study manager, unblindedclinical research associate). Unblinded clinician(s) who are not direct members of the study
team will review unblinded protocol deviations.
6.3.4. Breaking the Blind
The IRT will be programmed with blind-breaking instructions. In case of an emergency, theinvestigator has the sole responsibility for determining if unblinding of a participant’s study
intervention assignment is warranted. Participant safety must always be the firstconsideration in making such a determination. If the investigator decides that unblinding iswarranted, the investigator should make every effort to contact the sponsor prior to
unblinding a participant’s vaccine assignment unless this could delay further management of
the participant. If a participant’s vaccine assignment is unblinded, the sponsor must be
notified within 24 hours after breaking the blind. The date and reason that the blind was
broken must be recorded in the source documentation and CRF.
The study-specific IRT reference manual and IP manual will provide the contact informationand further details on the use of the IRT system.

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6.4. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from theinvestigator or designee, under medical supervision. The date and time of each dose
administered in the clinic will be recorded in the source documents and recorded in the CRF.
The dose of study intervention and study participant identification will be confirmed at thetime of dosing by a member of the study site staff other than the person administering thestudy intervention.
6.5. Concomitant Therapy

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)The following concomitant medications and vaccinations will be recorded in the CRF:
All vaccinations received from 28 days prior to study enrollment until the 6-monthfollow-up visit (Visit 8 for Stage 1 sentinel cohorts, Visit 5 for Stage 1 nonsentinelcohorts and Stage 2 participants, and Visit 4 for Stage 3 participants).

Prohibited medications listed in Section 6.5.1 will be recorded, to include start and stop
dates, name of the medication, dose, unit, route, and frequency.

In addition, for participants enrolled in the Stage 1 sentinel cohorts, all current
medication at baseline will be recorded, to include start date, name of the medication,dose, unit, route, and frequency.

6.5.1. Prohibited During the Study
Receipt of the following vaccines and medications during the time periods listed below may
exclude a participant from the per-protocol analysis, and may require vaccinations to bediscontinued in that participant; however, it is anticipated that the participant would not be
withdrawn from the study (see Section 7). Medications should not be withheld if required fora participant’s medical care.
Unless considered medically necessary, no vaccines other than study intervention should be
administered within 28 days before and 28 days after each study vaccination. One exception
to this is that seasonal and pandemic influenza vaccine can be given at least 14 days after, orat least 14 days prior to, the administration of study intervention.
Receipt of chronic systemic treatment with known immunosuppressant medications, orradiotherapy, within 60 days before enrollment through conclusion of the study.
Receipt of systemic corticosteroids (≥20 mg/day of prednisone or equivalent) for ≥14 days is
prohibited from 28 days prior to enrollment to Visit 7 for Stage 1 sentinel cohorts, Visit 4 forStage 1 nonsentinel cohorts and Stage 2 participants, and Visit 3 for Stage 3 participants).
Receipt of inhaled/nebulized corticosteroids from 28 days prior to enrollment to Visit 7(1-month follow-up visit) for Stage 1 sentinel cohorts.

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Receipt of blood/plasma products or immunoglobulins within 60 days before enrollment
through conclusion of the study.
Receipt of any other (nonstudy) coronavirus vaccine at any time prior to or during study
participation is prohibited.
Prophylactic antipyretics and other pain medication to prevent symptoms associated withstudy intervention administration are not permitted. However, if a participant is taking a
medication for another condition, even if it may have antipyretic or pain-relieving properties,
it should not be withheld prior to study vaccination.
6.5.2. Permitted During the Study
The use of antipyretics and other pain medication to treat symptoms associated with study
intervention administration or ongoing conditions is permitted.

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Medication other than that described as prohibited in Section 6.5.1 required for treatment ofpreexisting stable conditions is permitted.
Inhaled (except in Stage 1 sentinel cohorts – see Section 6.5.1), topical, or localized
injections of corticosteroids (eg, intra-articular or intrabursal administration) are permitted.
6.6. Dose Modification
Individual participant dose modifications will not be made in this study.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANTDISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study
intervention (definitive discontinuation). Reasons for definitive discontinuation of study
intervention may include the following: AEs; participant request; investigator request;
pregnancy; protocol deviation (including no longer meeting all the inclusion criteria, or
meeting 1 or more exclusion criteria).
Note that discontinuation of study intervention does not represent withdrawal from the study.
Per the study estimands, if study intervention is definitively discontinued, the participant willremain in the study to be evaluated for safety, immunogenicity, and potential efficacy. See
the SoA for data to be collected at the time of discontinuation of study intervention andfollow-up for any further evaluations that need to be completed.
In the event of discontinuation of study intervention, it must be documented on theappropriate CRF/in the medical records whether the participant is discontinuing further
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receipt of study intervention or also from study procedures, posttreatment study follow-up,
and/or future collection of additional information.
7.2. Participant Discontinuation/Withdrawal From the Study

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)A participant may withdraw from the study at any time at his/her own request. Reasons fordiscontinuation from the study may include the following:

Refused further follow-up;

Lost to follow-up;



Death;



Study terminated by sponsor;



AEs;



Participant request;

Investigator request;Protocol deviation.

If a participant does not return for a scheduled visit, every effort should be made to contact
the participant. All attempts to contact the participant and information received duringcontact attempts must be documented in the participant’s source document. In any
circumstance, every effort should be made to document participant outcome, if possible.
The investigator or his or her designee should capture the reason for withdrawal in the CRF
for all participants.
If a participant withdraws from the study, he/she may request destruction of any remaining
samples taken and not tested, and the investigator must document any such requests in thesite study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1)
for disclosure of future information, no further evaluations should be performed and no
additional data should be collected. The sponsor may retain and continue to use any datacollected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not beviewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent
Participants who request to discontinue receipt of study intervention will remain in the study
and must continue to be followed for protocol-specified follow-up procedures. The only
exception to this is when a participant specifically withdraws consent for any further contact
with him or her or persons previously authorized by the participant to provide thisinformation. Participants should notify the investigator in writing of the decision to
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withdraw consent from future follow-up, whenever possible. The withdrawal of consent
should be explained in detail in the medical records by the investigator, as to whether thewithdrawal is only from further receipt of study intervention or also from study procedures
and/or posttreatment study follow-up, and entered on the appropriate CRF page. In the eventthat vital status (whether the participant is alive or dead) is being measured, publicly
available information should be used to determine vital status only as appropriately directedin accordance with local law.
7.3. Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return forscheduled visits and is unable to be contacted by the study site.

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)The following actions must be taken if a participant fails to attend a required study visit:The site must attempt to contact the participant and reschedule the missed visit as soon as
possible and counsel the participant on the importance of maintaining the assigned visit
schedule and ascertain whether or not the participant wishes to and/or should continue inthe study;

Before a participant is deemed lost to follow-up, the investigator or designee must makeevery effort to regain contact with the participant (where possible, 3 telephone calls and,if necessary, a certified letter to the participant’s last known mailing address or local
equivalent methods). These contact attempts should be documented in the participant’s
medical record;Should the participant continue to be unreachable, he/she will be considered to havewithdrawn from the study.

8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed anddated ICD before performing any study-specific procedures.
The full date of birth will be collected to critically evaluate the immune response and safety
profile by age.
Study procedures and their timing are summarized in the SoA. Protocol waivers or
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence orawareness to determine whether the participant should continue or discontinue study
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential
and required for study conduct.

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All screening evaluations must be completed and reviewed to confirm that potential
participants meet all eligibility criteria. The investigator will maintain a screening log torecord details of all participants screened and to confirm eligibility or record reasons forscreening failure, as applicable.
Every effort should be made to ensure that protocol-required tests and procedures arecompleted as described. However, it is anticipated that from time to time there may becircumstances outside the control of the investigator that may make it unfeasible to performthe test. In these cases, the investigator must take all steps necessary to ensure the safety andwell-being of the participant. When a protocol-required test cannot be performed, theinvestigator will document the reason for the missed test and any corrective and preventive
actions that he or she has taken to ensure that required processes are adhered to as soon as
possible. The study team must be informed of these incidents in a timely manner.

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For samples being collected and shipped, detailed collection, processing, storage, andshipment instructions and contact information will be provided to the investigator site prior
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately
530 mL for participants in the Stage 1 sentinel cohorts; 350 mL for participants in the Stage 1
nonsentinel cohorts and Stage 2 participants; and 200 mL for Stage 3 participants.
Additionally, 50 mL of blood will be taken at an unplanned convalescent visit at any time aparticipant develops respiratory symptoms indicating a potential COVID-19 infection. Other
additional blood samples may be taken for safety assessments at times specified by Pfizer,
provided the total volume taken during the study does not exceed 550 mL during any periodof 60 consecutive days.
8.1. Efficacy and/or Immunogenicity Assessments
Efficacy will be assessed throughout a participant’s involvement in the study throughsurveillance for potential cases of COVID-19. If, at any time, a participant develops acuterespiratory illness (see Section 8.13), for the purposes of the study he or she will beconsidered to potentially have COVID-19 illness.9 In this circumstance, the participant
should contact the site, a telehealth visit should occur, and assessments should be conducted
as specified in the SoA. The assessments will include a nasal (midturbinate) swab, which will
be tested at a central laboratory using a reverse transcription–polymerase chain reaction(RT-PCR) test (Cepheid; FDA approved under EUA), or other equivalent nucleic acidamplification–based test (ie, NAAT), to detect SARS-CoV-2. In addition, clinicalinformation and results from local standard-of-care tests (as detailed in Section 8.13) will beassessed. Four definitions of potential SARS-CoV-2–related cases will be considered:Centrally confirmed COVID-19: presence of at least 1 symptom described in
Section 8.13 and SARS-CoV-2 NAAT positive at central laboratory

Locally confirmed COVID-19: presence of at least 1 symptom described in Section 8.13
and investigator-confirmed SARS-CoV-2 NAAT positive at a local testing facility
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Centrally confirmed symptomatic seroconversion to SARS-CoV-2 (exploratory):presence of at least 1 symptom described in Section 8.13 and a positive nonvaccine
antigen SARS-CoV-2 antibody result in a participant whose most recent prior nonvaccine
antigen SARS-CoV-2 antibody result was negativeCentrally confirmed asymptomatic seroconversion to SARS-CoV-2 (exploratory):
positive nonvaccine antigen SARS-CoV-2 antibody result in a participant with a priornonvaccine antigen SARS-CoV-2 antibody result was negative

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Serum samples will be obtained for immunogenicity testing at the visits specified in the SoA.
The following assays will be performed:

SARS-CoV-2 serum neutralization assay

SARS-CoV-2 S1-specific IgG direct Luminex immunoassay

SARS-CoV-2 RBD-specific IgG direct Luminex immunoassay

Nonvaccine antigen (NVA) Ig direct Luminex immunoassay. The NVA will include a
SARS-CoV-2 target antigen that is not derived from the S glycoprotein, most likely anantigen derived from the SARS-CoV-2 nucleoprotein.

Note that all immunogenicity analyses will be based upon samples analyzed at the central
laboratory; the rapid test will only be performed at screening by all sites recruiting
participants in Stage 1 sentinel cohorts (see Section 8.11.1.1) to determine eligibility.
8.1.1. Biological Samples
Blood and nasal swab samples will be used only for scientific research. Each sample will belabeled with a code so that the laboratory personnel testing the samples will not know theparticipant’s identity. Samples that remain after performing assays outlined in the protocol
may be stored by Pfizer. Unless a time limitation is required by local regulations or ethicalrequirements, the samples will be stored for up to 15 years after the end of the study and thendestroyed. If allowed by the ICD, stored samples may be used for additional testing to better
understand the immune responses to the vaccine(s) under study in this protocol, to inform thedevelopment of other products, and/or for vaccine-related assay work supporting vaccine
programs. No testing of the participant’s DNA will be performed.
The participant may request that his or her samples, if still identifiable, be destroyed at any
time; however, any data already collected from those samples will still be used for thisresearch. The biological samples may be shared with other researchers as long asconfidentiality is maintained and no testing of the participant’s DNA is performed.

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8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinicallaboratory measurements may be obtained at any time during the study to assess any
perceived safety issues.
A clinical assessment, including medical history, will be performed on all participants at
his/her first visit to establish a baseline. Significant medical history and observations fromany physical examination, if performed, will be documented in the CRF.
AEs and SAEs are collected, recorded, and reported as defined in Section 8.3.
Acute reactions within the first 4 hours after administration of the study intervention (for the
first 5 participants vaccinated in each Stage 1 sentinel group), and within the first 30 minutes(for the remainder of participants), will be assessed and documented in the AE CRF.

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)The safety parameters also include e-diary reports of local reactions and systemic events(including fever), and use of antipyretic medication that occur in the 7 days afteradministration of the study intervention. These prospectively self-collected occurrences of
local reactions and systemic events are graded as described in Section 8.2.2.
8.2.1. Clinical Safety Laboratory Assessments (Sentinel-Cohort Participants Only)
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for
the timing and frequency. All protocol-required laboratory assessments, as defined inAppendix 2, must be conducted in accordance with the laboratory manual and the SoA.
Unscheduled clinical laboratory measurements may be obtained at any time during the study
to assess any perceived safety issues.
The investigator must review the laboratory report, document this review, and record any
clinically relevant changes occurring during the study in the AE section of the CRF. See
Appendix 2 for the grading scale for assessment of clinically significant abnormal laboratory
findings. Clinically significant abnormal laboratory findings are those which are notassociated with the underlying disease, unless judged by the investigator to be more severe
than expected for the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during
participation in the study or within 28 days after the last dose of study intervention should be
repeated until the values return to normal or baseline or are no longer considered clinicallysignificant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 5 for suggested actions and follow-up assessments in the event of potential
drug-induced liver injury.

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8.2.2. Electronic Diary
Participants will be required to complete an e-diary through an application installed on aprovisioned device or on the participant’s own personal device. The participant will be asked
to monitor and record local reactions, systemic events, and antipyretic medication usage for7 days following administration of the study intervention. The e-diary allows recording ofthese assessments only within a fixed time window, thus providing the accurate
representation of the participant’s experience at that time. Data on local reactions andsystemic events reported in the e-diary will be transferred electronically to a third-party
vendor, where they will be available for review by investigators and the Pfizer clinicians at
all times via an internet-based portal.
At intervals agreed to by the vendor and Pfizer, these data will be transferred electronicallyinto Pfizer's database for analysis and reporting. These data do not need to be reported by theinvestigator in the CRF as AEs.

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Investigators (or designee) will be required to review the e-diary data online at frequentintervals as part of the ongoing safety review.
The investigator or designee must obtain stop dates from the participant for any ongoing
local reactions, systemic events, or use of antipyretic medication on the last day that thee-diary was completed. The stop dates should be documented in the source documents andthe information entered in the CRF.
8.2.2.1. Grading Scales
The grading scales used in this study to assess local reactions and systemic events as
described below are derived from the FDA Center for Biologics Evaluation and Research(CBER) guidelines on toxicity grading scales for healthy adult volunteers enrolled inpreventive vaccine clinical trials.8
8.2.2.2. Local Reactions
During the e-diary reporting period, participants will be asked to assess redness, swelling,
and pain at the injection site and to record the symptoms in the e-diary. If a local reaction
persists beyond the end of the e-diary period following vaccination, the participant will be
requested to report that information. The investigator will enter this additional information in
the CRF.
Redness and swelling will be measured and recorded in measuring device units(range: 1 to 21) and then categorized during analysis as absent, mild, moderate, or severe
based on the grading scale in Table 2. Measuring device units can be converted tocentimeters according to the following formula: 1 measuring device unit = 0.5 cm. Pain at
the injection site will be assessed by the participant as absent, mild, moderate, or severe
according the grading scale in Table 2.

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If a Grade 3 local reaction is reported in the e-diary, a telephone contact should occur toascertain further details and determine whether a site visit is clinically indicated. Only an
investigator or medically qualified person is able to classify a participant’s local reaction as
Grade 4. If a participant experiences a confirmed Grade 4 local reaction, the investigatormust immediately notify the sponsor and, if it is determined to be related to theadministration of the study intervention, further vaccinations will be discontinued in thatparticipant.
Table 2.

Local Reaction Grading Scale
Mild(Grade 1)

Pain at the
injection site

Does not interferewith activity

Interferes withactivity

Redness

2.0 cm to 5.0 cm(5 to 10 measuring
device units)
2.0 cm to 5.0 cm(5 to 10 measuring
device units)>5.0 cm to 10.0 cm(11 to 20 measuring
device units)>5.0 cm to 10.0 cm(11 to 20 measuring
device units)

Swelling

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Moderate(Grade 2)

Severe(Grade 3)

Potentially Life
Threatening(Grade 4)
Prevents daily activity Emergency room visit
or hospitalization forsevere pain
>10 cmNecrosis or(≥21 measuringexfoliative dermatitis
device units)>10 cmNecrosis(≥21 measuring
device units)

8.2.2.3. Systemic Events
During the e-diary reporting period, participants will be asked to assess vomiting, diarrhea,
headache, fatigue, chills, new or worsened muscle pain, and new or worsened joint pain andto record the symptoms in the e-diary. The symptoms will be assessed by the participant as
absent, mild, moderate, or severe according to the grading scale in Table 3.
If a Grade 3 systemic event is reported in the e-diary, a telephone contact should occur toascertain further details and determine whether a site visit is clinically indicated. Only an
investigator or medically qualified person is able to classify a participant’s systemic event as
Grade 4. If a participant experiences a confirmed Grade 4 systemic event, the investigatormust immediately notify the sponsor and, if it is determined to be related to theadministration of the study intervention, further vaccinations will be discontinued in thatparticipant.

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Table 3.

Systemic Event Grading Scale

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Mild(Grade 1)

Moderate(Grade 2)>2 times in
24 hours

Severe(Grade 3)

Vomiting

1-2 times in
24 hours

Requires IV
hydration

Diarrhea

2 to 3 loose stools 4 to 5 loose stools
in 24 hours
in 24 hours

6 or more loosestools in 24 hours

Headache

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Fatigue/tiredness

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Chills

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

New orworsened
muscle pain

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Does not interfere Some interference
New orwith activity
with activity
worsened
joint pain
Abbreviation: IV = intravenous.

Prevents daily
routine activity

Potentially Life
Threatening(Grade 4)
Emergency room visit or
hospitalization for
hypotensive shock
Emergency room visit or
hospitalization for severe
diarrhea
Emergency room visit or
hospitalization for severe
headache
Emergency room visit or
hospitalization for severe
fatigue
Emergency room visit or
hospitalization for severe
chillsEmergency room visit or
hospitalization for severe
new or worsened muscle
painEmergency room visit or
hospitalization for severe
new or worsened joint pain

8.2.2.4. Fever
In order to record information on fever, a thermometer will be given to participants with
instructions on how to measure oral temperature at home. Temperature will be collected in
the e-diary in the evening daily during the e-diary reporting period. It will also be collected
at any time during the e-diary data collection periods when fever is suspected. Fever isdefined as an oral temperature of ≥38.0°C (100.4°F). The highest temperature for each day
will be recorded in the e-diary. Temperature will be measured and recorded to 1 decimal
place and then categorized during analysis according to the scale shown in Table 4.
If a fever of ≥39.0°C (102.1°F) is reported in the e-diary, a telephone contact should occur toascertain further details and determine whether a site visit is clinically indicated. Only an
investigator or medically qualified person is able to confirm a participant’s fever as >40.0°C(>104.0°F). If a participant experiences a confirmed fever >40.0°C (>104.0°F), theinvestigator must immediately notify the sponsor and, if it is determined to be related to theadministration of the study intervention, further vaccinations will be discontinued in thatparticipant.

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Table 4.

Scale for Fever≥38.0-38.4°C (100.4-101.1°F)>38.4-38.9°C (101.2-102.0°F)>38.9-40.0°C (102.1-104.0°F)>40.0°C (>104.0°F)

8.2.2.5. Antipyretic Medication
The use of antipyretic medication to treat symptoms associated with study intervention
administration will be recorded in the e-diary daily during the reporting period (Day 1 to
Day 7).
8.2.3. Stopping Rules

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)The following stopping rules are in place for all Stage 1 sentinel-cohort participants, basedon review of AE data and e-diary reactogenicity data. These data will be monitored on an
ongoing basis by the investigator (or medically qualified designee) and sponsor in order topromptly identify and flag any event that potentially contributes to a stopping rule.
The sponsor study team will be unblinded during the Stage 1, so will be able to assess
whether or not a stopping rule has been met on the basis of a participant’s individual study
intervention allocation.
In the event that sponsor personnel confirm that a stopping rule is met, the following actions
will commence:The IRC will review all appropriate data.

The stopping rule will PAUSE randomization and study intervention administration for
the impacted vaccine candidate all dose levels and age groups.



The DMC will review all appropriate data.

For all participants vaccinated, all other routine study conduct activities, including
ongoing data entry, reporting of AEs, participant e-diary completion, blood sample
collection, and participant follow-up, will continue during the pause.

A stopping rule is met if any of the following rules occur after administration of
investigational BNT162 vaccine; data from placebo recipients will not contribute to thestopping rules. E-diary data confirmed by the investigator as being entered by the participant
in error will not contribute toward a stopping rule.
BNT162 RNA platforms (ie, a, b, and c) will be evaluated for contribution to stopping rules
individually; vaccine candidate dose levels within a platform and age groups will contribute

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to stopping rules together. However, it is possible that the recommendations may include
halting or continuing randomization with any of the BNT162 vaccine candidates.
Stopping Rule Criteria for Each BNT162 Vaccine Candidate:
1. If any participant vaccinated with the BNT162 candidate (at any dose level) develops an
SAE that is assessed by the investigator as possibly related, or for which there is noalternative, plausible, attributable cause.
2. If any participant vaccinated with the BNT162 candidate (at any dose level) develops a
Grade 4 local reaction or systemic event after vaccination (see Section 8.2.2) that is
assessed as possibly related by the investigator, or for which there is no alternative,plausible, attributable cause.

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3. If any participant vaccinated with the BNT162 candidate (at any dose level) develops afever >40.0°C (>104.0°F) for at least 1 daily measurement after vaccination(see Section 8.2.2.4) that is assessed as possibly related by the investigator, or for which
there is no alternative, plausible, attributable cause.
4. If any 2 participants vaccinated with the BNT162 candidate (at any dose level) report thesame or similar severe (Grade 3) AE (including laboratory abnormalities) after
vaccination, assessed as possibly related by the investigator, or for which there is noalternative, plausible, attributable cause.
5. If any participant dies or requires ICU admission due to SARS-CoV-2 infection; if thisstopping rule is met, all available clinical and preclinical safety and immunogenicity data
should be reviewed to evaluate for enhanced COVID-19 disease.
8.2.3.1. Randomization and Vaccination After a Stopping Rule Is Met
Once the IRC and DMC have reviewed the safety data and provided guidance, a notification
will be sent from the sponsor to the sites with guidance on how to proceed.
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19 Disease
As this is a sponsor open-label study during Stages 1 and 2, the sponsor will conduct
unblinded reviews of the data during the course of the study, including for the purpose ofsafety assessment.
Participants in all stages of the study will be surveilled for potential COVID-19 illness from
Visit 1 onwards (see Section 8.13). All NAAT-confirmed cases will be reviewed
contemporaneously by the IRC and the DMC (see Section 9.6). In addition, instances ofsymptomatic and asymptomatic seroconversion to SARS-CoV-2 (see Section 8.1) will be
reviewed.
The purpose of these reviews will be to identify whether any features of each case appear
unusual, in particular greater severity, compared to available information at the time of
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review. Indicators of severity may include accelerated deterioration, need for hospitalization,need for ventilation, or death. Observed rates of these indicators will be compared with what
could be expected in a similar population to the study participants based upon available
information at the time of review. Since the DMC is able to review unblinded information, it
will also be able to compare cases in active vaccine and placebo recipients in Stage 3 (whensponsor staff will be blinded).
8.2.5. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA,
immediately before the administration of each vaccine dose. A negative pregnancy test result
will be required prior to the participant’s receiving the study intervention. Pregnancy tests
may also be repeated if requested by IRBs/ECs or if required by local regulations. In thecase of a positive confirmed pregnancy, the participant will be withdrawn fromadministration of study intervention but may remain in the study.
8.3. Adverse Events and Serious Adverse Events

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or
the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, andrecording events that meet the definition of an AE or SAE and remain responsible to pursue
and obtain adequate information both to determine the outcome and to assess whether the
event meets the criteria for classification as an SAE or caused the participant to discontinue
the study intervention (see Section 7.1).
Each participant will be questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection
period”) for each participant begins from the time the participant provides informed consent,
which is obtained before the participant’s participation in the study (ie, before undergoing
any study-related procedure and/or receiving study intervention), through and including
Visit 7 for Stage 1 sentinel-cohort participants, Visit 4 for Stage 1 nonsentinel participants
and Stage 2 participants, and Visit 3 for Stage 3 participants. In addition, any AEs occurring
up to 48 hours after each subsequent blood draw must be recorded on the CRF.
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cohort participants, Visit 5 for Stage 1 nonsentinel cohort participants and Stage 2
participants, and Visit 4 for Stage 3 participants).
Follow-up by the investigator continues throughout and after the active collection period anduntil the AE or SAE or its sequelae resolve or stabilize at a level acceptable to theinvestigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of
future information, the active collection period ends when consent is withdrawn.

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If a participant definitively discontinues or temporarily discontinues study intervention
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE
reported using the Vaccines SAE Report Form.
Investigators are not obligated to actively seek AEs or SAEs after the participant has
concluded study participation. However, if the investigator learns of any SAE, including adeath, at any time after a participant has completed the study, and he/she considers the event
to be reasonably related to the study intervention, the investigator must promptly report the
SAE to Pfizer using the Vaccines SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in
Section 8.3.1 are reported to Pfizer Safety on the Vaccines SAE Report Form immediately
upon awareness and under no circumstance should this exceed 24 hours, as indicated inAppendix 3. The investigator will submit any updated SAE data to the sponsor within
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period as
described in Section 8.3.1 are recorded on the CRF. AEs and SAEs that begin after obtaining
informed consent but before the start of study intervention will be recorded on the Medical
History/Current Medical Conditions section of the CRF, not the AE section. AEs and SAEs
that begin after the start of study intervention are recorded on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and theprocedures for completing and transmitting SAE reports are provided in Appendix 3.

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Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended andnonleading verbal questioning of the participant is the preferred method to inquire about
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow eachparticipant at subsequent visits/contacts. For each event, the investigator must pursue andobtain adequate information until resolution, stabilization, the event is otherwise explained,or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail toallow for a complete medical assessment of the case and independent determination of
possible causality. Any information relevant to the event, such as concomitant medications
and illnesses, must be provided. In the case of a participant death, a summary of available
autopsy findings must be submitted as soon as possible to Pfizer Safety.
Further information on follow-up procedures is given in Appendix 3.

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8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal
obligations and ethical responsibilities towards the safety of participants and the safety of astudy intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and otherregulatory agencies about the safety of a study intervention under clinical investigation. The
sponsor will comply with country-specific regulatory requirements relating to safety
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding andoccupational exposure are reportable to Pfizer Safety within 24 hours of investigatorawareness.

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8.3.5.1. Exposure During Pregnancy

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)An EDP occurs if:A female participant is found to be pregnant while receiving or after discontinuing study
intervention.



A male participant who is receiving or has discontinued study intervention exposes afemale partner prior to or around the time of conception.



A female is found to be pregnant while being exposed or having been exposed to study
intervention due to environmental exposure. Below are examples of environmental
exposure during pregnancy:

A female family member or healthcare provider reports that she is pregnant after
having been exposed to the study intervention by inhalation or skin contact.

A male family member or healthcare provider who has been exposed to the study
intervention by inhalation or skin contact then exposes his female partner prior to or
around the time of conception.

The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s
awareness, irrespective of whether an SAE has occurred. The initial information submitted
should include the anticipated date of delivery (see below for information related totermination of pregnancy).


If EDP occurs in a participant or a participant’s partner, the investigator must report thisinformation to Pfizer Safety on the Vaccines SAE Report Form and an EDP
Supplemental Form, regardless of whether an SAE has occurred. Details of thepregnancy will be collected after the start of study intervention and until 6 months after
the last dose of study intervention.



If EDP occurs in the setting of environmental exposure, the investigator must report
information to Pfizer Safety using the Vaccines SAE Report Form and EDP
Supplemental Form. Since the exposure information does not pertain to the participant
enrolled in the study, the information is not recorded on a CRF; however, a copy of thecompleted Vaccines SAE Report Form is maintained in the investigator site file.

Follow-up is conducted to obtain general information on the pregnancy and its outcome for
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as afollow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural
integrity of the neonate can be assessed at the time of birth. In the event of a termination, thereason(s) for termination should be specified and, if clinically possible, the structural
integrity of the terminated fetus should be assessed by gross visual inspection (unless

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preprocedure test findings are conclusive for a congenital anomaly and the findings arereported).

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Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meetsthe criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal
demise, neonatal death, or congenital anomaly), the investigator should follow the procedures
for reporting SAEs. Additional information about pregnancy outcomes that are reported to
Pfizer Safety as SAEs follows:

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard tocausality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs
when the investigator assesses the infant death as related or possibly related to exposure
to the study intervention.

Additional information regarding the EDP may be requested by the sponsor. Further
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on
preterm infants to identify developmental delays). In the case of paternal exposure, theinvestigator will provide the participant with the Pregnant Partner Release of Information
Form to deliver to his partner. The investigator must document in the source documents thatthe participant was given the Pregnant Partner Release of Information Form to provide to his
partner.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if:A female participant is found to be breastfeeding while receiving or after discontinuing
study intervention.



A female is found to be breastfeeding while being exposed or having been exposed to
study intervention (ie, environmental exposure). An example of environmental exposure
during breastfeeding is a female family member or healthcare provider who reports that
she is breastfeeding after having been exposed to the study intervention by inhalation orskin contact.

The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hoursof the investigator’s awareness, irrespective of whether an SAE has occurred. The
information must be reported using the Vaccines SAE Report Form. When exposure during
breastfeeding occurs in the setting of environmental exposure, the exposure information does
not pertain to the participant enrolled in the study, so the information is not recorded on a
CRF. However, a copy of the completed Vaccines SAE Report Form is maintained in theinvestigator site file.

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An exposure during breastfeeding report is not created when a Pfizer drug specificallyapproved for use in breastfeeding women (eg, vitamins) is administered in accord withauthorized use. However, if the infant experiences an SAE associated with such a drug, theSAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with thestudy intervention, which may or may not lead to the occurrence of an AE. Such persons
may include healthcare providers, family members, and other roles that are involved in thetrial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of theinvestigator’s awareness, regardless of whether there is an associated SAE. The informationmust be reported using the Vaccines SAE Report Form. Since the information does not
pertain to a participant enrolled in the study, the information is not recorded on a CRF;
however, a copy of the completed Vaccines SAE Report Form is maintained in theinvestigator site file.

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8.3.6. Medication Errors
Medication errors may result from the administration or consumption of the study
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as
medication errors.
Safety Event

Recorded on the CRF

Reported on the Vaccines SAE Report
Form to Pfizer Safety Within 24 Hours
of Awareness

Medication errors

All (regardless of whether
associated with an AE)

Only if associated with an SAE

Medication errors include:Medication errors involving participant exposure to the study intervention;Potential medication errors or uses outside of what is foreseen in the protocol that do or
do not involve the study participant;The administration of expired study intervention;

The administration of an incorrect study intervention;

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The administration of an incorrect dosage;The administration of study intervention that has undergone temperature excursion fromthe specified storage range, unless it is determined by the sponsor that the study
intervention under question is acceptable for use.

Such medication errors occurring to a study participant are to be captured on the medication
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by theinvestigator, the medication error is recorded on the medication error page of the CRF and, if
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a Vaccines SAE
Report Form only when associated with an SAE.
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8.4. Treatment of Overdose
For this study, any dose of study intervention greater than 1 dose of study intervention within
a 24-hour time period will be considered an overdose.
Pfizer does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the medical monitor immediately.
2. Closely monitor the participant for any AEs/SAEs.
3. Document the quantity of the excess dose as well as the duration of the overdose in the
CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.

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8.7. Genetics
Genetics (specified analyses) are not evaluated in this study.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.9. Immunogenicity Assessments
Immunogenicity assessments are described in Section 8.1.
8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are notevaluated in this study.
8.11. Study Procedures
8.11.1. Stage 1 Sentinel Cohorts

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8.11.1.1. Screening: (0 to 14 Days Before Visit 1)
Before enrollment and before any study-related procedures are performed, voluntary, written
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.
It is anticipated that the procedures below will be conducted in a stepwise manner; however,the visit can occur over more than 1 day.
Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance.

Obtain details of any medications currently taken.

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Perform physical examination including vital signs (weight, height, body temperature,pulse rate, and seated blood pressure), evaluating any clinically significant abnormalities
within the following body systems: general appearance; skin; head, eyes, ears, nose, andthroat; heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph
nodes.



Collect a blood sample (approximately 20 mL) for potential future serological assessment
and to perform a rapid test for prior COVID-19 infection.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.

Collect a blood sample (approximately 10 mL) for HIV, HBsAg, HBc Ab, and HCV Ab
tests.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Record AEs as described in Section 8.3. AEs that occur prior to dosing should be notedon the Medical History CRF.



Ask the participant to contact the site staff or investigator immediately if any significant
illness or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

Complete the CRF.

8.11.1.2. Visit 1 – Vaccination 1: (Day 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.
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

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Review screening laboratory results (hematology and chemistry, and HIV, HBsAg,
HBc Ab, and HCV Ab tests).

Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested(if possible at the site, otherwise at the central laboratory) within 24 hours andvaccination will proceed only if it is NAAT-negative for SARS-CoV-2 genomes.
The second will be sent to the central laboratory for potential later testing.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Obtain the participant’s randomization number and study intervention allocation using
the IRT system. Either blinded site staff or unblinded site staff member may obtain thisinformation.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.



The first 5 participants vaccinated in each Stage 1 sentinel group must be observed byblinded site staff for any acute reactions for at least 4 hours after vaccination. For
participants enrolled thereafter, blinded site staff must observe the participant for at least
30 minutes after study intervention administration for any acute reactions. Record any
acute reactions (including time of onset) in the participant’s source documents and on the
AE page of the CRF, and on an SAE form as applicable.

Issue a measuring device to measure local reactions at the injection site and athermometer for recording daily temperatures and provide instructions on their use.
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Explain the e-diary technologies available for this study, and assist the participant indownloading the study application onto the participant’s own device or issue aprovisioned device if required. Provide instructions on e-diary completion and ask theparticipant to complete the e-diary from Day 1 to Day 7, with Day 1 being the day of
vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the e-diary data online
following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1 to 3 Days After Visit 1)

Record AEs as described in Section 8.3.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within the

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following body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.
Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the e-diary data online
following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

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8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to 8 Days After Visit 1)

Record AEs as described in Section 8.3.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

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Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the e-diary data online
following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1)

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It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



Review the participant’s e-diary data. Collect stop dates of any e-diary events ongoingon the last day that the e-diary was completed and record stop dates in the CRF if
required.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested (ifpossible at the site, otherwise at the central laboratory) within 24 hours and vaccination
will only proceed if it is NAAT-negative for SARS-CoV-2 genomes. The second will besent to the central laboratory for potential later testing.

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Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met. If not, the participant should not receive further study intervention but willremain in the study to be evaluated for safety, immunogenicity, and potential efficacy(see Section 7.1).

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection
site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and ask the participant to complete the ediary from Day 1 to Day 7, with Day 1 being the day of vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.

Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

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

Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the e-diary data online
following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

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8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to 8 Days After Visit 4)

Record AEs as described in Section 8.3.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).
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Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the e-diary data online
following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to 16 Days After Visit 4)

Record AEs as described in Section 8.3.



Review the participant’s e-diary data. Collect stop dates of any e-diary events ongoingon the last day that the e-diary was completed and record stop dates in the CRF if
required.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.
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Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Collect the participant’s e-diary or assist the participant to remove the study applicationfrom his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After Visit 4)

Record AEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (154 to 168 Days After Visit 4)

Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.1.10. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 4)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.1.11. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 4)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.2. Stage 1 Nonsentinel Cohorts and Stage 2 Cohorts

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8.11.2.1. Visit 1 – Vaccination 1: (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written,
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.
It is anticipated that the procedures below will be conducted in a stepwise manner.
Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance.



Perform physical examination including vital signs (weight, height, body temperature,pulse rate, and seated blood pressure), evaluating any clinically significant abnormalities
within the following body systems: general appearance; skin; head, eyes, ears, nose, andthroat; heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph
nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

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Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.



Record AEs as described in Section 8.3.

Obtain the participant’s randomization number and study intervention allocation using
the IRT system. Either blinded site staff or unblinded site staff member may obtain thisinformation.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Issue a measuring device to measure local reactions at the injection site and athermometer for recording daily temperatures and provide instructions on their use.



Explain the e-diary technologies available for this study, and assist the participant indownloading the study application onto the participant’s own device or issue aprovisioned device if required. Provide instructions on e-diary completion and ask theparticipant to complete the e-diary from Day 1 to Day 7, with Day 1 being the day of
vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.
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

Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the e-diary data online
following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days or 56 to 70 Days After Visit 1)
The window for Visit 2 is dependent on the dosing schedule for the assigned group.
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



Review the participant’s e-diary data. Collect stop dates of any e-diary events ongoingon the last day that the e-diary was completed and record stop dates in the CRF if
required.

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met. If not, the participant should not receive further study intervention but willremain in the study to be evaluated for safety, immunogenicity, and potential efficacy(see Section 7.1).
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

Measure the participant’s body temperature.

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection
site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and ask the participant to complete the
e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

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Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the e-diary data online
following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

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8.11.2.3. Visit 3 – 2-Week Follow-up Visit: (12 to 16 Days After Visit 2)

Record AEs as described in Section 8.3.



Review the participant’s e-diary data. Collect stop dates of any e-diary events ongoingon the last day that the e-diary was completed and record stop dates in the CRF if
required.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Collect the participant’s e-diary or assist the participant to remove the study applicationfrom his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.2.4. Visit 4 – 1-Month Follow-up Visit: (28 to 35 Days After Visit 2)

Record AEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.11.2.5. Visit 5 – 6-Month Follow-up Visit: (154 to 168 Days After Visit 2)

Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.
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Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.2.6. Visit 6 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 2)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.2.7. Visit 7 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 2)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.3. Stage 3 Cohort(s)8.11.3.1. Visit 1 – Vaccination 1: (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written,
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.
It is anticipated that the procedures below will be conducted in a stepwise manner.
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Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance.



Perform physical examination including vital signs (weight, height, body temperature,pulse rate, and seated blood pressure), evaluating any clinically significant abnormalities
within the following body systems: general appearance; skin; head, eyes, ears, nose, andthroat; heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph
nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.



Record AEs as described in Section 8.3.

Obtain the participant’s randomization number and study intervention allocation number
using the IRT system. Either blinded site staff or unblinded site staff member may obtain
this information.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

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Issue a measuring device to measure local reactions at the injection site and athermometer for recording daily temperatures and provide instructions on their use.



Explain the e-diary technologies available for this study, and assist the participant indownloading the study application onto the participant’s own device or issue aprovisioned device if required. Provide instructions on e-diary completion and ask theparticipant to complete the e-diary from Day 1 to Day 7, with Day 1 being the day of
vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.

The investigator or appropriately qualified designee reviews the e-diary data online following
vaccination to evaluate participant compliance and as part of the ongoing safety review.
Daily review is optimal during the active diary period.

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8.11.3.2. Visit 2 – Vaccination 2: (19 to 23 Days or 56 to 70 Days After Visit 1)
The window for Visit 2 is dependent on the dosing schedule(s) selected for Stage 3.

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It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



Review the participant’s e-diary data. Collect stop dates of any e-diary events ongoingon the last day that the e-diary was completed and record stop dates in the CRF if
required.

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met. If not, the participant should not receive further study intervention but willremain in the study to be evaluated for safety, immunogenicity, and potential efficacy(see Section 7.1).

Measure the participant’s body temperature.

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection
site and a thermometer for recording daily temperatures.
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Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and ask the participant to complete the
e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.

The investigator or appropriately qualified designee reviews the e-diary data online following
vaccination to evaluate participant compliance and as part of the ongoing safety review.
Daily review is optimal during the active diary period.
8.11.3.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2): (28 to 35 Days After
Visit 2)


Record AEs as described in Section 8.3.



Review the participant’s e-diary data. Collect stop dates of any e-diary events ongoingon the last day that the e-diary was completed and record stop dates in the CRF if
required.



Record nonstudy vaccinations as described in Section 6.5.
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

Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Collect the participant’s e-diary or assist the participant to remove the study applicationfrom his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.11.3.4. Visit 4 – 6-Month Safety Telephone Contact: (154 to 168 Days After Visit 2)Contact the participant by telephone in order to obtain the following information.



Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.3.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.3.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 2)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.3.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 2)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction
If a Grade 3 local reaction (Section 8.2.2.2), systemic event (Section 8.2.2.3), or fever(Section 8.2.2.4) is reported in the e-diary, a telephone contact should occur to ascertain
further details and determine whether a site visit is clinically indicated. If suspected Grade 4
local reaction (Section 8.2.2.2), systemic event (Section 8.2.2.3), or fever (Section 8.2.2.4) isreported in the e-diary, a telephone contact or site visit should occur to confirm whether the
event meets the criteria for Grade 4.
A site visit must be scheduled as soon as possible to assess the participant unless any of thefollowing is true:The participant is unable to attend the unscheduled visit.

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The local reaction/systemic event is no longer present at the time of the telephone
contact.



The participant recorded an incorrect value in the e-diary (confirmation of an e-diary data
entry error).



The PI or authorized designee determined it was not needed.

This telephone contact will be recorded in the participant’s source documentation and theCRF.
If the participant is unable to attend the unscheduled visit, or the PI or authorized designee
determined it was not needed, any ongoing local reactions/systemic events must be assessedat the next study visit.

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During the unscheduled visit, the reactions should be assessed by the investigator or a
medically qualified member of the study staff such as a study physician or a study nurse, asapplicable to the investigator’s local practice, who will:Measure body temperature (°F/°C).

Measure minimum and maximum diameters of redness (if present).

Measure minimum and maximum diameters of swelling (if present).



Assess injection site pain (if present) in accordance with the grades provided in
Section 8.2.2.2.

Assess systemic events (if present) in accordance with the grades provided in
Section 8.2.2.3.

Assess for other findings associated with the reaction and record on the AE page of the
CRF, if appropriate.

The investigator or an authorized designee will complete the unscheduled visit assessment
page of the CRF.
8.13. COVID-19 Disease Surveillance (All Participants)
If a participant experiences any of the following, he or she is instructed to contact the site
immediately, and if confirmed, participate in a telehealth visit as soon as possible, optimallywithin 3 days of symptom onset. Note that this does not substitute for a participant’s routine
medical care. Therefore participants should be encouraged to seek care, if appropriate, fromtheir usual provider.


A diagnosis of COVID-19;
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Fever;

New or increased cough;

New or increased shortness of breath;New or increased sore throat;

New or increased wheezing;New or increased sputum production;New or increased nasal congestion;New or increased nasal discharge;



Loss of taste/smell.

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8.13.1. Potential COVID-19 Illness Telehealth Visit: (Optimally Within 3 Days After
Potential COVID-19 Illness Onset)
This telehealth visit is expected to involve the sharing of healthcare information and services
via telecommunication technologies (eg, audio, video, video-conferencing software)remotely, thus allowing the participant and investigator to communicate on aspects of clinicalcare.
As a participant’s COVID-19 illness may evolve over time, several telehealth contacts may
be required to obtain the following information:


Record AEs, as appropriate as described in Section 8.3.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Instruct the participant to self-collect a nasal (midturbinate) swab and ship for assessment
at the central laboratory. The result from this swab will be provided to the site once it isavailable, but this will not be in real time, and cannot be relied upon to direct clinicalcare. Therefore, the participant should be encouraged to seek care, if appropriate, fromhis or her usual provider.

Collect COVID-19–related standard-of-care clinical and laboratory information. This
includes, but is not limited to:Symptoms

Clinical diagnosis
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

Local laboratory COVID-19 test resultFull blood countC-reactive protein

Number and type of any healthcare contact; duration of hospitalization and intensive
care unit stay

Need for oxygen therapy



Need for ventilation



Schedule an appointment for the participant to return for the potential COVID-19
convalescent visit once he or she has recovered.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After Potential
COVID-19 Illness Visit)

Record AEs, as appropriate as described in Section 8.3.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Collect/update COVID-19–related clinical and laboratory information (detailed in
Section 8.13.1).

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

9. STATISTICAL CONSIDERATIONS
Methodology for summary and statistical analyses of the data collected in this study is
described here and further detailed in a statistical analysis plan (SAP), which will bemaintained by the sponsor. The SAP may modify what is outlined in the protocol whereappropriate; however, any major modifications of the primary endpoint definitions or theiranalyses will also be reflected in a protocol amendment.

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9.1. Estimands and Statistical Hypotheses
9.1.1. Estimands
The estimand corresponding to each primary, secondary, and tertiary/exploratory objective is
described in the table in Section 3.
In the primary safety objective evaluations, missing e-diary data will not be imputed.
Missing AE dates will be imputed according to Pfizer safety rules. No other missing
information will be imputed in the safety analysis.

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)The estimands to evaluate the immunogenicity objectives are based on evaluable populations
for immunogenicity (Section 9.3). These estimands estimate the vaccine effect in the
hypothetical setting where participants follow the study schedules and protocol requirements
as directed. Missing antibody results will not be imputed. Immunogenicity results that are
below the LLOQ will be set to 0.5 × LLOQ in the analysis; this may be adjusted once
additional data on the assay characteristics become available.
The estimands to evaluate the efficacy objectives are based on evaluable populations for
efficacy (Section 9.3). These estimands estimate the vaccine effect in the hypotheticalsetting where participants follow the study schedules and protocol requirements as directed.
Missing laboratory results will not be imputed for the primary analysis, but missing data
imputation for the efficacy endpoint may be performed as a sensitivity analysis.
9.1.2. Statistical Hypotheses
At the end of Stage 3, the vaccine efficacy (VE) will be evaluated. VE is defined as
VE = 100 × (1 – IRR), where IRR is the illness rate ratio, the calculated ratio of the
COVID-19 illness rate in the active vaccine group to the incidence rate in the placebo group.
The efficacy hypothesis is:
H0: VE ≤20% vs Ha: VE >20%
where H0 and Ha represent null hypothesis and alternative hypothesis. For participants withmultiple illnesses, only the first COVID-19 confirmed case will contribute to the VE
calculation in the hypothesis test.
The efficacy will be demonstrated if the null hypothesis VE ≤20% is rejected at the 0.025
significance level, that is, when the lower limit of the 2-sided 95% CI for VE is >20%, which
is derived using the Clopper-Pearson method as described by Agresti.99.2. Sample Size Determination
The study sample size for the first 2 stages of the study is not based on any statistical
hypothesis testing. Stage 1 will comprise 15 participants (randomization ratio of 4:1 so that
12 receive active vaccine and 3 receive placebo) per group; up to 56 potential groups areforeseen; if all groups are fully enrolled, assuming 2 dose levels are selected following theinitial dose escalation, this corresponds to a total of 840 participants. Stage 2 will include 1 or
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more vaccine groups selected from Stage 1, and 225 participants will be randomized per
selected vaccine candidate in a 4:1 ratio to receive active vaccine (180 participants) orplacebo (45 participants).
For Stage 3, for the selected vaccine candidate/dose level, with assumptions of a true vaccine
efficacy (VE) of 70%, 53 cases of COVID-19 will provide 90% power to conclude true
VE >20%. This would be achieved with 3000 participants per group (1:1 randomization
ratio), based on the assumption of a 1.7% incidence rate in the placebo group, and 20% of theparticipants being nonevaluable.
For safety outcomes, Table 5 shows the probability of observing at least 1 AE for a given
true event rate of a particular AE, for various sample sizes. For example, if the true AE rate
is 10%, with 12 participants in a vaccine group, there is 72% probability of observing at least
1 AE.

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Table 5.

Probability of Observing at Least 1 AE by Assumed True Event Rates
With Different Sample Sizes

Assumed True Event
Rate of an AE
0.10%
0.50%
1.00%
2.00%
3.00%
5.00%
7.00%
10.00%

N=12

N=45

N=180

N=3000

0.01
0.06
0.11
0.22
0.31
0.46
0.58
0.72

0.04
0.20
0.36
0.60
0.75
0.90
0.96
0.99

0.16
0.59
0.84
0.97
>0.99
>0.99
>0.99
>0.99

0.95
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

9.3. Analysis Sets
For purposes of analysis, the following populations are defined:
Population
Enrolled
Randomized
Dose 1 evaluable
immunogenicity

Dose 2 evaluable
immunogenicity

Description
All participants who have a signed ICD.
All participants who are assigned a randomization number in
the IWR system.
All eligible randomized participants who receive the vaccine
to which they are randomly assigned at the first dose, have atleast 1 valid and determinate immunogenicity result 21 days
after Dose 1, have blood collection within an appropriate
window after Dose 1, and have no other major protocol
deviations as determined by the clinician.
All eligible randomized participants who receive 2 doses ofthe vaccine to which they are randomly assigned, within thepredefined window, have at least 1 valid and determinate

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Population

Dose 1 all-available
immunogenicity
Dose 2 all-available
immunogenicity
Evaluable efficacy

All-available efficacy

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SafetyDescription
immunogenicity result after Dose 2, have blood collection
within an appropriate window after Dose 2, and have no othermajor protocol deviations as determined by the clinician.
All participants who receive at least 1 dose of the study
intervention with at least 1 valid and determinate
immunogenicity result after Dose 1 but before Dose 2.
All participants who receive at least 1 dose of the study
intervention with at least 1 valid and determinate
immunogenicity result after Dose 2.
All eligible randomized participants who receive
vaccination(s) as randomized within the predefined window,
have the efficacy measurement after the last dose of study
intervention, and have no other major protocol deviations as
determined by the clinician.
All eligible randomized participants who receive at least
1 vaccination and have the efficacy measurement at any timeafter Dose 1.
All randomized participants who receive at least 1 dose of thestudy intervention.

9.4. Statistical Analyses
The SAP will be developed and finalized before database lock for any of the planned
analyses in Section 9.5.1. It will describe the participant populations to be included in theanalyses and the procedures for accounting for missing, unused, and spurious data. Thissection provides a summary of the planned statistical analyses of the primary, secondary, andtertiary/exploratory endpoints.
9.4.1. Immunogenicity Analyses
The statistical analysis of immunogenicity results will be primarily based on the evaluable
immunogenicity populations as defined in Section 9.3.
An additional analysis will be performed based on the all-available populations if there is alarge enough difference in sample size between the all-available immunogenicity populationand the evaluable immunogenicity population. Participants will be summarized according to
the vaccine group to which they were randomized.

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Endpoint
Secondaryimmunogenicity

Statistical Analysis Methods
Geometric mean titers/concentrations (GMTs/GMCs) of
SARS-CoV-2 serum neutralizing titers and SARS-CoV-2
S1-specific binding antibody and RBD-specific binding antibody

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2
S1-specific binding antibody levels and RBD-specific binding antibody
levels, GMTs/GMCs and 2-sided 95% CIs will be provided for each
investigational product (active/placebo) within each group before
vaccination and at each of the following time points:
Stage 1 sentinel cohorts: 7 and 21 days after Dose 1; 7 and
14 days and 1, 6, 12 and 24 months after Dose 2

Stage 1 nonsentinel cohorts and Stage 2 cohorts: 21 days after
Dose 1; 14 days and 1, 6, 12, and 24 months after Dose 2

Stage 3 cohort(s): 1, 12, and 24 months after Dose 2

Geometric means and the associated 2-sided CIs will be derived by
calculating means and CIs on the natural log scale based on thet-distribution, and then exponentiating the results.
GMFRs of SARS-CoV-2 serum neutralizing titers and
SARS-CoV-2 S1-specific binding antibody and RBD-specificbinding antibody
For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2
S1-specific antibody levels and RBD-specific binding antibody levels,
the GMFRs and 2-sided 95% CIs will be provided for each
investigational product within each group at each of the following time
points:Stage 1 sentinel cohorts: 7 and 21 days after Dose 1; 7 and
14 days and 1, 6, 12, and 24 months after Dose 2

Stage 1 nonsentinel cohorts and Stage 2 cohorts: 21 days after
Dose 1; 14 days and 1, 6, 12, and 24 months after Dose 2

Stage 3 cohort(s): 1, 12, and 24 months after Dose 2

GMFRs will be limited to participants with nonmissing values prior to
the first dose and at the postvaccination time point. The GMFR will becalculated as the mean of the difference of logarithmically transformed
assay results (later time point – earlier time point) and transformed
back to the original scale. Two-sided CIs will be obtained by
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Endpoint

Statistical Analysis Methods
calculating CIs using Student’s t-distribution for the mean difference ofthe logarithmically transformed assay results and transforming thelimits back to the original scale.
Percentage of participants with ≥4-fold rise in SARS-CoV-2 serum
neutralizing titers and SARS-CoV-2 S1-specific binding antibody
and RBD-specific binding antibody

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2
S1-specific antibody levels and RBD-specific binding antibody levels,
percentages (and 2-sided 95% CIs) of participants with ≥4-fold rise
will be provided for each investigational product within each group ateach of the following time points:
Stage 1 sentinel cohorts: 7 and 21 days after Dose 1; 7 and
14 days and 1, 6, 12, and 24 months after Dose 2

Stage 1 nonsentinel cohorts and Stage 2 cohorts: 21 days after
Dose 1; 14 days and 1, 6, 12, and 24 months after Dose 2

Stage 3 cohort(s): 1, 12, and 24 months after Dose 2

The Clopper-Pearson method will be used to calculate the CIs.
GMR of SARS-CoV-2 serum neutralizing titer to SARS-CoV-2
S1-specific antibody and SARS-CoV-2 RBD-specific binding
antibody
For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2
S1-specific binding antibody levels and RBD-specific binding antibody
levels, the GMRs and 2-sided 95% CIs will be provided for each
investigational product within each group at each of the following time
points:Stage 1 sentinel cohorts: 7 and 21 days after Dose 1; 7 and
14 days and 1, 6, 12, and 24 months after Dose 2

Stage 1 nonsentinel cohorts and Stage 2 cohorts: 21 days after
Dose 1; 14 days and 1, 6, 12, and 24 months after Dose 2

Stage 3 Cohort(s): 1, 12, and 24 months after Dose 2

GMRs will be limited to participants with nonmissing values for both
SARS-CoV-2 serum neutralizing titers and SARS-CoV-2 S1-specific
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Endpoint

Statistical Analysis Methods
antibody/SARS-CoV-2 RBD-specific binding antibody at each time
point. The GMR will be calculated as the mean of the difference oflogarithmically transformed assay results (eg, SARS-CoV-2 serum
neutralizing titers minus SARS-CoV-2 S1-specific antibody for eachparticipant) and transformed back to the original scale. Two-sided CIs
will be obtained by calculating CIs using Student’s t-distribution forthe mean difference of the logarithmically transformed assay results
and transforming the limits back to the original scale.
The same analysis methods will be applied to the immunogenicity
endpoints in Stages 2 and 3. For all the immunogenicity endpoints, theanalysis will be based on the Dose 1 and Dose 2 evaluable
immunogenicity populations. An additional analysis will be performed
based on the all-available immunogenicity populations if there is alarge enough difference in sample size between the all-available
immunogenicity populations and the evaluable immunogenicity
populations. Participants will be summarized according to the vaccine
group to which they were randomized. Missing serology data will not
be imputed.

Tertiary/
exploratory
immunogenicity

Correlation of an RT-PCR–confirmed COVID-19 infection andseropositivity/seroconversion measured by nonvaccine antigen
SARS-CoV-2 antibody
If sufficient data are collected, percentages (and 2-sided 95% CIs) ofparticipants with confirmed COVID-19 and nonvaccine antigen SARSCoV-2 antibody levels after Dose 1 and after Dose 2 will be provided.
RCDCs for immunogenicity results
Empirical RCDCs will be provided for SARS-CoV-2 serum
neutralizing titers, SARS-CoV-2 S1-specific antibody, and RBDspecific binding antibody after Dose 1 and after Dose 2.

9.4.2. Efficacy Analyses
The statistical analysis of efficacy will be based on the evaluable efficacy population(primary analysis) and the all-available efficacy population as defined in Section 9.3.

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Endpoint
Statistical Analysis Methods
Secondary efficacy Ratio of COVID-19 incidence per 1000 person-years of follow-up
for the active vaccine group to the placebo group
Vaccine efficacy will be estimated by 100 × (1 – IRR), where IRR is
the illness rate ratio, the calculated ratio of COVID-19 infection
incidence per 1000 person-years follow-up in the active vaccine groupto the corresponding incidence in the placebo group after 2 doses. The
2-sided 95% CI for VE will be derived using the Clopper-Pearson
method.

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)The analysis will be based on the evaluable efficacy population and the
all-available efficacy population. For the primary analysis, missing
efficacy data will not be imputed. A sensitivity analysis may be
performed by imputing missing values; details will be provided in the
SAP.

9.4.3. Safety Analyses
Endpoint
PrimaryStatistical Analysis Methods
Descriptive statistics will be provided for each reactogenicity
endpoint for each dose and vaccine group. Local reactions andsystemic events from Day 1 through Day 7 after each vaccination
will be presented by severity cumulatively across severity levels.
Descriptive summary statistics will include counts and percentagesof participants with the indicated endpoint and the associatedClopper-Pearson 95% CIs.

For Stage 1 sentinel cohorts, descriptive statistics will be provided
for abnormal hematology and chemistry laboratory values at 1 and7 days after Dose 1 and 7 days after Dose 2, including grading
shifts in hematology and chemistry laboratory assessments
between baseline and 1 and 7 days after Dose 1, and before Dose 2
and 7 days after Dose 2. Descriptive summary statistics will
include counts and percentages of participants with the indicatedendpoint and the associated Clopper-Pearson 2-sided 95% CIs.



AEs will be categorized according to the Medical Dictionary forRegulatory Activities (MedDRA) terms. A 3-tier approach will be
used to summarize AEs. Under this approach AEs are classified
into 1 of 3 tiers: (1) Tier 1 events are prespecified events ofclinical importance and are identified in a list in the product’s
safety review plan; (2) Tier 2 events are those that are not Tier 1
but are considered “relatively common”; a MedDRA preferred

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Endpoint

Statistical Analysis Methods
term is defined as a Tier 2 event if there are at least 1% ofparticipants in at least 1 vaccine group reporting the event; and (3)Tier 3 events are those that are neither Tier 1 nor Tier 2 events.
For both Tier 1 and Tier 2 events, 2-sided 95% CIs for thedifference between the vaccine and placebo groups in thepercentage of participants reporting the events based on the
Miettinen and Nurminen method10 will be provided. In addition,
for Tier 1 events, the asymptotic p-values will also be presented
for the difference between groups in the percentage of participants
reporting the events, based on the same test statistic and under theassumption that the test statistic is asymptotically normally
distributed.

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)Descriptive summary statistics (counts, percentages, andassociated Clopper-Pearson 95% CIs) will be provided for any
AE events for each vaccine group.



SAEs will be categorized according to MedDRA terms. Counts,
percentages, and the associated Clopper-Pearson 95% CIs of SAEs
from Dose 1 to 6 months after last dose will be provided for eachvaccine group.

The safety analyses are based on the safety population.
Participants will be summarized by vaccine group according to theinvestigational products they actually received. Missing e-diarydata will not be imputed; missing AE dates will be handledaccording to the Pfizer safety rules.

Secondary

Not applicable (N/A)

Exploratory

N/A

9.4.4. Other Analyses
The ratios of (GMFR A to GMFR B) and (GMFR A to GMFR C) may be explored, where
GMFR A is the geometric mean of the ratio of the SARS-CoV-2 serum neutralizing titer at
the postvaccination time point to the corresponding titer at the prevaccination time point,
GFMR B is the geometric mean of the ratio of the SARS-CoV-2 S1-specific binding
antibody level at the postvaccination time point to the corresponding antibody level at theprevaccination time point, and GMFR C is the geometric mean of the ratio of the
SARS-CoV-2 RBD-specific binding antibody level at the postvaccination time point to thecorresponding antibody level at the prevaccination time point.

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9.5. Interim Analyses
No formal interim analysis is planned in this study. As this is a sponsor open-label study
during Stages 1 and 2, the sponsor may conduct unblinded reviews of the data during thecourse of the study for the purpose of safety assessment, facilitating dose escalation
decisions, and/or supporting clinical development.
9.5.1. Analysis Timing

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Statistical analyses will be carried out when the following data are available:Complete safety and immunogenicity analysis approximately 3 weeks after Dose 2 forStage 1.

Complete safety and immunogenicity analysis approximately 3 weeks after Dose 2 forStage 2.

Complete safety and immunogenicity analysis approximately 6 months after Dose 2 for
all participants in Stage 3.

Complete efficacy and persistence-of-immunogenicity analysis after complete data are
available at the end of the study.

9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will use an IRC and a DMC. The IRC is independent of the study team andincludes only internal members. The DMC is independent of the study team and includes
only external members. The IRC and DMC charters describe the role of the IRC and DMC
in more detail.
The responsibilities of the IRC will include:

Review of safety data to permit dose escalations in the 18- to 55-year age cohort



Review of safety data in the case of a stopping rule being met

Review of safety and/or immunogenicity data to:Allow groups of participants of 65 to 85 years of age to proceed

Select vaccine candidate(s)/dose level(s) and schedule(s) to proceed into Stage 2.
Data supporting the selection, including results for both binding antibody levels andserum neutralizing titers, and the ratio between them, will also be submitted to the
FDA for reviewSelect vaccine candidate(s)/dose level(s) and schedule(s) to proceed into Stage 3.
Data supporting the selection, including results for both binding antibody levels and
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serum neutralizing titers, and the ratio between them, will also be submitted to the
FDA for review


Review of any available safety and/or immunogenicity data generated during the courseof this study, or the BioNTech study conducted in Germany, to determine:Whether any groups may not be started



Whether any groups may be terminated earlyWhether any groups may be added with dose levels below the lowest stated dose orintermediate between the lowest and highest stated doses

Contemporaneous review of all NAAT-confirmed COVID-19 illnesses

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)The DMC will be responsible for ongoing monitoring of the safety of participants in the
study according to the charter. This may include, but is not limited to:Contemporaneous review of related AEs up to 1 month after completion of thevaccination scheduleContemporaneous review of all SAEs up to 6 months after completion of the vaccination
schedule

Contemporaneous review of all NAAT-confirmed COVID-19 illnesses

The recommendations made by the DMC to alter the conduct of the study will be forwarded
to the appropriate Pfizer personnel for final decision. Pfizer will forward such decisions,which may include summaries of aggregate analyses of safety data, to regulatory authorities,
as appropriate.

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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:Consensus ethical principles derived from international guidelines including the
Declaration of Helsinki and CIOMS International Ethical Guidelines;Applicable ICH GCP guidelines;Applicable laws and regulations, including applicable privacy laws.

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents(eg, advertisements) must be reviewed and approved by the sponsor and submitted to an
IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study is
initiated.
Any amendments to the protocol will require IRB/EC approval before implementation ofchanges made to the study design, except for changes necessary to eliminate an immediate
hazard to study participants.
The investigator will be responsible for the following:Providing written summaries of the status of the study to the IRB/EC annually or more
frequently in accordance with the requirements, policies, and procedures established by
the IRB/EC;



Notifying the IRB/EC of SAEs or other significant safety findings as required by IRB/EC
procedures;Providing oversight of the conduct of the study at the site and adherence to requirementsof 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014 for clinicalstudies (if applicable), and all other applicable local regulations.

10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicableregulatory authority in any area of the world, or if the investigator is aware of any new
information that might influence the evaluation of the benefits and risks of the study
intervention, Pfizer should be informed immediately.
In addition, the investigator will inform Pfizer immediately of any urgent safety measurestaken by the investigator to protect the study participants against any immediate hazard, andof any serious breaches of this protocol or of ICH GCP that the investigator becomes awareof.
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10.1.2. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to theparticipant and answer all questions regarding the study. The participant should be given
sufficient time and opportunity to ask questions and to decide whether or not to participate in
the trial.
Participants must be informed that their participation is voluntary. Participants will be
required to sign a statement of informed consent that meets the requirements of 21 CFR 50,
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/EC
or study center.
The investigator must ensure that each study participant is fully informed about the natureand objectives of the study, the sharing of data related to the study, and possible risks
associated with participation, including the risks associated with the processing of theparticipant’s personal data.

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)The participant must be informed that his/her personal study-related data will be used by thesponsor in accordance with local data protection law. The level of disclosure must also be
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical
Quality Assurance auditors or other authorized personnel appointed by the sponsor, byappropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or
her right to access and correct his or her personal data and to withdraw consent for theprocessing of his or her personal data.
The medical record must include a statement that written informed consent was obtained
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their
participation in the study.
A copy of the ICD(s) must be provided to the participant. Participants who are rescreened are
required to sign a new ICD.
Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate
section that addresses the use of samples for optional additional research. The optional
additional research does not require the collection of any further samples. The investigator
or authorized designee will explain to each participant the objectives of the additional
research. Participants will be told that they are free to refuse to participate and may
withdraw their consent at any time and for any reason during the storage period.

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10.1.3. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementationof organizational and technical measures to ensure protection of participant data.

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Participants’ personal data will be stored at the study site in encrypted electronic and/or paper
form and will be password protected or secured in a locked room to ensure that only
authorized study staff have access. The study site will implement appropriate technical andorganizational measures to ensure that the personal data can be recovered in the event ofdisaster. In the event of a potential personal data breach, the study site will be responsiblefor determining whether a personal data breach has in fact occurred and, if so, providing
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personaldata, participants will be assigned a single, participant-specific numerical code. Any
participant records or data sets that are transferred to the sponsor will contain the numericalcode; participant names will not be transferred. All other identifiable data transferred to thesponsor will be identified by this single, participant-specific code. The study site will
maintain a confidential list of participants who participated in the study, linking eachparticipant’s numerical code to his or her actual identity and medical record identification. In
case of data transfer, the sponsor will protect the confidentiality of participants’ personal dataconsistent with the clinical study agreement and applicable privacy laws.
10.1.4. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting theresults of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or
www.pfizer.com, and other public registries in accordance with applicable local
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, andcomplete manner and are reported regardless of the outcome of the study or the country inwhich the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional
studies (conducted in patients) that evaluate the safety and/or efficacy of a product,
regardless of the geographical location in which the study is conducted. These results are
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies inaccordance with the format and timelines set forth by EU requirements.

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www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used
to identify individual participants have been removed) on www.pfizer.com for
Pfizer-sponsored interventional studies at the same time the corresponding study results areposted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinicaldata to the EMA website. Clinical data, under Phase 1 of this policy, includes clinicaloverviews, clinical summaries, CSRs, and appendices containing the protocol and protocol
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of thispolicy, includes the publishing of individual participant data. Policy 0070 applies to newmarketing authorization applications submitted via the centralized procedure since
01 January 2015 and applications for line extensions and for new indications submitted via
the centralized procedure since 01 July 2015.

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Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposesof “bona-fide scientific research” that contributes to the scientific understanding of thedisease, target, or compound class. Pfizer will make available data from these trials
24 months after study completion. Patient-level data will be anonymized in accordance withapplicable privacy laws and regulations. CSRs will have personally identifiable information
redacted.
Data requests are considered from qualified researchers with the appropriate competencies toperform the proposed analyses. Research teams must include a biostatistician. Data will not
be provided to applicants with significant conflicts of interest, including individuals
requesting access for commercial/competitive or legal purposes.
10.1.5. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unlesstransmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is
responsible for verifying that data entries are accurate and correct by physically orelectronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports theinformation entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted
electronic and/or paper form and are password protected or secured in a locked room toprevent access by unauthorized third parties.

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The investigator must permit study-related monitoring, audits, IRB/EC review, andregulatory agency inspections and provide direct access to source data documents. This
verification may also occur after study completion. It is important that the investigator(s)and their relevant personnel are available during the monitoring visits and possible audits orinspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality
such as risk management and mitigation strategies and analytical risk-based monitoring),
methods, responsibilities, and requirements, including handling of noncompliance issues andmonitoring techniques (central, remote, or on-site monitoring), are provided in themonitoring plan.

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)The sponsor or designee is responsible for the data management of this study, including
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data enteredinto the CRF by authorized site personnel are accurate, complete, and verifiable from source
documents; that the safety and rights of participants are being protected; and that the study is
being conducted in accordance with the currently approved protocol and any other study
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must
be retained by the investigator for 15 years after study completion unless local regulations or
institutional policies require a longer retention period. No records may be destroyed during
the retention period without the written approval of the sponsor. No records may betransferred to another location or party without written notification to the sponsor. The
investigator must ensure that the records continue to be stored securely for as long as they are
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of suchdata are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory
inspection notification in relation to the study. Furthermore, the investigator will cooperatewith the sponsor or its agents to prepare the investigator site for the inspection and will allow
the sponsor or its agent, whenever feasible, to be present during the inspection. The
investigator site and investigator will promptly resolve any discrepancies that are identified
between the study data and the participant's medical records. The investigator will promptly
provide copies of the inspection findings to the sponsor or its agent. Before response
submission to the regulatory authorities, the investigator will provide the sponsor or its
agents with an opportunity to review and comment on responses to any such findings.

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10.1.6. Source Documents
Source documents provide evidence for the existence of the participant and substantiate theintegrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be
consistent with the source documents or the discrepancies must be explained. The
investigator may need to request previous medical records or transfer records, depending on
the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the study monitoring plan.
Description of the use of computerized system is documented in the Data Management Plan.
10.1.7. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment ofparticipants.

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)The first act of recruitment is the date of the first participant’s first visit and will be the study
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any
time for any reason at the sole discretion of the sponsor. Study sites will be closed uponstudy completion. A study site is considered closed when all required documents and study
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor
or designee if requested to do so by the responsible IRB/EC or if such termination is required
to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limitedto:

Failure of the investigator to comply with the protocol, the requirements of the IRB/EC
or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.

If the study is prematurely terminated or suspended, the sponsor shall promptly inform theinvestigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of
the reason for termination or suspension, as specified by the applicable regulatory
requirements. The investigator shall promptly inform the participant and should assure
appropriate participant therapy and/or follow-up.

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Study termination is also provided for in the clinical study agreement. If there is any conflict
between the contract and this protocol, the contract will control as to termination rights.
10.1.8. Sponsor’s Qualified Medical Personnel

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)The contact information for the sponsor's appropriately qualified medical personnel for the
study is documented in the study contact list located in the supporting study documentation.
To facilitate access to appropriately qualified medical personnel on study-related medical
questions or problems, participants are provided with a contact card at the time of informed
consent. The contact card contains, at a minimum, protocol and study intervention
identifiers, participant numbers, contact information for the investigator site, and contact
details for a contact center in the event that the investigator site staff cannot be reached toprovide advice on a medical question or problem originating from another healthcare
professional not involved in the participant’s participation in the study. The contact number
can also be used by investigator staff if they are seeking advice on medical questions or
problems; however, it should be used only in the event that the established communication
pathways between the investigator site and the study team are not available. It is therefore
intended to augment, but not replace, the established communication pathways between theinvestigator site and the study team for advice on medical questions or problems that may
arise during the study. The contact number is not intended for use by the participant directly,
and if a participant calls that number, he or she will be directed back to the investigator site.

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10.2. Appendix 2: Clinical Laboratory Tests

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)The following safety laboratory tests will be performed at times defined in the SoA section ofthis protocol. Additional laboratory results may be reported on these samples as a result of
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived
from calculated values. These additional tests would not require additional collection ofblood. Unscheduled clinical laboratory measurements may be obtained at any time during
the study to assess any perceived safety issues.
Hematology
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet countWBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)Basophils (Abs)
Lymphocytes (Abs)

Chemistry
BUN and creatinine
AST, ALT
Total bilirubin
Alkaline phosphatase

Other Urine pregnancy test (β-hCG)
At screening only: Hepatitis B core antibody
 Hepatitis B surface antigen
 Hepatitis C antibody
 Human immunodeficiency virus

Investigators must document their review of each laboratory safety report.
Clinically significant abnormal laboratory findings should be recorded in the AE CRF in
accordance with the following grading scale (Table 6).
Table 6.
Hematology

Laboratory Abnormality Grading Scale
Mild (Grade 1)

Moderate(Grade 2)

Severe (Grade 3)

Hemoglobin
11.0 – 12.0
(Female) - g/dL
Hemoglobin
12.5 – 13.5
(Male) - g/dL
WBC increase 10,800 – 15,000
cells/mm3
WBC decrease 2,500 – 3,500
cells/mm3
Lymphocytes
750 – 1,000
decrease - cells/mm3
Neutrophils decrease 1,500 – 2,000- cells/mm3

9.5 – 10.9

8.0 – 9.4

Potentially Life
Threatening(Grade 4)<8.0

10.5 – 12.4

8.5 – 10.4

<8.5

15,001 – 20,000

20,001 – 25, 000>25,000

1,500 – 2,499

1,000 – 1,499<1,000500 – 749

250 – 499

<250

1,000 – 1,499

500 – 999

<500

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Table 6.

Laboratory Abnormality Grading Scale

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Hematology

Mild (Grade 1)

Moderate(Grade 2)

Severe (Grade 3)

Eosinophils 650 – 1500
cells/mm3
Platelets decreased - 125,000 – 140,000
cells/mm3
Chemistry
Mild (Grade 1)

1501 - 5000

>5000

Potentially Life
Threatening(Grade 4)Hypereosinophilic

100,000 – 124,000

25,000 – 99,000<25,000

Moderate(Grade 2)

Severe(Grade 3)

BUN - mg/dL
Creatinine – mg/dL

23 – 26
1.5 – 1.7

27 – 31
1.8 – 2.0> 31
2.1 – 2.5

Alkaline
phosphate –increase by factor
Liver function tests– ALT, AST
increase by factor
Bilirubin – whenaccompanied
by any increase inliver function test increase by factor
Bilirubin – whenliver function test is
normal - increase byfactor

1.1 – 2.0 x ULN

2.1 – 3.0 x ULN

3.1 – 10 x ULN

Potentially Life
Threatening(Grade 4)
Requires dialysis> 2.5 or requires
dialysis>10 x ULN

1.1 – 2.5 x ULN

2.6 – 5.0 x ULN

5.1 – 10 x ULN>10 x ULN

1.1 – 1.25 x ULN

1.26 – 1.5 x ULN

1.51 – 1.75 x ULN>1.75 x ULN

1.1 – 1.5 x ULN

1.6 – 2.0 x ULN

2.0 – 3.0 x ULN>3.0 x ULN

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen;
ULN = upper limit of normal; WBC = white blood cell.

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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition


An AE is any untoward medical occurrence in a patient or clinical study participant,temporally associated with the use of study intervention, whether or not consideredrelated to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including anabnormal laboratory finding), symptom, or disease (new or exacerbated) temporally
associated with the use of study intervention.

Events Meeting the AE Definition

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis)or other safety assessments (eg, ECG, radiological scans, vital sign measurements),
including those that worsen from baseline, considered clinically significant in the
medical and scientific judgment of the investigator Any abnormal laboratory test
results that meet any of the conditions below must be recorded as an AE:
Is associated with accompanying symptoms.



Requires additional diagnostic testing or medical/surgical intervention.



Leads to a change in study dosing (outside of any protocol-specified dose
adjustments) or discontinuation from the study, significant additional
concomitant drug treatment, or other therapy.



Exacerbation of a chronic or intermittent preexisting condition including either anincrease in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration eventhough it may have been present before the start of the study.



Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.



Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
intervention or a concomitant medication. Overdose per se will not be reported as
an AE/SAE unless it is an intentional overdose taken with possible suicidal/selfharming intent. Such overdoses should be reported regardless of sequelae.

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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safetyassessments which are associated with the underlying disease, unless judged by theinvestigator to be more severe than expected for the participant’s condition.



The disease/disorder being studied or expected progression, signs, or symptoms ofthe disease/disorder being studied, unless more severe than expected for theparticipant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).



Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present
or detected at the start of the study that do not worsen.

10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:a. Results in deathb. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which theparticipant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.

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In general, hospitalization signifies that the participant has been detained (usually involving
at least an overnight stay) at the hospital or emergency ward for observation and/or
treatment that would not have been appropriate in the physician’s office or outpatientsetting. Complications that occur during hospitalization are AEs. If a complication
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in
doubt as to whether “hospitalization” occurred or was necessary, the AE should beconsidered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen frombaseline is not considered an AE.

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)d. Results in persistent disability/incapacity


The term disability means a substantial disruption of a person’s ability to conduct
normal life functions.

This definition is not intended to include experiences of relatively minor medicalsignificance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza,
and accidental trauma (eg, sprained ankle) which may interfere with or prevent
everyday life functions but do not constitute a substantial disruption.

e. Is a congenital anomaly/birth defectf. Other situations:Medical or scientific judgment should be exercised in deciding whether SAE
reporting is appropriate in other situations such as important medical events that
may not be immediately life-threatening or result in death or hospitalization but may
jeopardize the participant or may require medical or surgical intervention to prevent
one of the other outcomes listed in the above definition. These events should
usually be considered serious.



Examples of such events include invasive or malignant cancers, intensive treatment
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or
convulsions that do not result in hospitalization, or development of drug dependency
or drug abuse.

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10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF andfor reporting serious adverse events on the Vaccines SAE Report Form to Pfizer Safety.
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious adverse
events (AEs); and (3) exposure to the study intervention under study during pregnancy orbreastfeeding, and occupational exposure.

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)It should be noted that the Vaccines SAE Report Form for reporting of SAE information is
not the same as the AE page of the CRF. When the same data are collected, the forms must
be completed in a consistent manner. AEs should be recorded using concise medical
terminology and the same AE term should be used on both the CRF and the Vaccines SAE
Report Form for reporting of SAE information.
Safety Event

Recorded on the CRF

Reported on the Vaccines
SAE Report Form to
Pfizer Safety Within 24
Hours of Awareness

SAE
Nonserious AE
Exposure to the study
intervention under study
during pregnancy orbreastfeeding, andoccupational exposure

All
All
None

All
None
All (and EDP supplemental
form for EDP)When an AE/SAE occurs, it is the responsibility of the investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostic
reports) related to the event.



The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s
medical records to Pfizer Safety in lieu of completion of the Vaccines SAE Report
Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases arerequested by Pfizer Safety. In this case, all participant identifiers, with the
exception of the participant number, will be redacted on the copies of the medical
records before submission to Pfizer Safety.
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The investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. Whenever possible, the diagnosis(not the individual signs/symptoms) will be documented as the AE/SAE.

Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during
the study and assign it to 1 of the following categories:

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)GRADE If required on the AE page of the CRF, the investigator will use theadjectives MILD, MODERATE, SEVERE, or LIFE-THREATENING todescribe the maximum intensity of the AE. For purposes of consistency,
these intensity grades are defined as follows:
1

MILD

Does not interfere with participant's usualfunction.

2

MODERATE

Interferes to some extent with participant's usualfunction.

3

SEVEREInterferes significantly with participant's usualfunction.

4

LIFE-THREATENING Life-threatening consequences; urgent
intervention indicated.

Assessment of Causality

The investigator is obligated to assess the relationship between study intervention
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence,
and/or arguments to suggest a causal relationship, rather than a relationship cannot
be ruled out.

The investigator will use clinical judgment to determine the relationship.



Alternative causes, such as underlying disease(s), concomitant therapy, and otherrisk factors, as well as the temporal relationship of the event to study intervention
administration, will be considered and investigated.

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The investigator will also consult the IB and/or product information, for marketed
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she
has reviewed the AE/SAE and has provided an assessment of causality.



There may be situations in which an SAE has occurred and the investigator has
minimal information to include in the initial report to the sponsor. However, it isvery important that the investigator always make an assessment of causality forevery event before the initial transmission of the SAE data to the sponsor.



The investigator may change his/her opinion of causality in light of follow-up
information and send an SAE follow-up report with the updated causality
assessment.



The causality assessment is one of the criteria used when determining regulatory
reporting requirements.



If the investigator does not know whether or not the study intervention caused theevent, then the event will be handled as “related to study intervention” for reporting
purposes, as defined by the sponsor. In addition, if the investigator determines thatan SAE is associated with study procedures, the investigator must record this causal
relationship in the source documents and CRF, and report such an assessment in the
dedicated section of the Vaccines SAE Report Form and in accordance with the
SAE reporting requirements.

Follow-up of AEs and SAEs


The investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by thesponsor to elucidate the nature and/or causality of the AE or SAE as fully as
possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other healthcare providers.



If a participant dies during participation in the study or during a recognizedfollow-up period, the investigator will provide Pfizer Safety with a copy of any
postmortem findings including histopathology.



New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours ofreceipt of the information.
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10.3.4. Reporting of SAEs

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SAE Reporting to Pfizer Safety via Vaccines SAE Report Form

Facsimile transmission of the Vaccines SAE Report Form is the preferred method totransmit this information to Pfizer Safety.



In circumstances when the facsimile is not working, notification by telephone isacceptable with a copy of the Vaccines SAE Report Form sent by overnight mail orcourier service.

Initial notification via telephone does not replace the need for the investigator tocomplete and sign the Vaccines SAE Report Form pages within the designatedreporting time frames.

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10.4. Appendix 4: Contraceptive Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during
the intervention period and for at least 28 days after the last dose of study intervention, whichcorresponds to the time needed to eliminate reproductive safety risk of the study
intervention(s):Refrain from donating sperm.

PLUS either:Be abstinent from heterosexual intercourse with a female of childbearing potential as
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) andagree to remain abstinent.

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Must agree to use a male condom when engaging in any activity that allows for passageof ejaculate to another person.



In addition to male condom use, a highly effective method of contraception may beconsidered in WOCBP partners of male participants (refer to the list of highly effective
methods below in Section 10.4.4).

10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using an acceptable contraceptive method as described below during
the intervention period (for a minimum of 28 days after the last dose of study
intervention). The investigator should evaluate the effectiveness of the contraceptive
method in relationship to the first dose of study intervention.

The investigator is responsible for review of medical history, menstrual history, and recent
sexual activity to decrease the risk for inclusion of a woman with an early undetected
pregnancy.

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10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot
be confirmed before the first dose of study intervention, additional evaluation should beconsidered.
Women in the following categories are not considered WOCBP:

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1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.

For individuals with permanent infertility due to an alternate medical cause other than theabove, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should beapplied to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s
review of the participant’s medical records, medical examination, or medical history
interview. The method of documentation should be recorded in the participant’s medical
record for the study.
2. Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause. In addition, ahigh FSH level in the postmenopausal range must be used to confirm apostmenopausal state in women under 60 years of age and not using hormonal
contraception or HRT.



Female on HRT and whose menopausal status is in doubt will be required to use
one of the nonestrogen hormonal highly effective contraception methods if theywish to continue their HRT during the study. Otherwise, they must discontinue
HRT to allow confirmation of postmenopausal status before study enrollment.

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10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations
regarding the use of contraceptive methods for those participating in clinical trials.
1. Implantable progestogen-only hormone contraception associated with inhibition ofovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner:

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Vasectomized partner is a highly effective contraceptive method provided that thepartner is the sole sexual partner of the woman of childbearing potential and theabsence of sperm has been confirmed. If not, an additional highly effective methodof contraception should be used. The spermatogenesis cycle is approximately
90 days.

6. Combined (estrogen- and progestogen-containing) hormonal contraception associatedwith inhibition of ovulation:


Oral;



Intravaginal;Transdermal;



Injectable.

7. Progestogen-only hormone contraception associated with inhibition of ovulation:


Oral;



Injectable.

8. Sexual abstinence:Sexual abstinence is considered a highly effective method only if defined as
refraining from heterosexual intercourse during the entire period of risk associatedwith the study intervention. The reliability of sexual abstinence needs to be evaluatedin relation to the duration of the study and the preferred and usual lifestyle of theparticipant.

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9. Progestogen-only oral hormonal contraception where inhibition of ovulation is not the
primary mode of action.
10. Male or female condom with or without spermicide.
11. Cervical cap, diaphragm, or sponge with spermicide.

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12. A combination of male condom with either cervical cap, diaphragm, or sponge with
spermicide (double-barrier methods).

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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations intransaminases) are termed “tolerators,” while those who show transient liver injury, but adapt
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of amore serious potential outcome. These participants fail to adapt and therefore are"susceptible" to progressive and serious liver injury, commonly referred to as DILI.
Participants who experience a transaminase elevation above 3 × ULN should be monitored
more frequently to determine if they are an “adaptor” or are “susceptible.”

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LFTs are not required as a routine safety monitoring procedure for all participants in thisstudy. However, should an investigator deem it necessary to assess LFTs because aparticipant presents with clinical signs/symptoms, such LFT results should be managed andfollowed as described below.
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will beelevated within the same laboratory sample). In rare instances, by the time TBili elevations
are detected, AST/ALT values might have decreased. This occurrence is still regarded as apotential DILI. Therefore, abnormal elevations in either AST OR ALT in addition to TBili
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law
criteria) cases and should always be considered important medical events, even before allother possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on theparticipant’s individual baseline values and underlying conditions. Participants who present
with the following laboratory abnormalities should be evaluated further as potential DILI
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:Participants with AST/ALT and TBili baseline values within the normal range who
subsequently present with AST OR ALT values >3 × ULN AND a TBili value >2 × ULN
with no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or notavailable.

For participants with baseline AST OR ALT OR TBili values above the ULN, thefollowing threshold values are used in the definition mentioned above, as needed,
depending on which values are above the ULN at baseline:Preexisting AST or ALT baseline values above the normal range: AST or ALT values>2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is smaller).

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Rises in AST/ALT and TBili separated by more than a few weeks should be assessedindividually based on clinical judgment; any case where uncertainty remains as to whether it
represents a potential Hy’s law case should be reviewed with the sponsor.

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)The participant should return to the investigator site and be evaluated as soon as possible,
preferably within 48 hours from awareness of the abnormal results. This evaluation should
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili for suspected cases ofHy’s law, additional laboratory tests should include albumin, CK, direct and indirect
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should
also be given to drawing a separate tube of clotted blood and an anticoagulated tube of bloodfor further testing, as needed, for further contemporaneous analyses at the time of therecognized initial abnormalities to determine etiology. A detailed history, including relevant
information, such as review of ethanol, acetaminophen/paracetamol (either by itself or as a
coformulated product in prescription or over-the-counter medications), recreational drug,
supplement (herbal) use and consumption, family history, sexual history, travel history,
history of contact with a jaundiced person, surgery, blood transfusion, history of liver orallergic disease, and potential occupational exposure to chemicals, should be collected.
Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary
tract) and collection of serum samples for acetaminophen/paracetamol drug and/or protein
adduct levels may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if noother reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law)cases are to be reported as SAEs, irrespective of availability of all the results of theinvestigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results ofreasonable investigations have been received and have excluded an alternative etiology.

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10.6. Appendix 6: Abbreviations

090177e1938f5b07\Approved\Approved On: 29-May-2020 13:08 (GMT)The following is a list of abbreviations that may be used in the protocol.
Abbreviation
2019-nCoV
Abs
AE
ALT
AST
-hCG
BMI
BUN
CBER
CFR
CI
CIOMS
CONSORT
COVID-19
CRF
CRO
CSR
CT
DILI
DMC
DNA
DU
EC
ECG
eCRF
e-diary
EDP
EMA
EU
EUA
EudraCT
FDA
FSH
GCP
GGT
GMC
GMFR
GMR
GMT

Term
novel coronavirus 2019absolute (in Appendix 2)
adverse event
alanine aminotransferase
aspartate aminotransferase
beta-human chorionic gonadotropin
body mass index
blood urea nitrogen
Center for Biologics Evaluation and Research
Code of Federal Regulations
confidence interval
Council for International Organizations of Medical Sciences
Consolidated Standards of Reporting Trials
coronavirus disease 2019case report form
contract research organization
clinical study reportclinical trial
drug-induced liver injury
data monitoring committee
deoxyribonucleic aciddosing unit
ethics committee
electrocardiogram
electronic case report form
electronic diary
exposure during pregnancy
European Medicines Agency
European Union
emergency use application
European Clinical Trials Database
Food and Drug Administration
follicle-stimulating hormone
Good Clinical Practice
gamma-glutamyl transferase
geometric mean concentrationgeometric mean fold risegeometric mean ratio
geometric mean titer

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Abbreviation
HBc Ab
HBsAg
HBV
HCV
HCV Ab
HIPAA
HIV
HRT
IB
ICD
ICH
ICU
ID
Ig
IgG
IgM
IMP
IND
INR
IP manual
IPAL
IRB
IRC
IRR
IRT
IV
IWR
LFT
LLOQ
LNP
LPX
MCH
MCHC
MCV
MedDRAMERS
modRNA
N/A
NAAT
NVA
P2 S

Term
hepatitis B core antibody
hepatitis B surface antigen
hepatitis B virus
hepatitis C virus
hepatitis C virus antibody
Health Insurance Portability and Accountability Act
human immunodeficiency virus
hormone replacement therapy
investigator’s brochure
informed consent document
International Council for Harmonisation
intensive care unit
identification
immunoglobulin
immunoglobulin G
immunoglobulin M
investigational medicinal productinvestigational new druginternational normalized ratio
investigational product manual
Investigational Product Accountability Log
institutional review board
internal review committee
illness rate ratio
interactive response technology
intravenous(ly)interactive Web-based response
liver function test
lower limit of quantitation
lipid nanoparticle
lipoplexmean corpuscular hemoglobinmean corpuscular hemoglobin concentration
mean corpuscular volume
Medical Dictionary for Regulatory Activities
Middle East respiratory syndrome
nucleoside-modified messenger ribonucleic acidnot applicable
nucleic acid amplification test
nonvaccine antigen
SARS-CoV-2 full-length, P2 mutant, “heads up,” prefusion spikeglycoprotein

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Abbreviation
PCR
PI
PPE
PT
RBC
RBD
RCDC
RNA
RSV
RT-PCR
S1
SAE
SAP
saRNA
SARS
SARS-CoV-2
SoA
SOP
SRSD
SUSAR
TBD
TBili
ULN
uRNA
US
vax
VE
WBC
WHO
WOCBP

Term
polymerase chain reaction
principal investigatorpersonal protective equipment
prothrombin time
red blood cell
receptor-binding domain
reverse cumulative distribution curve
ribonucleic acidrespiratory syncytial virus
reverse transcription–polymerase chain reaction
spike protein S1 subunit
serious adverse event
statistical analysis planself-amplifying messenger ribonucleic acidsevere acute respiratory syndrome
severe acute respiratory syndrome coronavirus 2schedule of activities
standard operating procedure
single reference safety document
suspected unexpected serious adverse reaction
to be determinedtotal bilirubin
upper limit of normal
unmodified messenger ribonucleic acid
United States
vaccination
vaccine efficacy
white blood cell
World Health Organization
woman/women of childbearing potential

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11. REFERENCES
1

World Health Organization. WHO Director-General's opening remarks at the media
briefing on COVID-19. Available from: https://www.who.int/dg/speeches/detail/whodirector-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march2020. Published: 11 Mar 2020. Accessed: 01 Apr 2020.

2

World Health Organization. Coronavirus disease 2019 (COVID-19) situation report - 70.
In: Data as reported by national authorities by 10:00 CET 30 March 2020. Geneva,
Switzerland: World Health Organization; 2020.

3

Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19):
therapeutic options. Available from: https://www.cdc.gov/coronavirus/2019ncov/hcp/therapeutic-options.html. Accessed: 12 Apr 2020.

4

Rauch S, Jasny E, Schmidt KE, et al. New vaccine technologies to combat outbreaksituations. Front Immunol 2018;9:1963.

5

Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics—developing a new class ofdrugs. Nat Rev Drug Discov 2014;13(10):759-80.

6

BioNTech RNA Pharmaceuticals GmbH. CorVAC/BNT162 Investigator’s Brochure.
Mainz, Germany: BioNTech RNA Pharmaceuticals GmbH; 25 Mar 2020.

7

Feldman RA, Fuhr R, Smolenov I, et al. mRNA vaccines against H10N8 and H7N9
influenza viruses of pandemic potential are immunogenic and well tolerated in healthy
adults in phase 1 randomized clinical trials. Vaccine. 2019;37(25):3326-34.

8

US Food and Drug Administration. Guidance for industry: toxicity grading scale forhealthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials.
Rockville, MD: Center for Biologics Evaluation and Research; September 2007.

9

Agresti A. Introduction: distributions and inference for categorical data. In: Agresti A,
ed. Categorical data analysis. 2nd ed. Hoboken, NJ: John Wiley & Sons; 2002:1-35.

10

Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med
1985;4(2):213-26.

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Document Approval Record
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FDA-CBER-2021-5683-0015211

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Protocol Amendment 1, 13 May 2020090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)A PHASE 1/2, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLIND,
DOSE-FINDING STUDY TO DESCRIBE THE SAFETY, TOLERABILITY,IMMUNOGENICITY, AND POTENTIAL EFFICACY OF SARS-COV-2 RNAVACCINE CANDIDATES AGAINST COVID-19 IN HEALTHY ADULTS

Study Sponsor:

BioNTechStudy Conducted By:

PfizerStudy Intervention Number:

PF-07302048

Study Intervention Name:

RNA-Based COVID-19 Vaccines

US IND Number:

19736

EudraCT Number:

N/A

Protocol Number:

C4591001

Phase:
1/2
Short Title: A Phase 1/2 Study to Describe the Safety, Tolerability, Immunogenicity, andPotential Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Adults

This document and accompanying materials contain confidential information belonging to Pfizer. Except asotherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold thisinformation in confidence and not copy or disclose it to others (except where required by applicable law) or
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer
must be promptly notified.

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Protocol Amendment Summary of Changes Table

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Document History
Document

Version Date

Summary and Rationale for Changes

Protocolamendment 1

13 May 2020

Following regulatory feedback: Modified exclusion criteria andprohibited inhaled/nebulized
corticosteroids for sentinel participants inStage 1
 Clarified that the rapid test for prior
COVID-19 infection for sentinel
participants in Stage 1 will be used only
for screening purposes Removed time frames for stopping rules
 Stated that data supporting the selectionof vaccine candidate(s)/dose level(s) andschedule(s) for Stages 2 and 3 will be
submitted to the FDA for review
Following preliminary experience in the
BioNTech study conducted in Germany(BNT162-01):
 Decreased the dose levels for BNT162a1
and BNT162c2
Additionally: Clarified the roles of BioNTech andPfizer Amended text so that the IRC decision toprogress group(s) into Stages 2 and 3 canbe based upon safety andimmunogenicity data after Dose 1 or 2
 Clarified safety data requirements topermit dose escalation
 Amended text so that the progression toparticipants 65 to 85 years of age can bebased upon data from the same RNA
platform Incorporated a protocol administrativechange to correct the variant designationand the encoded antigen to BNT162c2

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Protocol Amendment 1, 13 May 2020

 Clarified that the SARS-CoV-2
neutralizing assay does not employ wildtype virus
 Clarified that the SARS-CoV-2 spike
protein–binding antibody assay is
specific for the S1 subunit
 Clarified that efficacy against COVID-19
is based upon illness (not infection) rate
ratio
 Incorporated a protocol administrativechange to state that the study placebo
may be supplied in a glass or plastic vial Corrected a typographical error in
Section 6.5.1 regarding the time framefor prior receipt of blood/plasma
products or immunoglobulins
 Corrected a typographical error in Table
2 regarding the lower limit of diameter(cm) for mild redness and swelling Updated the °C fever scale in Table 4 toensure that all potential °F values arecorrectly assigned
 Incorporated a protocol administrativechange to clarify that a rapid test forprior COVID-19 infection will be
performed for sentinel participants inStage 1, and a serum sample will bedrawn for potential future assessment
 Clarified that, after screening, physicalexaminations in sentinel participants inStage 1 will be directed Clarified the descriptions of the
populations for analysis to align with thestatistical analysis plan
 Added a complete safety andimmunogenicity analysis approximately
6 months after Dose 2 for all participantsin Stage 3
 Amended text so that the stopping rules
apply to an RNA platform rather than aspecific vaccine candidate
Original protocol
15 April 2020
N/A
This amendment incorporates all revisions to date, including amendments made at therequest of country health authorities and IRBs/ECs.
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................9
1. PROTOCOL SUMMARY...................................................................................................11
1.1. Synopsis ..................................................................................................................11
1.2. Schema ....................................................................................................................16
1.3. Schedule of Activities .............................................................................................171.3.1. Stage 1 Sentinel Cohorts.............................................................................17
1.3.2. Stage 1 Nonsentinel Cohorts and Stage 2 Cohorts .....................................21
1.3.3. Stage 3 Cohort(s) ........................................................................................23
2. INTRODUCTION ...............................................................................................................25
2.1. Study Rationale .......................................................................................................25

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2.2. Background .............................................................................................................25
2.2.1. Clinical Overview.......................................................................................26
2.3. Benefit/Risk Assessment.........................................................................................26
2.3.1. Risk Assessment .........................................................................................28
2.3.2. Benefit Assessment.....................................................................................29
2.3.3. Overall Benefit/Risk Conclusion................................................................29
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................29
4. STUDY DESIGN.................................................................................................................31
4.1. Overall Design.........................................................................................................31
4.1.1. Stage 1 ........................................................................................................32
4.1.2. Stage 2 ........................................................................................................33
4.1.3. Stage 3 ........................................................................................................33
4.2. Scientific Rationale for Study Design .....................................................................33
4.3. Justification for Dose ..............................................................................................34
4.4. End of Study Definition ..........................................................................................34
5. STUDY POPULATION ......................................................................................................35
5.1. Inclusion Criteria.....................................................................................................35
5.2. Exclusion Criteria....................................................................................................36
5.3. Lifestyle Considerations..........................................................................................38
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5.3.1. Contraception..............................................................................................38
5.4. Screen Failures ........................................................................................................38
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study
Intervention Administration ......................................................................................39
6. STUDY INTERVENTION..................................................................................................39
6.1. Study Intervention(s) Administered ........................................................................43
6.1.1. Administration ............................................................................................44
6.2. Preparation/Handling/Storage/Accountability ........................................................44
6.2.1. Preparation and Dispensing ........................................................................45
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................45
6.3.1. Allocation to Study Intervention ................................................................45
6.3.2. Blinding of Site Personnel ..........................................................................46
6.3.3. Blinding of the Sponsor ..............................................................................46
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6.3.4. Breaking the Blind......................................................................................46
6.4. Study Intervention Compliance...............................................................................47
6.5. Concomitant Therapy..............................................................................................47
6.5.1. Prohibited During the Study .......................................................................47
6.5.2. Permitted During the Study ........................................................................48
6.6. Dose Modification...................................................................................................48
6.7. Intervention After the End of the Study ..................................................................48
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANTDISCONTINUATION/WITHDRAWAL...........................................................................48
7.1. Discontinuation of Study Intervention ....................................................................48
7.2. Participant Discontinuation/Withdrawal From the Study .......................................49
7.2.1. Withdrawal of Consent ...............................................................................49
7.3. Lost to Follow-up ....................................................................................................50
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................50
8.1. Efficacy and/or Immunogenicity Assessments .......................................................51
8.1.1. Biological Samples .....................................................................................52
8.2. Safety Assessments .................................................................................................53
8.2.1. Clinical Safety Laboratory Assessments (Sentinel-Cohort
Participants Only) ............................................................................................53
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8.2.2. Electronic Diary..........................................................................................54
8.2.2.1. Grading Scales...........................................................................54
8.2.2.2. Local Reactions .........................................................................54
8.2.2.3. Systemic Events ........................................................................55
8.2.2.4. Fever..........................................................................................56
8.2.2.5. Antipyretic Medication .............................................................57
8.2.3. Stopping Rules............................................................................................57
8.2.3.1. Randomization and Vaccination After a Stopping Rule Is
Met.....................................................................................................58
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19
Disease .............................................................................................................58
8.2.5. Pregnancy Testing ......................................................................................59
8.3. Adverse Events and Serious Adverse Events..........................................................59
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8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......59
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................60
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................60
8.3.2. Method of Detecting AEs and SAEs ..........................................................60
8.3.3. Follow-up of AEs and SAEs.......................................................................61
8.3.4. Regulatory Reporting Requirements for SAEs...........................................61
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational
Exposure ..........................................................................................................61
8.3.5.1. Exposure During Pregnancy......................................................62
8.3.5.2. Exposure During Breastfeeding ................................................63
8.3.5.3. Occupational Exposure .............................................................64
8.3.6. Medication Errors .......................................................................................64
8.4. Treatment of Overdose............................................................................................65
8.5. Pharmacokinetics ....................................................................................................65
8.6. Pharmacodynamics..................................................................................................65
8.7. Genetics ...................................................................................................................66
8.8. Biomarkers ..............................................................................................................66
8.9. Immunogenicity Assessments .................................................................................66
8.10. Health Economics .................................................................................................66
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8.11. Study Procedures...................................................................................................66
8.11.1. Stage 1 Sentinel Cohorts...........................................................................66
8.11.1.1. Screening: (0 to 14 Days Before Visit 1) ................................66
8.11.1.2. Visit 1 – Vaccination 1: (Day 1) .............................................67
8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1to 3 Days After Visit 1) .....................................................................69
8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to
8 Days After Visit 1) .........................................................................71
8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1) ...........72
8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to
8 Days After Visit 4) .........................................................................74
8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to
16 Days After Visit 4) .......................................................................75

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8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After
Visit 4) ...............................................................................................76
8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (154 to 168 Days
After Visit 4)......................................................................................77
8.11.1.10. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 4)......................................................................................77
8.11.1.11. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 4)......................................................................................78
8.11.2. Stage 1 Nonsentinel Cohorts and Stage 2 Cohorts ...................................78
8.11.2.1. Visit 1 – Vaccination 1: (Day 1) .............................................78
8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days or 56 to 70 Days
After Visit 1)......................................................................................80
8.11.2.3. Visit 3 – 2-Week Follow-up Visit: (12 to 16 Days After
Visit 2) ...............................................................................................82
8.11.2.4. Visit 4 – 1-Month Follow-up Visit: (28 to 35 Days After
Visit 2) ...............................................................................................83
8.11.2.5. Visit 5 – 6-Month Follow-up Visit: (154 to 168 Days
After Visit 2)......................................................................................83
8.11.2.6. Visit 6 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 2)......................................................................................84
8.11.2.7. Visit 7 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 2)......................................................................................84
8.11.3. Stage 3 Cohort(s) ......................................................................................84
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8.11.3.1. Visit 1 – Vaccination 1: (Day 1) .............................................84
8.11.3.2. Visit 2 – Vaccination 2: (19 to 23 Days or 56 to 70 Days
After Visit 1)......................................................................................86
8.11.3.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2):(28 to 35 Days After Visit 2).............................................................88
8.11.3.4. Visit 4 – 6-Month Safety Telephone Contact: (154 to
168 Days After Visit 2) .....................................................................89
8.11.3.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 2)......................................................................................89
8.11.3.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 2)......................................................................................90
8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction ........................90
8.13. COVID-19 Disease Surveillance (All Participants)..............................................91

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8.13.1. Potential COVID-19 Illness Telehealth Visit: (Optimally Within 3
Days After Potential COVID-19 Illness Onset)...............................................92
8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After
Potential COVID-19 Illness Visit)..................................................................93
9. STATISTICAL CONSIDERATIONS ................................................................................93
9.1. Estimands and Statistical Hypotheses .....................................................................93
9.1.1. Estimands....................................................................................................93
9.1.2. Statistical Hypotheses.................................................................................94
9.2. Sample Size Determination.....................................................................................94
9.3. Analysis Sets ...........................................................................................................95
9.4. Statistical Analyses .................................................................................................96
9.4.1. Immunogenicity Analyses ..........................................................................96
9.4.2. Efficacy Analyses .......................................................................................99
9.4.3. Safety Analyses ........................................................................................100
9.4.4. Other Analyses..........................................................................................101
9.5. Interim Analyses ...................................................................................................102
9.5.1. Analysis Timing........................................................................................102
9.6. Data Monitoring Committee or Other Independent Oversight Committee...........102
10. SUPPORTING DOCUMENTATION AND OPERATIONALCONSIDERATIONS ........................................................................................................104
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .............104
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10.1.1. Regulatory and Ethical Considerations ..................................................104
10.1.1.1. Reporting of Safety Issues and Serious Breaches of theProtocol or ICH GCP.......................................................................104
10.1.2. Informed Consent Process ......................................................................105
10.1.3. Data Protection .......................................................................................106
10.1.4. Dissemination of Clinical Study Data ....................................................106
10.1.5. Data Quality Assurance ..........................................................................107
10.1.6. Source Documents ..................................................................................109
10.1.7. Study and Site Start and Closure ............................................................109
10.1.8. Sponsor’s Qualified Medical Personnel .................................................110
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................111
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting ....................................................................113
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10.3.1. Definition of AE .....................................................................................113
10.3.2. Definition of SAE ...................................................................................114
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.....................116
10.3.4. Reporting of SAEs..................................................................................11910.4. Appendix 4: Contraceptive Guidance .................................................................120
10.4.1. Male Participant Reproductive Inclusion Criteria ..................................120
10.4.2. Female Participant Reproductive Inclusion Criteria...............................120
10.4.3. Woman of Childbearing Potential ..........................................................120
10.4.4. Contraception Methods...........................................................................121
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ......123
10.6. Appendix 6: Abbreviations .................................................................................125
11. REFERENCES ................................................................................................................128
LIST OF TABLES
Table 1.

Potential Groups in Stage 1 ......................................................................40

Table 2.

Local Reaction Grading Scale ..................................................................55

Table 3.

Systemic Event Grading Scale..................................................................56

Table 4.

Scale for Fever..........................................................................................57

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Table 5.

Probability of Observing at Least 1 AE by Assumed True Event
Rates With Different Sample Sizes ..........................................................95

Table 6.

Laboratory Abnormality Grading Scale .................................................111

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1. PROTOCOL SUMMARY
1.1. Synopsis
Short Title: A Phase 1/2 Study to Describe the Safety, Tolerability, Immunogenicity, andPotential Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Adults
Rationale

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A pneumonia of unknown cause detected in Wuhan, China, was first reported in
December 2019. On 08 January 2020, the pathogen causing this outbreak was identified as anovel coronavirus 2019. The outbreak was declared a Public Health Emergency ofInternational Concern on 30 January 2020. On 12 February 2020, the virus was officiallynamed as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the WHO
officially named the disease caused by SARS-CoV-2 as coronavirus disease 2019
(COVID-19). On 11 March 2020, the WHO upgraded the status of the COVID-19 outbreakfrom epidemic to pandemic, which is now spreading globally at high speed.
There are currently no vaccines to prevent infection with SARS-CoV-2 or antiviral drugs totreat COVID-19. Given the rapid transmission of COVID-19 and incidence of disease in the
United States and elsewhere, the rapid development of an effective vaccine is of utmost
importance.
BioNTech has developed RNA-based vaccine candidates using a platform approach thatenables the rapid development of vaccines against emerging viral diseases, including
SARS-CoV-2. Each vaccine candidate is based on 1 of 3 RNA platforms: unmodified
messenger RNA (uRNA, BNT162a), nucleoside-modified messenger RNA (modRNA,
BNT162b), or self-amplifying messenger RNA (saRNA, BNT162c). Each vaccine candidate
expresses 1 of 2 antigens: the SARS-CoV-2 full-length, P2 mutant, “heads up,” prefusion
spike glycoprotein (P2 S) (version 9) or a trimerized SARS-CoV-2 spike glycoprotein
receptor-binding domain (RBD) (version 5). The 4 SARS-CoV-2 vaccine candidates that will
be tested in this study are therefore:
BNT162a1 (variant RBL063.3): a uRNA encoding the RBD;
BNT162b1 (variant RBP020.3): a modRNA encoding the RBD;
BNT162b2 (variant RBP020.2): a modRNA encoding P2 S;
BNT162c2 (variant RBS004.2): an saRNA encoding the P2 S.
All candidates are formulated in the same lipid nanoparticle (LNP) composition. This study
is intended to investigate the safety, immunogenicity, and potential efficacy of these
4 prophylactic BNT162 vaccines against COVID-19.

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It is expected that the various candidate vaccines may not all be available from the start ofthe study, in which case they will be rolled into the study in a consecutive fashion as they are
released. A Phase 1/2 study of the same vaccine candidates (BNT162-01), conducted inGermany by BioNTech in adults 18 to 55 years of age, is planned to start in April 2020.
Study C4591001 is designed to complement and expand upon the German study and confirm
the optimal vaccine candidate(s) (BNT162a1, BNT162b1, BNT162b2, or BNT162c2), doselevel(s), number of doses, and schedule of administration.

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Objectives, Estimands, and Endpoints
Objectives

Estimands

Endpoints

Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Primary:
In participants receiving at least 1 doseof study intervention and having safety
data reported after any vaccination, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each doseAdverse events (AEs) from
Dose 1 to 1 month after the lastdose
 Serious AEs (SAEs) from Dose 1
to 6 months after the last doseIn addition, in sentinel cohorts from
Stage 1, the percentage of participantswith:
Abnormal hematology andchemistry laboratory values 1 and7 days after Dose 1; and 7 days
after Dose 2
Grading shifts in hematology andchemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2
Secondary:In participants complying with the key
protocol criteria (evaluableparticipants) at the following time
points after receipt of study
intervention:

Primary:
Local reactions (pain at the
injection site, redness, andswelling)

Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs

Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Hematology and chemistry laboratory
parameters detailed in Section 10.2

Secondary:Stage 1 Sentinel Cohorts: 7 and21 days after Dose 1; 7 and 14 days and1, 6, 12, and 24 months after Dose 2
Stage 1 Nonsentinel Cohorts andStage 2 Cohorts: 21 days after Dose 1;
14 days and 1, 6, 12, and 24 months
after Dose 2
Stage 3 Cohort(s): 1, 12, and24 months after Dose 2

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Objectives

Estimands










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Endpoints

Geometric mean titers (GMTs) at SARS-CoV-2 serum neutralizing titers
each time point
Geometric mean fold rise (GMFR)
from before vaccination to eachsubsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
SARS-CoV-2-S1–specific binding
Geometric mean concentrations
antibody levels and RBD-specific(GMCs) at each time point
binding antibody levels
GMFR from rise from before
vaccination to each subsequent
time point after vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
SARS-CoV-2 serum neutralizing
Geometric mean ratio (GMR),
titersestimated by the ratio of thegeometric mean of SARS-CoV-2 
SARS-CoV-2-S1–specific binding
serum neutralizing titers to theantibody levels
geometric mean of SARS-CoV-2– 
SARS-CoV-2 RBD–specificspecific binding antibody levels at
binding antibody levels
each time point

To evaluate the efficacy of prophylactic In participants complying with the key
BNT162 vaccines against confirmed
protocol criteria (evaluable
COVID-19
participants) following receipt of thelast dose of study intervention:
100 × (1 – illness rate ratio) [ratio ofactive vaccine to placebo]
Tertiary/Exploratory:
Tertiary/Exploratory:
To describe the relationship between
SARS-CoV-2 serological parametersand:
NAAT-confirmed COVID-19

Symptomatic SARS-CoV-2
infection
Asymptomatic SARS-CoV-2
infection

COVID-19 incidence per 1000 personyears of follow-up

Tertiary/Exploratory:
Nonvaccine antigen SARS-CoV-2
antibody levels

Overall Design
This is a Phase 1/2, randomized, placebo-controlled, observer-blind, dose-finding, andvaccine candidate–selection study in healthy adults.
The study will evaluate the safety, tolerability, immunogenicity, and potential efficacy of up
to 4 different SARS-CoV-2 RNA vaccine candidates against COVID-19:


As a 2-dose (separated by 21 or 60 days) or single-dose schedule

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At up to 3 different dose levels

In 3 age groups (18 to 55 years of age, 65 to 85 years of age, and 18 to 85 years of age[stratified as ≤55 or >55 years of age])

Dependent upon safety and/or immunogenicity data generated during the course of thisstudy, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
may be started at the next highest dose, groups may not be started, groups may be terminatedearly, and/or groups may be added with dose levels below the lowest stated dose orintermediate between the lowest and highest stated doses.
The study consists of 3 stages. Stage 1: to identify preferred vaccine candidate(s), doselevel(s), number of doses, and schedule of administration (with the first 15 participants ateach dose level of each vaccine candidate comprising a sentinel cohort); Stage 2: an
expanded-cohort stage; and Stage 3: a final candidate/dose large-scale stage. These stages,
and the progression between them, are detailed in the schema (Section 1.2).

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Number of Participants
Each group in Stage 1 will comprise 15 participants (12 receiving active vaccine and3 receiving placebo). In this stage, assuming 2 dose levels are selected following the initial
dose escalation, up to 56 potential groups are foreseen; if all groups are fully enrolled, thiscorresponds to a total of 840 participants.
Each group in Stage 2 will comprise 225 participants (180 receiving active vaccine and
45 receiving placebo). The total number of participants to be enrolled in this stage depends
on the number of groups to be pursued.
The vaccine candidate/dose level selected for Stage 3 will comprise 3000 participants. An
equal number of participants will receive placebo, ie, randomized in a 1:1 ratio.
Intervention Groups and Duration
The study may evaluate single-dose and 2-dose (separated by 21 or 60 days) schedules of
3 different dose levels of 4 investigational RNA vaccine candidates for active immunization
against COVID-19 in 3 age groups (18 to 55 years of age, 65 to 85 years of age, and18 to 85 years of age [stratified as ≤55 or >55 years of age]):

BNT162a1 (RNA-LNP vaccine utilizing uRNA and encoding the RBD): 0.1 µg, 0.3 µg,
1 µg

BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 30 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 30 µg, 100 µg
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

BNT162c2 (BNT162 RNA-LNP vaccine utilizing saRNA and encoding the RBD):
0.1 µg, 0.3 µg, 1 µg

Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Stage 1 andStage 2 dosing arms that are not evaluated in Stage 3.
Data Monitoring Committee or Other Independent Oversight Committee
The study will utilize an IRC, an internal Pfizer committee that will review data to allow
dose escalation or changes to continuation of specific groups.
An external data monitoring committee (DMC) will be formed and will review cumulative
unblinded data throughout the study.

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Statistical Methods
The study sample size for the first 2 stages of the study is not based on any statistical
hypothesis testing. For the third stage, with assumptions of a true vaccine efficacy (VE) of
70%, 53 cases of COVID-19 will provide 90% power to conclude true VE >20%. This would
be achieved with 3000 participants per group, based on the assumption of a 1.7% incidence
rate in the placebo group, and 20% of the participants being nonevaluable.
The primary safety objective will be evaluated by descriptive summary statistics for local
reactions, systemic events, abnormal hematology and chemistry laboratory parameters(sentinel cohorts only), and AEs and SAEs, for each vaccine group. A 3-tier approach will be
used to summarize AEs.
The secondary immunogenicity objectives will be evaluated descriptively by GMT, GMC,
GMFR, percentage of participants with ≥4-fold rise, and GMC ratio, and the associated 95%
confidence intervals (CIs), for SARS-CoV-2 serum neutralizing titers, SARS-CoV-2-S1–
specific binding antibody levels, and RBD-specific binding antibody levels at the various
time points.
For the secondary efficacy objective, VE is defined as VE = 100 × (1 – IRR), where IRR is
the illness rate ratio, the calculated ratio of COVID-19 incidence in the active vaccine groupto the incidence in the placebo group. The null hypothesis (VE ≤ 20%) will be rejected if thelower bound of the 95% CI for VE is >20%; no interim analysis of VE is planned.

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1.2. SchemaStage 1

(4:1 randomization active:placebo)
For each vaccine candidate

Age: 18-55 y
Low-dose-level 2-dose group (n=15):
SENTINEL

Age: 65-85 y

IRC (safety & immunogenicity

IRC (safety)

after Dose 1)

Low-dose-level 2-dose group (n=15):
SENTINEL

Mid-dose-level 2-dose group (n=15):
SENTINEL

IRC (safety)
IRC (safety & immunogenicity

IRC (safety)

Mid-dose-level 2-dose group (n=15):
SENTINEL

after Dose 1)

High-dose-level 2-dose group (n=15):
SENTINEL

IRC (safety)
IRC (safety & immunogenicity
after Dose 1)

High-dose-level 2-dose group (n=15):
SENTINEL

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IRC choice of group(s) for Stages 2 & 3(safety & immunogenicity after Dose 1 or 2)
Dose level(s) selected for Stage 2: 2dose (60 days apart) group(s) (n=15)

Dose level(s) selected for Stage 2: 2dose (60 days apart) group(s) (n=15)&
Dose level(s) selected for Stage 2: 1dose group(s) (n=15)&
Dose level(s) selected for Stage 2: 1dose group(s) (n=15)(4:1 randomization active:placebo)

Stage 2Age: 18-85(Stratified 18-55 or 56-85)
Group for each selected vaccine
candidate/dose level(n=180 per active group)

IRC ongoing review ofsafety & immunogenicity data
Stage 3

(1:1 randomization active:placebo)

Age: 18-85(Stratified 18-55 or 56-85)
Selected vaccine candidate/dose level(n=3000 per group)
Abbreviation: IRC = internal review committee.

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1.3. Schedule of Activities

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with theprotocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations orassessments required to protect the well-being of the participant.
1.3.1. Stage 1 Sentinel Cohorts
An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 10 (24-month follow-up visit) that COVID-19 is suspected.
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit Telehealth
Visit
Visit

Visit Window (Days)

0 to 14
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

X

X

X

X

X

Obtain informed consent

X

Assign participant number

X

Obtain demography andmedical history data

X

Obtain details of medications
currently taken

X

Perform physical examination

X

2

3

4

5

6

7

8

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset

X

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Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit Telehealth
Visit
Visit

Visit Window (Days)

0 to 14
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

Measure vital signs(including body temperature)

X

X

X

X

X

X

Collect blood sample forhematology and chemistrylaboratory testsa~10 mL~10 mL~10 mL~10 mL~10 mL

Collect screening blood
sample for HIV, HBsAg,
HBc Ab, and HCV Ab tests~10 mL

Serological test for prior
COVID-19 infection~20 mL

Perform urine pregnancy test
(if appropriate)X

Obtain nasal (midturbinate)swab(s)b

2

3

4

X

X

X

X

Collect nonstudy vaccine
information

X

X

Confirm eligibility

X

X

Collect prohibited medicationuse
Review hematology andchemistry results

X

Review temporary delay
criteria

X

X

X

X

X

X
X

5

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset
X

X
X

X

X

X

X

X

X

X

X

X

X

X

X
X

X

X

X

X

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Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

4

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit Telehealth
Visit
Visit

Visit Window (Days)

0 to 14
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

Confirm use of contraceptives(if appropriate)

X

X

X

X

X

X

X

X

~50 mL~50 mL~50 mL~50 mL~50 mL~50 mL~50 mL~50 mL

X

X

X

X

Obtain randomization number
and study intervention
allocation

X

Collect blood sample for
immunogenicity assessment~50 mL

Administer study intervention

X

X

Assess acute reactions for atleast 30 minutes after study
intervention administrationc

X

X

Provide participant with 7day e-diary, thermometer, andmeasuring device

X

X

5

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset~50 mL

Review e-diary data (daily
review is optimal during theactive diary period)
Review ongoing e-diary
symptoms and obtain stopdatesCollect AEs and SAEs as
appropriate

X

X

X

X

X

X

X

X

X

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Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit Telehealth
Visit
Visit

Visit Window (Days)

0 to 14
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 46 to 8Days
After
Visit 1

4

5

Collect e-diary or assist theparticipant to delete
application

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset
X

Collection of COVID-19–
related clinical and laboratory
information (including local
diagnosis)

X

X

Abbreviations: e-diary = electronic diary; HBc Ab = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HCV Ab = hepatitis C virus antibody; HIV = humanimmunodeficiency virus; NAAT = nucleic acid amplification test; vax = vaccination.
a. Hematology: hemoglobin, complete blood count with differential, and platelets. Blood chemistry: alanine aminotransferase (ALT), aspartate aminotransferase (AST),
alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), and creatinine.
b. Two swabs will be taken at Visits 1 and 4. One will be tested (if possible at the site, otherwise at the central laboratory) within 24 hours and vaccination will only proceed if
it is NAAT-negative for SARS-CoV-2 genomes. The second will be sent to the central laboratory for potential later testing.
c. The first 5 participants in in each sentinel group will be observed at the site for at least 4 hours after study intervention administration. Further vaccination will commence nosooner than 24 hours after the fifth participant received his or her vaccination.

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1.3.2. Stage 1 Nonsentinel Cohorts and Stage 2 Cohorts
An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 7 (24-month follow-up visit) that COVID-19 is suspected.

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Visit Number
Visit Description

Visit Window (Days)

1

2

3

4

5

6

7

Unplanned

Unplanned

2-WeekFollow-up
Visit

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
COVID-19
Illness
Telehealth
Visit

Potential
COVID-19
ConvalescentVisit

19 to 23 Days 12 to 16 Days 28 to 35 Days
After Visit 1 After Visit 2 After Visit 2
or56 to 70 Days
After Visit 1a

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19 Illness Visit
Illness Onset

X

X

Vaccination 1 Vaccination 2

Day 1

Obtain informed consent

X

Assign participant number

X

Obtain demography and medical
history data

X

Perform physical examination

X

Measure vital signs

X

Perform urine pregnancy test
(if appropriate)

X

X

Collect nonstudy vaccine information

X

X

X

X

X

X

X

X

X

X

X

Collect prohibited medication use
Confirm eligibility

X

X

Measure temperature (body)

X

X

Review temporary delay criteria

X

X

Confirm use of contraceptives(if appropriate)

X

X

Obtain randomization number andstudy intervention allocation

X

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Visit Number

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Visit Description

Visit Window (Days)

Collect blood sample for
immunogenicity assessment

1

2

3

4

5

6

7

Unplanned

Unplanned

2-WeekFollow-up
Visit

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
COVID-19
Illness
Telehealth
Visit

Potential
COVID-19
ConvalescentVisit

19 to 23 Days 12 to 16 Days 28 to 35 Days
After Visit 1 After Visit 2 After Visit 2
or56 to 70 Days
After Visit 1a

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19 Illness Visit
Illness Onset~50 mL~50 mL~50 mL

Vaccination 1 Vaccination 2

Day 1~50 mL~50 mL

Obtain nasal (midturbinate) swab

X

X

Administer study intervention

X

X

Assess acute reactions for at least 30
minutes after study intervention
administration

X

X

Provide participant with 7-day e-diary,
thermometer, and measuring device

XX~50 mL~50 mL~50 mL
X

Review e-diary data (daily review is
optimal during the active diary period)
Review ongoing e-diary symptoms andobtain stop dates
Collect AEs and SAEs as appropriate
Collect e-diary or assist the participant
to delete application

X

X

X

X

X

X

X

X

X

X

X

X

X

X

Collection of COVID-19–related
clinical and laboratory information(including local diagnosis)
Abbreviation: e-diary = electronic diary.
a. The window for Visit 2 is dependent on the dosing schedule for the assigned group.

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1.3.3. Stage 3 Cohort(s)An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 6 (24-month follow-up visit) that COVID-19 is suspected.

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Visit Number
Visit Description

Visit Window (Days)

1

2

3

4

5

6

Unplanned

Unplanned

1-MonthFollow-up
Visit

6-Month
SafetyTelephoneContact

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
COVID-19
Illness
Telehealth
Visit

Potential
COVID-19
ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2
or56 to 70 Days
After Visit 1a

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

X

X~50 mL~50 mL

Vaccination 1 Vaccination 2

Day 1

Obtain informed consent

X

Assign participant number

X

Obtain demography and medical history data

X

Perform physical examination

X

Measure vital signs

X

Perform urine pregnancy test (if appropriate)

X

X

Collect nonstudy vaccine information

X

X

X

X

X

X

X

Collect prohibited medication use
Confirm eligibility

X

X

Measure temperature (body)

X

X

Review temporary delay criteria

X

X

Confirm use of contraceptives (if appropriate)

X

X

Obtain randomization number and study
intervention allocation

X

Collect blood sample for immunogenicity
assessment~50 mL

Obtain nasal (midturbinate) swab

X

X

X

X

~50 mLX~50 mLX

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Visit Number

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Visit Description

2

3

4

5

6

Unplanned

Unplanned

1-MonthFollow-up
Visit

6-Month
SafetyTelephoneContact

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
COVID-19
Illness
Telehealth
Visit

Potential
COVID-19
ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2
or56 to 70 Days
After Visit 1a

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

X

X

X

Vaccination 1 Vaccination 2

Visit Window (Days)

Day 1

Administer study intervention

X

X

Assess acute reactions for at least 30 minutes after
study intervention administration

X

X

Provide participant with 7-day e-diary,
thermometer, and measuring device

X

X

Review e-diary data (daily review is optimal during
the active diary period)
Review ongoing e-diary symptoms and obtain stopdatesCollect AEs and SAEs as appropriate

X

Collect e-diary or assist the participant to delete
application

X

X

X

X

X

X

X

X

X

Telephone contact

X

Collection of COVID-19–related clinical andlaboratory information (including local diagnosis)
Abbreviation: e-diary = electronic diary.
a. The window for Visit 2 is dependent on the dosing schedule(s) selected for the Stage 3.

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2. INTRODUCTION
The BNT162 RNA-based COVID-19 vaccines are currently being investigated forprevention of COVID-19 in healthy adults.
2.1. Study Rationale
The purpose of the study is to rapidly describe the safety, tolerability, immunogenicity, andpotential efficacy of 4 BNT162 RNA-based COVID-19 vaccine candidates against
COVID-19 in healthy adults. There are currently no vaccines to prevent infection with
SARS-CoV-2 or antiviral drugs to treat COVID-19. Given the global crisis of COVID-19
and fast expansion of the disease in the United States and elsewhere, the rapid developmentof an effective vaccine is of utmost importance.

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2.2. Background
In December 2019, a pneumonia outbreak of unknown cause occurred in Wuhan, China.
In January 2020, it became clear that a novel coronavirus (2019-nCoV) was the underlying
cause. Later in January, the genetic sequence of the 2019-nCoV became available to theWorld Health Organization (WHO) and public (MN908947.3), and the virus was categorized
in the Betacoronavirus subfamily. By sequence analysis, the phylogenetic tree revealed acloser relationship to severe acute respiratory syndrome (SARS) virus isolates than to anothercoronavirus infecting humans, the Middle East respiratory syndrome (MERS) virus.
SARS-CoV-2 infections and the resulting disease, COVID-19, have spread globally,affecting a growing number of countries.
On 11 March 2020, the WHO characterized the COVID-19 outbreak as a pandemic.1
The WHO Situation Update Report dated 30 March 2020 noted 693,224 confirmed caseswith 33,106 deaths globally, including 142,081 confirmed cases with 2457 deaths in theAmericas.2 The United States currently has the most reported cases globally. At the time ofthis communication, the number of confirmed cases continues to rise globally. There are
currently no vaccines or effective antiviral drugs to treat SARS-CoV-2 infections or the
disease it causes, COVID-19.3
A prophylactic, RNA-based SARS-CoV-2 vaccine provides one of the most flexible andfastest approaches available to immunize against the emerging virus.4,5The development of an RNA-based vaccine encoding a viral antigen, which is then expressedby the vaccine recipient as a protein capable of eliciting protective immune responses,
provides significant advantages over more traditional vaccine approaches. Unlike live
attenuated vaccines, RNA vaccines do not carry the risks associated with infection and may
be given to people who cannot be administered live virus (eg, pregnant women andimmunocompromised persons). RNA-based vaccines are manufactured via a cell-free invitro transcription process, which allows an easy and rapid production and the prospect of
producing high numbers of vaccination doses within a shorter time period than achieved with

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traditional vaccine approaches. This capability is pivotal to enable the most effective
response in outbreak scenarios.

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Four SARS-CoV-2–RNA lipid nanoparticle (RNA-LNP) vaccines utilizing different RNA
formats will be evaluated in this study. Each vaccine candidate is based on 1 of 3 RNA
platforms: unmodified messenger RNA (uRNA, BNT162a), nucleoside-modified messenger
RNA (modRNA, BNT162b), or self-amplifying messenger RNA (saRNA, BNT162c). Eachvaccine candidate expresses 1 of 2 antigens: the SARS-CoV-2 full-length, P2 mutant, “heads
up,” prefusion spike glycoprotein (P2 S) (version 9) or a trimerized SARS-CoV-2 spikeglycoprotein receptor binding domain (RBD) (version 5). The 4 SARS-CoV-2 vaccine
candidates that will be tested in this study are therefore:

BNT162a1 (variant RBL063.3): non–nucleoside-modified uridine-containing messenger
RNA (uRNA) with high intrinsic adjuvanticity, encoding the RBD.



BNT162b1 (variant RBP020.3): nucleoside-modified messenger RNA (modRNA) withblunted innate immune sensor–activating capacity and augmented expression encoding
the RBD.



BNT162b2 (variant RBP020.2): nucleoside-modified messenger RNA (modRNA) as
above but encoding P2 S.



BNT162c2 (variant RBS004.2): self-amplifying messenger RNA (saRNA) encoding theP2 S, in which higher amounts of protein per injected RNA template can be produced.

2.2.1. Clinical Overview
BNT162 vaccines have not been administered to humans before and thus there are no
previous clinical data with these specific vaccines. However, given clinical data from othersimilarly formulated uRNA liposomal vaccines from BioNTech in oncology trials6 andrecent published results from clinical trials using modRNA influenza vaccines by Moderna,7
the BNT162 vaccines are expected to have a favorable safety profile with mild, localized,
and transient effects.
2.3. Benefit/Risk Assessment
There is an ongoing global pandemic of COVID-19 with no preventative or therapeutic
options available. While there are currently no data available from clinical trials on the use of
BNT162 vaccines in humans, available nonclinical data with these vaccines, and data from
nonclinical studies and clinical trials with the same or related RNA components, or antigens,support a favorable risk/benefit profile. Anticipated AEs after vaccination are expected to be
manageable using routine symptom-driven standard of care as determined by theinvestigators and, as a result, the profile of these vaccine candidates support initiation of thisPhase 1/2 clinical study.

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More detailed information about the known and expected benefits and risks and reasonably
expected AEs of BNT162 RNA-based COVID-19 vaccines may be found in theinvestigator’s brochure (IB), which is the SRSD for this study.

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2.3.1. Risk Assessment
Potential Risk of ClinicalSignificance

Summary of Data/Rationale for Risk

Mitigation Strategy

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Study Intervention: BNT162 RNA-Based COVID-19 Vaccine
Potential for local reactions (injection These are common adverse reactions seensite redness, injection site swelling, with other vaccines, as noted in the FDA
and injection site pain) and systemic Center for Biologics Evaluation andResearch (CBER) guidelines on toxicity
events (fever, fatigue, headache,
grading scales for healthy adult volunteers
chills, vomiting, diarrhea, muscle
pain, and joint pain) following
enrolled in preventive vaccine clinicalvaccination.
trials.8

The study design includes the use of sentinel cohorts and dose escalation toclosely monitor and limit the rate of enrollment to ensure participant safety.
The study employs the use of an e-diary to monitor local reactions andsystemic events in real time. Stopping rules are also in place for sentinelcohorts. The first 5 sentinel-cohort participants in each group will beobserved for 4 hours after vaccination to assess any immediate AEs.

Unknown AEs and laboratory
abnormalities with a novel vaccine.

The study design includes the use of sentinel cohorts and dose escalation toThis study is one of the first 2 parallelrunning clinical studies with the BNT162 closely monitor and limit the rate of enrollment to ensure participant safety.
vaccine candidates and as such there are no An IRC and DMC will also review safety data throughout the study.
Stopping rules are also in place for sentinel cohorts. The first 5 sentinel
clinical data available for this vaccine.
cohort participants in each group will be observed for 4 hours after
vaccination to assess any immediate AEs.

Potential for COVID-19 diseaseenhancement.

Disease enhancement has been seen
following vaccination with respiratorysyncytial virus (RSV), feline coronavirus,
and Dengue virus vaccines.

The study excludes participants with likely previous or current COVID-19.
All participants are followed for SARS-CoV-2 antigen-specific antibody
and SARS-CoV-2 serum neutralizing titers, and COVID-19 illness,
including markers of severity.

Study Procedures
Participants will be required to attend Without appropriate social distancing andhealthcare facilities during the global PPE, there is a potential for increased
exposure to SARS-CoV-2.
SARS-CoV-2 pandemic.
Venipuncture will be performed
during the study.

There is the risk of bleeding, bruising,hematoma formation, and infection at the
venipuncture site.

Pfizer will work with sites to ensure an appropriate COVID-19 prevention
strategy.
Only appropriately qualified personnel would obtain the blood draw.

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2.3.2. Benefit Assessment
Benefits to individual participants may include:Receipt of a potentially efficacious COVID-19 vaccine during a global pandemicAccess to COVID-19 diagnostic and antibody testingContributing to research to help others in a time of global pandemic

2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in thisstudy, the potential risks identified in association with BNT162 RNA-based COVID-19
vaccine are justified by the anticipated benefits that may be afforded to healthy participants.

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3. OBJECTIVES, ESTIMANDS, AND ENDPOINTSObjectives

Estimands

Endpoints

Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Primary:
In participants receiving at least 1 doseof study intervention and having safety
data reported after any vaccination, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each doseAdverse events (AEs) from
Dose 1 to 1 month after the lastdose
 Serious AEs (SAEs) from Dose 1
to 6 months after the last doseIn addition, in sentinel cohorts from
Stage 1, the percentage of participantswith:
Abnormal hematology andchemistry laboratory values 1 and7 days after Dose 1; and 7 days
after Dose 2
Grading shifts in hematology andchemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2

Primary:
Local reactions (pain at the
injection site, redness, andswelling)

Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs

Hematology and chemistry laboratory
parameters detailed in Section 10.2

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Objectives

Estimands

Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Secondary:In participants complying with the key
protocol criteria (evaluableparticipants) at the following time
points after receipt of study
intervention:

Endpoints
Secondary:Stage 1 Sentinel Cohorts: 7 and21 days after Dose 1; 7 and 14 days and1, 6, 12, and 24 months after Dose 2
Stage 1 Nonsentinel Cohorts andStage 2 Cohorts: 21 days after Dose 1;
14 days and 1, 6, 12, and 24 months
after Dose 2
Stage 3 Cohort(s): 1, 12, and24 months after Dose 2
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







Geometric mean titers (GMTs) at SARS-CoV-2 serum neutralizing titers
each time point
Geometric mean fold rise (GMFR)
from before vaccination to eachsubsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
SARS-CoV-2-S1–specific binding
Geometric mean concentrations
antibody levels and RBD-specific(GMCs) at each time point
GMFR from prior to first dose of binding antibody levels
study intervention to eachsubsequent time point
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
SARS-CoV-2 serum neutralizing
Geometric mean ratio (GMR),
titersestimated by the ratio of thegeometric mean of SARS-CoV-2

SARS-CoV-2-S1–specific binding
serum neutralizing titers to theantibody levels
geometric mean of SARS-CoV-2–
specific binding antibody levels at each time point

To evaluate the efficacy of prophylactic In participants complying with the key
BNT162 vaccines against confirmed
protocol criteria (evaluable
COVID-19
participants) following receipt of thelast dose of study intervention:
100 × (1 – illness rate ratio)[ratio of active vaccine to placebo]

SARS-CoV-2 RBD–specificbinding antibody levels

COVID-19 incidence per 1000 personyears of follow-up

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Objectives
Tertiary/Exploratory:
To describe the relationship between
SARS-CoV-2 serological parametersand:
NAAT-confirmed COVID-19

Symptomatic SARS-CoV-2
infection
Asymptomatic SARS-CoV-2
infection

Estimands
Tertiary/Exploratory:

Endpoints
Tertiary/Exploratory:
Nonvaccine antigen SARS-CoV-2
antibody levels

4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1/2, randomized, placebo-controlled, observer-blind, dose-finding, andvaccine candidate–selection study in healthy adults.

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)The study will evaluate the safety, tolerability, immunogenicity, and potential efficacy of up
to 4 different SARS-CoV-2 RNA vaccine candidates against COVID-19:


As a 2-dose (separated by 21 or 60 days) or single-dose scheduleAt up to 3 different dose levels

In 3 age groups (18 to 55 years of age, 65 to 85 years of age, and 18 to 85 years of age[stratified as ≤55 or >55 years of age])

Dependent upon safety and/or immunogenicity data generated during the course of thisstudy, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
may be started at the next highest dose, groups may not be started, groups may be terminatedearly, and/or groups may be added with dose levels below the lowest stated dose orintermediate between the lowest and highest stated doses.
The study consists of 3 stages. Stage 1: to identify preferred vaccine candidate(s), doselevel(s), number of doses, and schedule of administration (with the first 15 participants ateach dose level of each vaccine candidate comprising a sentinel cohort); Stage 2: an
expanded-cohort stage; and Stage 3; a final candidate/dose large-scale stage. These stages,
and the progression between them, are detailed in the schema (Section 1.2).
The study is observer-blinded, as the physical appearance of the investigational vaccine
candidates and the placebo may differ. The participant, investigator, study coordinator, andother site staff will be blinded. At the study site, only the dispenser(s)/administrator(s) are
unblinded.
To facilitate rapid review of data in real time, sponsor staff will be unblinded to vaccine
allocation for the participants in Stage 1 and Stage 2.

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4.1.1. Stage 1
Each group (vaccine candidate/dose level/age group/number of doses) will comprise
15 participants; 12 participants will be randomized to receive active vaccine and 3 to receive
placebo. On Day 22, those in 2-dose groups will receive the same vaccine they received on
Day 1; for those in single-dose groups, all will receive placebo. Full details of all potential
groups in Stage 1 may be found in Table 1.

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)For each vaccine candidate/dose level/age group, the 15 participants randomized into each 2dose group will comprise a sentinel cohort, to which the following apply:Additional safety assessments (see Section 8.2)

Controlled enrollment:No more than 5 participants (4 active, 1 placebo) can be vaccinated on the first day

The first 5 participants must be observed by blinded site staff for at least 4 hours after
vaccination for any acute reactions

Vaccination of the remaining participants will commence no sooner than 24 hours
after the fifth participant received his or her vaccination

Application of stopping rules

IRC review of safety data to determine escalation to the next dose level:Escalation between dose levels in the 18- to 55-year age cohort will be based on IRC
review of at least 7-day post–Dose 1 safety data in this study and/or the BioNTech
study conducted in Germany (BNT162-01)



Escalation between dose levels in the 65- to 85-year age cohort will be based on IRC
review of:At least 4-week post–Dose 1 safety data for the corresponding dose level in the
18- to 55-year age cohort in this study and/or the BioNTech study conducted inGermany (BNT162-01) and

At least 24-hour post–Dose 1 safety data in this study for the prior dose level inthe 65- to 85-year age cohort

Note that, for candidates based upon the same RNA platform (eg, BNT162b1 and
BNT162b2), the stated observation periods may be shortened to 24 hours for thesecond candidate studied, if the safety profile of the first candidate studied wasdeemed acceptable at the same dose level by the IRC

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Groups of participants 65 to 85 years of age will not be started until safety andimmunogenicity data for the same RNA platform/dose level have been deemed acceptable inthe 18- to 55-year age cohort by the IRC.
Once the IRC has selected a vaccine candidate/dose level to proceed into Stage 2, for eachage cohort, 2 additional groups will be enrolled into Stage 1 for that vaccine candidate/doselevel:
A 2-dose group, with the 2 doses administered 60 days apart rather than 21

A 1-dose group

In this stage, assuming 2 dose levels are selected following the initial dose escalation, up to
56 potential groups are foreseen; if all groups are fully enrolled, this corresponds to a total of
840 participants.

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4.1.2. Stage 2
On the basis of safety and/or immunogenicity data generated during the course of this study,
and/or the BioNTech study conducted in Germany (BNT162-01), 1 or more groups (vaccine
candidate/dose level) may be selected to proceed into Stage 2. Participants in this stage willbe 18 to 85 years of age, stratified equally: 18 to 55 or 56 to 85 years. Commencement ofeach age stratum will be dependent upon satisfactory safety and immunogenicity data fromthe 18- to 55-year and 65- to 85-year groups from Stage 1, respectively. It is therefore
possible that the 2 age strata may not start concurrently.
In each group selected for Stage 2, it is intended that 225 participants will be randomized in a
4:1 ratio to receive active vaccine (180 participants) or placebo (45 participants).
4.1.3. Stage 3
On the basis of safety and/or immunogenicity data generated during the course of this study,
and/or the BioNTech study conducted in Germany (BNT162-01), 1 group may be selected toproceed into Stage 3. Participants in this stage will be 18 to 85 years of age, stratified
equally: 18 to 55 years or 56 to 85 years. As in Stage 2, it is possible that the 2 age strata may
not start concurrently.
The vaccine candidate/dose level selected for Stage 3 will comprise 3000 participants. An
equal number of participants will receive placebo, ie, randomized in a 1:1 ratio.
Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Stage 1 andStage 2 dosing arms that are not evaluated in Stage 3.
4.2. Scientific Rationale for Study Design
Additional surveillance for COVID-19 will be conducted as part of the study, given thepotential risk of disease enhancement. If a participant experiences respiratory symptoms, as
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detailed in Section 8.13, a COVID-19 illness and subsequent convalescent visit will occur.
As part of these visits, samples (nasal [midturbinate] swab and blood) will be taken for
antigen and antibody assessment as well as recording of COVID-19–related clinical andlaboratory information (including local diagnosis).
Human reproductive safety data are not available for BNT162 RNA-based COVID-19
vaccines, but there is no suspicion of human teratogenicity based on the intended mechanismof action of the compound. Therefore, the use of a highly effective method of contraception
is required (see Appendix 4).

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4.3. Justification for Dose
Because of the requirement for a rapid response to the newly emerged COVID-19 pandemic,
sufficient data are not currently available to experimentally validate the dose selection andinitial starting dose. Therefore, the original planned starting doses of 3 µg (for BNT162a1
and BNT162c2) and 10 µg (for BNT162b1 and BNT162b2) in this study were based on
nonclinical experience with the same RNAs encoding other viral antigens (such as influenza
and HIV antigens). The general safety and effectiveness of uRNA and modRNA platforms
have been demonstrated in oncological clinical trials with different administration routes(NCT02410733, NCT03871348). Doses of up to 400 µg total uRNA have been administered
IV as RNA lipoplex (RNA-LPX) and doses of up to 1000 µg total naked modRNA have been
administered intratumorally, both without signs of unpredictable overstimulation of theimmune system.
Based on nonclinical data of the RNA components (uRNA, modRNA, saRNA), with otherliposomes or in conjunction with the lipid nanoparticles as will be tested clinically in thisstudy, it was expected that doses in the 1- to 5-µg range would be immunogenic and induce
neutralizing antibodies; however, it was anticipated that 3- to 10-fold higher doses would
likely be required to elicit a stronger antibody response. Based on previous clinical andnonclinical experience, it was expected that doses of up to 100 µg would be well tolerated.
Update as part of protocol amendment 1: preliminary experience in the BioNTech study
conducted in Germany (BNT162-01), following vaccination of 6 participants with 3 µg of
BNT162a1, demonstrated an undesirable level of systemic reactogenicity. Therefore,
potential dose levels for BNT162a1 and BNT162c2 (which are both based upon unmodifiedRNA) dependent upon further data from the BNT162-01 study, are each reduced 30-fold to
0.1 µg, 0.3 µg, and 1 µg.
Taken together, the planned starting doses in this study in healthy participants are considered
to be safe, but still sufficient to induce an antiviral immune response.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases ofthe study, including the last visit. Note that participants enrolled in Stages 1 and 2 in groups
that do not proceed to Stage 3 may be followed for fewer than 24 months (but no less than
6 months after the last vaccination).
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The end of the study is defined as the date of last visit of the last participant in the study.
5. STUDY POPULATIONThis study can fulfill its objectives only if appropriate participants are enrolled. The
following eligibility criteria are designed to select participants for whom participation in the
study is considered appropriate. All relevant medical and nonmedical conditions should betaken into consideration when deciding whether a particular participant is suitable for thisprotocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:

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Age and Sex:
1. Male or female participants between the ages of 18 and 55 years, inclusive, 65 and85 years, inclusive, or 18 and 85 years, inclusive, at randomization (dependent uponstudy stage).


Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female(Section 10.4.2) participants.

Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, vaccination
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Healthy participants who are determined by medical history, physical examination, andclinical judgment of the investigator to be eligible for inclusion in the study.
Note: Healthy participants with preexisting stable disease, defined as disease notrequiring significant change in therapy or hospitalization for worsening disease during
the 6 weeks before enrollment, can be included.
Informed Consent:
4. Capable of giving personal signed informed consent as described in Appendix 1, which
includes compliance with the requirements and restrictions listed in the ICD and in thisprotocol.

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5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Other medical or psychiatric condition including recent (within the past year) or active
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study
participation or, in the investigator’s judgment, make the participant inappropriate for the
study.
2. Known infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or
hepatitis B virus (HBV).
3. History of severe adverse reaction associated with a vaccine and/or severe allergic
reaction (eg, anaphylaxis) to any component of the study intervention(s).
4. Receipt of medications intended to prevent COVID-19.

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5. Stages 1 and 2 only: Previous clinical or microbiological diagnosis of COVID-19.
6. Sentinel participants in Stage 1 only: Individuals at high risk for severe COVID-19,
including those with any of the following risk factors:Hypertension

Diabetes mellitus

Chronic pulmonary diseaseAsthma

Current vaping or smoking

History of chronic smoking within the prior year

Chronic liver diseaseStage 3 or worse chronic kidney disease (glomerular filtration rate <60
mL/min/1.73 m2)



Resident in a long-term facility

BMI >30 kg/m2

Anticipating the need for immunosuppressive treatment within the next 6 months

7. Sentinel participants in Stage 1 only: Individuals currently working in occupations withhigh risk of exposure to SARS-CoV-2 (eg, healthcare worker, emergency response
personnel).

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8. Immunocompromised individuals with known or suspected immunodeficiency, as
determined by history and/or laboratory/physical examination.
9. Individuals with a history of autoimmune disease or an active autoimmune diseaserequiring therapeutic intervention, including but not limited to: systemic or cutaneous
lupus erythematosus, autoimmune arthritis/rheumatoid arthritis, Guillain-Barré
syndrome, multiple sclerosis, Sjögren’s syndrome, idiopathic thrombocytopenia purpura,glomerulonephritis, autoimmune thyroiditis, giant cell arteritis (temporal arteritis),
psoriasis, and insulin-dependent diabetes mellitus (type 1).
10. Bleeding diathesis or condition associated with prolonged bleeding that would, in theopinion of the investigator, contraindicate intramuscular injection.
11. Women who are pregnant or breastfeeding.
Prior/Concomitant Therapy:

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12. Previous vaccination with any coronavirus vaccine.
13. Individuals who receive treatment with immunosuppressive therapy, including cytotoxic
agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned
receipt throughout the study. If systemic corticosteroids have been administered shortterm (<14 days) for treatment of an acute illness, participants should not be enrolled into
the study until corticosteroid therapy has been discontinued for at least 28 days before
study intervention administration. Inhaled/nebulized (except for sentinel participants inStage 1 – see exclusion criterion 14), intra-articular, intrabursal, or topical (skin or eyes)corticosteroids are permitted.
14. Sentinel participants in Stage 1 only: Regular receipt of inhaled/nebulized
corticosteroids.
15. Receipt of blood/plasma products or immunoglobulin, from 60 days before study
intervention administration or planned receipt throughout the study.
Prior/Concurrent Clinical Study Experience:
16. Participation in other studies involving study intervention within 28 days prior to study
entry and/or during study participation.
17. Previous participation in other studies involving study intervention containing lipid
nanoparticles.
Diagnostic Assessments:
18. Sentinel participants in Stage 1 only: Positive serological test for SARS-CoV-2 IgM
and/or IgG antibodies at the screening visit.
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19. Sentinel participants in Stage 1 only: Any screening hematology and/or blood
chemistry laboratory value that meets the definition of a ≥ Grade 1 abnormality.
Note: With the exception of bilirubin, participants with any stable Grade 1 abnormalities(according to the toxicity grading scale) may be considered eligible at the discretion of
the investigator. (Note: A “stable” Grade 1 laboratory abnormality is defined as a reportof Grade 1 on an initial blood sample that remains ≤ Grade 1 upon repeat testing on asecond sample from the same participant.)
20. Sentinel participants in Stage 1 only: Positive test for HIV, hepatitis B surface antigen(HBsAg), hepatitis B core antibodies (HBc Abs), or hepatitis C virus antibodies(HCV Abs) at the screening visit.
21. Sentinel participants in Stage 1 only: SARS-CoV-2 NAAT-positive nasal swab within
24 hours before receipt of study intervention.
Other Exclusions:

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22. Investigator site staff or Pfizer employees directly involved in the conduct of the study,site staff otherwise supervised by the investigator, and their respective family members.
5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm thatthe participant has selected an appropriate method of contraception for the individual
participant and his or her partner(s) from the permitted list of contraception methods(see Appendix 4, Section 10.4.4) and will confirm that the participant has been instructed inits consistent and correct use. At time points indicated in the SoA, the investigator ordesignee will inform the participant of the need to use highly effective contraception
consistently and correctly and document the conversation and the participant’s affirmation in
the participant’s chart (participants need to affirm their consistent and correct use of at least 1of the selected methods of contraception). In addition, the investigator or designee will
instruct the participant to call immediately if the selected contraception method is
discontinued or if pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but
are not subsequently randomly assigned to study intervention. A minimal set of screen
failure information is required to ensure transparent reporting of screen failure participants tomeet the CONSORT publishing requirements and to respond to queries from regulatory
authorities. Minimal information includes demography, screen failure details, eligibility
criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may berescreened under a different participant number.
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5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention
Administration
The following conditions are temporary or self-limiting and a participant may be vaccinatedonce the condition(s) has/have resolved and no other exclusion criteria are met.

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1. Current febrile illness (body temperature ≥100.4°F [≥38°C]) or other acute illness within
48 hours before study intervention administration. This includes current symptoms that
could represent a potential COVID-19 illness:

New or increased cough;

New or increased shortness of breath;New or increased sore throat;

New or increased wheezing;New or increased sputum production;New or increased nasal congestion;New or increased nasal discharge;



Loss of taste/smell.

2. Receipt of any seasonal or pandemic influenza vaccine within 14 days, or any othernonstudy vaccine within 28 days, before study intervention administration.
3. Anticipated receipt of any seasonal or pandemic influenza vaccine within 14 days, or any
other nonstudy vaccine within 28 days, after study intervention administration.
4. Receipt of short-term (<14 days) systemic corticosteroids. Study intervention
administration should be delayed until systemic corticosteroid use has been discontinued
for at least 28 days. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin oreyes) corticosteroids are permitted.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s),placebo, medical device(s), or study procedure(s) intended to be administered to a study
participant according to the study protocol.
The study may evaluate 2-dose (separated by 21 or 60 days) and single-dose schedules of
3 different dose levels of 4 investigational RNA vaccine candidates for active immunization
against COVID-19 in 3 age groups (18 to 55 years of age, 65 to 85 years of age, and18 to 85 years of age [stratified as ≤55 or >55 years of age]). These 4 investigational RNA
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vaccine candidates, with the addition of saline placebo, are the 5 potential study interventions
that may be administered to a study participant:

BNT162a1 (RNA-LNP vaccine utilizing uRNA and encoding the RBD): 0.1 µg, 0.3 µg,
1 µg

BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 30 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 30 µg, 100 µg



BNT162c2 (BNT162 RNA-LNP vaccine utilizing saRNA and encoding the RBD):
0.1 µg, 0.3 µg, 1 µg

Normal saline (0.9% sodium chloride solution for injection)

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A list of all potential groups in the Stage 1 are shown in Table 1. Each of these groups may
or may not progress to the later stages of the study.
Table 1.

Potential Groups in Stage 1

GroupsN

2-Dose Groups (Sentinel Cohorts)
a-0.1-2-Y (Sentinel)
15[uRNA 0.1 µg (2 doses)]a-0.3-2-Y (Sentinel)
15[uRNA 0.3 µg (2 doses)]a-1-2-Y (Sentinel)
15[uRNA 1 µg (2 doses)]

Age
Group
(Years)18 to 55
18 to 55
18 to 55

b1-10-2-Y (Sentinel)[modRNA 10 µg (2 doses)]b1-30-2-Y (Sentinel)[modRNA 30 µg (2 doses)]b1-100-2-Y (Sentinel)[modRNA 100 µg (2doses)]

15

18 to 55

15

18 to 55

15

18 to 55

b2-10-2-Y (Sentinel)[modRNA 10 µg (2 doses)]b2-30-2-Y (Sentinel)[modRNA 30 µg (2 doses)]b2-100-2-Y (Sentinel)[modRNA 100 µg (2doses)]

15

18 to 55

15

18 to 55

15

18 to 55

Dose 1
Day 1
BNT162a1
Placebo
BNT162a1
Placebo
BNT162a1
Placebo

0.1 µg0.3 µg
1 µg

Dose 2(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

Day 22
BNT162a1
Placebo
BNT162a1
Placebo
BNT162a1
Placebo

0.1 µg0.3 µg
1 µg

BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo

10 µg(n=12)(n=3)
30 µg (n=12)(n=3)
100 µg (n=12)(n=3)

BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo

10 µg

BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo

10 µg

BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo

10 µg(n=12)(n=3)
30 µg (n=12)(n=3)
100 µg (n=12)(n=3)

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30 µg (n=12)(n=3)
100 µg (n=12)(n=3)(n=12)(n=3)
30 µg (n=12)(n=3)
100 µg (n=12)(n=3)

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Table 1.

Potential Groups in Stage 1

GroupsNc-0.1-2-Y (Sentinel)[saRNA 0.1 µg (2 doses)]c-0.3-2-Y (Sentinel)[saRNA 0.3 µg (2 doses)]c-1-2-Y (Sentinel)[saRNA 1 µg (2 doses)]

15

Age
Group
(Years)18 to 55

15

18 to 55

15

18 to 55

15

65 to 8515

65 to 8515

65 to 85b1-10-2-O (Sentinel)[modRNA 10 µg (2 doses)]b1-30-2-O (Sentinel)[modRNA 30 µg (2 doses)]b1-100-2-O (Sentinel)[modRNA 100 µg (2doses)]

15

65 to 8515

65 to 8515

65 to 85b2-10-2-O (Sentinel)[modRNA 10 µg (2 doses)]b2-30-2-O (Sentinel)[modRNA 30 µg (2 doses)]b2-100-2-O (Sentinel)[modRNA 100 µg (2doses)]

15

65 to 8515

65 to 8515

65 to 85c-0.1-2-O (Sentinel)[saRNA 0.1 µg (2 doses)]c-0.3-2-O (Sentinel)[saRNA 0.3 µg (2 doses)]c-1-2-O (Sentinel)[saRNA 1 µg (2 doses)]

15

65 to 8515

65 to 8515

65 to 8515

18 to 55

15

18 to 5515

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a-0.1-2-O (Sentinel)[uRNA 0.1 µg (2 doses)]a-0.3-2-O (Sentinel)[uRNA 0.3 µg (2 doses)]a-1-2-O (Sentinel)[uRNA 1 µg (2 doses)]

Single-Dose Groups
a-x-1-Y[uRNA dose level(s)selected for Stage 2(1 dose)]b1-x-1-Y[modRNA dose level(s)selected for Stage 2(1 dose)]b2-x-1-Y[modRNA dose level(s)selected for Stage 2(1 dose)]c-x-1-Y

Dose 1
BNT162c2
Placebo
BNT162c2
Placebo
BNT162c2
Placebo

0.1 µg

BNT162a1
Placebo
BNT162a1
Placebo
BNT162a1
Placebo

0.1 µg

BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo

Dose 2(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

BNT162c2
Placebo
BNT162c2
Placebo
BNT162c2
Placebo

0.1 µg(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

BNT162a1
Placebo
BNT162a1
Placebo
BNT162a1
Placebo

0.1 µg10 µg(n=12)(n=3)
30 µg (n=12)(n=3)
100 µg (n=12)(n=3)

BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo

10 µg

BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo

10 µg(n=12)(n=3)
30 µg (n=12)(n=3)
100 µg (n=12)(n=3)

BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo

10 µg

BNT162c2
Placebo
BNT162c2
Placebo
BNT162c2
Placebo

0.1 µg

BNT162c2
Placebo
BNT162c2
Placebo
BNT162c2
Placebo

0.1 µg

Day 1
BNT162a1
Placebo

0.3 µg1 µg

0.3 µg1 µg

0.3 µg1 µg(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

1 µg

0.3 µg1 µg(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)
30 µg (n=12)(n=3)
100 µg (n=12)(n=3)(n=12)(n=3)
30 µg (n=12)(n=3)
100 µg (n=12)(n=3)

0.3 µg1 µg(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

Day 22
Placebo(n=15)(n=12)(n=3)

Placebo(n=15)

TBD(n=12)(n=3)

Placebo(n=15)

TBD(n=12)(n=3)

Placebo(n=15)

TBD(n=12)(n=3)

BNT162b1
Placebo

TBD

18 to 55

BNT162b2
Placebo18 to 55

BNT162c2
Placebo

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Table 1.

Potential Groups in Stage 1

Groups

N

Age
Group
(Years)

Dose 1

Dose 215

65 to 85

BNT162a1
Placebo

TBD(n=12)(n=3)

Placebo(n=15)

15

65 to 85

BNT162b1
Placebo

TBD(n=12)(n=3)

Placebo(n=15)

15

65 to 85

BNT162b2
Placebo

TBD(n=12)(n=3)

Placebo(n=15)

15

65 to 85

BNT162c2
Placebo

TBD(n=12)(n=3)

Placebo(n=15)

TBD(n=12)(n=3)

Day 61
BNT162a1
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a-x-1-O[uRNA dose level(s)selected for Stage 2(1 dose)]b1-x-1-O[modRNA dose level(s)selected for Stage 2(1 dose)]b2-x-1-O[modRNA dose level(s)selected for Stage 2(1 dose)]c-x-1-O[saRNA dose level(s)selected for Stage 2(1 dose)]

2-Dose Groups (Longer Schedule)
a-x-2L-Y
15[uRNA dose level(s)selected for Stage 2(2 doses)]b1-x-2L-Y
15[modRNA dose level(s)selected for Stage 2(2 doses)]b2-x-2L-Y
15[modRNA dose level(s)selected for Stage 2(2 doses)]c-x-2L-Y
15[saRNA dose level(s)selected for Stage 2(2 doses)]a-x-2L-O[uRNA dose level(s)selected for Stage 2(2 doses)]b1-x-2L-O[modRNA dose level(s)selected for Stage 2(2 doses)]b2-x-2L-O[modRNA dose level(s)selected for Stage 2(2 doses)]c-x-2L-O

18 to 55

Day 1
BNT162a1
Placebo

TBD(n=12)(n=3)

18 to 55

BNT162b1
Placebo

TBD(n=12)(n=3)

BNT162b1
Placebo

TBD(n=12)(n=3)

18 to 55

BNT162b2
Placebo

TBD(n=12)(n=3)

BNT162b2
Placebo

TBD(n=12)(n=3)

18 to 55

BNT162c2
Placebo

TBD(n=12)(n=3)

BNT162c2
Placebo

TBD(n=12)(n=3)

15

65 to 85

BNT162a1
Placebo

TBD(n=12)(n=3)

BNT162a1
Placebo

TBD(n=12)(n=3)

15

65 to 85

BNT162b1
Placebo

TBD(n=12)(n=3)

BNT162b1
Placebo

TBD(n=12)(n=3)

15

65 to 85

BNT162b2
Placebo

TBD(n=12)(n=3)

BNT162b2
Placebo

TBD(n=12)(n=3)

15

65 to 85

BNT162c2
Placebo

TBD(n=12)(n=3)

BNT162c2
Placebo

TBD(n=12)(n=3)

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Table 1.

Potential Groups in Stage 1

Groups

N

Age
Group
(Years)

Dose 1

Dose 2[saRNA dose level(s)selected for Stage 2(2 doses)]Abbreviations: modRNA = nucleoside-modified messenger ribonucleic acid; saRNA = self-amplifying messenger
ribonucleic acid; TBD = to be determined; uRNA = uridine-containing messenger ribonucleic acid.

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6.1. Study Intervention(s) Administered
Intervention
Name

BNT162a1(BNT 162 RNALNP vaccine
utilizing uRNA)

BNT162b1(BNT162 RNALNP vaccine
utilizing
modRNA)

BNT162b2(BNT162 RNALNP vaccine
utilizing
modRNA)

BNT162c2(BNT162 RNALNP vaccine
utilizing saRNA

Saline placebo

Type
Dose
Formulation

VaccineuRNA

VaccinemodRNA

VaccinemodRNA

VaccinesaRNA

Unit DoseStrength(s)Dosage Level(s)aRoute of
AdministrationUse
IMP or NIMP
Sourcing

250 µg/0.5 mL

250 µg/0.5 mL

250 µg/0.5 mL

250 µg/0.5 mL

Placebo
Normal saline(0.9% sodium
chloride solution
for injection)
N/A

0.1-, 0.3-, 1-µg
Intramuscular
injection
Experimental
IMP
Provided centrally
by the sponsor
Study intervention
will be provided ina glass vial as
open-label supply.
Each vial will belabeled as required
per country
requirement

10-, 30-, 100-µg
Intramuscular
injection
Experimental
IMP
Provided centrally
by the sponsor
Study intervention
will be provided ina glass vial as
open-label supply.
Each vial will belabeled as required
per country
requirement

10-, 30-, 100-µg
Intramuscular
injection
Experimental
IMP
Provided centrally
by the sponsor
Study intervention
will be provided ina glass vial as
open-label supply.
Each vial will belabeled as required
per country
requirement

0.1-, 0.3-, 1-µg
Intramuscular
injection
Experimental
IMP
Provided centrally
by the sponsor
Study intervention
will be provided ina glass vial as
open-label supply.
Each vial will belabeled as required
per country
requirement

Packaging andLabeling

N/A
Intramuscular
injection
PlaceboIMP
Provided centrally
by the sponsor
Study intervention
will be provided ina glass or plastic
vial as open-label
supply. Each vial
will be labeled as
required per
countryrequirementa. Dependent upon safety and/or immunogenicity data generated during the course of this study, or the
BioNTech study conducted in Germany (BNT162-01), it is possible that groups may be started at the next
highest dose, groups may not be started, groups may be terminated early, and/or groups may be added withdose levels below the lowest stated dose or intermediate between the lowest and highest stated doses.

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6.1.1. Administration
Participants will receive 1 dose (0.5 mL) of study intervention as randomized at eachvaccination visit (Visits 1 and 4 for Stage 1 sentinel cohort participants, Visits 1 and 2 for allother participants) in accordance with the study’s SoA.
Study intervention should be administered intramuscularly into the deltoid muscle, preferablyof the nondominant arm, by an unblinded administrator.
Standard vaccination practices must be observed and vaccine must not be injected into bloodvessels. Appropriate medication and other supportive measures for management of an acute
hypersensitivity reaction should be available in accordance with local guidelines for standard
immunization practices.
Administration of study interventions should be performed by an appropriately qualified,
GCP-trained, and vaccine-experienced member of the study staff (eg, physician, nurse,
physician’s assistant, nurse practitioner, pharmacist, or medical assistant) as allowed by
local, state, and institutional guidance.

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Study intervention administration details will be recorded on the CRF.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study interventions received and any discrepancies arereported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only
authorized site staff may supply or administer study intervention. All study interventions
must be stored in a secure, environmentally controlled, and monitored (manual or
automated recording) area in accordance with the labeled storage conditions with accesslimited to the investigator and authorized site staff. At a minimum, daily minimum andmaximum temperatures for all site storage locations must be documented and available
upon request. Data for nonworking days must indicate the minimum and maximum
temperatures since previously documented for all site storage locations upon return tobusiness.
3. Any excursions from the study intervention label storage conditions should be reported to
Pfizer upon discovery along with any actions taken. The site should actively pursue
options for returning the study intervention to the storage conditions described in thelabeling, as soon as possible. Once an excursion is identified, the study intervention must
be quarantined and not used until Pfizer provides permission to use the study
intervention. Specific details regarding the definition of an excursion and information thesite should report for each excursion will be provided to the site in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage conditions
stated on the label.
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5. Study interventions should be stored in their original containers.
6. See the IP manual for storage conditions of the study intervention.
7. The investigator, institution, or the head of the medical institution (where applicable) is
responsible for study intervention accountability, reconciliation, and record maintenance(ie, receipt, reconciliation, and final disposition records), such as the IPAL or sponsorapproved equivalent. All study interventions will be accounted for using a study
intervention accountability form/record.
8. Further guidance and information for the final disposition of unused study interventions
are provided in the IP manual. All destruction must be adequately documented. If
destruction is authorized to take place at the investigator site, the investigator must ensurethat the materials are destroyed in compliance with applicable environmental regulations,institutional policy, and any special instructions provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of
discovery as described in the IP manual.
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6.2.1. Preparation and Dispensing
See the IP manual for instructions on how to prepare the study intervention foradministration. Study intervention should be prepared and dispensed by an appropriately
qualified and experienced member of the study staff (eg, physician, nurse, physician’s
assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as allowed by
local, state, and institutional guidance. A second staff member will verify the dispensing.
Study intervention and placebo will be prepared by qualified unblinded site personnel
according to the IP manual. The study intervention will be administered in such a way toensure the participants remain blinded.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
Allocation (randomization) of participants to vaccine groups will proceed through the use of
an IRT system (IWR). The site personnel (study coordinator or specified designee) will be
required to enter or select information including but not limited to the user’s ID andpassword, the protocol number, and the participant number. The site personnel will then be
provided with a vaccine assignment and randomization number. The IRT system will
provide a confirmation report containing the participant number, randomization number, andstudy intervention allocation assigned. The confirmation report must be stored in the site’s
files.
The study-specific IRT reference manual and IP manual will provide the contact informationand further details on the use of the IRT system.
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6.3.2. Blinding of Site Personnel
In this observer blinded study, the study staff receiving, storing, dispensing, preparing, andadministering the study interventions will be unblinded. All other study and site personnel,
including the investigator, investigator staff, and participants, will be blinded to study
intervention assignments. In particular, the individuals who evaluate participant safety willbe blinded. Because the BNT162 RNA-based COVID-19 vaccine candidates and placebo
are different in physical appearance, the study intervention syringes will be administered in amanner that prevents the study participants from identifying the study intervention type basedon its appearance.
The responsibility of the unblinded dispenser and administrator must be assigned to anindividual or individuals who will not participate in the evaluation of any study participants.
Contact between the unblinded dispenser and study participants and unblinded administrator
and study participants should be kept to a minimum. The remaining site personnel must notknow study intervention assignments.

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6.3.3. Blinding of the Sponsor
To facilitate rapid review of data in real time, sponsor staff will be unblinded to study
intervention allocation for the participants in Stage 1 and in Stage 2. Sponsor staff will beblinded to study intervention allocation in Stage 3. All laboratory testing personnel
performing serology assays will remain blinded to study intervention assigned/received
throughout the study.
Those study team members who are involved in ensuring that protocol requirements forstudy intervention preparation, handling, allocation, and administration are fulfilled at the site
will be unblinded for the duration of the study (eg, unblinded study manager, unblindedclinical research associate). Unblinded clinician(s) who are not direct members of the study
team will review unblinded protocol deviations.
6.3.4. Breaking the Blind
The IRT will be programmed with blind-breaking instructions. In case of an emergency, theinvestigator has the sole responsibility for determining if unblinding of a participant’s study
intervention assignment is warranted. Participant safety must always be the firstconsideration in making such a determination. If the investigator decides that unblinding iswarranted, the investigator should make every effort to contact the sponsor prior to
unblinding a participant’s vaccine assignment unless this could delay further management of
the participant. If a participant’s vaccine assignment is unblinded, the sponsor must be
notified within 24 hours after breaking the blind. The date and reason that the blind was
broken must be recorded in the source documentation and CRF.
The study-specific IRT reference manual and IP manual will provide the contact informationand further details on the use of the IRT system.

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6.4. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from theinvestigator or designee, under medical supervision. The date and time of each dose
administered in the clinic will be recorded in the source documents and recorded in the CRF.
The dose of study intervention and study participant identification will be confirmed at thetime of dosing by a member of the study site staff other than the person administering thestudy intervention.
6.5. Concomitant Therapy

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)The following concomitant medications and vaccinations will be recorded in the CRF:
All vaccinations received from 28 days prior to study enrollment until the 6-monthfollow-up visit (Visit 8 for Stage 1 sentinel cohorts, Visit 5 for Stage 1 nonsentinelcohorts and Stage 2 participants, and Visit 4 for Stage 3 participants).

Prohibited medications listed in Section 6.5.1 will be recorded, to include start and stop
dates, name of the medication, dose, unit, route, and frequency.

In addition, for participants enrolled in the Stage 1 sentinel cohorts, all current
medication at baseline will be recorded, to include start date, name of the medication,dose, unit, route, and frequency.

6.5.1. Prohibited During the Study
Receipt of the following vaccines and medications during the time periods listed below may
exclude a participant from the per-protocol analysis, and may require vaccinations to bediscontinued in that participant; however, it is anticipated that the participant would not be
withdrawn from the study (see Section 7). Medications should not be withheld if required fora participant’s medical care.
Unless considered medically necessary, no vaccines other than study intervention should be
administered within 28 days before and 28 days after each study vaccination. One exception
to this is that seasonal and pandemic influenza vaccine can be given at least 14 days after, orat least 14 days prior to, the administration of study intervention.
Receipt of chronic systemic treatment with known immunosuppressant medications, orradiotherapy, within 60 days before enrollment through conclusion of the study.
Receipt of systemic corticosteroids (≥20 mg/day of prednisone or equivalent) for ≥14 days is
prohibited from 28 days prior to enrollment to Visit 7 for Stage 1 sentinel cohorts, Visit 4 forStage 1 nonsentinel cohorts and Stage 2 participants, and Visit 3 for Stage 3 participants).
Receipt of inhaled/nebulized corticosteroids from 28 days prior to enrollment to Visit 7(1-month follow-up visit) for Stage 1 sentinel cohorts.

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Receipt of blood/plasma products or immunoglobulins within 60 days before enrollment
through conclusion of the study.
Receipt of any other (nonstudy) coronavirus vaccine at any time prior to or during study
participation is prohibited.
Prophylactic antipyretics and other pain medication to prevent symptoms associated withstudy intervention administration are not permitted. However, if a participant is taking a
medication for another condition, even if it may have antipyretic or pain-relieving properties,
it should not be withheld prior to study vaccination.
6.5.2. Permitted During the Study
The use of antipyretics and other pain medication to treat symptoms associated with study
intervention administration or ongoing conditions is permitted.

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Medication other than that described as prohibited in Section 6.5.1 required for treatment ofpreexisting stable conditions is permitted.
Inhaled (except in Stage 1 sentinel cohorts – see Section 6.5.1), topical, or localized
injections of corticosteroids (eg, intra-articular or intrabursal administration) are permitted.
6.6. Dose Modification
Individual participant dose modifications will not be made in this study.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANTDISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study
intervention (definitive discontinuation). Reasons for definitive discontinuation of study
intervention may include the following: AEs; participant request; investigator request;
pregnancy; protocol deviation (including no longer meeting all the inclusion criteria, or
meeting 1 or more exclusion criteria).
Note that discontinuation of study intervention does not represent withdrawal from the study.
Per the study estimands, if study intervention is definitively discontinued, the participant willremain in the study to be evaluated for safety, immunogenicity, and potential efficacy. See
the SoA for data to be collected at the time of discontinuation of study intervention andfollow-up for any further evaluations that need to be completed.
In the event of discontinuation of study intervention, it must be documented on theappropriate CRF/in the medical records whether the participant is discontinuing further
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receipt of study intervention or also from study procedures, posttreatment study follow-up,
and/or future collection of additional information.
7.2. Participant Discontinuation/Withdrawal From the Study

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)A participant may withdraw from the study at any time at his/her own request. Reasons fordiscontinuation from the study may include the following:

Refused further follow-up;

Lost to follow-up;



Death;



Study terminated by sponsor;



AEs;



Participant request;

Investigator request;Protocol deviation.

If a participant does not return for a scheduled visit, every effort should be made to contact
the participant. All attempts to contact the participant and information received duringcontact attempts must be documented in the participant’s source document. In any
circumstance, every effort should be made to document participant outcome, if possible.
The investigator or his or her designee should capture the reason for withdrawal in the CRF
for all participants.
If a participant withdraws from the study, he/she may request destruction of any remaining
samples taken and not tested, and the investigator must document any such requests in thesite study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1)
for disclosure of future information, no further evaluations should be performed and no
additional data should be collected. The sponsor may retain and continue to use any datacollected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not beviewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent
Participants who request to discontinue receipt of study intervention will remain in the study
and must continue to be followed for protocol-specified follow-up procedures. The only
exception to this is when a participant specifically withdraws consent for any further contact
with him or her or persons previously authorized by the participant to provide thisinformation. Participants should notify the investigator in writing of the decision to
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withdraw consent from future follow-up, whenever possible. The withdrawal of consent
should be explained in detail in the medical records by the investigator, as to whether thewithdrawal is only from further receipt of study intervention or also from study procedures
and/or posttreatment study follow-up, and entered on the appropriate CRF page. In the eventthat vital status (whether the participant is alive or dead) is being measured, publicly
available information should be used to determine vital status only as appropriately directedin accordance with local law.
7.3. Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return forscheduled visits and is unable to be contacted by the study site.

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)The following actions must be taken if a participant fails to attend a required study visit:The site must attempt to contact the participant and reschedule the missed visit as soon as
possible and counsel the participant on the importance of maintaining the assigned visit
schedule and ascertain whether or not the participant wishes to and/or should continue inthe study;

Before a participant is deemed lost to follow-up, the investigator or designee must makeevery effort to regain contact with the participant (where possible, 3 telephone calls and,if necessary, a certified letter to the participant’s last known mailing address or local
equivalent methods). These contact attempts should be documented in the participant’s
medical record;Should the participant continue to be unreachable, he/she will be considered to havewithdrawn from the study.

8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed anddated ICD before performing any study-specific procedures.
The full date of birth will be collected to critically evaluate the immune response and safety
profile by age.
Study procedures and their timing are summarized in the SoA. Protocol waivers or
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence orawareness to determine whether the participant should continue or discontinue study
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential
and required for study conduct.

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All screening evaluations must be completed and reviewed to confirm that potential
participants meet all eligibility criteria. The investigator will maintain a screening log torecord details of all participants screened and to confirm eligibility or record reasons forscreening failure, as applicable.
Every effort should be made to ensure that protocol-required tests and procedures arecompleted as described. However, it is anticipated that from time to time there may becircumstances outside the control of the investigator that may make it unfeasible to performthe test. In these cases, the investigator must take all steps necessary to ensure the safety andwell-being of the participant. When a protocol-required test cannot be performed, theinvestigator will document the reason for the missed test and any corrective and preventive
actions that he or she has taken to ensure that required processes are adhered to as soon as
possible. The study team must be informed of these incidents in a timely manner.

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For samples being collected and shipped, detailed collection, processing, storage, andshipment instructions and contact information will be provided to the investigator site prior
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately
530 mL for participants in the Stage 1 sentinel cohorts; 350 mL for participants in the Stage 1
nonsentinel cohorts and Stage 2 participants; and 200 mL for Stage 3 participants.
Additionally, 50 mL of blood will be taken at an unplanned convalescent visit at any time aparticipant develops respiratory symptoms indicating a potential COVID-19 infection. Other
additional blood samples may be taken for safety assessments at times specified by Pfizer,
provided the total volume taken during the study does not exceed 550 mL during any periodof 60 consecutive days.
8.1. Efficacy and/or Immunogenicity Assessments
Efficacy will be assessed throughout a participant’s involvement in the study throughsurveillance for potential cases of COVID-19. If, at any time, a participant develops acuterespiratory illness (see Section 8.13), for the purposes of the study he or she will beconsidered to potentially have COVID-19 illness.9 In this circumstance, the participant
should contact the site, a telehealth visit should occur, and assessments should be conducted
as specified in the SoA. The assessments will include a nasal (midturbinate) swab, which will
be tested at a central laboratory using a reverse transcription–polymerase chain reaction (RTPCR) test (Cepheid; FDA approved under EUA), or other equivalent nucleic acidamplification–based test (ie, NAAT), to detect SARS-CoV-2. In addition, clinicalinformation and results from local standard-of-care tests (as detailed in Section 8.13) will beassessed. Four definitions of potential SARS-CoV-2–related cases will be considered:Centrally confirmed COVID-19: presence of at least 1 symptom described in
Section 8.13 and SARS-CoV-2 NAAT positive at central laboratory

Locally confirmed COVID-19: presence of at least 1 symptom described in Section 8.13
and investigator-confirmed SARS-CoV-2 NAAT positive at a local testing facility
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Centrally confirmed symptomatic seroconversion to SARS-CoV-2 (exploratory):presence of at least 1 symptom described in Section 8.13 and a positive nonvaccine
antigen SARS-CoV-2 antibody result in a participant whose most recent prior nonvaccine
antigen SARS-CoV-2 antibody result was negativeCentrally confirmed asymptomatic seroconversion to SARS-CoV-2 (exploratory):
positive nonvaccine antigen SARS-CoV-2 antibody result in a participant with a priornonvaccine antigen SARS-CoV-2 antibody result was negative

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Serum samples will be obtained for immunogenicity testing at the visits specified in the SoA.
The following assays will be performed:

SARS-CoV-2 serum neutralization assay

SARS-CoV-2-S1–specific IgG direct Luminex immunoassay

SARS-CoV-2 RBD–specific IgG direct Luminex immunoassay

Nonvaccine antigen (NVA) Ig direct Luminex immunoassay. The NVA will include a
SARS-CoV-2 target antigen that is not derived from the S glycoprotein, most likely anantigen derived from the SARS-CoV-2 nucleoprotein.

Note that all immunogenicity analyses will be based upon samples analyzed at the central
laboratory; the rapid test will only be performed at screening by all sites recruiting
participants in Stage 1 sentinel cohorts (see Section 8.11.1.1) to determine eligibility.
8.1.1. Biological Samples
Blood and nasal swab samples will be used only for scientific research. Each sample will belabeled with a code so that the laboratory personnel testing the samples will not know theparticipant’s identity. Samples that remain after performing assays outlined in the protocol
may be stored by Pfizer. Unless a time limitation is required by local regulations or ethicalrequirements, the samples will be stored for up to 15 years after the end of the study and thendestroyed. If allowed by the ICD, stored samples may be used for additional testing to better
understand the immune responses to the vaccine(s) under study in this protocol, to inform thedevelopment of other products, and/or for vaccine-related assay work supporting vaccine
programs. No testing of the participant’s DNA will be performed.
The participant may request that his or her samples, if still identifiable, be destroyed at any
time; however, any data already collected from those samples will still be used for thisresearch. The biological samples may be shared with other researchers as long asconfidentiality is maintained and no testing of the participant’s DNA is performed.

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8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinicallaboratory measurements may be obtained at any time during the study to assess any
perceived safety issues.
A clinical assessment, including medical history, will be performed on all participants at
his/her first visit to establish a baseline. Significant medical history and observations fromany physical examination, if performed, will be documented in the CRF.
AEs and SAEs are collected, recorded, and reported as defined in Section 8.3.
Acute reactions within the first 4 hours after administration of the study intervention (for the
first 5 participants vaccinated in each Stage 1 sentinel group), and within the first 30 minutes(for the remainder of participants), will be assessed and documented in the AE CRF.

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)The safety parameters also include e-diary reports of local reactions and systemic events(including fever), and use of antipyretic medication that occur in the 7 days afteradministration of the study intervention. These prospectively self-collected occurrences of
local reactions and systemic events are graded as described in Section 8.2.2.
8.2.1. Clinical Safety Laboratory Assessments (Sentinel-Cohort Participants Only)
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for
the timing and frequency. All protocol-required laboratory assessments, as defined inAppendix 2, must be conducted in accordance with the laboratory manual and the SoA.
Unscheduled clinical laboratory measurements may be obtained at any time during the study
to assess any perceived safety issues.
The investigator must review the laboratory report, document this review, and record any
clinically relevant changes occurring during the study in the AE section of the CRF. See
Appendix 2 for the grading scale for assessment of clinically significant abnormal laboratory
findings. Clinically significant abnormal laboratory findings are those which are notassociated with the underlying disease, unless judged by the investigator to be more severe
than expected for the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during
participation in the study or within 28 days after the last dose of study intervention should be
repeated until the values return to normal or baseline or are no longer considered clinicallysignificant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 5 for suggested actions and follow-up assessments in the event of potential
drug-induced liver injury.

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8.2.2. Electronic Diary
Participants will be required to complete an e-diary through an application installed on aprovisioned device or on the participant’s own personal device. The participant will be asked
to monitor and record local reactions, systemic events, and antipyretic medication usage for7 days following administration of the study intervention. The e-diary allows recording ofthese assessments only within a fixed time window, thus providing the accurate
representation of the participant’s experience at that time. Data on local reactions andsystemic events reported in the e-diary will be transferred electronically to a third-party
vendor, where they will be available for review by investigators and the Pfizer clinicians at
all times via an internet-based portal.
At intervals agreed to by the vendor and Pfizer, these data will be transferred electronicallyinto Pfizer's database for analysis and reporting. These data do not need to be reported by theinvestigator in the CRF as AEs.

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Investigators (or designee) will be required to review the e-diary data online at frequentintervals as part of the ongoing safety review.
The investigator or designee must obtain stop dates from the participant for any ongoing
local reactions, systemic events, or use of antipyretic medication on the last day that thee-diary was completed. The stop dates should be documented in the source documents andthe information entered in the CRF.
8.2.2.1. Grading Scales
The grading scales used in this study to assess local reactions and systemic events as
described below are derived from the FDA Center for Biologics Evaluation and Research(CBER) guidelines on toxicity grading scales for healthy adult volunteers enrolled inpreventive vaccine clinical trials.8
8.2.2.2. Local Reactions
During the e-diary reporting period, participants will be asked to assess redness, swelling,
and pain at the injection site and to record the symptoms in the e-diary. If a local reaction
persists beyond the end of the e-diary period following vaccination, the participant will be
requested to report that information. The investigator will enter this additional information in
the CRF.
Redness and swelling will be measured and recorded in measuring device units(range: 1 to 21) and then categorized during analysis as absent, mild, moderate, or severe
based on the grading scale in Table 2. Measuring device units can be converted tocentimeters according to the following formula: 1 measuring device unit = 0.5 cm. Pain at
the injection site will be assessed by the participant as absent, mild, moderate, or severe
according the grading scale in Table 2.

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If a Grade 3 local reaction is reported in the e-diary, a telephone contact should occur toascertain further details and determine whether a site visit is clinically indicated. Only an
investigator or medically qualified person is able to classify a participant’s local reaction as
Grade 4. If a participant experiences a confirmed Grade 4 local reaction, the investigatormust immediately notify the sponsor and, if it is determined to be related to theadministration of the study intervention, further vaccinations will be discontinued in thatparticipant.
Table 2.

Local Reaction Grading Scale
Mild(Grade 1)

Pain at the
injection site

Does not interferewith activity

Interferes withactivity

Redness

2.0 cm to 5.0 cm(5 to 10 measuring
device units)
2.0 cm to 5.0 cm(5 to 10 measuring
device units)>5.0 cm to 10.0 cm(11 to 20 measuring
device units)>5.0 cm to 10.0 cm(11 to 20 measuring
device units)

Swelling

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Moderate(Grade 2)

Severe(Grade 3)

Potentially Life
Threatening(Grade 4)
Prevents daily activity Emergency room visit
or hospitalization forsevere pain
>10 cmNecrosis or(≥21 measuringexfoliative dermatitis
device units)>10 cmNecrosis(≥21 measuring
device units)

8.2.2.3. Systemic Events
During the e-diary reporting period, participants will be asked to assess vomiting, diarrhea,
headache, fatigue, chills, new or worsened muscle pain, and new or worsened joint pain andto record the symptoms in the e-diary. The symptoms will be assessed by the participant as
absent, mild, moderate, or severe according to the grading scale in Table 3.
If a Grade 3 systemic event is reported in the e-diary, a telephone contact should occur toascertain further details and determine whether a site visit is clinically indicated. Only an
investigator or medically qualified person is able to classify a participant’s systemic event as
Grade 4. If a participant experiences a confirmed Grade 4 systemic event, the investigatormust immediately notify the sponsor and, if it is determined to be related to theadministration of the study intervention, further vaccinations will be discontinued in thatparticipant.

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Table 3.

Systemic Event Grading Scale

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Mild(Grade 1)

Moderate(Grade 2)>2 times in
24 hours

Severe(Grade 3)

Vomiting

1-2 times in
24 hours

Requires IV
hydration

Diarrhea

2 to 3 loose stools 4 to 5 loose stools
in 24 hours
in 24 hours

6 or more loosestools in 24 hours

Headache

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Fatigue/tiredness

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Chills

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

New orworsened
muscle pain

Does not interfere Some interferencewith activity
with activity

Prevents daily
routine activity

Does not interfere Some interference
New orwith activity
with activity
worsened
joint pain
Abbreviation: IV = intravenous.

Prevents daily
routine activity

Potentially Life
Threatening(Grade 4)
Emergency room visit or
hospitalization for
hypotensive shock
Emergency room visit or
hospitalization for severe
diarrhea
Emergency room visit or
hospitalization for severe
headache
Emergency room visit or
hospitalization for severe
fatigue
Emergency room visit or
hospitalization for severe
chillsEmergency room visit or
hospitalization for severe
new or worsened muscle
painEmergency room visit or
hospitalization for severe
new or worsened joint pain

8.2.2.4. Fever
In order to record information on fever, a thermometer will be given to participants with
instructions on how to measure oral temperature at home. Temperature will be collected in
the e-diary in the evening daily during the e-diary reporting period. It will also be collected
at any time during the e-diary data collection periods when fever is suspected. Fever isdefined as an oral temperature of ≥38.0°C (100.4°F). The highest temperature for each day
will be recorded in the e-diary. Temperature will be measured and recorded to 1 decimal
place and then categorized during analysis according to the scale shown in Table 4.
If a fever of ≥39.0°C (102.1°F) is reported in the e-diary, a telephone contact should occur toascertain further details and determine whether a site visit is clinically indicated. Only an
investigator or medically qualified person is able to confirm a participant’s fever as >40.0°C(>104.0°F). If a participant experiences a confirmed fever >40.0°C (>104.0°F), theinvestigator must immediately notify the sponsor and, if it is determined to be related to theadministration of the study intervention, further vaccinations will be discontinued in thatparticipant.

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Table 4.

Scale for Fever≥38.0-38.4°C (100.4-101.1°F)>38.4-38.9°C (101.2-102.0°F)>38.9-40.0°C (102.1-104.0°F)>40.0°C (>104.0°F)

8.2.2.5. Antipyretic Medication
The use of antipyretic medication to treat symptoms associated with study intervention
administration will be recorded in the e-diary daily during the reporting period (Day 1 to
Day 7).
8.2.3. Stopping Rules

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)The following stopping rules are in place for all Stage 1 sentinel-cohort participants, basedon review of AE data and e-diary reactogenicity data. These data will be monitored on an
ongoing basis by the investigator (or medically qualified designee) and sponsor in order topromptly identify and flag any event that potentially contributes to a stopping rule.
The sponsor study team will be unblinded during the Stage 1, so will be able to assess
whether or not a stopping rule has been met on the basis of a participant’s individual study
intervention allocation.
In the event that sponsor personnel confirm that a stopping rule is met, the following actions
will commence:The IRC will review all appropriate data.

The stopping rule will PAUSE randomization and study intervention administration for
the impacted vaccine candidate all dose levels and age groups.



The DMC will review all appropriate data.

For all participants vaccinated, all other routine study conduct activities, including
ongoing data entry, reporting of AEs, participant e-diary completion, blood sample
collection, and participant follow-up, will continue during the pause.

A stopping rule is met if any of the following rules occur after administration of
investigational BNT162 vaccine; data from placebo recipients will not contribute to thestopping rules. E-diary data confirmed by the investigator as being entered by the participant
in error will not contribute toward a stopping rule.
BNT162 RNA platforms (ie, a, b, and c) will be evaluated for contribution to stopping rules
individually; vaccine candidate dose levels within a platform and age groups will contribute

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to stopping rules together. However, it is possible that the recommendations may include
halting or continuing randomization with any of the BNT162 vaccine candidates.
Stopping Rule Criteria for Each BNT162 Vaccine Candidate:
1. If any participant vaccinated with the BNT162 candidate (at any dose level) develops an
SAE that is assessed by the investigator as possibly related, or for which there is noalternative, plausible, attributable cause.
2. If any participant vaccinated with the BNT162 candidate (at any dose level) develops a
Grade 4 local reaction or systemic event after vaccination (see Section 8.2.2) that is
assessed as possibly related by the investigator, or for which there is no alternative,plausible, attributable cause.

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3. If any participant vaccinated with the BNT162 candidate (at any dose level) develops afever >40.0°C (>104.0°F) for at least 1 daily measurement after vaccination (seeSection 8.2.2.4) that is assessed as possibly related by the investigator, or for which there
is no alternative, plausible, attributable cause.
4. If any 2 participants vaccinated with the BNT162 candidate (at any dose level) report thesame or similar severe (Grade 3) AE (including laboratory abnormalities) after
vaccination, assessed as possibly related by the investigator, or for which there is noalternative, plausible, attributable cause.
5. If any participant dies or requires ICU admission due to SARS-CoV-2 infection; if thisstopping rule is met, all available clinical and preclinical safety and immunogenicity data
should be reviewed to evaluate for enhanced COVID-19 disease.
8.2.3.1. Randomization and Vaccination After a Stopping Rule Is Met
Once the IRC and DMC have reviewed the safety data and provided guidance, a notification
will be sent from the sponsor to the sites with guidance on how to proceed.
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19 Disease
As this is a sponsor open-label study during Stages 1 and 2, the sponsor will conduct
unblinded reviews of the data during the course of the study, including for the purpose ofsafety assessment.
Participants in all stages of the study will be surveilled for potential COVID-19 illness from
Visit 1 onwards (see Section 8.13). All NAAT-confirmed cases will be reviewed
contemporaneously by the IRC and the DMC (see Section 9.6). In addition, instances ofsymptomatic and asymptomatic seroconversion to SARS-CoV-2 (see Section 8.1) will be
reviewed.
The purpose of these reviews will be to identify whether any features of each case appear
unusual, in particular greater severity, compared to available information at the time of
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review. Indicators of severity may include accelerated deterioration, need for hospitalization,need for ventilation, or death. Observed rates of these indicators will be compared with what
could be expected in a similar population to the study participants based upon available
information at the time of review. Since the DMC is able to review unblinded information, it
will also be able to compare cases in active vaccine and placebo recipients in Stage 3 (whensponsor staff will be blinded).
8.2.5. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA,
immediately before the administration of each vaccine dose. A negative pregnancy test result
will be required prior to the participant’s receiving the study intervention. Pregnancy tests
may also be repeated if requested by IRBs/ECs or if required by local regulations. In thecase of a positive confirmed pregnancy, the participant will be withdrawn fromadministration of study intervention but may remain in the study.
8.3. Adverse Events and Serious Adverse Events

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or
the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, andrecording events that meet the definition of an AE or SAE and remain responsible to pursue
and obtain adequate information both to determine the outcome and to assess whether the
event meets the criteria for classification as an SAE or caused the participant to discontinue
the study intervention (see Section 7.1).
Each participant will be questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection
period”) for each participant begins from the time the participant provides informed consent,
which is obtained before the participant’s participation in the study (ie, before undergoing
any study-related procedure and/or receiving study intervention), through and including
Visit 7 for Stage 1 sentinel-cohort participants, Visit 4 for Stage 1 nonsentinel participants
and Stage 2 participants, and Visit 3 for Stage 3 participants. In addition, any AEs occurring
up to 48 hours after each subsequent blood draw must be recorded on the CRF.
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cohort participants, Visit 5 for Stage 1 nonsentinel cohort participants and Stage 2
participants, and Visit 4 for Stage 3 participants).
Follow-up by the investigator continues throughout and after the active collection period anduntil the AE or SAE or its sequelae resolve or stabilize at a level acceptable to theinvestigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of
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If a participant definitively discontinues or temporarily discontinues study intervention
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE
reported using the Vaccines SAE Report Form.
Investigators are not obligated to actively seek AEs or SAEs after the participant has
concluded study participation. However, if the investigator learns of any SAE, including adeath, at any time after a participant has completed the study, and he/she considers the event
to be reasonably related to the study intervention, the investigator must promptly report the
SAE to Pfizer using the Vaccines SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in
Section 8.3.1 are reported to Pfizer Safety on the Vaccines SAE Report Form immediately
upon awareness and under no circumstance should this exceed 24 hours, as indicated inAppendix 3. The investigator will submit any updated SAE data to the sponsor within
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period as
described in Section 8.3.1 are recorded on the CRF. AEs and SAEs that begin after obtaining
informed consent but before the start of study intervention will be recorded on the Medical
History/Current Medical Conditions section of the CRF, not the AE section. AEs and SAEs
that begin after the start of study intervention are recorded on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and theprocedures for completing and transmitting SAE reports are provided in Appendix 3.

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Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended andnonleading verbal questioning of the participant is the preferred method to inquire about
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow eachparticipant at subsequent visits/contacts. For each event, the investigator must pursue andobtain adequate information until resolution, stabilization, the event is otherwise explained,or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail toallow for a complete medical assessment of the case and independent determination of
possible causality. Any information relevant to the event, such as concomitant medications
and illnesses, must be provided. In the case of a participant death, a summary of available
autopsy findings must be submitted as soon as possible to Pfizer Safety.
Further information on follow-up procedures is given in Appendix 3.

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8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal
obligations and ethical responsibilities towards the safety of participants and the safety of astudy intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and otherregulatory agencies about the safety of a study intervention under clinical investigation. The
sponsor will comply with country-specific regulatory requirements relating to safety
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding andoccupational exposure are reportable to Pfizer Safety within 24 hours of investigatorawareness.

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8.3.5.1. Exposure During Pregnancy

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)An EDP occurs if:A female participant is found to be pregnant while receiving or after discontinuing study
intervention.



A male participant who is receiving or has discontinued study intervention exposes afemale partner prior to or around the time of conception.



A female is found to be pregnant while being exposed or having been exposed to study
intervention due to environmental exposure. Below are examples of environmental
exposure during pregnancy:

A female family member or healthcare provider reports that she is pregnant after
having been exposed to the study intervention by inhalation or skin contact.

A male family member or healthcare provider who has been exposed to the study
intervention by inhalation or skin contact then exposes his female partner prior to or
around the time of conception.

The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s
awareness, irrespective of whether an SAE has occurred. The initial information submitted
should include the anticipated date of delivery (see below for information related totermination of pregnancy).


If EDP occurs in a participant or a participant’s partner, the investigator must report thisinformation to Pfizer Safety on the Vaccines SAE Report Form and an EDP
Supplemental Form, regardless of whether an SAE has occurred. Details of thepregnancy will be collected after the start of study intervention and until 6 months after
the last dose of study intervention.



If EDP occurs in the setting of environmental exposure, the investigator must report
information to Pfizer Safety using the Vaccines SAE Report Form and EDP
Supplemental Form. Since the exposure information does not pertain to the participant
enrolled in the study, the information is not recorded on a CRF; however, a copy of thecompleted Vaccines SAE Report Form is maintained in the investigator site file.

Follow-up is conducted to obtain general information on the pregnancy and its outcome for
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as afollow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural
integrity of the neonate can be assessed at the time of birth. In the event of a termination, thereason(s) for termination should be specified and, if clinically possible, the structural
integrity of the terminated fetus should be assessed by gross visual inspection (unless

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preprocedure test findings are conclusive for a congenital anomaly and the findings arereported).

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Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meetsthe criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal
demise, neonatal death, or congenital anomaly), the investigator should follow the procedures
for reporting SAEs. Additional information about pregnancy outcomes that are reported to
Pfizer Safety as SAEs follows:

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard tocausality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs
when the investigator assesses the infant death as related or possibly related to exposure
to the study intervention.

Additional information regarding the EDP may be requested by the sponsor. Further
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on
preterm infants to identify developmental delays). In the case of paternal exposure, theinvestigator will provide the participant with the Pregnant Partner Release of Information
Form to deliver to his partner. The investigator must document in the source documents thatthe participant was given the Pregnant Partner Release of Information Form to provide to his
partner.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if:A female participant is found to be breastfeeding while receiving or after discontinuing
study intervention.



A female is found to be breastfeeding while being exposed or having been exposed to
study intervention (ie, environmental exposure). An example of environmental exposure
during breastfeeding is a female family member or healthcare provider who reports that
she is breastfeeding after having been exposed to the study intervention by inhalation orskin contact.

The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hoursof the investigator’s awareness, irrespective of whether an SAE has occurred. The
information must be reported using the Vaccines SAE Report Form. When exposure during
breastfeeding occurs in the setting of environmental exposure, the exposure information does
not pertain to the participant enrolled in the study, so the information is not recorded on a
CRF. However, a copy of the completed Vaccines SAE Report Form is maintained in theinvestigator site file.

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An exposure during breastfeeding report is not created when a Pfizer drug specificallyapproved for use in breastfeeding women (eg, vitamins) is administered in accord withauthorized use. However, if the infant experiences an SAE associated with such a drug, theSAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with thestudy intervention, which may or may not lead to the occurrence of an AE. Such persons
may include healthcare providers, family members, and other roles that are involved in thetrial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of theinvestigator’s awareness, regardless of whether there is an associated SAE. The informationmust be reported using the Vaccines SAE Report Form. Since the information does not
pertain to a participant enrolled in the study, the information is not recorded on a CRF;
however, a copy of the completed Vaccines SAE Report Form is maintained in theinvestigator site file.

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8.3.6. Medication Errors
Medication errors may result from the administration or consumption of the study
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as
medication errors.
Safety Event

Recorded on the CRF

Reported on the Vaccines SAE Report
Form to Pfizer Safety Within 24 Hours
of Awareness

Medication errors

All (regardless of whether
associated with an AE)

Only if associated with an SAE

Medication errors include:Medication errors involving participant exposure to the study intervention;Potential medication errors or uses outside of what is foreseen in the protocol that do or
do not involve the study participant;The administration of expired study intervention;

The administration of an incorrect study intervention;

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The administration of an incorrect dosage;The administration of study intervention that has undergone temperature excursion fromthe specified storage range, unless it is determined by the sponsor that the study
intervention under question is acceptable for use.

Such medication errors occurring to a study participant are to be captured on the medication
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by theinvestigator, the medication error is recorded on the medication error page of the CRF and, if
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a Vaccines SAE
Report Form only when associated with an SAE.
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8.4. Treatment of Overdose
For this study, any dose of study intervention greater than 1 dose of study intervention within
a 24-hour time period will be considered an overdose.
Pfizer does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the medical monitor immediately.
2. Closely monitor the participant for any AEs/SAEs.
3. Document the quantity of the excess dose as well as the duration of the overdose in the
CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.

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8.7. Genetics
Genetics (specified analyses) are not evaluated in this study.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.9. Immunogenicity Assessments
Immunogenicity assessments are described in Section 8.1.
8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are notevaluated in this study.
8.11. Study Procedures
8.11.1. Stage 1 Sentinel Cohorts

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8.11.1.1. Screening: (0 to 14 Days Before Visit 1)
Before enrollment and before any study-related procedures are performed, voluntary, written
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.
It is anticipated that the procedures below will be conducted in a stepwise manner; however,the visit can occur over more than 1 day.
Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance.

Obtain details of any medications currently taken.

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Perform physical examination including vital signs (weight, height, body temperature,pulse rate, and seated blood pressure), evaluating any clinically significant abnormalities
within the following body systems: general appearance; skin; head, eyes, ears, nose, andthroat; heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph
nodes.



Collect a blood sample (approximately 20 mL) for potential future serological assessment
and to perform a rapid test for prior COVID-19 infection.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.

Collect a blood sample (approximately 10 mL) for HIV, HBsAg, HBc Ab, and HCV Ab
tests.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Record AEs as described in Section 8.3. AEs that occur prior to dosing should be notedon the Medical History CRF.



Ask the participant to contact the site staff or investigator immediately if any significant
illness or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

Complete the CRF.

8.11.1.2. Visit 1 – Vaccination 1: (Day 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.
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

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Review screening laboratory results (hematology and chemistry, and HIV, HBsAg,
HBc Ab, and HCV Ab tests).

Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested(if possible at the site, otherwise at the central laboratory) within 24 hours andvaccination will proceed only if it is NAAT-negative for SARS-CoV-2 genomes.
The second will be sent to the central laboratory for potential later testing.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Obtain the participant’s randomization number and study intervention allocation using
the IRT system. Either blinded site staff or unblinded site staff member may obtain thisinformation.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.



The first 5 participants vaccinated in each Stage 1 sentinel group must be observed byblinded site staff for any acute reactions for at least 4 hours after vaccination. For
participants enrolled thereafter, blinded site staff must observe the participant for at least
30 minutes after study intervention administration for any acute reactions. Record any
acute reactions (including time of onset) in the participant’s source documents and on the
AE page of the CRF, and on an SAE form as applicable.

Issue a measuring device to measure local reactions at the injection site and athermometer for recording daily temperatures and provide instructions on their use.
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Explain the e-diary technologies available for this study, and assist the participant indownloading the study application onto the participant’s own device or issue aprovisioned device if required. Provide instructions on e-diary completion and ask theparticipant to complete the e-diary from Day 1 to Day 7, with Day 1 being the day of
vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the e-diary data online
following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1 to 3 Days After Visit 1)

Record AEs as described in Section 8.3.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within the

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following body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.
Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the e-diary data online
following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

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8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to 8 Days After Visit 1)

Record AEs as described in Section 8.3.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

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Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the e-diary data online
following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1)

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It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



Review the participant’s e-diary data. Collect stop dates of any e-diary events ongoingon the last day that the e-diary was completed and record stop dates in the CRF if
required.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested (ifpossible at the site, otherwise at the central laboratory) within 24 hours and vaccination
will only proceed if it is NAAT-negative for SARS-CoV-2 genomes. The second will besent to the central laboratory for potential later testing.

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Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met. If not, the participant should not receive further study intervention but willremain in the study to be evaluated for safety, immunogenicity, and potential efficacy(see Section 7.1).

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection
site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and ask the participant to complete the ediary from Day 1 to Day 7, with Day 1 being the day of vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.

Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

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

Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the e-diary data online
following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

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8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to 8 Days After Visit 4)

Record AEs as described in Section 8.3.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).
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Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the e-diary data online
following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to 16 Days After Visit 4)

Record AEs as described in Section 8.3.



Review the participant’s e-diary data. Collect stop dates of any e-diary events ongoingon the last day that the e-diary was completed and record stop dates in the CRF if
required.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if
indicated by any change in the participant’s health since the previous visit, perform aphysical examination, evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.
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Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Collect the participant’s e-diary or assist the participant to remove the study applicationfrom his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After Visit 4)

Record AEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (154 to 168 Days After Visit 4)

Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.1.10. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 4)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.1.11. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 4)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.2. Stage 1 Nonsentinel Cohorts and Stage 2 Cohorts

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8.11.2.1. Visit 1 – Vaccination 1: (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written,
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.
It is anticipated that the procedures below will be conducted in a stepwise manner.
Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance.



Perform physical examination including vital signs (weight, height, body temperature,pulse rate, and seated blood pressure), evaluating any clinically significant abnormalities
within the following body systems: general appearance; skin; head, eyes, ears, nose, andthroat; heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph
nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

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Protocol Amendment 1, 13 May 2020

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.



Record AEs as described in Section 8.3.

Obtain the participant’s randomization number and study intervention allocation using
the IRT system. Either blinded site staff or unblinded site staff member may obtain thisinformation.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Issue a measuring device to measure local reactions at the injection site and athermometer for recording daily temperatures and provide instructions on their use.



Explain the e-diary technologies available for this study, and assist the participant indownloading the study application onto the participant’s own device or issue aprovisioned device if required. Provide instructions on e-diary completion and ask theparticipant to complete the e-diary from Day 1 to Day 7, with Day 1 being the day of
vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.
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Protocol Amendment 1, 13 May 2020



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the e-diary data online
following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days or 56 to 70 Days After Visit 1)
The window for Visit 2 is dependent on the dosing schedule for the assigned group.
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



Review the participant’s e-diary data. Collect stop dates of any e-diary events ongoingon the last day that the e-diary was completed and record stop dates in the CRF if
required.

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met. If not, the participant should not receive further study intervention but willremain in the study to be evaluated for safety, immunogenicity, and potential efficacy(see Section 7.1).
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Protocol Amendment 1, 13 May 2020



Measure the participant’s body temperature.

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection
site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and ask the participant to complete the
e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

CONFIDENTIAL
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Protocol Amendment 1, 13 May 2020Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the e-diary data online
following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)

8.11.2.3. Visit 3 – 2-Week Follow-up Visit: (12 to 16 Days After Visit 2)

Record AEs as described in Section 8.3.



Review the participant’s e-diary data. Collect stop dates of any e-diary events ongoingon the last day that the e-diary was completed and record stop dates in the CRF if
required.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Collect the participant’s e-diary or assist the participant to remove the study applicationfrom his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.2.4. Visit 4 – 1-Month Follow-up Visit: (28 to 35 Days After Visit 2)

Record AEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.11.2.5. Visit 5 – 6-Month Follow-up Visit: (154 to 168 Days After Visit 2)

Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.
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

Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.2.6. Visit 6 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 2)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.2.7. Visit 7 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 2)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.3. Stage 3 Cohort(s)8.11.3.1. Visit 1 – Vaccination 1: (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written,
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.
It is anticipated that the procedures below will be conducted in a stepwise manner.
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Protocol C4591001
Protocol Amendment 1, 13 May 2020

Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance.



Perform physical examination including vital signs (weight, height, body temperature,pulse rate, and seated blood pressure), evaluating any clinically significant abnormalities
within the following body systems: general appearance; skin; head, eyes, ears, nose, andthroat; heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph
nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.



Record AEs as described in Section 8.3.

Obtain the participant’s randomization number and study intervention allocation number
using the IRT system. Either blinded site staff or unblinded site staff member may obtain
this information.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

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Protocol C4591001
Protocol Amendment 1, 13 May 2020

Issue a measuring device to measure local reactions at the injection site and athermometer for recording daily temperatures and provide instructions on their use.



Explain the e-diary technologies available for this study, and assist the participant indownloading the study application onto the participant’s own device or issue aprovisioned device if required. Provide instructions on e-diary completion and ask theparticipant to complete the e-diary from Day 1 to Day 7, with Day 1 being the day of
vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.

The investigator or appropriately qualified designee reviews the e-diary data online following
vaccination to evaluate participant compliance and as part of the ongoing safety review.
Daily review is optimal during the active diary period.
8.11.3.2. Visit 2 – Vaccination 2: (19 to 23 Days or 56 to 70 Days After Visit 1)
The window for Visit 2 is dependent on the dosing schedule(s) selected for Stage 3.

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It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



Review the participant’s e-diary data. Collect stop dates of any e-diary events ongoingon the last day that the e-diary was completed and record stop dates in the CRF if
required.

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met. If not, the participant should not receive further study intervention but willremain in the study to be evaluated for safety, immunogenicity, and potential efficacy(see Section 7.1).

Measure the participant’s body temperature.

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection
site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and ask the participant to complete the
e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination.
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Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.

The investigator or appropriately qualified designee reviews the e-diary data online following
vaccination to evaluate participant compliance and as part of the ongoing safety review.
Daily review is optimal during the active diary period.
8.11.3.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2): (28 to 35 Days After
Visit 2)


Record AEs as described in Section 8.3.



Review the participant’s e-diary data. Collect stop dates of any e-diary events ongoingon the last day that the e-diary was completed and record stop dates in the CRF if
required.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.
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

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Collect the participant’s e-diary or assist the participant to remove the study applicationfrom his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.11.3.4. Visit 4 – 6-Month Safety Telephone Contact: (154 to 168 Days After Visit 2)Contact the participant by telephone in order to obtain the following information.



Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.3.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.11.3.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 2)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

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Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.3.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 2)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction
If a Grade 3 local reaction (Section 8.2.2.2), systemic event (Section 8.2.2.3), or fever(Section 8.2.2.4) is reported in the e-diary, a telephone contact should occur to ascertain
further details and determine whether a site visit is clinically indicated. If suspected Grade 4
local reaction (Section 8.2.2.2), systemic event (Section 8.2.2.3), or fever (Section 8.2.2.4) isreported in the e-diary, a telephone contact or site visit should occur to confirm whether the
event meets the criteria for Grade 4.
A site visit must be scheduled as soon as possible to assess the participant unless any of thefollowing is true:The participant is unable to attend the unscheduled visit.

The local reaction/systemic event is no longer present at the time of the telephone
contact.



The participant recorded an incorrect value in the e-diary (confirmation of an e-diary data
entry error).



The PI or authorized designee determined it was not needed.

This telephone contact will be recorded in the participant’s source documentation and the
CRF.
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If the participant is unable to attend the unscheduled visit, or the PI or authorized designee
determined it was not needed, any ongoing local reactions/systemic events must be assessedat the next study visit.

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During the unscheduled visit, the reactions should be assessed by the investigator or a
medically qualified member of the study staff such as a study physician or a study nurse, asapplicable to the investigator’s local practice, who will:Measure body temperature (°F/°C).

Measure minimum and maximum diameters of redness (if present).

Measure minimum and maximum diameters of swelling (if present).



Assess injection site pain (if present) in accordance with the grades provided in
Section 8.2.2.2.

Assess systemic events (if present) in accordance with the grades provided in
Section 8.2.2.3.

Assess for other findings associated with the reaction and record on the AE page of the
CRF, if appropriate.

The investigator or an authorized designee will complete the unscheduled visit assessment
page of the CRF.
8.13. COVID-19 Disease Surveillance (All Participants)
If a participant experiences any of the following, he or she is instructed to contact the site
immediately, and if confirmed, participate in a telehealth visit as soon as possible, optimallywithin 3 days of symptom onset. Note that this does not substitute for a participant’s routine
medical care. Therefore participants should be encouraged to seek care, if appropriate, fromtheir usual provider.


A diagnosis of COVID-19;



Fever;

New or increased cough;

New or increased shortness of breath;New or increased sore throat;

New or increased wheezing;New or increased sputum production;
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New or increased nasal congestion;New or increased nasal discharge;



Loss of taste/smell.

8.13.1. Potential COVID-19 Illness Telehealth Visit: (Optimally Within 3 Days After
Potential COVID-19 Illness Onset)
This telehealth visit is expected to involve the sharing of healthcare information and services
via telecommunication technologies (eg, audio, video, video-conferencing software)remotely, thus allowing the participant and investigator to communicate on aspects of clinicalcare.

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)As a participant’s COVID-19 illness may evolve over time, several telehealth contacts may
be required to obtain the following information:


Record AEs, as appropriate as described in Section 8.3.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Instruct the participant to self-collect a nasal (midturbinate) swab and ship for assessment
at the central laboratory. The result from this swab will be provided to the site once it isavailable, but this will not be in real time, and cannot be relied upon to direct clinicalcare. Therefore, the participant should be encouraged to seek care, if appropriate, fromhis or her usual provider.

Collect COVID-19–related standard-of-care clinical and laboratory information. This
includes, but is not limited to:Symptoms

Clinical diagnosis

Local laboratory COVID-19 test resultFull blood countC-reactive protein

Number and type of any healthcare contact; duration of hospitalization and intensive
care unit stay

Need for oxygen therapy



Need for ventilation
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Schedule an appointment for the participant to return for the potential COVID-19
convalescent visit once he or she has recovered.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After Potential
COVID-19 Illness Visit)

Record AEs, as appropriate as described in Section 8.3.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Collect/update COVID-19–related clinical and laboratory information (detailed in
Section 8.13.1).

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

9. STATISTICAL CONSIDERATIONS
Methodology for summary and statistical analyses of the data collected in this study is
described here and further detailed in a statistical analysis plan (SAP), which will bemaintained by the sponsor. The SAP may modify what is outlined in the protocol whereappropriate; however, any major modifications of the primary endpoint definitions or theiranalyses will also be reflected in a protocol amendment.
9.1. Estimands and Statistical Hypotheses
9.1.1. Estimands
The estimand corresponding to each primary, secondary, and tertiary/exploratory objective is
described in the table in Section 3.
In the primary safety objective evaluations, missing e-diary data will not be imputed.
Missing AE dates will be imputed according to Pfizer safety rules. No other missing
information will be imputed in the safety analysis.
The estimands to evaluate the immunogenicity objectives are based on evaluable populations
for immunogenicity (Section 9.3). These estimands estimate the vaccine effect in the
hypothetical setting where participants follow the study schedules and protocol requirements
as directed. Missing antibody results will not be imputed. Immunogenicity results that are

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below the LLOQ will be set to 0.5 × LLOQ in the analysis; this may be adjusted once
additional data on the assay characteristics become available.
The estimands to evaluate the efficacy objectives are based on evaluable populations for
efficacy (Section 9.3). These estimands estimate the vaccine effect in the hypotheticalsetting where participants follow the study schedules and protocol requirements as directed.
Missing laboratory results will not be imputed for the primary analysis, but missing data
imputation for the efficacy endpoint may be performed as a sensitivity analysis.
9.1.2. Statistical Hypotheses
At the end of Stage 3, the vaccine efficacy (VE) will be evaluated. VE is defined as
VE = 100 × (1 – IRR), where IRR is the illness rate ratio, the calculated ratio of the
COVID-19 illness rate in the active vaccine group to the incidence rate in the placebo group.
The efficacy hypothesis is:090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)

H0: VE ≤20% vs Ha: VE >20%
where H0 and Ha represent null hypothesis and alternative hypothesis. For participants withmultiple illnesses, only the first COVID-19 confirmed case will contribute to the VE
calculation in the hypothesis test.
The efficacy will be demonstrated if the null hypothesis VE ≤20% is rejected at the 0.025
significance level, that is, when the lower limit of the 2-sided 95% CI for VE is >20%, which
is derived using the Clopper-Pearson method as described by Agresti.99.2. Sample Size Determination
The study sample size for the first 2 stages of the study is not based on any statistical
hypothesis testing. Stage 1 will comprise 15 participants (randomization ratio of 4:1 so that
12 receive active vaccine and 3 receive placebo) per group; up to 56 potential groups areforeseen; if all groups are fully enrolled, assuming 2 dose levels are selected following theinitial dose escalation, this corresponds to a total of 840 participants. Stage 2 will include 1 ormore vaccine groups selected from Stage 1, and 225 participants will be randomized per
selected vaccine candidate in a 4:1 ratio to receive active vaccine (180 participants) orplacebo (45 participants).
For Stage 3, for the selected vaccine candidate/dose level, with assumptions of a true vaccine
efficacy (VE) of 70%, 53 cases of COVID-19 will provide 90% power to conclude true
VE >20%. This would be achieved with 3000 participants per group (1:1 randomization
ratio), based on the assumption of a 1.7% incidence rate in the placebo group, and 20% of theparticipants being nonevaluable.
For safety outcomes, Table 5 shows the probability of observing at least 1 AE for a given
true event rate of a particular AE, for various sample sizes. For example, if the true AE rate
is 10%, with 12 participants in a vaccine group, there is 72% probability of observing at least
1 AE.
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Table 5.

Probability of Observing at Least 1 AE by Assumed True Event Rates
With Different Sample Sizes

Assumed True Event
Rate of an AE
0.10%
0.50%
1.00%
2.00%
3.00%
5.00%
7.00%
10.00%

N=12

N=45

N=180

N=3000

0.01
0.06
0.11
0.22
0.31
0.46
0.58
0.72

0.04
0.20
0.36
0.60
0.75
0.90
0.96
0.99

0.16
0.59
0.84
0.97
>0.99
>0.99
>0.99
>0.99

0.95
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

9.3. Analysis Sets

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)For purposes of analysis, the following populations are defined:
Population
Enrolled
Randomized
Dose 1 evaluable
immunogenicity

Dose 2 evaluable
immunogenicity

Dose 1 all-available
immunogenicity
Dose 2 all-available
immunogenicity

Description
All participants who have a signed ICD.
All participants who are assigned a randomization number in
the IWR system.
All eligible randomized participants who receive the vaccine
to which they are randomly assigned at the first dose, have atleast 1 valid and determinate immunogenicity result 21 days
after Dose 1, have blood collection within an appropriate
window after Dose 1, and have no other major protocol
deviations as determined by the clinician.
All eligible randomized participants who receive 2 doses ofthe vaccine to which they are randomly assigned, within thepredefined window, have at least 1 valid and determinate
immunogenicity result after Dose 2, have blood collection
within an appropriate window after Dose 2, and have no othermajor protocol deviations as determined by the clinician.
All participants who receive at least 1 dose of the study
intervention with at least 1 valid and determinate
immunogenicity result after Dose 1 but before Dose 2.
All participants who receive at least 1 dose of the study
intervention with at least 1 valid and determinate
immunogenicity result after Dose 2.

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Population
Evaluable efficacy

All-available efficacy
SafetyDescription
All eligible randomized participants who receive
vaccination(s) as randomized within the predefined window,
have the efficacy measurement after the last dose of study
intervention, and have no other major protocol deviations as
determined by the clinician.
All eligible randomized participants who receive at least
1 vaccination and have the efficacy measurement at any timeafter Dose 1.
All randomized participants who receive at least 1 dose of thestudy intervention.

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9.4. Statistical Analyses
The SAP will be developed and finalized before database lock for any of the planned
analyses in Section 9.5.1. It will describe the participant populations to be included in theanalyses and the procedures for accounting for missing, unused, and spurious data. Thissection provides a summary of the planned statistical analyses of the primary, secondary, andtertiary/exploratory endpoints.
9.4.1. Immunogenicity Analyses
The statistical analysis of immunogenicity results will be primarily based on the evaluable
immunogenicity populations as defined in Section 9.3.
An additional analysis will be performed based on the all-available populations if there is alarge enough difference in sample size between the all-available immunogenicity populationand the evaluable immunogenicity population. Participants will be summarized according to
the vaccine group to which they were randomized.

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Endpoint
Secondaryimmunogenicity

Statistical Analysis Methods
Geometric mean titers/concentrations (GMTs/GMCs) of
SARS-CoV-2 serum neutralizing titers and SARS-CoV-2-S1–
specific binding antibody and RBD-specific binding antibody

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2-S1–
specific binding antibody levels and RBD-specific binding antibody
levels, GMTs/GMCs and 2-sided 95% CIs will be provided for each
investigational product (active/placebo) within each group before
vaccination and at each of the following time points:
Stage 1 sentinel cohorts: 7 and 21 days after Dose 1; 7 and 14
days and 1, 6, 12 and 24 months after Dose 2

Stage 1 nonsentinel cohorts and Stage 2 cohorts: 21 days after
Dose 1; 14 days and 1, 6, 12, and 24 months after Dose 2

Stage 3 cohort(s): 1, 12, and 24 months after Dose 2

Geometric means and the associated 2-sided CIs will be derived by
calculating means and CIs on the natural log scale based on thet-distribution, and then exponentiating the results.
GMFRs of SARS-CoV-2 serum neutralizing titers and
SARS-CoV-2-S1–specific binding antibody and RBD-specificbinding antibody
For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2-S1–
specific antibody levels and RBD-specific binding antibody levels, the
GMFRs and 2-sided 95% CIs will be provided for each investigational
product within each group at each of the following time points:
Stage 1 sentinel cohorts: 7 and 21 days after Dose 1; 7 and 14
days and 1, 6, 12, and 24 months after Dose 2

Stage 1 nonsentinel cohorts and Stage 2 cohorts: 21 days after
Dose 1; 14 days and 1, 6, 12, and 24 months after Dose 2

Stage 3 cohort(s): 1, 12, and 24 months after Dose 2

GMFRs will be limited to participants with nonmissing values prior to
the first dose and at the postvaccination time point. The GMFR will becalculated as the mean of the difference of logarithmically transformed
assay results (later time point – earlier time point) and transformed
back to the original scale. Two-sided CIs will be obtained by
calculating CIs using Student’s t-distribution for the mean difference of
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Statistical Analysis Methods
the logarithmically transformed assay results and transforming thelimits back to the original scale.
Percentage of participants with ≥4-fold rise in SARS-CoV-2 serum
neutralizing titers and SARS-CoV-2-S1–specific binding antibody
and RBD-specific binding antibody

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2-S1–
specific antibody levels and RBD-specific binding antibody levels,
percentages (and 2-sided 95% CIs) of participants with ≥4-fold rise
will be provided for each investigational product within each group ateach of the following time points:
Stage 1 sentinel cohorts: 7 and 21 days after Dose 1; 7 and 14
days and 1, 6, 12, and 24 months after Dose 2

Stage 1 nonsentinel cohorts and Stage 2 cohorts: 21 days after
Dose 1; 14 days and 1, 6, 12, and 24 months after Dose 2

Stage 3 cohort(s): 1, 12, and 24 months after Dose 2

The Clopper-Pearson method will be used to calculate the CIs.
GMR of SARS-CoV-2 serum neutralizing titer to SARS-CoV-2S1–specific antibody and SARS-CoV-2 RBD–specific binding
antibody
For SARS-CoV-2 serum neutralizing titers and SARS-CoV-2-S1–
specific binding antibody levels and RBD-specific binding antibody
levels, the GMRs and 2-sided 95% CIs will be provided for each
investigational product within each group at each of the following time
points:Stage 1 sentinel cohorts: 7 and 21 days after Dose 1; 7 and 14
days and 1, 6, 12, and 24 months after Dose 2

Stage 1 nonsentinel cohorts and Stage 2 cohorts: 21 days after
Dose 1; 14 days and 1, 6, 12, and 24 months after Dose 2

Stage 3 Cohort(s): 1, 12, and 24 months after Dose 2

GMRs will be limited to participants with nonmissing values for both
SARS-CoV-2 serum neutralizing titers and SARS-CoV-2-S1–specificantibody/SARS-CoV-2 RBD–specific binding antibody at each time
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point. The GMR will be calculated as the mean of the difference oflogarithmically transformed assay results (eg, SARS-CoV-2 serum
neutralizing titers minus SARS-CoV-2-S1–specific antibody for eachparticipant) and transformed back to the original scale. Two-sided CIs
will be obtained by calculating CIs using Student’s t-distribution forthe mean difference of the logarithmically transformed assay results
and transforming the limits back to the original scale.

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)The same analysis methods will be applied to the immunogenicity
endpoints in Stages 2 and 3. For all the immunogenicity endpoints, theanalysis will be based on the Dose 1 and Dose 2 evaluable
immunogenicity populations. An additional analysis will be performed
based on the all-available immunogenicity populations if there is alarge enough difference in sample size between the all-available
immunogenicity populations and the evaluable immunogenicity
populations. Participants will be summarized according to the vaccine
group to which they were randomized. Missing serology data will not
be imputed.
Tertiary/
exploratory
immunogenicity

Correlation of an RT-PCR–confirmed COVID-19 infection andseropositivity/seroconversion measured by nonvaccine antigen
SARS-CoV-2 antibody
If sufficient data are collected, percentages (and 2-sided 95% CIs) ofparticipants with confirmed COVID-19 and nonvaccine antigen SARSCoV-2 antibody levels after Dose 1 and after Dose 2 will be provided.
RCDCs for immunogenicity results
Empirical RCDCs will be provided for SARS-CoV-2 serum
neutralizing titers, SARS-CoV-2-S1–specific antibody, and RBDspecific binding antibody after Dose 1 and after Dose 2.

9.4.2. Efficacy Analyses
The statistical analysis of efficacy will be based on the evaluable efficacy population(primary analysis) and the all-available efficacy population as defined in Section 9.3.

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Statistical Analysis Methods
Secondary efficacy Ratio of COVID-19 incidence per 1000 person-years of follow-up
for the active vaccine group to the placebo group
Vaccine efficacy will be estimated by 100 × (1 – IRR), where IRR is
the illness rate ratio, the calculated ratio of COVID-19 infection
incidence per 1000 person-years follow-up in the active vaccine groupto the corresponding incidence in the placebo group after 2 doses. The
2-sided 95% CI for VE will be derived using the Clopper-Pearson
method.

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)The analysis will be based on the evaluable efficacy population and the
all-available efficacy population. For the primary analysis, missing
efficacy data will not be imputed. A sensitivity analysis may be
performed by imputing missing values; details will be provided in the
SAP.

9.4.3. Safety Analyses
Endpoint
PrimaryStatistical Analysis Methods
Descriptive statistics will be provided for each reactogenicity
endpoint for each dose and vaccine group. Local reactions andsystemic events from Day 1 through Day 7 after each vaccination
will be presented by severity cumulatively across severity levels.
Descriptive summary statistics will include counts and percentagesof participants with the indicated endpoint and the associatedClopper-Pearson 95% CIs.

For Stage 1 sentinel cohorts, descriptive statistics will be provided
for abnormal hematology and chemistry laboratory values at 1 and7 days after Dose 1 and 7 days after Dose 2, including grading
shifts in hematology and chemistry laboratory assessments
between baseline and 1 and 7 days after Dose 1, and before Dose 2
and 7 days after Dose 2. Descriptive summary statistics will
include counts and percentages of participants with the indicatedendpoint and the associated Clopper-Pearson 2-sided 95% CIs.



AEs will be categorized according to the Medical Dictionary forRegulatory Activities (MedDRA) terms. A 3-tier approach will be
used to summarize AEs. Under this approach AEs are classified
into 1 of 3 tiers: (1) Tier 1 events are prespecified events ofclinical importance and are identified in a list in the product’s
safety review plan; (2) Tier 2 events are those that are not Tier 1
but are considered “relatively common”; a MedDRA preferred

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term is defined as a Tier 2 event if there are at least 1% ofparticipants in at least 1 vaccine group reporting the event; and (3)Tier 3 events are those that are neither Tier 1 nor Tier 2 events.
For both Tier 1 and Tier 2 events, 2-sided 95% CIs for thedifference between the vaccine and placebo groups in thepercentage of participants reporting the events based on the
Miettinen and Nurminen method10 will be provided. In addition,
for Tier 1 events, the asymptotic p-values will also be presented
for the difference between groups in the percentage of participants
reporting the events, based on the same test statistic and under theassumption that the test statistic is asymptotically normally
distributed.

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)Descriptive summary statistics (counts, percentages, andassociated Clopper-Pearson 95% CIs) will be provided for any
AE events for each vaccine group.



SAEs will be categorized according to MedDRA terms. Counts,
percentages, and the associated Clopper-Pearson 95% CIs of SAEs
from Dose 1 to 6 months after last dose will be provided for eachvaccine group.

The safety analyses are based on the safety population.
Participants will be summarized by vaccine group according to theinvestigational products they actually received. Missing e-diarydata will not be imputed; missing AE dates will be handledaccording to the Pfizer safety rules.

Secondary

Not applicable (N/A)

Exploratory

N/A

9.4.4. Other Analyses
The ratios of (GMFR A to GMFR B) and (GMFR A to GMFR C) may be explored, where
GMFR A is the geometric mean of the ratio of the SARS-CoV-2 serum neutralizing titer at
the postvaccination time point to the corresponding titer at the prevaccination time point,
GFMR B is the geometric mean of the ratio of the SARS-CoV-2 S1–specific binding
antibody level at the postvaccination time point to the corresponding antibody level at theprevaccination time point, and GMFR C is the geometric mean of the ratio of the
SARS-CoV-2 RBD–specific binding antibody level at the postvaccination time point to thecorresponding antibody level at the prevaccination time point.

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9.5. Interim Analyses
No formal interim analysis is planned in this study. As this is a sponsor open-label study
during Stages 1 and 2, the sponsor may conduct unblinded reviews of the data during thecourse of the study for the purpose of safety assessment, facilitating dose escalation
decisions, and/or supporting clinical development.
9.5.1. Analysis Timing

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Statistical analyses will be carried out when the following data are available:Complete safety and immunogenicity analysis approximately 3 weeks after Dose 2 forStage 1.

Complete safety and immunogenicity analysis approximately 3 weeks after Dose 2 forStage 2.

Complete safety and immunogenicity analysis approximately 6 months after Dose 2 for
all participants in Stage 3.

Complete efficacy and persistence-of-immunogenicity analysis after complete data are
available at the end of the study.

9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will use an IRC and a DMC. The IRC is independent of the study team andincludes only internal members. The DMC is independent of the study team and includes
only external members. The IRC and DMC charters describe the role of the IRC and DMC
in more detail.
The responsibilities of the IRC will include:

Review of safety data to permit dose escalations



Review of safety data in the case of a stopping rule being met

Review of safety and immunogenicity data to:Allow groups of participants of 65 to 85 years of age to proceed

Select vaccine candidate(s)/dose level(s) and schedule(s) to proceed into Stage 2.
Data supporting the selection, including results for both binding antibody levels andserum neutralizing titers, and the ratio between them, will also be submitted to the
FDA for reviewSelect vaccine candidate(s)/dose level(s) and schedule(s) to proceed into Stage 3.
Data supporting the selection, including results for both binding antibody levels and
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serum neutralizing titers, and the ratio between them, will also be submitted to the
FDA for review


Review of any available safety and/or immunogenicity data generated during the courseof this study, or the BioNTech study conducted in Germany, to determine:Whether any groups may not be started



Whether any groups may be terminated earlyWhether any groups may be added with dose levels below the lowest stated dose orintermediate between the lowest and highest stated doses

Contemporaneous review of all NAAT-confirmed COVID-19 illnesses

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)The DMC will be responsible for ongoing monitoring of the safety of participants in the
study according to the charter. This may include, but is not limited to:Contemporaneous review of related AEs up to 1 month after completion of thevaccination scheduleContemporaneous review of all SAEs up to 6 months after completion of the vaccination
schedule

Contemporaneous review of all NAAT-confirmed COVID-19 illnesses

The recommendations made by the DMC to alter the conduct of the study will be forwarded
to the appropriate Pfizer personnel for final decision. Pfizer will forward such decisions,which may include summaries of aggregate analyses of safety data, to regulatory authorities,
as appropriate.

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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:Consensus ethical principles derived from international guidelines including the
Declaration of Helsinki and CIOMS International Ethical Guidelines;Applicable ICH GCP guidelines;Applicable laws and regulations, including applicable privacy laws.

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents(eg, advertisements) must be reviewed and approved by the sponsor and submitted to an
IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study is
initiated.
Any amendments to the protocol will require IRB/EC approval before implementation ofchanges made to the study design, except for changes necessary to eliminate an immediate
hazard to study participants.
The investigator will be responsible for the following:Providing written summaries of the status of the study to the IRB/EC annually or more
frequently in accordance with the requirements, policies, and procedures established by
the IRB/EC;



Notifying the IRB/EC of SAEs or other significant safety findings as required by IRB/EC
procedures;Providing oversight of the conduct of the study at the site and adherence to requirementsof 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014 for clinicalstudies (if applicable), and all other applicable local regulations.

10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicableregulatory authority in any area of the world, or if the investigator is aware of any new
information that might influence the evaluation of the benefits and risks of the study
intervention, Pfizer should be informed immediately.
In addition, the investigator will inform Pfizer immediately of any urgent safety measurestaken by the investigator to protect the study participants against any immediate hazard, andof any serious breaches of this protocol or of ICH GCP that the investigator becomes awareof.
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10.1.2. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to theparticipant and answer all questions regarding the study. The participant should be given
sufficient time and opportunity to ask questions and to decide whether or not to participate in
the trial.
Participants must be informed that their participation is voluntary. Participants will be
required to sign a statement of informed consent that meets the requirements of 21 CFR 50,
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/EC
or study center.
The investigator must ensure that each study participant is fully informed about the natureand objectives of the study, the sharing of data related to the study, and possible risks
associated with participation, including the risks associated with the processing of theparticipant’s personal data.

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)The participant must be informed that his/her personal study-related data will be used by thesponsor in accordance with local data protection law. The level of disclosure must also be
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical
Quality Assurance auditors or other authorized personnel appointed by the sponsor, byappropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or
her right to access and correct his or her personal data and to withdraw consent for theprocessing of his or her personal data.
The medical record must include a statement that written informed consent was obtained
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their
participation in the study.
A copy of the ICD(s) must be provided to the participant. Participants who are rescreened are
required to sign a new ICD.
Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate
section that addresses the use of samples for optional additional research. The optional
additional research does not require the collection of any further samples. The investigator
or authorized designee will explain to each participant the objectives of the additional
research. Participants will be told that they are free to refuse to participate and may
withdraw their consent at any time and for any reason during the storage period.

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10.1.3. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementationof organizational and technical measures to ensure protection of participant data.

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Participants’ personal data will be stored at the study site in encrypted electronic and/or paper
form and will be password protected or secured in a locked room to ensure that only
authorized study staff have access. The study site will implement appropriate technical andorganizational measures to ensure that the personal data can be recovered in the event ofdisaster. In the event of a potential personal data breach, the study site will be responsiblefor determining whether a personal data breach has in fact occurred and, if so, providing
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personaldata, participants will be assigned a single, participant-specific numerical code. Any
participant records or data sets that are transferred to the sponsor will contain the numericalcode; participant names will not be transferred. All other identifiable data transferred to thesponsor will be identified by this single, participant-specific code. The study site will
maintain a confidential list of participants who participated in the study, linking eachparticipant’s numerical code to his or her actual identity and medical record identification. In
case of data transfer, the sponsor will protect the confidentiality of participants’ personal dataconsistent with the clinical study agreement and applicable privacy laws.
10.1.4. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting theresults of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or
www.pfizer.com, and other public registries in accordance with applicable local
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, andcomplete manner and are reported regardless of the outcome of the study or the country inwhich the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional
studies (conducted in patients) that evaluate the safety and/or efficacy of a product,
regardless of the geographical location in which the study is conducted. These results are
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies inaccordance with the format and timelines set forth by EU requirements.

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www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used
to identify individual participants have been removed) on www.pfizer.com for
Pfizer-sponsored interventional studies at the same time the corresponding study results areposted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinicaldata to the EMA website. Clinical data, under Phase 1 of this policy, includes clinicaloverviews, clinical summaries, CSRs, and appendices containing the protocol and protocol
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of thispolicy, includes the publishing of individual participant data. Policy 0070 applies to newmarketing authorization applications submitted via the centralized procedure since
01 January 2015 and applications for line extensions and for new indications submitted via
the centralized procedure since 01 July 2015.

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Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposesof “bona-fide scientific research” that contributes to the scientific understanding of thedisease, target, or compound class. Pfizer will make available data from these trials
24 months after study completion. Patient-level data will be anonymized in accordance withapplicable privacy laws and regulations. CSRs will have personally identifiable information
redacted.
Data requests are considered from qualified researchers with the appropriate competencies toperform the proposed analyses. Research teams must include a biostatistician. Data will not
be provided to applicants with significant conflicts of interest, including individuals
requesting access for commercial/competitive or legal purposes.
10.1.5. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unlesstransmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is
responsible for verifying that data entries are accurate and correct by physically orelectronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports theinformation entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted
electronic and/or paper form and are password protected or secured in a locked room toprevent access by unauthorized third parties.

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The investigator must permit study-related monitoring, audits, IRB/EC review, andregulatory agency inspections and provide direct access to source data documents. This
verification may also occur after study completion. It is important that the investigator(s)and their relevant personnel are available during the monitoring visits and possible audits orinspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality
such as risk management and mitigation strategies and analytical risk-based monitoring),
methods, responsibilities, and requirements, including handling of noncompliance issues andmonitoring techniques (central, remote, or on-site monitoring), are provided in themonitoring plan.

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)The sponsor or designee is responsible for the data management of this study, including
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data enteredinto the CRF by authorized site personnel are accurate, complete, and verifiable from source
documents; that the safety and rights of participants are being protected; and that the study is
being conducted in accordance with the currently approved protocol and any other study
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must
be retained by the investigator for 15 years after study completion unless local regulations or
institutional policies require a longer retention period. No records may be destroyed during
the retention period without the written approval of the sponsor. No records may betransferred to another location or party without written notification to the sponsor. The
investigator must ensure that the records continue to be stored securely for as long as they are
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of suchdata are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory
inspection notification in relation to the study. Furthermore, the investigator will cooperatewith the sponsor or its agents to prepare the investigator site for the inspection and will allow
the sponsor or its agent, whenever feasible, to be present during the inspection. The
investigator site and investigator will promptly resolve any discrepancies that are identified
between the study data and the participant's medical records. The investigator will promptly
provide copies of the inspection findings to the sponsor or its agent. Before response
submission to the regulatory authorities, the investigator will provide the sponsor or its
agents with an opportunity to review and comment on responses to any such findings.

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10.1.6. Source Documents
Source documents provide evidence for the existence of the participant and substantiate theintegrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be
consistent with the source documents or the discrepancies must be explained. The
investigator may need to request previous medical records or transfer records, depending on
the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the study monitoring plan.
Description of the use of computerized system is documented in the Data Management Plan.
10.1.7. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment ofparticipants.

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)The first act of recruitment is the date of the first participant’s first visit and will be the study
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any
time for any reason at the sole discretion of the sponsor. Study sites will be closed uponstudy completion. A study site is considered closed when all required documents and study
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor
or designee if requested to do so by the responsible IRB/EC or if such termination is required
to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limitedto:

Failure of the investigator to comply with the protocol, the requirements of the IRB/EC
or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.

If the study is prematurely terminated or suspended, the sponsor shall promptly inform theinvestigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of
the reason for termination or suspension, as specified by the applicable regulatory
requirements. The investigator shall promptly inform the participant and should assure
appropriate participant therapy and/or follow-up.

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Study termination is also provided for in the clinical study agreement. If there is any conflict
between the contract and this protocol, the contract will control as to termination rights.
10.1.8. Sponsor’s Qualified Medical Personnel

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)The contact information for the sponsor's appropriately qualified medical personnel for the
study is documented in the study contact list located in the supporting study documentation.
To facilitate access to appropriately qualified medical personnel on study-related medical
questions or problems, participants are provided with a contact card at the time of informed
consent. The contact card contains, at a minimum, protocol and study intervention
identifiers, participant numbers, contact information for the investigator site, and contact
details for a contact center in the event that the investigator site staff cannot be reached toprovide advice on a medical question or problem originating from another healthcare
professional not involved in the participant’s participation in the study. The contact number
can also be used by investigator staff if they are seeking advice on medical questions or
problems; however, it should be used only in the event that the established communication
pathways between the investigator site and the study team are not available. It is therefore
intended to augment, but not replace, the established communication pathways between theinvestigator site and the study team for advice on medical questions or problems that may
arise during the study. The contact number is not intended for use by the participant directly,
and if a participant calls that number, he or she will be directed back to the investigator site.

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10.2. Appendix 2: Clinical Laboratory Tests

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)The following safety laboratory tests will be performed at times defined in the SoA section ofthis protocol. Additional laboratory results may be reported on these samples as a result of
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived
from calculated values. These additional tests would not require additional collection ofblood. Unscheduled clinical laboratory measurements may be obtained at any time during
the study to assess any perceived safety issues.
Hematology
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet countWBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)Basophils (Abs)
Lymphocytes (Abs)

Chemistry
BUN and creatinine
AST, ALT
Total bilirubin
Alkaline phosphatase

Other Urine pregnancy test (β-hCG)
At screening only: Hepatitis B core antibody
 Hepatitis B surface antigen
 Hepatitis C antibody
 Human immunodeficiency virus

Investigators must document their review of each laboratory safety report.
Clinically significant abnormal laboratory findings should be recorded in the AE CRF in
accordance with the following grading scale (Table 6).
Table 6.

Laboratory Abnormality Grading Scale

Hematology

Mild (Grade 1)

Moderate(Grade 2)

Severe (Grade 3)

Hemoglobin(Female) - g/dL
Hemoglobin(Female)change frombaselinevalue - g/dL
Hemoglobin(Male) - g/dL
Hemoglobin(Male)
change frombaselinevalue – g/dL

11.0 – 12.0

9.5 – 10.9

8.0 – 9.4

Potentially Life
Threatening(Grade 4)<8.0

Any decrease – 1.5

1.6 – 2.0

2.1 – 5.0

>5.0

12.5 – 13.5

10.5 – 12.4

8.5 – 10.4

<8.5

Any decrease – 1.5

1.6 – 2.0

2.1 – 5.0

>5.0

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Table 6.

Laboratory Abnormality Grading Scale

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Hematology

Mild (Grade 1)

Moderate(Grade 2)

Severe (Grade 3)

WBC increase 10,800 – 15,000
cells/mm3
WBC decrease 2,500 – 3,500
cells/mm3
Lymphocytes
750 – 1,000
decrease - cells/mm3
Neutrophils decrease 1,500 – 2,000- cells/mm3
Eosinophils 650 – 1500
cells/mm3
Platelets decreased - 125,000 – 140,000
cells/mm3
Chemistry
Mild (Grade 1)

15,001 – 20,000

20,001 – 25, 000

Potentially Life
Threatening(Grade 4)>25,000

1,500 – 2,499

1,000 – 1,499<1,000500 – 749

250 – 499

<250

1,000 – 1,499

500 – 999

<500

1501 - 5000

>5000

Hypereosinophilic

100,000 – 124,000

25,000 – 99,000<25,000

Moderate(Grade 2)

Severe(Grade 3)

BUN - mg/dL
Creatinine – mg/dL

23 – 26
1.5 – 1.7

27 – 31
1.8 – 2.0> 31
2.1 – 2.5

Alkaline phosphate–increase by factor
Liver function tests– ALT, AST
increase by factor
Bilirubin – whenaccompanied
by any increase inliver function test increase by factor
Bilirubin – whenliver function test is
normal - increase byfactor

1.1 – 2.0 x ULN

2.1 – 3.0 x ULN

3.1 – 10 x ULN

Potentially Life
Threatening(Grade 4)
Requires dialysis> 2.5 or requires
dialysis>10 x ULN

1.1 – 2.5 x ULN

2.6 – 5.0 x ULN

5.1 – 10 x ULN>10 x ULN

1.1 – 1.25 x ULN

1.26 – 1.5 x ULN

1.51 – 1.75 x ULN>1.75 x ULN

1.1 – 1.5 x ULN

1.6 – 2.0 x ULN

2.0 – 3.0 x ULN>3.0 x ULN

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen;
ULN = upper limit of normal; WBC = white blood cell.

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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition


An AE is any untoward medical occurrence in a patient or clinical study participant,temporally associated with the use of study intervention, whether or not consideredrelated to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including anabnormal laboratory finding), symptom, or disease (new or exacerbated) temporally
associated with the use of study intervention.

Events Meeting the AE Definition

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Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis)or other safety assessments (eg, ECG, radiological scans, vital sign measurements),
including those that worsen from baseline, considered clinically significant in the
medical and scientific judgment of the investigator Any abnormal laboratory test
results that meet any of the conditions below must be recorded as an AE:
Is associated with accompanying symptoms.



Requires additional diagnostic testing or medical/surgical intervention.



Leads to a change in study dosing (outside of any protocol-specified dose
adjustments) or discontinuation from the study, significant additional
concomitant drug treatment, or other therapy.



Exacerbation of a chronic or intermittent preexisting condition including either anincrease in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration eventhough it may have been present before the start of the study.



Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.



Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
intervention or a concomitant medication. Overdose per se will not be reported as
an AE/SAE unless it is an intentional overdose taken with possible suicidal/selfharming intent. Such overdoses should be reported regardless of sequelae.

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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safetyassessments which are associated with the underlying disease, unless judged by theinvestigator to be more severe than expected for the participant’s condition.



The disease/disorder being studied or expected progression, signs, or symptoms ofthe disease/disorder being studied, unless more severe than expected for theparticipant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).



Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present
or detected at the start of the study that do not worsen.

10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:a. Results in deathb. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which theparticipant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.

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In general, hospitalization signifies that the participant has been detained (usually involving
at least an overnight stay) at the hospital or emergency ward for observation and/or
treatment that would not have been appropriate in the physician’s office or outpatientsetting. Complications that occur during hospitalization are AEs. If a complication
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in
doubt as to whether “hospitalization” occurred or was necessary, the AE should beconsidered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen frombaseline is not considered an AE.

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)d. Results in persistent disability/incapacity


The term disability means a substantial disruption of a person’s ability to conduct
normal life functions.

This definition is not intended to include experiences of relatively minor medicalsignificance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza,
and accidental trauma (eg, sprained ankle) which may interfere with or prevent
everyday life functions but do not constitute a substantial disruption.

e. Is a congenital anomaly/birth defectf. Other situations:Medical or scientific judgment should be exercised in deciding whether SAE
reporting is appropriate in other situations such as important medical events that
may not be immediately life-threatening or result in death or hospitalization but may
jeopardize the participant or may require medical or surgical intervention to prevent
one of the other outcomes listed in the above definition. These events should
usually be considered serious.



Examples of such events include invasive or malignant cancers, intensive treatment
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or
convulsions that do not result in hospitalization, or development of drug dependency
or drug abuse.

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10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF andfor reporting serious adverse events on the Vaccines SAE Report Form to Pfizer Safety.
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious adverse
events (AEs); and (3) exposure to the study intervention under study during pregnancy orbreastfeeding, and occupational exposure.

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)It should be noted that the Vaccines SAE Report Form for reporting of SAE information is
not the same as the AE page of the CRF. When the same data are collected, the forms must
be completed in a consistent manner. AEs should be recorded using concise medical
terminology and the same AE term should be used on both the CRF and the Vaccines SAE
Report Form for reporting of SAE information.
Safety Event

Recorded on the CRF

Reported on the Vaccines
SAE Report Form to
Pfizer Safety Within 24
Hours of Awareness

SAE
Nonserious AE
Exposure to the study
intervention under study
during pregnancy orbreastfeeding, andoccupational exposure

All
All
None

All
None
All (and EDP supplemental
form for EDP)When an AE/SAE occurs, it is the responsibility of the investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostic
reports) related to the event.



The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s
medical records to Pfizer Safety in lieu of completion of the Vaccines SAE Report
Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases arerequested by Pfizer Safety. In this case, all participant identifiers, with the
exception of the participant number, will be redacted on the copies of the medical
records before submission to Pfizer Safety.

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The investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. Whenever possible, the diagnosis(not the individual signs/symptoms) will be documented as the AE/SAE.

Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during
the study and assign it to 1 of the following categories:

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)GRADE If required on the AE page of the CRF, the investigator will use theadjectives MILD, MODERATE, SEVERE, or LIFE-THREATENING todescribe the maximum intensity of the AE. For purposes of consistency,
these intensity grades are defined as follows:
1

MILD

Does not interfere with participant's usualfunction.

2

MODERATE

Interferes to some extent with participant's usualfunction.

3

SEVEREInterferes significantly with participant's usualfunction.

4

LIFE-THREATENING Life-threatening consequences; urgent
intervention indicated.

Assessment of Causality

The investigator is obligated to assess the relationship between study intervention
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence,
and/or arguments to suggest a causal relationship, rather than a relationship cannot
be ruled out.

The investigator will use clinical judgment to determine the relationship.



Alternative causes, such as underlying disease(s), concomitant therapy, and otherrisk factors, as well as the temporal relationship of the event to study intervention
administration, will be considered and investigated.

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The investigator will also consult the IB and/or product information, for marketed
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she
has reviewed the AE/SAE and has provided an assessment of causality.



There may be situations in which an SAE has occurred and the investigator has
minimal information to include in the initial report to the sponsor. However, it isvery important that the investigator always make an assessment of causality forevery event before the initial transmission of the SAE data to the sponsor.



The investigator may change his/her opinion of causality in light of follow-up
information and send an SAE follow-up report with the updated causality
assessment.



The causality assessment is one of the criteria used when determining regulatory
reporting requirements.



If the investigator does not know whether or not the study intervention caused theevent, then the event will be handled as “related to study intervention” for reporting
purposes, as defined by the sponsor. In addition, if the investigator determines thatan SAE is associated with study procedures, the investigator must record this causal
relationship in the source documents and CRF, and report such an assessment in the
dedicated section of the Vaccines SAE Report Form and in accordance with the
SAE reporting requirements.

Follow-up of AEs and SAEs


The investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by thesponsor to elucidate the nature and/or causality of the AE or SAE as fully as
possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other healthcare providers.



If a participant dies during participation in the study or during a recognizedfollow-up period, the investigator will provide Pfizer Safety with a copy of any
postmortem findings including histopathology.



New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours ofreceipt of the information.
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10.3.4. Reporting of SAEs

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SAE Reporting to Pfizer Safety via Vaccines SAE Report Form

Facsimile transmission of the Vaccines SAE Report Form is the preferred method totransmit this information to Pfizer Safety.



In circumstances when the facsimile is not working, notification by telephone isacceptable with a copy of the Vaccines SAE Report Form sent by overnight mail orcourier service.

Initial notification via telephone does not replace the need for the investigator tocomplete and sign the Vaccines SAE Report Form pages within the designatedreporting time frames.

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10.4. Appendix 4: Contraceptive Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during
the intervention period and for at least 28 days after the last dose of study intervention, whichcorresponds to the time needed to eliminate reproductive safety risk of the study
intervention(s):Refrain from donating sperm.

PLUS either:Be abstinent from heterosexual intercourse with a female of childbearing potential as
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) andagree to remain abstinent.

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)OR

Must agree to use a male condom when engaging in any activity that allows for passageof ejaculate to another person.



In addition to male condom use, a highly effective method of contraception may beconsidered in WOCBP partners of male participants (refer to the list of highly effective
methods below in Section 10.4.4).

10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using an acceptable contraceptive method as described below during
the intervention period (for a minimum of 28 days after the last dose of study
intervention). The investigator should evaluate the effectiveness of the contraceptive
method in relationship to the first dose of study intervention.

The investigator is responsible for review of medical history, menstrual history, and recent
sexual activity to decrease the risk for inclusion of a woman with an early undetected
pregnancy.
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal
unless permanently sterile (see below).
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If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot
be confirmed before the first dose of study intervention, additional evaluation should beconsidered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)

For individuals with permanent infertility due to an alternate medical cause other than theabove, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should beapplied to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s
review of the participant’s medical records, medical examination, or medical history
interview. The method of documentation should be recorded in the participant’s medical
record for the study.
2. Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause. In addition, ahigh FSH level in the postmenopausal range must be used to confirm apostmenopausal state in women under 60 years of age and not using hormonal
contraception or HRT.



Female on HRT and whose menopausal status is in doubt will be required to use
one of the nonestrogen hormonal highly effective contraception methods if theywish to continue their HRT during the study. Otherwise, they must discontinue
HRT to allow confirmation of postmenopausal status before study enrollment.

10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations
regarding the use of contraceptive methods for those participating in clinical trials.
1. Implantable progestogen-only hormone contraception associated with inhibition ofovulation.
2. Intrauterine device.

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3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner:


Vasectomized partner is a highly effective contraceptive method provided that thepartner is the sole sexual partner of the woman of childbearing potential and theabsence of sperm has been confirmed. If not, an additional highly effective methodof contraception should be used. The spermatogenesis cycle is approximately
90 days.

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)

6. Combined (estrogen- and progestogen-containing) hormonal contraception associatedwith inhibition of ovulation:


Oral;



Intravaginal;Transdermal;



Injectable.

7. Progestogen-only hormone contraception associated with inhibition of ovulation:


Oral;



Injectable.

8. Sexual abstinence:Sexual abstinence is considered a highly effective method only if defined as
refraining from heterosexual intercourse during the entire period of risk associatedwith the study intervention. The reliability of sexual abstinence needs to be evaluatedin relation to the duration of the study and the preferred and usual lifestyle of theparticipant.

9. Progestogen-only oral hormonal contraception where inhibition of ovulation is not the
primary mode of action.
10. Male or female condom with or without spermicide.
11. Cervical cap, diaphragm, or sponge with spermicide.
12. A combination of male condom with either cervical cap, diaphragm, or sponge with
spermicide (double-barrier methods).
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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations intransaminases) are termed “tolerators,” while those who show transient liver injury, but adapt
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of amore serious potential outcome. These participants fail to adapt and therefore are"susceptible" to progressive and serious liver injury, commonly referred to as DILI.
Participants who experience a transaminase elevation above 3 × ULN should be monitored
more frequently to determine if they are an “adaptor” or are “susceptible.”

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LFTs are not required as a routine safety monitoring procedure for all participants in thisstudy. However, should an investigator deem it necessary to assess LFTs because aparticipant presents with clinical signs/symptoms, such LFT results should be managed andfollowed as described below.
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will beelevated within the same laboratory sample). In rare instances, by the time TBili elevations
are detected, AST/ALT values might have decreased. This occurrence is still regarded as apotential DILI. Therefore, abnormal elevations in either AST OR ALT in addition to TBili
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law
criteria) cases and should always be considered important medical events, even before allother possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on theparticipant’s individual baseline values and underlying conditions. Participants who present
with the following laboratory abnormalities should be evaluated further as potential DILI
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:Participants with AST/ALT and TBili baseline values within the normal range who
subsequently present with AST OR ALT values >3 × ULN AND a TBili value >2 × ULN
with no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or notavailable.

For participants with baseline AST OR ALT OR TBili values above the ULN, thefollowing threshold values are used in the definition mentioned above, as needed,
depending on which values are above the ULN at baseline:Preexisting AST or ALT baseline values above the normal range: AST or ALT values>2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is smaller).

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Rises in AST/ALT and TBili separated by more than a few weeks should be assessedindividually based on clinical judgment; any case where uncertainty remains as to whether it
represents a potential Hy’s law case should be reviewed with the sponsor.

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)The participant should return to the investigator site and be evaluated as soon as possible,
preferably within 48 hours from awareness of the abnormal results. This evaluation should
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili for suspected cases ofHy’s law, additional laboratory tests should include albumin, CK, direct and indirect
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should
also be given to drawing a separate tube of clotted blood and an anticoagulated tube of bloodfor further testing, as needed, for further contemporaneous analyses at the time of therecognized initial abnormalities to determine etiology. A detailed history, including relevant
information, such as review of ethanol, acetaminophen/paracetamol (either by itself or as a
coformulated product in prescription or over-the-counter medications), recreational drug,
supplement (herbal) use and consumption, family history, sexual history, travel history,
history of contact with a jaundiced person, surgery, blood transfusion, history of liver orallergic disease, and potential occupational exposure to chemicals, should be collected.
Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary
tract) and collection of serum samples for acetaminophen/paracetamol drug and/or protein
adduct levels may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if noother reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law)cases are to be reported as SAEs, irrespective of availability of all the results of theinvestigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results ofreasonable investigations have been received and have excluded an alternative etiology.

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10.6. Appendix 6: Abbreviations

090177e193765358\Approved\Approved On: 14-May-2020 15:30 (GMT)The following is a list of abbreviations that may be used in the protocol.
Abbreviation
2019-nCoV
Abs
AE
ALT
AST
-hCG
BMI
BUN
CBER
CFR
CI
CIOMS
CONSORT
COVID-19
CRF
CRO
CSR
CT
DILI
DMC
DNA
DU
EC
ECG
eCRF
e-diary
EDP
EMA
EU
EUA
EudraCT
FDA
FSH
GCP
GGT
GMC
GMFR
GMR
GMT

Term
novel coronavirus 2019absolute (in Appendix 2)
adverse event
alanine aminotransferase
aspartate aminotransferase
beta-human chorionic gonadotropin
body mass index
blood urea nitrogen
Center for Biologics Evaluation and Research
Code of Federal Regulations
confidence interval
Council for International Organizations of Medical Sciences
Consolidated Standards of Reporting Trials
coronavirus disease 2019case report form
contract research organization
clinical study reportclinical trial
drug-induced liver injury
data monitoring committee
deoxyribonucleic aciddosing unit
ethics committee
electrocardiogram
electronic case report form
electronic diary
exposure during pregnancy
European Medicines Agency
European Union
emergency use application
European Clinical Trials Database
Food and Drug Administration
follicle-stimulating hormone
Good Clinical Practice
gamma-glutamyl transferase
geometric mean concentrationgeometric mean fold risegeometric mean ratio
geometric mean titer

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Abbreviation
HBc Ab
HBsAg
HBV
HCV
HCV Ab
HIPAA
HIV
HRT
IB
ICD
ICH
ICU
ID
Ig
IgG
IgM
IMP
IND
INR
IP manual
IPAL
IRB
IRC
IRR
IRT
IV
IWR
LFT
LLOQ
LNP
LPX
MCH
MCHC
MCV
MedDRAMERS
modRNA
N/A
NAAT
NVA
P2 S

Term
hepatitis B core antibody
hepatitis B surface antigen
hepatitis B virus
hepatitis C virus
hepatitis C virus antibody
Health Insurance Portability and Accountability Act
human immunodeficiency virus
hormone replacement therapy
investigator’s brochure
informed consent document
International Council for Harmonisation
intensive care unit
identification
immunoglobulin
immunoglobulin G
immunoglobulin M
investigational medicinal productinvestigational new druginternational normalized ratio
investigational product manual
Investigational Product Accountability Log
institutional review board
internal review committee
illness rate ratio
interactive response technology
intravenous(ly)interactive Web-based response
liver function test
lower limit of quantitation
lipid nanoparticle
lipoplexmean corpuscular hemoglobinmean corpuscular hemoglobin concentration
mean corpuscular volume
Medical Dictionary for Regulatory Activities
Middle East respiratory syndrome
nucleoside-modified messenger ribonucleic acidnot applicable
nucleic acid amplification test
nonvaccine antigen
SARS-CoV-2 full-length, P2 mutant, “heads up,” prefusion spikeglycoprotein

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Abbreviation
PCR
PI
PPE
PT
RBC
RBD
RCDC
RNA
RSV
RT-PCR
S1
SAE
SAP
saRNA
SARS
SARS-CoV-2
SoA
SOP
SRSD
SUSAR
TBD
TBili
ULN
uRNA
US
vax
VE
WBC
WHO
WOCBP

Term
polymerase chain reaction
principal investigatorpersonal protective equipment
prothrombin time
red blood cell
receptor-binding domain
reverse cumulative distribution curve
ribonucleic acidrespiratory syncytial virus
reverse transcription–polymerase chain reaction
spike protein S1 subunit
serious adverse event
statistical analysis planself-amplifying messenger ribonucleic acidsevere acute respiratory syndrome
severe acute respiratory syndrome coronavirus 2schedule of activities
standard operating procedure
single reference safety document
suspected unexpected serious adverse reaction
to be determinedtotal bilirubin
upper limit of normal
uridine-containing messenger ribonucleic acid
United States
vaccination
vaccine efficacy
white blood cell
World Health Organization
woman/women of childbearing potential

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11. REFERENCES
1

World Health Organization. WHO Director-General's opening remarks at the media
briefing on COVID-19. Available from: https://www.who.int/dg/speeches/detail/whodirector-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march2020. Published: 11 Mar 2020. Accessed: 01 Apr 2020.

2

World Health Organization. Coronavirus disease 2019 (COVID-19) situation report - 70.
In: Data as reported by national authorities by 10:00 CET 30 March 2020. Geneva,
Switzerland: World Health Organization; 2020.

3

Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19):
therapeutic options. Available from: https://www.cdc.gov/coronavirus/2019ncov/hcp/therapeutic-options.html. Accessed: 12 Apr 2020.

4

Rauch S, Jasny E, Schmidt KE, et al. New vaccine technologies to combat outbreaksituations. Front Immunol 2018;9:1963.

5

Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics—developing a new class ofdrugs. Nat Rev Drug Discov 2014;13(10):759-80.

6

BioNTech RNA Pharmaceuticals GmbH. CorVAC/BNT162 Investigator’s Brochure.
Mainz, Germany: BioNTech RNA Pharmaceuticals GmbH; 25 Mar 2020.

7

Feldman RA, Fuhr R, Smolenov I, et al. mRNA vaccines against H10N8 and H7N9
influenza viruses of pandemic potential are immunogenic and well tolerated in healthy
adults in phase 1 randomized clinical trials. Vaccine. 2019;37(25):3326-34.

8

US Food and Drug Administration. Guidance for industry: toxicity grading scale forhealthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials.
Rockville, MD: Center for Biologics Evaluation and Research; September 2007.

9

Agresti A. Introduction: distributions and inference for categorical data. In: Agresti A,
ed. Categorical data analysis. 2nd ed. Hoboken, NJ: John Wiley & Sons; 2002:1-35.

10

Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med
1985;4(2):213-26.

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Document Approval Record
Document Name:

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Page 1287

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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol, 15 April 2020090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)A PHASE 1/2, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLIND,
DOSE-FINDING STUDY TO DESCRIBE THE SAFETY, TOLERABILITY,IMMUNOGENICITY, AND POTENTIAL EFFICACY OF SARS-COV-2 RNAVACCINE CANDIDATES AGAINST COVID-19 IN HEALTHY ADULTS

Study Intervention Number:

PF-07302048

Study Intervention Name:

RNA-Based COVID-19 Vaccines

US IND Number:

19736

EudraCT Number:

N/A

Protocol Number:

C4591001

Phase:
1/2
Short Title: A Phase 1/2 Study to Describe the Safety, Tolerability, Immunogenicity, andPotential Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Adults

This document and accompanying materials contain confidential information belonging to Pfizer. Except asotherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in
confidence and not copy or disclose it to others (except where required by applicable law) or use it forunauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer must be
promptly notified.

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Protocol Amendment Summary of Changes Table

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Document History
Document

Version Date

Summary and Rationale for Changes

Original protocol

15 April 2020

N/A

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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
1. PROTOCOL SUMMARY...................................................................................................10
1.1. Synopsis ..................................................................................................................10
1.2. Schema ....................................................................................................................15
1.3. Schedule of Activities .............................................................................................16
1.3.1. Stage 1 Sentinel Cohorts.............................................................................16
1.3.2. Stage 1 Nonsentinel Cohorts and Stage 2 Cohorts .....................................20
1.3.3. Stage 3 Cohort(s) ........................................................................................22
2. INTRODUCTION ...............................................................................................................242.1. Study Rationale .......................................................................................................24
2.2. Background .............................................................................................................24

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2.2.1. Clinical Overview.......................................................................................25
2.3. Benefit/Risk Assessment.........................................................................................25
2.3.1. Risk Assessment .........................................................................................27
2.3.2. Benefit Assessment.....................................................................................28
2.3.3. Overall Benefit/Risk Conclusion................................................................28
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................28
4. STUDY DESIGN.................................................................................................................30
4.1. Overall Design.........................................................................................................30
4.1.1. Stage 1 ........................................................................................................30
4.1.2. Stage 2 ........................................................................................................31
4.1.3. Stage 3 ........................................................................................................32
4.2. Scientific Rationale for Study Design .....................................................................32
4.3. Justification for Dose ..............................................................................................32
4.4. End of Study Definition ..........................................................................................33
5. STUDY POPULATION ......................................................................................................33
5.1. Inclusion Criteria.....................................................................................................33
5.2. Exclusion Criteria....................................................................................................34
5.3. Lifestyle Considerations..........................................................................................36
5.3.1. Contraception..............................................................................................36

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5.4. Screen Failures ........................................................................................................36
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study
Intervention Administration ......................................................................................37
6. STUDY INTERVENTION..................................................................................................37
6.1. Study Intervention(s) Administered ........................................................................41
6.1.1. Administration ............................................................................................41
6.2. Preparation/Handling/Storage/Accountability ........................................................426.2.1. Preparation and Dispensing ........................................................................43
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................43
6.3.1. Allocation to Study Intervention ................................................................43
6.3.2. Blinding of Site Personnel ..........................................................................43
6.3.3. Blinding of the Sponsor ..............................................................................44
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6.4. Study Intervention Compliance...............................................................................44
6.5. Concomitant Therapy..............................................................................................44
6.5.1. Prohibited During the Study .......................................................................45
6.5.2. Permitted During the Study ........................................................................45
6.6. Dose Modification...................................................................................................46
6.7. Intervention After the End of the Study ..................................................................46
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANTDISCONTINUATION/WITHDRAWAL...........................................................................46
7.1. Discontinuation of Study Intervention ....................................................................46
7.2. Participant Discontinuation/Withdrawal From the Study .......................................46
7.2.1. Withdrawal of Consent ...............................................................................47
7.3. Lost to Follow-up ....................................................................................................47
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................48
8.1. Efficacy and/or Immunogenicity Assessments .......................................................49
8.1.1. Biological Samples .....................................................................................50
8.2. Safety Assessments .................................................................................................50
8.2.1. Clinical Safety Laboratory Assessments (Sentinel-Cohort
Participants Only) ............................................................................................50
8.2.2. Electronic Diary..........................................................................................51
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8.2.2.1. Grading Scales...........................................................................52
8.2.2.2. Local Reactions .........................................................................52
8.2.2.3. Systemic Events ........................................................................53
8.2.2.4. Fever..........................................................................................53
8.2.2.5. Antipyretic Medication .............................................................54
8.2.3. Stopping Rules............................................................................................54
8.2.3.1. Randomization and Vaccination After a Stopping Rule Is
Met.....................................................................................................55
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19
Disease .............................................................................................................56
8.2.5. Pregnancy Testing ......................................................................................56
8.3. Adverse Events and Serious Adverse Events..........................................................56
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......57
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8.3.1.1. Reporting SAEs to Pfizer Safety...............................................57
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................57
8.3.2. Method of Detecting AEs and SAEs ..........................................................58
8.3.3. Follow-up of AEs and SAEs.......................................................................58
8.3.4. Regulatory Reporting Requirements for SAEs...........................................58
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational
Exposure ..........................................................................................................59
8.3.5.1. Exposure During Pregnancy......................................................59
8.3.5.2. Exposure During Breastfeeding ................................................60
8.3.5.3. Occupational Exposure .............................................................61
8.3.6. Medication Errors .......................................................................................61
8.4. Treatment of Overdose............................................................................................62
8.5. Pharmacokinetics ....................................................................................................62
8.6. Pharmacodynamics..................................................................................................63
8.7. Genetics ...................................................................................................................63
8.8. Biomarkers ..............................................................................................................63
8.9. Immunogenicity Assessments .................................................................................63
8.10. Health Economics .................................................................................................63
8.11. Study Procedures...................................................................................................63
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8.11.1. Stage 1 Sentinel Cohorts...........................................................................63
8.11.1.1. Screening: (0 to 14 Days Before Visit 1) ................................63
8.11.1.2. Visit 1 – Vaccination 1: (Day 1) .............................................64
8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1to 3 Days After Visit 1) .....................................................................66
8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to
8 Days After Visit 1) .........................................................................67
8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1) ...........69
8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to
8 Days After Visit 4) .........................................................................71
8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to
16 Days After Visit 4) .......................................................................72

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8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After
Visit 4) ...............................................................................................73
8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (154 to 168 Days
After Visit 4)......................................................................................73
8.11.1.10. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 4)......................................................................................74
8.11.1.11. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 4)......................................................................................74
8.11.2. Stage 1 Nonsentinel Cohorts and Stage 2 Cohorts ...................................75
8.11.2.1. Visit 1 – Vaccination 1: (Day 1) .............................................75
8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days or 56 to 70 Days
After Visit 1)......................................................................................77
8.11.2.3. Visit 3 – 2-Week Follow-up Visit: (12 to 16 Days After
Visit 2) ...............................................................................................79
8.11.2.4. Visit 4 – 1-Month Follow-up Visit: (28 to 35 Days After
Visit 2) ...............................................................................................79
8.11.2.5. Visit 5 – 6-Month Follow-up Visit: (154 to 168 Days
After Visit 2)......................................................................................80
8.11.2.6. Visit 6 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 2)......................................................................................80
8.11.2.7. Visit 7 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 2)......................................................................................81
8.11.3. Stage 3 Cohort(s) ......................................................................................81
8.11.3.1. Visit 1 – Vaccination 1: (Day 1) .............................................81
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8.11.3.2. Visit 2 – Vaccination 2: (19 to 23 Days or 56 to 70 Days
After Visit 1)......................................................................................83
8.11.3.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2):(28 to 35 Days After Visit 2).............................................................85
8.11.3.4. Visit 4 – 6-Month Safety Telephone Contact: (154 to
168 Days After Visit 2) .....................................................................86
8.11.3.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 2)......................................................................................86
8.11.3.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 2)......................................................................................86
8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction ........................87
8.13. COVID-19 Disease Surveillance (All Participants)..............................................88

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8.13.1. Potential COVID-19 Illness Telehealth Visit: (Optimally Within 3
Days After Potential COVID-19 Illness Onset)...............................................88
8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After
Potential COVID-19 Illness Visit)..................................................................90
9. STATISTICAL CONSIDERATIONS ................................................................................90
9.1. Estimands and Statistical Hypotheses .....................................................................90
9.1.1. Estimands....................................................................................................90
9.1.2. Statistical Hypotheses.................................................................................91
9.2. Sample Size Determination.....................................................................................91
9.3. Analysis Sets ...........................................................................................................92
9.4. Statistical Analyses .................................................................................................93
9.4.1. Immunogenicity Analyses ..........................................................................93
9.4.2. Efficacy Analyses .......................................................................................96
9.4.3. Safety Analyses ..........................................................................................97
9.4.4. Other Analyses............................................................................................98
9.5. Interim Analyses .....................................................................................................99
9.5.1. Analysis Timing..........................................................................................99
9.6. Data Monitoring Committee or Other Independent Oversight Committee.............99
10. SUPPORTING DOCUMENTATION AND OPERATIONALCONSIDERATIONS ........................................................................................................101
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .............101
10.1.1. Regulatory and Ethical Considerations ..................................................101
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10.1.1.1. Reporting of Safety Issues and Serious Breaches of theProtocol or ICH GCP.......................................................................101
10.1.2. Informed Consent Process ......................................................................102
10.1.3. Data Protection .......................................................................................103
10.1.4. Dissemination of Clinical Study Data ....................................................103
10.1.5. Data Quality Assurance ..........................................................................104
10.1.6. Source Documents ..................................................................................106
10.1.7. Study and Site Start and Closure ............................................................106
10.1.8. Sponsor’s Qualified Medical Personnel .................................................107
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................108
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting ....................................................................110
10.3.1. Definition of AE .....................................................................................110
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10.3.2. Definition of SAE ...................................................................................111
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.....................113
10.3.4. Reporting of SAEs..................................................................................116
10.4. Appendix 4: Contraceptive Guidance .................................................................117
10.4.1. Male Participant Reproductive Inclusion Criteria ..................................117
10.4.2. Female Participant Reproductive Inclusion Criteria...............................117
10.4.3. Woman of Childbearing Potential ..........................................................117
10.4.4. Contraception Methods...........................................................................118
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ......120
10.6. Appendix 6: Abbreviations .................................................................................122
11. REFERENCES ................................................................................................................125
LIST OF TABLES
Table 1.

Potential Groups in Stage 1 ......................................................................38

Table 2.

Local Reaction Grading Scale ..................................................................52

Table 3.

Systemic Event Grading Scale..................................................................53

Table 4.

Scale for Fever..........................................................................................54

Table 5.

Probability of Observing at Least 1 AE by Assumed True Event
Rates With Different Sample Sizes ..........................................................92
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Table 6.

Laboratory Abnormality Grading Scale .................................................108

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1. PROTOCOL SUMMARY
1.1. Synopsis
Short Title: A Phase 1/2 Study to Describe the Safety, Tolerability, Immunogenicity, andPotential Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Adults
Rationale

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A pneumonia of unknown cause detected in Wuhan, China, was first reported in
December 2019. On 08 January 2020, the pathogen causing this outbreak was identified as anovel coronavirus 2019. The outbreak was declared a Public Health Emergency ofInternational Concern on 30 January 2020. On 12 February 2020, the virus was officiallynamed as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the WHO
officially named the disease caused by SARS-CoV-2 as coronavirus disease 2019
(COVID-19). On 11 March 2020, the WHO upgraded the status of the COVID-19 outbreakfrom epidemic to pandemic, which is now spreading globally at high speed.
There are currently no vaccines to prevent infection with SARS-CoV-2 or antiviral drugs totreat COVID-19. Given the rapid transmission of COVID-19 and incidence of disease in the
United States and elsewhere, the rapid development of an effective vaccine is of utmost
importance.
BioNTech has developed RNA-based vaccine candidates using a platform approach thatenables the rapid development of vaccines against emerging viral diseases, including
SARS-CoV-2. Each vaccine candidate is based on 1 of 3 RNA platforms: unmodified
messenger RNA (uRNA), nucleoside-modified messenger RNA (modRNA), or selfamplifying messenger RNA (saRNA). Each vaccine candidate expresses 1 of 2 antigens: the
SARS-CoV-2 full-length, P2 mutant, “heads up,” prefusion spike glycoprotein (P2 S)(version 9) or a trimerized SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD)(version 5). The 4 SARS-CoV-2 vaccine candidates that will be tested in this study are
therefore:
BNT162a1 (variant RBL063.3): a uRNA encoding the RBD;
BNT162b1 (variant RBP020.3): a modRNA encoding the RBD;
BNT162b2 (variant RBP020.2): a modRNA encoding P2 S;
BNT162c2 (variant RBP020.3): an saRNA encoding the RBD.
All candidates are formulated in the same lipid nanoparticle (LNP) composition. This study
is intended to investigate the safety, immunogenicity, and potential efficacy of these
4 prophylactic BNT162 vaccines against COVID-19.

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It is expected that the various candidate vaccines may not all be available from the start ofthe study, in which case they will be rolled into the study in a consecutive fashion as they are
released. A Phase 1/2 study of the same vaccine candidates (BNT162-01), conducted inGermany by BioNTech in adults 18 to 55 years of age, is planned to start in April 2020.
Study C4591001 is designed to complement and expand upon the German study and confirm
the optimal vaccine candidate(s) (BNT162a1, BNT162b1, BNT162b2, or BNT162c2), doselevel(s), number of doses, and schedule of administration.

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Objectives, Estimands, and Endpoints
Objectives

Estimands

Endpoints

Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Primary:
In participants receiving at least 1 doseof study intervention and having safety
data reported after any vaccination, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each doseAdverse events (AEs) from Dose 1
to 1 month after the last dose
 Serious AEs (SAEs) from Dose 1
to 6 months after the last doseIn addition, in sentinel cohorts from
Stage 1, the percentage of participantswith:
Abnormal hematology andchemistry laboratory values 1 and7 days after Dose 1; and 7 days
after Dose 2
Grading shifts in hematology andchemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2
Secondary:In participants complying with the key
protocol criteria (evaluable participants)
at the following time points after receipt
of study intervention:

Primary:
Local reactions (pain at the
injection site, redness, andswelling)

Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs

Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Hematology and chemistry laboratory
parameters detailed in Section 10.2

Secondary:Stage 1 Sentinel Cohorts: 7 and21 days after Dose 1; 7 and 14 days and1, 6, 12, and 24 months after Dose 2
Stage 1 Nonsentinel Cohorts and Stage
2 Cohorts: 21 days after Dose 1;
14 days and 1, 6, 12, and 24 months
after Dose 2
Stage 3 Cohort(s): 1, 12, and 24 months
after Dose 2

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Objectives

Estimands










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Geometric mean titers (GMTs) ateach time point
Geometric mean fold rise (GMFR)
from before vaccination to eachsubsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
Geometric mean concentrations(GMCs) at each time point
GMFR from rise from before
vaccination to each subsequent
time point after vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
Geometric mean ratio (GMR),
estimated by the ratio of thegeometric mean of SARS-CoV-2–
specific WT serum neutralizing
titers to the geometric mean of
SARS-CoV-2–specific binding
antibody levels at each time point

To evaluate the efficacy of prophylactic In participants complying with the key
BNT162 vaccines against confirmed
protocol criteria (evaluable participants)
COVID-19
following receipt of the last dose of
study intervention:
100 × (1 – infection rate ratio) [ratio ofactive vaccine to placebo]
Tertiary/Exploratory:
Tertiary/Exploratory:
To describe the relationship between
SARS-CoV-2 serological parametersand:
NAAT-confirmed COVID-19

Symptomatic SARS-CoV-2
infection
Asymptomatic SARS-CoV-2
infection

Endpoints
SARS-CoV-2–specific WT serum
neutralizing titers

SARS-CoV-2-spike protein–specificbinding antibody levels and RBDspecific binding antibody levels

SARS-CoV-2–specific WT serum
neutralizing titers
SARS-CoV-2-spike protein–
specific binding antibody levels
SARS-CoV-2 RBD–specificbinding antibody levels

COVID-19 incidence per 1000 personyears of follow-up

Tertiary/Exploratory:
Nonvaccine antigen SARS-CoV-2
antibody levels

Overall Design
This is a Phase 1/2, randomized, placebo-controlled, observer-blind, dose-finding, andvaccine candidate–selection study in healthy adults.
The study will evaluate the safety, tolerability, immunogenicity, and potential efficacy of up
to 4 different SARS-CoV-2 RNA vaccine candidates against COVID-19:


As a 2-dose (separated by 21 or 60 days) or single-dose schedule

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At up to 3 different dose levels

In 3 age groups (18 to 55 years of age, 65 to 85 years of age, and 18 to 85 years of age[stratified as ≤55 or >55 years of age])

Dependent upon safety and/or immunogenicity data generated during the course of thisstudy, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
may be started at the next highest dose, groups may not be started, groups may be terminatedearly, and/or groups may be added with dose levels below the lowest stated dose orintermediate between the lowest and highest stated doses.
The study consists of 3 stages. Stage 1: to identify preferred vaccine candidate(s), doselevel(s), number of doses, and schedule of administration (with the first 15 participants ateach dose level of each vaccine candidate comprising a sentinel cohort); Stage 2: an
expanded-cohort stage; and Stage 3: a final candidate/dose large-scale stage. These stages,
and the progression between them, are detailed in the schema (Section 1.2).

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Number of Participants
Each group in Stage 1 will comprise 15 participants (12 receiving active vaccine and3 receiving placebo). In this stage, assuming 2 dose levels are selected following the initial
dose escalation, up to 56 potential groups are foreseen; if all groups are fully enrolled, thiscorresponds to a total of 840 participants.
Each group in Stage 2 will comprise 225 participants (180 receiving active vaccine and
45 receiving placebo). The total number of participants to be enrolled in this stage depends
on the number of groups to be pursued.
The vaccine candidate/dose level selected for Stage 3 will comprise 3000 participants. An
equal number of participants will receive placebo, ie, randomized in a 1:1 ratio.
Intervention Groups and Duration
The study may evaluate single-dose and 2-dose (separated by 21 or 60 days) schedules of
3 different dose levels of 4 investigational RNA vaccine candidates for active immunization
against COVID-19 in 3 age groups (18 to 55 years of age, 65 to 85 years of age, and18 to 85 years of age [stratified as ≤55 or >55 years of age]):

BNT162a1 (RNA-LNP vaccine utilizing uRNA and encoding the RBD): 3 µg, 10 µg,
30 µg



BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 30 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 30 µg, 100 µg
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

BNT162c2 (BNT162 RNA-LNP vaccine utilizing saRNA and encoding the RBD): 3 µg,
10 µg, 30 µg

Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Stage 1 andStage 2 dosing arms that are not evaluated in Stage 3.
Data Monitoring Committee or Other Independent Oversight Committee
The study will utilize an IRC, an internal Pfizer committee that will review data to allow
dose escalation or changes to continuation of specific groups.
An external data monitoring committee (DMC) will be formed and will review cumulative
unblinded data throughout the study.

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Statistical Methods
The study sample size for the first 2 stages of the study is not based on any statistical
hypothesis testing. For the third stage, with assumptions of a true vaccine efficacy (VE) of
70%, 53 cases of COVID-19 will provide 90% power to conclude true VE >20%. This would
be achieved with 3000 participants per group, based on the assumption of a 1.7% incidence
rate in the placebo group, and 20% of the participants being nonevaluable.
The primary safety objective will be evaluated by descriptive summary statistics for local
reactions, systemic events, abnormal hematology and chemistry laboratory parameters(sentinel cohorts only), and AEs and SAEs, for each vaccine group. A 3-tier approach will be
used to summarize AEs.
The secondary immunogenicity objectives will be evaluated descriptively by GMT, GMC,
GMFR, percentage of participants with ≥4-fold rise, and GMC ratio, and the associated 95%
confidence intervals (CIs), for SARS-CoV-2–specific WT serum neutralizing titers,
SARS-CoV-2-spike protein–specific binding antibody levels, and RBD-specific binding
levels at the various time points.
For the secondary efficacy objective, VE is defined as VE = 100 × (1 – IRR), where IRR is
the infection rate ratio, the calculated ratio of COVID-19 incidence in the active vaccine
group to the incidence in the placebo group. The null hypothesis (VE ≤ 20%) will be rejected
if the lower bound of the 95% CI for VE is >20%; no interim analysis of VE is planned.

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1.2. SchemaStage 1

(4:1 randomization active:placebo)
For each vaccine candidate

Age: 18-55 y
Low dose level 2-dose group (n=15):
SENTINEL

Age: 65-85 y

IRC (safety & immunogenicity

IRC (safety)

after Dose 1)

Low dose level 2-dose group (n=15):
SENTINEL

Mid dose level 2-dose group (n=15):
SENTINEL

IRC (safety)
IRC (safety & immunogenicity

IRC (safety)

after Dose 1)

Mid dose level 2-dose group (n=15):
SENTINEL

High dose level 2-dose group (n=15):
SENTINEL

IRC (safety)
IRC (safety & immunogenicity
after Dose 1)

High dose level 2-dose group (n=15):
SENTINEL

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IRC choice of group(s) for Stage 2(safety & immunogenicity after Dose 2)
Dose level(s) selected for Stage 2: 2dose (60 days apart) group(s) (n=15)

Dose level(s) selected for Stage 2: 2dose (60 days apart) group(s) (n=15)&
Dose level(s) selected for Stage 2: 1dose group(s) (n=15)&
Dose level(s) selected for Stage 2: 1dose group(s) (n=15)

Stage 2

(4:1 randomization active:placebo)
Age: 18-85(Stratified 18-55 or 56-85)
Group for each selected vaccine
candidate/dose level(n=180 per active group)
IRC choice of group(s) for Stage 3(safety & immunogenicity after Dose 2)

Stage 3

(1:1 randomization active:placebo)

Age: 18-85(Stratified 18-55 or 56-85)
Selected vaccine candidate/dose level(n=3000 per group)
Abbreviation: IRC = internal review committee.

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1.3. Schedule of Activities

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with theprotocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations orassessments required to protect the well-being of the participant.
1.3.1. Stage 1 Sentinel Cohorts
An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 10 (24-month follow-up visit) that COVID-19 is suspected.
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit Telehealth
Visit
Visit

Visit Window (Days)

0 to 14
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

X

X

X

X

X

Obtain informed consent

X

Assign participant number

X

Obtain demography andmedical history data

X

Obtain details of medications
currently taken

X

Perform physical examination

X

2

3

4

5

6

7

8

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset

X

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Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit Telehealth
Visit
Visit

Visit Window (Days)

0 to 14
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

Measure vital signs(including body temperature)

X

X

X

X

X

X

Collect blood sample forhematology and chemistrylaboratory testsa~10 mL~10 mL~10 mL~10 mL~10 mL

Collect screening blood
sample for HIV, HBsAg,
HBc Ab, and HCV Ab tests~10 mL

Serological test for prior
COVID-19 infection~20 mL

Perform urine pregnancy test
(if appropriate)X

Obtain nasal (midturbinate)swab(s)b

2

3

4

X

X

X

X

Collect nonstudy vaccine
information

X

X

Confirm eligibility

X

X

Collect prohibited medicationuse
Review hematology andchemistry results

X

Review temporary delay
criteria

X

X

X

X

X
X

X

5

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset
X

X
X

X

X

X

X

X

X

X

X

X

X

X

X
X

X

X

X

X

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Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit Telehealth
Visit
Visit

Visit Window (Days)

0 to 14
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 1

6 to 8Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 4

Confirm use of contraceptives(if appropriate)

X

X

X

X

X

X

X

X

~50 mL~50 mL~50 mL~50 mL~50 mL~50 mL~50 mL~50 mL

X

X

X

X

Obtain randomization number
and study intervention
allocation

X

Collect blood sample for
immunogenicity assessment~50 mL2

3

4

Administer study intervention

X

X

Assess acute reactions for atleast 30 minutes after study
intervention administrationc

X

X

Provide participant with 7-day
e-diary, thermometer, andmeasuring device

X

X

5

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset~50 mL

Review e-diary data (daily
review is optimal during theactive diary period)
Review ongoing e-diary
symptoms and obtain stopdatesCollect AEs and SAEs as
appropriate

X

X

X

X

X

X

X

X

X

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Visit Number

Screening

1

Visit Description

Screening

Vax 1

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)(Vax 1)

2

3

Vax 2

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent(Vax 2) (Vax 2)
up Visit up Visit Telehealth
Visit
Visit

Visit Window (Days)

0 to 14
Days
BeforeVisit 1Day 1

1 to 3
Days
After
Visit 119 to 23
Days
After
Visit 1

6 to 8Days
After
Visit 46 to 8Days
After
Visit 1

4

5

Collect e-diary or assist theparticipant to delete
application

6

7

8

9

10

Unplanned

Unplanned

12 to 16 28 to 35 154 to
350 to714 to Optimally 28 to 35 Days
Days
Days 168 Days 378 Days 742 Days Within 3
After
After
After
After
After
After Days After
Potential
Visit 4
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
COVID-19 Illness Visit
Illness
Onset
X

Collection of COVID-19–
related clinical and laboratory
information (including local
diagnosis)

X

X

Abbreviations: e-diary = electronic diary; HBc Ab = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HCV Ab = hepatitis C virus antibody; HIV = humanimmunodeficiency virus; NAAT = nucleic acid amplification test; vax = vaccination.
a. Hematology: hemoglobin, complete blood count with differential, and platelets. Blood chemistry: alanine aminotransferase (ALT), aspartate aminotransferase (AST),
alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), and creatinine.
b. Two swabs will be taken at Visits 1 and 4. One will be tested (if possible at the site, otherwise at the central laboratory) within 24 hours and vaccination will only proceed if it
is NAAT-negative for SARS-CoV-2 genomes. The second will be sent to the central laboratory for potential later testing.
c. The first 5 participants in in each sentinel group will be observed at the site for at least 4 hours after study intervention administration. Further vaccination will commence nosooner than 24 hours after the fifth participant received his or her vaccination.

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1.3.2. Stage 1 Nonsentinel Cohorts and Stage 2 Cohorts
An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 7 (24-month follow-up visit) that COVID-19 is suspected.
090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)

Visit Number
Visit Description

Visit Window (Days)

1

2

3

4

5

6

7

Unplanned

Unplanned

2-WeekFollow-up
Visit

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
COVID-19
Illness
Telehealth
Visit

Potential
COVID-19
ConvalescentVisit

19 to 23 Days 12 to 16 Days 28 to 35 Days
After Visit 1 After Visit 2 After Visit 2
or56 to 70 Days
After Visit 1a

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19 Illness Visit
Illness Onset

X

X

Vaccination 1 Vaccination 2

Day 1

Obtain informed consent

X

Assign participant number

X

Obtain demography and medical
history data

X

Perform physical examination

X

Measure vital signs

X

Perform urine pregnancy test
(if appropriate)

X

X

Collect nonstudy vaccine information

X

X

X

X

X

X

X

X

X

X

X

Collect prohibited medication use
Confirm eligibility

X

X

Measure temperature (body)

X

X

Review temporary delay criteria

X

X

Confirm use of contraceptives(if appropriate)

X

X

Obtain randomization number andstudy intervention allocation

X

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Visit Number

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Visit Description

Visit Window (Days)

Collect blood sample for
immunogenicity assessment

1

2

3

4

5

6

7

Unplanned

Unplanned

2-WeekFollow-up
Visit

1-MonthFollow-up
Visit

6-MonthFollow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
COVID-19
Illness
Telehealth
Visit

Potential
COVID-19
ConvalescentVisit

19 to 23 Days 12 to 16 Days 28 to 35 Days
After Visit 1 After Visit 2 After Visit 2
or56 to 70 Days
After Visit 1a

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19 Illness Visit
Illness Onset~50 mL~50 mL~50 mL

Vaccination 1 Vaccination 2

Day 1~50 mL~50 mL

Obtain nasal (midturbinate) swab

X

X

Administer study intervention

X

X

Assess acute reactions for at least 30
minutes after study intervention
administration

X

X

Provide participant with 7-day e-diary,
thermometer, and measuring device

XX~50 mL~50 mL~50 mL
X

Review e-diary data (daily review is
optimal during the active diary period)
Review ongoing e-diary symptoms andobtain stop dates
Collect AEs and SAEs as appropriate
Collect e-diary or assist the participant
to delete application

X

X

X

X

X

X

X

X

X

X

X

X

X

X

Collection of COVID-19–related
clinical and laboratory information(including local diagnosis)
Abbreviation: e-diary = electronic diary.
a. The window for Visit 2 is dependent on the dosing schedule for the assigned group.

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1.3.3. Stage 3 Cohort(s)An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 6 (24-month follow-up visit) that COVID-19 is suspected.

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Visit Number
Visit Description

Visit Window (Days)

1

2

3

4

5

6

Unplanned

Unplanned

1-MonthFollow-up
Visit

6-Month
SafetyTelephoneContact

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
COVID-19
Illness
Telehealth
Visit

Potential
COVID-19
ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2
or56 to 70 Days
After Visit 1a

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

X

X~50 mL~50 mL

Vaccination 1 Vaccination 2

Day 1

Obtain informed consent

X

Assign participant number

X

Obtain demography and medical history data

X

Perform physical examination

X

Measure vital signs

X

Perform urine pregnancy test (if appropriate)

X

X

Collect nonstudy vaccine information

X

X

X

X

X

X

X

Collect prohibited medication use
Confirm eligibility

X

X

Measure temperature (body)

X

X

Review temporary delay criteria

X

X

Confirm use of contraceptives (if appropriate)

X

X

Obtain randomization number and study
intervention allocation

X

Collect blood sample for immunogenicity
assessment~50 mL

Obtain nasal (midturbinate) swab

X

X

X

X

~50 mLX~50 mLX

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Visit Number

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Visit Description

2

3

4

5

6

Unplanned

Unplanned

1-MonthFollow-up
Visit

6-Month
SafetyTelephoneContact

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
COVID-19
Illness
Telehealth
Visit

Potential
COVID-19
ConvalescentVisit

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2
or56 to 70 Days
After Visit 1a

154 to 168
Days After
Visit 2350 to 378
Days After
Visit 2714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

X

X

X

Vaccination 1 Vaccination 2

Visit Window (Days)

Day 1

Administer study intervention

X

X

Assess acute reactions for at least 30 minutes after
study intervention administration

X

X

Provide participant with 7-day e-diary,
thermometer, and measuring device

X

X

Review e-diary data (daily review is optimal during
the active diary period)
Review ongoing e-diary symptoms and obtain stopdatesCollect AEs and SAEs as appropriate

X

Collect e-diary or assist the participant to delete
application

X

X

X

X

X

X

X

X

X

Telephone contact

X

Collection of COVID-19–related clinical andlaboratory information (including local diagnosis)
Abbreviation: e-diary = electronic diary.
a. The window for Visit 2 is dependent on the dosing schedule(s) selected for the Stage 3.

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2. INTRODUCTION
The BNT162 RNA-based COVID-19 vaccines are currently being investigated forprevention of COVID-19 in healthy adults.
2.1. Study Rationale
The purpose of the study is to rapidly describe the safety, tolerability, immunogenicity, andpotential efficacy of 4 BNT162 RNA-based COVID-19 vaccine candidates against
COVID-19 in healthy adults. There are currently no vaccines to prevent infection with
SARS-CoV-2 or antiviral drugs to treat COVID-19. Given the global crisis of COVID-19
and fast expansion of the disease in the United States and elsewhere, the rapid developmentof an effective vaccine is of utmost importance.

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2.2. Background
In December 2019, a pneumonia outbreak of unknown cause occurred in Wuhan, China.
In January 2020, it became clear that a novel coronavirus (2019-nCoV) was the underlying
cause. Later in January, the genetic sequence of the 2019-nCoV became available to theWorld Health Organization (WHO) and public (MN908947.3), and the virus was categorized
in the Betacoronavirus subfamily. By sequence analysis, the phylogenetic tree revealed acloser relationship to severe acute respiratory syndrome (SARS) virus isolates than to anothercoronavirus infecting humans, the Middle East respiratory syndrome (MERS) virus.
SARS-CoV-2 infections and the resulting disease, COVID-19, have spread globally,affecting a growing number of countries.
On 11 March 2020, the WHO characterized the COVID-19 outbreak as a pandemic.1
The WHO Situation Update Report dated 30 March 2020 noted 693,224 confirmed caseswith 33,106 deaths globally, including 142,081 confirmed cases with 2457 deaths in theAmericas.2 The United States currently has the most reported cases globally. At the time ofthis communication, the number of confirmed cases continues to rise globally. There are
currently no vaccines or effective antiviral drugs to treat SARS-CoV-2 infections or the
disease it causes, COVID-19.3
A prophylactic, RNA-based SARS-CoV-2 vaccine provides one of the most flexible andfastest approaches available to immunize against the emerging virus.4,5The development of an RNA-based vaccine encoding a viral antigen, which is then expressedby the vaccine recipient as a protein capable of eliciting protective immune responses,
provides significant advantages over more traditional vaccine approaches. Unlike live
attenuated vaccines, RNA vaccines do not carry the risks associated with infection and may
be given to people who cannot be administered live virus (eg, pregnant women andimmunocompromised persons). RNA-based vaccines are manufactured via a cell-free invitro transcription process, which allows an easy and rapid production and the prospect of
producing high numbers of vaccination doses within a shorter time period than achieved with

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traditional vaccine approaches. This capability is pivotal to enable the most effective
response in outbreak scenarios.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)

Four SARS-CoV-2–RNA lipid nanoparticle (RNA-LNP) vaccines utilizing different RNA
formats will be evaluated in this study. Each vaccine candidate is based on 1 of 3 RNA
platforms: unmodified messenger RNA (uRNA), nucleoside-modified messenger RNA(modRNA), or self-amplifying messenger RNA (saRNA). Each vaccine candidate expresses
1 of 2 antigens: the SARS-CoV-2 full-length, P2 mutant, “heads up,” prefusion spikeglycoprotein (P2 S) (version 9) or a trimerized SARS-CoV-2 spike glycoprotein receptor
binding domain (RBD) (version 5). The 4 SARS-CoV-2 vaccine candidates that will betested in this study are therefore:

BNT162a1 (variant RBL063.3): non–nucleoside-modified uridine-containing messenger
RNA (uRNA) with high intrinsic adjuvanticity, encoding the RBD.



BNT162b1 (variant RBP020.3): nucleoside-modified messenger RNA (modRNA) withblunted innate immune sensor–activating capacity and augmented expression encoding
the RBD.



BNT162b2 (variant RBP020.2): nucleoside-modified messenger RNA (modRNA) as
above but encoding P2 S.



BNT162c2 (variant RBP020.3): self-amplifying messenger RNA (saRNA) encoding the
RBD, in which higher amounts of protein per injected RNA template can be produced.

2.2.1. Clinical Overview
BNT162 vaccines have not been administered to humans before and thus there are no
previous clinical data with these specific vaccines. However, given clinical data from othersimilarly formulated uRNA liposomal vaccines from BioNTech in oncology trials6 andrecent published results from clinical trials using modRNA influenza vaccines by Moderna,7
the BNT162 vaccines are expected to have a favorable safety profile with mild, localized,
and transient effects.
2.3. Benefit/Risk Assessment
There is an ongoing global pandemic of COVID-19 with no preventative or therapeutic
options available. While there are currently no data available from clinical trials on the use of
BNT162 vaccines in humans, available nonclinical data with these vaccines, and data from
nonclinical studies and clinical trials with the same or related RNA components, or antigens,support a favorable risk/benefit profile. Anticipated AEs after vaccination are expected to be
manageable using routine symptom-driven standard of care as determined by theinvestigators and, as a result, the profile of these vaccine candidates support initiation of thisPhase 1/2 clinical study.

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More detailed information about the known and expected benefits and risks and reasonably
expected AEs of BNT162 RNA-based COVID-19 vaccines may be found in theinvestigator’s brochure (IB), which is the SRSD for this study.

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2.3.1. Risk Assessment
Potential Risk of ClinicalSignificance

Summary of Data/Rationale for Risk

Mitigation Strategy

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Study Intervention: BNT162 RNA-Based COVID-19 Vaccine
Potential for local reactions (injection
site redness, injection site swelling,
and injection site pain) and systemic
events (fever, fatigue, headache,chills, vomiting, diarrhea, muscle
pain, and joint pain) following
vaccination.

These are common adverse reactions seen
with other vaccines, as noted in the FDA
Center for Biologics Evaluation andResearch (CBER) guidelines on toxicity
grading scales for healthy adult volunteers
enrolled in preventive vaccine clinical
trials.8

The study design includes the use of sentinel cohorts and dose escalation toclosely monitor and limit the rate of enrollment to ensure participant safety.
The study employs the use of an e-diary to monitor local reactions andsystemic events in real time. Stopping rules are also in place for sentinelcohorts. The first 5 sentinel-cohort participants in each group will beobserved for 4 hours after vaccination to assess any immediate AEs.

Unknown AEs and laboratory
abnormalities with a novel vaccine.

This study is one of the first 2 parallelrunning clinical studies with the BNT162
vaccine candidates and as such there are noclinical data available for this vaccine.

The study design includes the use of sentinel cohorts and dose escalation toclosely monitor and limit the rate of enrollment to ensure participant safety.
An IRC and DMC will also review safety data throughout the study.
Stopping rules are also in place for sentinel cohorts. The first 5 sentinelcohort participants in each group will be observed for 4 hours after
vaccination to assess any immediate AEs.

Potential for COVID-19 diseaseenhancement.

Disease enhancement has been seen
following vaccination with respiratorysyncytial virus (RSV), feline coronavirus,
and Dengue virus vaccines.

The study excludes participants with likely previous or current COVID-19.
All participants are followed for SARS-CoV-2 antigen-specific antibody
and SARS-CoV-2–specific WT serum neutralizing titers, and COVID-19
illness, including markers of severity.

Study Procedures
Participants will be required to attend Without appropriate social distancing andhealthcare facilities during the global PPE, there is a potential for increased
exposure to SARS-CoV-2.
SARS-CoV-2 pandemic.
Venipuncture will be performed
during the study.

There is the risk of bleeding, bruising,hematoma formation, and infection at the
venipuncture site.

Pfizer will work with sites to ensure an appropriate COVID-19 prevention
strategy.
Only appropriately qualified personnel would obtain the blood draw.

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2.3.2. Benefit Assessment
Benefits to individual participants may include:Receipt of a potentially efficacious COVID-19 vaccine during a global pandemicAccess to COVID-19 diagnostic and antibody testingContributing to research to help others in a time of global pandemic

2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in thisstudy, the potential risks identified in association with BNT162 RNA-based COVID-19
vaccine are justified by the anticipated benefits that may be afforded to healthy participants.

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3. OBJECTIVES, ESTIMANDS, AND ENDPOINTSObjectives

Estimands

Endpoints

Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Primary:
In participants receiving at least 1 doseof study intervention and having safety
data reported after any vaccination, thepercentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each doseAdverse events (AEs) from Dose 1
to 1 month after the last dose
 Serious AEs (SAEs) from Dose 1
to 6 months after the last doseIn addition, in sentinel cohorts from
Stage 1, the percentage of participantswith:
Abnormal hematology andchemistry laboratory values 1 and7 days after Dose 1; and 7 days
after Dose 2
Grading shifts in hematology andchemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2

Primary:
Local reactions (pain at the
injection site, redness, andswelling)

Systemic events (fever, fatigue,headache, chills, vomiting,diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs
Hematology and chemistry laboratory
parameters detailed in Section 10.2

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Objectives
Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Estimands

Endpoints

Secondary:
Secondary:In participants complying with the key
protocol criteria (evaluable participants)
at the following time points after receipt
of study intervention:
Stage 1 Sentinel Cohorts: 7 and21 days after Dose 1; 7 and 14 days and1, 6, 12, and 24 months after Dose 2
Stage 1 Nonsentinel Cohorts and Stage
2 Cohorts: 21 days after Dose 1; 14days and 1, 6, 12, and 24 months after
Dose 2
Stage 3 Cohort(s): 1, 12, and 24 months
after Dose 2
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







Geometric mean titers (GMTs) ateach time point
Geometric mean fold rise (GMFR)
from before vaccination to eachsubsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
Geometric mean concentrations(GMCs) at each time point
GMFR from prior to first dose of
study intervention to eachsubsequent time point
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
Geometric mean ratio (GMR),
estimated by the ratio of thegeometric mean of SARS-CoV-2–
specific WT serum neutralizing
titers to the geometric mean of
SARS-CoV-2–specific binding
antibody levels at each time point

To evaluate the efficacy of prophylactic In participants complying with the key
protocol criteria (evaluable participants)
BNT162 vaccines against confirmed
COVID-19
following receipt of the last dose of
study intervention:
100 × (1 – infection rate ratio)[ratio of active vaccine to placebo]
Tertiary/Exploratory:
Tertiary/Exploratory:
To describe the relationship between
SARS-CoV-2 serological parametersand:
NAAT-confirmed COVID-19

Symptomatic SARS-CoV-2
infection
Asymptomatic SARS-CoV-2
infection

SARS-CoV-2–specific WT serum
neutralizing titers

SARS-CoV-2-spike protein–specificbinding antibody levels and RBDspecific binding antibody levels



SARS-CoV2–specific WT serum
neutralizing titers

SARS-CoV-2-spike protein–
specific binding antibody levels



SARS-CoV-2 RBD–specificbinding antibody levels

COVID-19 incidence per 1000 personyears of follow-up

Tertiary/Exploratory:
Nonvaccine antigen SARS-CoV-2
antibody levels

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4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1/2, randomized, placebo-controlled, observer-blind, dose-finding, andvaccine candidate–selection study in healthy adults.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)The study will evaluate the safety, tolerability, immunogenicity, and potential efficacy of up
to 4 different SARS-CoV-2 RNA vaccine candidates against COVID-19:


As a 2-dose (separated by 21 or 60 days) or single-dose scheduleAt up to 3 different dose levels

In 3 age groups (18 to 55 years of age, 65 to 85 years of age, and 18 to 85 years of age[stratified as ≤55 or >55 years of age])

Dependent upon safety and/or immunogenicity data generated during the course of thisstudy, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
may be started at the next highest dose, groups may not be started, groups may be terminatedearly, and/or groups may be added with dose levels below the lowest stated dose orintermediate between the lowest and highest stated doses.
The study consists of 3 stages. Stage 1: to identify preferred vaccine candidate(s), doselevel(s), number of doses, and schedule of administration (with the first 15 participants ateach dose level of each vaccine candidate comprising a sentinel cohort); Stage 2: an
expanded-cohort stage; and Stage 3; a final candidate/dose large-scale stage. These stages,
and the progression between them, are detailed in the schema (Section 1.2).
The study is observer-blinded, as the physical appearance of the investigational vaccine
candidates and the placebo may differ. The participant, investigator, study coordinator, andother site staff will be blinded. At the study site, only the dispenser(s)/administrator(s) are
unblinded.
To facilitate rapid review of data in real time, sponsor staff will be unblinded to vaccine
allocation for the participants in Stage 1 and Stage 2.
4.1.1. Stage 1
Each group (vaccine candidate/dose level/age group/number of doses) will comprise
15 participants; 12 participants will be randomized to receive active vaccine and 3 to receive
placebo. On Day 22, those in 2-dose groups will receive the same vaccine they received on
Day 1; for those in single-dose groups, all will receive placebo. Full details of all potential
groups in Stage 1 may be found in Table 1.

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Controlled enrollment:No more than 5 participants (4 active, 1 placebo) can be vaccinated on the first day

The first 5 participants must be observed by blinded site staff for at least 4 hours after
vaccination for any acute reactions

Vaccination of the remaining participants will commence no sooner than 24 hours
after the fifth participant received his or her vaccination

Application of stopping rules

IRC review of safety data to determine escalation to the next dose level

Groups of participants 65 to 85 years of age will not be started until safety andimmunogenicity data for the same vaccine candidate/dose level have been deemed acceptablein the 18- to 55-year age cohort by the IRC.
Once the IRC has selected a vaccine candidate/dose level to proceed into Stage 2, for eachage cohort, 2 additional groups will be enrolled into Stage 1 for that vaccine candidate/doselevel:
A 2-dose group, with the 2 doses administered 60 days apart rather than 21

A 1-dose group

In this stage, assuming 2 dose levels are selected following the initial dose escalation, up to
56 potential groups are foreseen; if all groups are fully enrolled, this corresponds to a total of
840 participants.
4.1.2. Stage 2
On the basis of safety and/or immunogenicity data generated during the course of this study,
and/or the BioNTech study conducted in Germany (BNT162-01), 1 or more groups (vaccine
candidate/dose level) may be selected to proceed into Stage 2. Participants in this stage willbe 18 to 85 years of age, stratified equally: 18 to 55 or 56 to 85 years. Commencement ofeach age stratum will be dependent upon satisfactory safety and immunogenicity data fromthe 18- to 55-year and 65- to 85-year groups from Stage 1, respectively. It is therefore
possible that the 2 age strata may not start concurrently.
In each group selected for Stage 2, it is intended that 225 participants will be randomized in a
4:1 ratio to receive active vaccine (180 participants) or placebo (45 participants).
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4.1.3. Stage 3
On the basis of safety and/or immunogenicity data generated during the course of this study,
and/or the BioNTech study conducted in Germany (BNT162-01), 1 group may be selected toproceed into Stage 3. Participants in this stage will be 18 to 85 years of age, stratified
equally: 18 to 55 years or 56 to 85 years. As in Stage 2, it is possible that the 2 age strata may
not start concurrently.
The vaccine candidate/dose level selected for Stage 3 will comprise 3000 participants. An
equal number of participants will receive placebo, ie, randomized in a 1:1 ratio.
Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Stage 1 andStage 2 dosing arms that are not evaluated in Stage 3.

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4.2. Scientific Rationale for Study Design
Additional surveillance for COVID-19 will be conducted as part of the study, given thepotential risk of disease enhancement. If a participant experiences respiratory symptoms, asdetailed in Section 8.13, a COVID-19 illness and subsequent convalescent visit will occur.
As part of these visits, samples (nasal [midturbinate] swab and blood) will be taken for
antigen and antibody assessment as well as recording of COVID-19–related clinical andlaboratory information (including local diagnosis).
Human reproductive safety data are not available for BNT162 RNA-based COVID-19
vaccines, but there is no suspicion of human teratogenicity based on the intended mechanismof action of the compound. Therefore, the use of a highly effective method of contraception
is required (see Appendix 4).
4.3. Justification for Dose
Because of the requirement for a rapid response to the newly emerged COVID-19 pandemic,
sufficient data are not currently available to experimentally validate the dose selection andinitial starting dose. Therefore, the planned starting doses of 3 µg (for BNT162a1 and
BNT162c2) and 10 µg (for BNT162b1 and BNT162b2) in this study are based on nonclinicalexperience with the same RNAs encoding other viral antigens (such as influenza and HIV
antigens). The general safety and effectiveness of uRNA and modRNA platforms have been
demonstrated in oncological clinical trials with different administration routes(NCT02410733, NCT03871348). Doses of up to 400 µg total uRNA have been administered
IV as RNA lipoplex (RNA-LPX) and doses of up to 1000 µg total naked modRNA have been
administered intratumorally, both without signs of unpredictable overstimulation of theimmune system.
Based on nonclinical data of the RNA components (uRNA, modRNA, saRNA), with otherliposomes or in conjunction with the lipid nanoparticles as will be tested clinically in thisstudy, it is expected that doses in the 1- to 5-µg range will be immunogenic and induce
neutralizing antibodies; however, it is anticipated that 3- to 10-fold higher doses will likely
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be required to elicit a stronger antibody response. Based on previous clinical and nonclinicalexperience, it is expected that doses of up to 100 µg will be well tolerated.
Taken together, the planned starting doses in this study in healthy participants are considered
to be safe, but still sufficient to induce an antiviral immune response.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases ofthe study, including the last visit. Note that participants enrolled in Stages 1 and 2 in groups
that do not proceed to Stage 3 may be followed for fewer than 24 months (but no less than
6 months after the last vaccination).
The end of the study is defined as the date of last visit of the last participant in the study.

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5. STUDY POPULATIONThis study can fulfill its objectives only if appropriate participants are enrolled. The
following eligibility criteria are designed to select participants for whom participation in the
study is considered appropriate. All relevant medical and nonmedical conditions should betaken into consideration when deciding whether a particular participant is suitable for thisprotocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male or female participants between the ages of 18 and 55 years, inclusive, 65 and85 years, inclusive, or 18 and 85 years, inclusive, at randomization (dependent uponstudy stage).


Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female(Section 10.4.2) participants.

Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, vaccination
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Healthy participants who are determined by medical history, physical examination, andclinical judgment of the investigator to be eligible for inclusion in the study.

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Note: Healthy participants with preexisting stable disease, defined as disease notrequiring significant change in therapy or hospitalization for worsening disease during
the 6 weeks before enrollment, can be included.
Informed Consent:
4. Capable of giving personal signed informed consent as described in Appendix 1, which
includes compliance with the requirements and restrictions listed in the ICD and in thisprotocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:

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1. Other medical or psychiatric condition including recent (within the past year) or active
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study
participation or, in the investigator’s judgment, make the participant inappropriate for the
study.
2. Known infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or
hepatitis B virus (HBV).
3. History of severe adverse reaction associated with a vaccine and/or severe allergic
reaction (eg, anaphylaxis) to any component of the study intervention(s).
4. Receipt of medications intended to prevent COVID-19.
5. Stages 1 and 2 only: Previous clinical or microbiological diagnosis of COVID-19.
6. Sentinel participants in Stage 1 only: Individuals at high risk for severe COVID-19,
including those with any of the following risk factors:Hypertension

Diabetes mellitus

Chronic pulmonary diseaseAsthma

Current vaping or smoking

History of chronic smoking within the prior year



BMI >30 kg/m2

Anticipating the need for immunosuppressive treatment within the next 6 months

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7. Sentinel participants in Stage 1 only: Individuals currently working in occupations withhigh risk of exposure to SARS-CoV-2 (eg, healthcare worker, emergency response
personnel).
8. Immunocompromised individuals with known or suspected immunodeficiency, as
determined by history and/or laboratory/physical examination.
9. Individuals with a history of autoimmune disease or an active autoimmune diseaserequiring therapeutic intervention, including but not limited to: systemic or cutaneous
lupus erythematosus, autoimmune arthritis/rheumatoid arthritis, Guillain-Barré
syndrome, multiple sclerosis, Sjögren’s syndrome, idiopathic thrombocytopenia purpura,glomerulonephritis, autoimmune thyroiditis, giant cell arteritis (temporal arteritis),
psoriasis, and insulin-dependent diabetes mellitus (type 1).
10. Bleeding diathesis or condition associated with prolonged bleeding that would, in theopinion of the investigator, contraindicate intramuscular injection.
11. Women who are pregnant or breastfeeding.
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Prior/Concomitant Therapy:
12. Previous vaccination with any coronavirus vaccine.
13. Individuals who receive treatment with immunosuppressive therapy, including cytotoxic
agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned
receipt throughout the study. If systemic corticosteroids have been administered shortterm (<14 days) for treatment of an acute illness, participants should not be enrolled into
the study until corticosteroid therapy has been discontinued for at least 28 days before
study intervention administration. Inhaled/nebulized, intra-articular, intrabursal, or
topical (skin or eyes) corticosteroids are permitted.
14. Receipt of blood/plasma products or immunoglobulin, from 60 days before study
intervention administration or planned receipt throughout the study.
Prior/Concurrent Clinical Study Experience:
15. Participation in other studies involving study intervention within 28 days prior to study
entry and/or during study participation.
16. Previous participation in other studies involving study intervention containing lipid
nanoparticles.
Diagnostic Assessments:
17. Sentinel participants in Stage 1 only: Positive serological test for SARS-CoV-2 IgM
and/or IgG antibodies at the screening visit.
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18. Sentinel participants in Stage 1 only: Any screening hematology and/or blood
chemistry laboratory value that meets the definition of a ≥ Grade 1 abnormality.
Note: With the exception of bilirubin, participants with any stable Grade 1 abnormalities(according to the toxicity grading scale) may be considered eligible at the discretion of
the investigator. (Note: A “stable” Grade 1 laboratory abnormality is defined as a reportof Grade 1 on an initial blood sample that remains ≤ Grade 1 upon repeat testing on asecond sample from the same participant.)
19. Sentinel participants in Stage 1 only: Positive test for HIV, hepatitis B surface antigen(HBsAg), hepatitis B core antibodies (HBc Abs), or hepatitis C virus antibodies(HCV Abs) at the screening visit.
20. Sentinel participants in Stage 1 only: SARS-CoV-2 NAAT-positive nasal swab within
24 hours before receipt of study intervention.
Other Exclusions:

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21. Investigator site staff or Pfizer employees directly involved in the conduct of the study,site staff otherwise supervised by the investigator, and their respective family members.
5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm thatthe participant has selected an appropriate method of contraception for the individual
participant and his or her partner(s) from the permitted list of contraception methods(see Appendix 4, Section 10.4.4) and will confirm that the participant has been instructed inits consistent and correct use. At time points indicated in the SoA, the investigator ordesignee will inform the participant of the need to use highly effective contraception
consistently and correctly and document the conversation and the participant’s affirmation in
the participant’s chart (participants need to affirm their consistent and correct use of at least 1of the selected methods of contraception). In addition, the investigator or designee will
instruct the participant to call immediately if the selected contraception method is
discontinued or if pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but
are not subsequently randomly assigned to study intervention. A minimal set of screen
failure information is required to ensure transparent reporting of screen failure participants tomeet the CONSORT publishing requirements and to respond to queries from regulatory
authorities. Minimal information includes demography, screen failure details, eligibility
criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may berescreened under a different participant number.
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5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention
Administration
The following conditions are temporary or self-limiting and a participant may be vaccinatedonce the condition(s) has/have resolved and no other exclusion criteria are met.

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1. Current febrile illness (body temperature ≥100.4°F [≥38°C]) or other acute illness within
48 hours before study intervention administration. This includes current symptoms that
could represent a potential COVID-19 illness:

New or increased cough;

New or increased shortness of breath;New or increased sore throat;

New or increased wheezing;New or increased sputum production;New or increased nasal congestion;New or increased nasal discharge;



Loss of taste/smell.

2. Receipt of any seasonal or pandemic influenza vaccine within 14 days, or any othernonstudy vaccine within 28 days, before study intervention administration.
3. Anticipated receipt of any seasonal or pandemic influenza vaccine within 14 days, or any
other nonstudy vaccine within 28 days, after study intervention administration.
4. Receipt of short-term (<14 days) systemic corticosteroids. Study intervention
administration should be delayed until systemic corticosteroid use has been discontinued
for at least 28 days. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin oreyes) corticosteroids are permitted.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s),placebo, medical device(s), or study procedure(s) intended to be administered to a study
participant according to the study protocol.
The study may evaluate 2-dose (separated by 21 or 60 days) and single-dose schedules of
3 different dose levels of 4 investigational RNA vaccine candidates for active immunization
against COVID-19 in 3 age groups (18 to 55 years of age, 65 to 85 years of age, and18 to 85 years of age [stratified as ≤55 or >55 years of age]). These 4 investigational RNA
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vaccine candidates, with the addition of saline placebo, are the 5 potential study interventions
that may be administered to a study participant:

BNT162a1 (RNA-LNP vaccine utilizing uRNA and encoding the RBD): 3 µg, 10 µg,
30 µg



BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 30 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 30 µg, 100 µg



BNT162c2 (BNT162 RNA-LNP vaccine utilizing saRNA and encoding the RBD): 3 µg,
10 µg, 30 µgNormal saline (0.9% sodium chloride solution for injection)

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A list of all potential groups in the Stage 1 are shown in Table 1. Each of these groups may
or may not progress to the later stages of the study.
Table 1.

Potential Groups in Stage 1

GroupsN

2-Dose Groups (Sentinel Cohorts)
a-3-2-Y (Sentinel)
15[uRNA 3 µg (2 doses)]a-10-2-Y (Sentinel)
15[uRNA 10 µg (2 doses)]a-30-2-Y (Sentinel)
15[uRNA 30 µg (2 doses)]

Age
Group
(Years)18 to 55
18 to 55
18 to 55

b1-10-2-Y (Sentinel)[modRNA 10 µg (2 doses)]b1-30-2-Y (Sentinel)[modRNA 30 µg (2 doses)]b1-100-2-Y (Sentinel)[modRNA 100 µg (2 doses)]15

18 to 55

15

18 to 55

15

18 to 55

b2-10-2-Y (Sentinel)[modRNA 10 µg (2 doses)]b2-30-2-Y (Sentinel)[modRNA 30 µg (2 doses)]b2-100-2-Y (Sentinel)[modRNA 100 µg (2 doses)]15

18 to 55

15

18 to 55

15

18 to 55

Dose 1
Day 1
BNT162a1
Placebo
BNT162a1
Placebo
BNT162a1
Placebo

3 µg
10 µg
30 µg

BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo

10 µg

BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo

10 µg

30 µg
100 µg30 µg100 µg

Dose 2(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

Day 22
BNT162a1
Placebo
BNT162a1
Placebo
BNT162a1
Placebo(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo

10 µg(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo

10 µg

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3 µg
10 µg
30 µg

30 µg
100 µg30 µg100 µg(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

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Table 1.

Potential Groups in Stage 1

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)GroupsNc-3-2-Y (Sentinel)[saRNA 3 µg (2 doses)]c-10-2-Y (Sentinel)[saRNA 10 µg (2 doses)]c-30-2-Y (Sentinel)[saRNA 30 µg (2 doses)]

15

Age
Group
(Years)18 to 55

15

18 to 55

15

18 to 55

a-3-2-O (Sentinel)[uRNA 3 µg (2 doses)]a-10-2-O (Sentinel)[uRNA 10 µg (2 doses)]a-30-2-O (Sentinel)[uRNA 30 µg (2 doses)]

15

65 to 8515

65 to 8515

65 to 85b1-10-2-O (Sentinel)[modRNA 10 µg (2 doses)]b1-30-2-O (Sentinel)[modRNA 30 µg (2 doses)]b1-100-2-O (Sentinel)[modRNA 100 µg (2 doses)]

15

65 to 8515

65 to 8515

65 to 85b2-10-2-O (Sentinel)[modRNA 10 µg (2 doses)]b2-30-2-O (Sentinel)[modRNA 30 µg (2 doses)]b2-100-2-O (Sentinel)[modRNA 100 µg (2 doses)]

15

65 to 8515

65 to 8515

65 to 85c-3-2-O (Sentinel)[saRNA 3 µg (2 doses)]c-10-2-O (Sentinel)[saRNA 10 µg (2 doses)]c-30-2-O (Sentinel)[saRNA 30 µg (2 doses)]

15

65 to 8515

65 to 8515

65 to 8515

18 to 55

15

18 to 55

15

15

Single-Dose Groups
a-x-1-Y[uRNA dose level(s)selected for Stage 2(1 dose)]b1-x-1-Y[modRNA dose level(s)selected for Stage 2(1 dose)]b2-x-1-Y[modRNA dose level(s)selected for Stage 2(1 dose)]c-x-1-Y[saRNA dose level(s)selected for Stage 2(1 dose)]

Dose 1
BNT162c2
Placebo
BNT162c2
Placebo
BNT162c2
Placebo

3 µg

BNT162a1
Placebo
BNT162a1
Placebo
BNT162a1
Placebo

3 µg

BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo

10 µg

BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo

10 µg

BNT162c2
Placebo
BNT162c2
Placebo
BNT162c2
Placebo

3 µg

Day 1
BNT162a1
Placebo

10 µg
30 µg

10 µg
30 µg

30 µg
100 µg30 µg100 µg

10 µg
30 µg

Dose 2(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

BNT162c2
Placebo
BNT162c2
Placebo
BNT162c2
Placebo

3 µg(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

BNT162a1
Placebo
BNT162a1
Placebo
BNT162a1
Placebo

3 µg(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

BNT162b1
Placebo
BNT162b1
Placebo
BNT162b1
Placebo

10 µg(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo

10 µg(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

BNT162c2
Placebo
BNT162c2
Placebo
BNT162c2
Placebo

3 µg

30 µg

10 µg
30 µg

30 µg
100 µg30 µg100 µg

10 µg
30 µg

(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)(n=12)(n=3)

Day 22
Placebo(n=15)(n=12)(n=3)

Placebo(n=15)

TBD(n=12)(n=3)

Placebo(n=15)

TBD(n=12)(n=3)

Placebo(n=15)

TBD(n=12)(n=3)

BNT162b1
Placebo

TBD

18 to 55

BNT162b2
Placebo18 to 55

BNT162c2
Placebo

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Table 1.

Potential Groups in Stage 1

Groups

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a-x-1-O[uRNA dose level(s)selected for Stage 2(1 dose)]b1-x-1-O[modRNA dose level(s)selected for Stage 2(1 dose)]b2-x-1-O[modRNA dose level(s)selected for Stage 2(1 dose)]c-x-1-O[saRNA dose level(s)selected for Stage 2(1 dose)]

N

Age
Group
(Years)15

65 to 85

BNT162a1
Placebo

TBD(n=12)(n=3)

Placebo(n=15)

15

65 to 85

BNT162b1
Placebo

TBD(n=12)(n=3)

Placebo(n=15)

15

65 to 85

BNT162b2
Placebo

TBD(n=12)(n=3)

Placebo(n=15)

15

65 to 85

BNT162c2
Placebo

TBD(n=12)(n=3)

Placebo(n=15)

TBD(n=12)(n=3)

Day 61
BNT162a1
Placebo

2-Dose Groups (Longer Schedule)
a-x-2L-Y
15[uRNA dose level(s)selected for Stage 2(2 doses)]b1-x-2L-Y
15[modRNA dose level(s)selected for Stage 2(2 doses)]b2-x-2L-Y
15[modRNA dose level(s)selected for Stage 2(2 doses)]c-x-2L-Y
15[saRNA dose level(s)selected for Stage 2(2 doses)]

18 to 55

Dose 1

Day 1
BNT162a1
Placebo

Dose 2TBD(n=12)(n=3)

18 to 55

BNT162b1
Placebo

TBD(n=12)(n=3)

BNT162b1
Placebo

TBD(n=12)(n=3)

18 to 55

BNT162b2
Placebo

TBD(n=12)(n=3)

BNT162b2
Placebo

TBD(n=12)(n=3)

18 to 55

BNT162c2
Placebo

TBD(n=12)(n=3)

BNT162c2
Placebo

TBD(n=12)(n=3)

a-x-2L-O
15
65 to 85
BNT162a1
TBD(n=12)
BNT162a1
TBD[uRNA dose level(s)Placebo(n=3)
Placeboselected for Stage 2(2 doses)]b1-x-2L-O
15
65 to 85
BNT162b1
TBD(n=12)
BNT162b1 TBD[modRNA dose level(s)Placebo(n=3)
Placeboselected for Stage 2(2 doses)]b2-x-2L-O
15
65 to 85
BNT162b2
TBD(n=12)
BNT162b2 TBD[modRNA dose level(s)Placebo(n=3)
Placeboselected for Stage 2(2 doses)]c-x-2L-O
15
65 to 85
BNT162c2
TBD(n=12)
BNT162c2
TBD[saRNA dose level(s)Placebo(n=3)
Placeboselected for Stage 2(2 doses)]Abbreviations: modRNA = nucleoside-modified messenger ribonucleic acid; saRNA = self-amplifying messenger
ribonucleic acid; TBD = to be determined; uRNA = uridine-containing messenger ribonucleic acid.

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6.1. Study Intervention(s) Administered
Intervention
Name

BNT162b1(BNT162 RNALNP vaccine
utilizing
modRNA)

BNT162b2(BNT162 RNALNP vaccine
utilizing
modRNA)

BNT162c2(BNT162 RNALNP vaccine
utilizing saRNA

Saline placebo

Type
VaccineDose Formulation uRNA

VaccinemodRNA

VaccinemodRNA

VaccinesaRNA

Unit DoseStrength(s)Dosage Level(s)Route of
AdministrationUse
IMP or NIMP
Sourcing

250 µg/0.5 mL

250 µg/0.5 mL

250 µg/0.5 mL

250 µg/0.5 mL

Placebo
Normal saline(0.9% sodium
chloride solution
for injection)
N/A

3-, 10-, 30-µg
Intramuscular
injection
Experimental
IMP
Provided centrally
by the sponsor
Study intervention
will be provided ina glass vial as
open-label supply.
Each vial will belabeled as required
per country
requirement

10-, 30-, 100-µg
Intramuscular
injection
Experimental
IMP
Provided centrally
by the sponsor
Study intervention
will be provided ina glass vial as
open-label supply.
Each vial will belabeled as required
per country
requirement

10-, 30-, 100-µg
Intramuscular
injection
Experimental
IMP
Provided centrally
by the sponsor
Study intervention
will be provided ina glass vial as
open-label supply.
Each vial will belabeled as required
per country
requirement3-, 10-, 30-µg
Intramuscular
injection
Experimental
IMP
Provided centrally
by the sponsor
Study intervention
will be provided ina glass vial as
open-label supply.
Each vial will belabeled as required
per country
requirement

N/A
Intramuscular
injection
PlaceboIMP
Provided centrally
by the sponsor
Study intervention
will be provided ina glass vial as
open-label supply.
Each vial will belabeled as required
per country
requirement

Packaging andLabeling

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BNT162a1(BNT 162 RNALNP vaccine
utilizing uRNA)

6.1.1. Administration
Participants will receive 1 dose (0.5 mL) of study intervention as randomized at eachvaccination visit (Visits 1 and 4 for Stage 1 sentinel cohort participants, Visits 1 and 2 for allother participants) in accordance with the study’s SoA.
Study intervention should be administered intramuscularly into the deltoid muscle, preferablyof the nondominant arm, by an unblinded administrator.
Standard vaccination practices must be observed and vaccine must not be injected into bloodvessels. Appropriate medication and other supportive measures for management of an acute
hypersensitivity reaction should be available in accordance with local guidelines for standard
immunization practices.
Administration of study interventions should be performed by an appropriately qualified,
GCP-trained, and vaccine-experienced member of the study staff (eg, physician, nurse,
physician’s assistant, nurse practitioner, pharmacist, or medical assistant) as allowed by
local, state, and institutional guidance.
Study intervention administration details will be recorded on the CRF.

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6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study interventions received and any discrepancies arereported and resolved before use of the study intervention.

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2. Only participants enrolled in the study may receive study intervention and only
authorized site staff may supply or administer study intervention. All study interventions
must be stored in a secure, environmentally controlled, and monitored (manual or
automated recording) area in accordance with the labeled storage conditions with accesslimited to the investigator and authorized site staff. At a minimum, daily minimum andmaximum temperatures for all site storage locations must be documented and available
upon request. Data for nonworking days must indicate the minimum and maximum
temperatures since previously documented for all site storage locations upon return tobusiness.
3. Any excursions from the study intervention label storage conditions should be reported to
Pfizer upon discovery along with any actions taken. The site should actively pursue
options for returning the study intervention to the storage conditions described in thelabeling, as soon as possible. Once an excursion is identified, the study intervention must
be quarantined and not used until Pfizer provides permission to use the study
intervention. Specific details regarding the definition of an excursion and information thesite should report for each excursion will be provided to the site in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage conditions
stated on the label.
5. Study interventions should be stored in their original containers.
6. See the IP manual for storage conditions of the study intervention.
7. The investigator, institution, or the head of the medical institution (where applicable) is
responsible for study intervention accountability, reconciliation, and record maintenance(ie, receipt, reconciliation, and final disposition records), such as the IPAL or sponsorapproved equivalent. All study interventions will be accounted for using a study
intervention accountability form/record.
8. Further guidance and information for the final disposition of unused study interventions
are provided in the IP manual. All destruction must be adequately documented. If
destruction is authorized to take place at the investigator site, the investigator must ensurethat the materials are destroyed in compliance with applicable environmental regulations,institutional policy, and any special instructions provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of
discovery as described in the IP manual.

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6.2.1. Preparation and Dispensing
See the IP manual for instructions on how to prepare the study intervention foradministration. Study intervention should be prepared and dispensed by an appropriately
qualified and experienced member of the study staff (eg, physician, nurse, physician’s
assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as allowed by
local, state, and institutional guidance. A second staff member will verify the dispensing.
Study intervention and placebo will be prepared by qualified unblinded site personnel
according to the IP manual. The study intervention will be administered in such a way toensure the participants remain blinded.
6.3. Measures to Minimize Bias: Randomization and Blinding

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6.3.1. Allocation to Study Intervention
Allocation (randomization) of participants to vaccine groups will proceed through the use of
an IRT system (IWR). The site personnel (study coordinator or specified designee) will be
required to enter or select information including but not limited to the user’s ID andpassword, the protocol number, and the participant number. The site personnel will then be
provided with a vaccine assignment and randomization number. The IRT system will
provide a confirmation report containing the participant number, randomization number, andstudy intervention allocation assigned. The confirmation report must be stored in the site’s
files.
The study-specific IRT reference manual and IP manual will provide the contact informationand further details on the use of the IRT system.
6.3.2. Blinding of Site Personnel
In this observer blinded study, the study staff receiving, storing, dispensing, preparing, andadministering the study interventions will be unblinded. All other study and site personnel,
including the investigator, investigator staff, and participants, will be blinded to study
intervention assignments. In particular, the individuals who evaluate participant safety willbe blinded. Because the BNT162 RNA-based COVID-19 vaccine candidates and placebo
are different in physical appearance, the study intervention syringes will be administered in amanner that prevents the study participants from identifying the study intervention type basedon its appearance.
The responsibility of the unblinded dispenser and administrator must be assigned to anindividual or individuals who will not participate in the evaluation of any study participants.
Contact between the unblinded dispenser and study participants and unblinded administrator
and study participants should be kept to a minimum. The remaining site personnel must notknow study intervention assignments.

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6.3.3. Blinding of the Sponsor
To facilitate rapid review of data in real time, sponsor staff will be unblinded to study
intervention allocation for the participants in Stage 1 and in Stage 2. Sponsor staff will beblinded to study intervention allocation in Stage 3. All laboratory testing personnel
performing serology assays will remain blinded to study intervention assigned/received
throughout the study.
Those study team members who are involved in ensuring that protocol requirements forstudy intervention preparation, handling, allocation, and administration are fulfilled at the site
will be unblinded for the duration of the study (eg, unblinded study manager, unblindedclinical research associate). Unblinded clinician(s) who are not direct members of the study
team will review unblinded protocol deviations.

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6.3.4. Breaking the Blind
The IRT will be programmed with blind-breaking instructions. In case of an emergency, theinvestigator has the sole responsibility for determining if unblinding of a participant’s study
intervention assignment is warranted. Participant safety must always be the firstconsideration in making such a determination. If the investigator decides that unblinding iswarranted, the investigator should make every effort to contact the sponsor prior to
unblinding a participant’s vaccine assignment unless this could delay further management of
the participant. If a participant’s vaccine assignment is unblinded, the sponsor must be
notified within 24 hours after breaking the blind. The date and reason that the blind was
broken must be recorded in the source documentation and CRF.
The study-specific IRT reference manual and IP manual will provide the contact informationand further details on the use of the IRT system.
6.4. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from theinvestigator or designee, under medical supervision. The date and time of each dose
administered in the clinic will be recorded in the source documents and recorded in the CRF.
The dose of study intervention and study participant identification will be confirmed at thetime of dosing by a member of the study site staff other than the person administering thestudy intervention.
6.5. Concomitant Therapy
The following concomitant medications and vaccinations will be recorded in the CRF:
All vaccinations received from 28 days prior to study enrollment until the 6-monthfollow-up visit (Visit 8 for Stage 1 sentinel cohorts, Visit 5 for Stage 1 nonsentinelcohorts and Stage 2 participants, and Visit 4 for Stage 3 participants).

Prohibited medications listed in Section 6.5.1 will be recorded, to include start and stop
dates, name of the medication, dose, unit, route, and frequency.
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In addition, for participants enrolled in the Stage 1 sentinel cohorts, all current
medication at baseline will be recorded, to include start date, name of the medication,dose, unit, route, and frequency.

6.5.1. Prohibited During the Study
Receipt of the following vaccines and medications during the time periods listed below may
exclude a participant from the per-protocol analysis, and may require vaccinations to bediscontinued in that participant; however, it is anticipated that the participant would not be
withdrawn from the study (see Section 7). Medications should not be withheld if required fora participant’s medical care.
Unless considered medically necessary, no vaccines other than study intervention should be
administered within 28 days before and 28 days after each study vaccination. One exception
to this is that seasonal and pandemic influenza vaccine can be given at least 14 days after, orat least 14 days prior to, the administration of study intervention.

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Receipt of chronic systemic treatment with known immunosuppressant medications, orradiotherapy, within 60 days before enrollment through conclusion of the study.
Receipt of systemic corticosteroids (≥20 mg/day of prednisone or equivalent) for ≥14 days is
prohibited from 28 days prior to enrollment to Visit 7 for Stage 1 sentinel cohorts, Visit 4 forStage 1 nonsentinel cohorts and Stage 2 participants, and Visit 3 for Stage 3 participants).
Receipt of blood/plasma products or immunoglobulins within 6 months before enrollment
through conclusion of the study.
Receipt of any other (nonstudy) coronavirus vaccine at any time prior to or during study
participation is prohibited.
Prophylactic antipyretics and other pain medication to prevent symptoms associated withstudy intervention administration are not permitted. However, if a participant is taking a
medication for another condition, even if it may have antipyretic or pain-relieving properties,
it should not be withheld prior to study vaccination.
6.5.2. Permitted During the Study
The use of antipyretics and other pain medication to treat symptoms associated with study
intervention administration or ongoing conditions is permitted.
Medication other than that described as prohibited in Section 6.5.1 required for treatment ofpreexisting stable conditions is permitted.
Inhaled, topical, or localized injections of corticosteroids (eg, intra-articular or intrabursal
administration) are permitted.

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6.6. Dose Modification
Individual participant dose modifications will not be made in this study.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANTDISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention

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In rare instances, it may be necessary for a participant to permanently discontinue study
intervention (definitive discontinuation). Reasons for definitive discontinuation of study
intervention may include the following: AEs; participant request; investigator request;
pregnancy; protocol deviation (including no longer meeting all the inclusion criteria, or
meeting 1 or more exclusion criteria).
Note that discontinuation of study intervention does not represent withdrawal from the study.
Per the study estimands, if study intervention is definitively discontinued, the participant willremain in the study to be evaluated for safety, immunogenicity, and potential efficacy. See
the SoA for data to be collected at the time of discontinuation of study intervention andfollow-up for any further evaluations that need to be completed.
In the event of discontinuation of study intervention, it must be documented on theappropriate CRF/in the medical records whether the participant is discontinuing further
receipt of study intervention or also from study procedures, posttreatment study follow-up,
and/or future collection of additional information.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request. Reasons fordiscontinuation from the study may include the following:

Refused further follow-up;

Lost to follow-up;



Death;



Study terminated by sponsor;



AEs;



Participant request;

Investigator request;Protocol deviation.

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If a participant does not return for a scheduled visit, every effort should be made to contact
the participant. All attempts to contact the participant and information received duringcontact attempts must be documented in the participant’s source document. In any
circumstance, every effort should be made to document participant outcome, if possible.
The investigator or his or her designee should capture the reason for withdrawal in the CRF
for all participants.
If a participant withdraws from the study, he/she may request destruction of any remaining
samples taken and not tested, and the investigator must document any such requests in thesite study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1)
for disclosure of future information, no further evaluations should be performed and no
additional data should be collected. The sponsor may retain and continue to use any datacollected before such withdrawal of consent.

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Lack of completion of all or any of the withdrawal/early termination procedures will not beviewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent
Participants who request to discontinue receipt of study intervention will remain in the study
and must continue to be followed for protocol-specified follow-up procedures. The only
exception to this is when a participant specifically withdraws consent for any further contact
with him or her or persons previously authorized by the participant to provide thisinformation. Participants should notify the investigator in writing of the decision towithdraw consent from future follow-up, whenever possible. The withdrawal of consent
should be explained in detail in the medical records by the investigator, as to whether thewithdrawal is only from further receipt of study intervention or also from study procedures
and/or posttreatment study follow-up, and entered on the appropriate CRF page. In the eventthat vital status (whether the participant is alive or dead) is being measured, publicly
available information should be used to determine vital status only as appropriately directedin accordance with local law.
7.3. Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return forscheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to attend a required study visit:The site must attempt to contact the participant and reschedule the missed visit as soon as
possible and counsel the participant on the importance of maintaining the assigned visit
schedule and ascertain whether or not the participant wishes to and/or should continue inthe study;

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Before a participant is deemed lost to follow-up, the investigator or designee must makeevery effort to regain contact with the participant (where possible, 3 telephone calls and,if necessary, a certified letter to the participant’s last known mailing address or local
equivalent methods). These contact attempts should be documented in the participant’s
medical record;Should the participant continue to be unreachable, he/she will be considered to havewithdrawn from the study.

8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed anddated ICD before performing any study-specific procedures.
The full date of birth will be collected to critically evaluate the immune response and safety
profile by age.

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Study procedures and their timing are summarized in the SoA. Protocol waivers or
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence orawareness to determine whether the participant should continue or discontinue study
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential
participants meet all eligibility criteria. The investigator will maintain a screening log torecord details of all participants screened and to confirm eligibility or record reasons forscreening failure, as applicable.
Every effort should be made to ensure that protocol-required tests and procedures arecompleted as described. However, it is anticipated that from time to time there may becircumstances outside the control of the investigator that may make it unfeasible to performthe test. In these cases, the investigator must take all steps necessary to ensure the safety andwell-being of the participant. When a protocol-required test cannot be performed, theinvestigator will document the reason for the missed test and any corrective and preventive
actions that he or she has taken to ensure that required processes are adhered to as soon as
possible. The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, andshipment instructions and contact information will be provided to the investigator site prior
to initiation of the study.

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The total blood sampling volume for individual participants in this study is approximately
530 mL for participants in the Stage 1 sentinel cohorts; 350 mL for participants in the Stage 1
nonsentinel cohorts and Stage 2 participants; and 200 mL for Stage 3 participants.
Additionally, 50 mL of blood will be taken at an unplanned convalescent visit at any time aparticipant develops respiratory symptoms indicating a potential COVID-19 infection. Other
additional blood samples may be taken for safety assessments at times specified by Pfizer,
provided the total volume taken during the study does not exceed 550 mL during any periodof 60 consecutive days.

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8.1. Efficacy and/or Immunogenicity Assessments
Efficacy will be assessed throughout a participant’s involvement in the study throughsurveillance for potential cases of COVID-19. If, at any time, a participant develops acuterespiratory illness (see Section 8.13), for the purposes of the study he or she will beconsidered to potentially have COVID-19 illness.9 In this circumstance, the participant
should contact the site, a telehealth visit should occur, and assessments should be conducted
as specified in the SoA. The assessments will include a nasal (midturbinate) swab, which will
be tested at a central laboratory using a reverse transcription–polymerase chain reaction (RTPCR) test (Cepheid; FDA approved under EUA), or other equivalent nucleic acidamplification–based test (ie, NAAT), to detect SARS-CoV-2. In addition, clinicalinformation and results from local standard-of-care tests (as detailed in Section 8.13) will beassessed. Four definitions of potential SARS-CoV-2–related cases will be considered:Centrally confirmed COVID-19: presence of at least 1 symptom described in
Section 8.13 and SARS-CoV-2 NAAT positive at central laboratory

Locally confirmed COVID-19: presence of at least 1 symptom described in Section 8.13
and investigator-confirmed SARS-CoV-2 NAAT positive at a local testing facilityCentrally confirmed symptomatic seroconversion to SARS-CoV-2 (exploratory):presence of at least 1 symptom described in Section 8.13 and a positive nonvaccine
antigen SARS-CoV-2 antibody result in a participant whose most recent prior nonvaccine
antigen SARS-CoV-2 antibody result was negativeCentrally confirmed asymptomatic seroconversion to SARS-CoV-2 (exploratory):
positive nonvaccine antigen SARS-CoV-2 antibody result in a participant with a priornonvaccine antigen SARS-CoV-2 antibody result was negative

Serum samples will be obtained for immunogenicity testing at the visits specified in the SoA.
The following assays will be performed:

SARS-CoV-2–specific WT serum neutralization assay

SARS-CoV-2-spike (S) protein–specific IgG direct Luminex immunoassay

SARS-CoV-2 RBD–specific IgG direct Luminex immunoassay
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Nonvaccine antigen (NVA) Ig direct Luminex immunoassay. The NVA will include a
SARS-CoV-2 target antigen that is not derived from the S glycoprotein, most likely anantigen derived from the SARS-CoV-2 nucleoprotein.

8.1.1. Biological Samples
Blood and nasal swab samples will be used only for scientific research. Each sample will belabeled with a code so that the laboratory personnel testing the samples will not know theparticipant’s identity. Samples that remain after performing assays outlined in the protocol
may be stored by Pfizer. Unless a time limitation is required by local regulations or ethicalrequirements, the samples will be stored for up to 15 years after the end of the study and thendestroyed. If allowed by the ICD, stored samples may be used for additional testing to better
understand the immune responses to the vaccine(s) under study in this protocol, to inform thedevelopment of other products, and/or for vaccine-related assay work supporting vaccine
programs. No testing of the participant’s DNA will be performed.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)The participant may request that his or her samples, if still identifiable, be destroyed at any
time; however, any data already collected from those samples will still be used for thisresearch. The biological samples may be shared with other researchers as long asconfidentiality is maintained and no testing of the participant’s DNA is performed.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinicallaboratory measurements may be obtained at any time during the study to assess any
perceived safety issues.
A clinical assessment, including medical history, will be performed on all participants at
his/her first visit to establish a baseline. Significant medical history and observations fromany physical examination, if performed, will be documented in the CRF.
AEs and SAEs are collected, recorded, and reported as defined in Section 8.3.
Acute reactions within the first 4 hours after administration of the study intervention (for the
first 5 participants vaccinated in each Stage 1 sentinel group), and within the first 30 minutes(for the remainder of participants), will be assessed and documented in the AE CRF.
The safety parameters also include e-diary reports of local reactions and systemic events(including fever), and use of antipyretic medication that occur in the 7 days afteradministration of the study intervention. These prospectively self-collected occurrences of
local reactions and systemic events are graded as described in Section 8.2.2.
8.2.1. Clinical Safety Laboratory Assessments (Sentinel-Cohort Participants Only)
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for
the timing and frequency. All protocol-required laboratory assessments, as defined inAppendix 2, must be conducted in accordance with the laboratory manual and the SoA.
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Unscheduled clinical laboratory measurements may be obtained at any time during the study
to assess any perceived safety issues.
The investigator must review the laboratory report, document this review, and record any
clinically relevant changes occurring during the study in the AE section of the CRF. See
Appendix 2 for the grading scale for assessment of clinically significant abnormal laboratory
findings. Clinically significant abnormal laboratory findings are those which are notassociated with the underlying disease, unless judged by the investigator to be more severe
than expected for the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during
participation in the study or within 28 days after the last dose of study intervention should be
repeated until the values return to normal or baseline or are no longer considered clinicallysignificant by the investigator or medical monitor.

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If such values do not return to normal/baseline within a period of time judged reasonable by
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 5 for suggested actions and follow-up assessments in the event of potential
drug-induced liver injury.
8.2.2. Electronic Diary
Participants will be required to complete an e-diary through an application installed on aprovisioned device or on the participant’s own personal device. The participant will be asked
to monitor and record local reactions, systemic events, and antipyretic medication usage for7 days following administration of the study intervention. The e-diary allows recording ofthese assessments only within a fixed time window, thus providing the accurate
representation of the participant’s experience at that time. Data on local reactions andsystemic events reported in the e-diary will be transferred electronically to a third-party
vendor, where they will be available for review by investigators and the Pfizer clinicians at
all times via an internet-based portal.
At intervals agreed to by the vendor and Pfizer, these data will be transferred electronicallyinto Pfizer's database for analysis and reporting. These data do not need to be reported by theinvestigator in the CRF as AEs.
Investigators (or designee) will be required to review the e-diary data online at frequentintervals as part of the ongoing safety review.
The investigator or designee must obtain stop dates from the participant for any ongoing
local reactions, systemic events, or use of antipyretic medication on the last day that thee-diary was completed. The stop dates should be documented in the source documents andthe information entered in the CRF.

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8.2.2.1. Grading Scales
The grading scales used in this study to assess local reactions and systemic events as
described below are derived from the FDA Center for Biologics Evaluation and Research(CBER) guidelines on toxicity grading scales for healthy adult volunteers enrolled inpreventive vaccine clinical trials.8
8.2.2.2. Local Reactions

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During the e-diary reporting period, participants will be asked to assess redness, swelling,
and pain at the injection site and to record the symptoms in the e-diary. If a local reaction
persists beyond the end of the e-diary period following vaccination, the participant will be
requested to report that information. The investigator will enter this additional information in
the CRF.
Redness and swelling will be measured and recorded in measuring device units(range: 1 to 21) and then categorized during analysis as absent, mild, moderate, or severe
based on the grading scale in Table 2. Measuring device units can be converted tocentimeters according to the following formula: 1 measuring device unit = 0.5 cm. Pain at
the injection site will be assessed by the participant as absent, mild, moderate, or severe
according the grading scale in Table 2.
If a Grade 3 local reaction is reported in the e-diary, a telephone contact should occur toascertain further details and determine whether a site visit is clinically indicated. Only an
investigator or medically qualified person is able to classify a participant’s local reaction as
Grade 4. If a participant experiences a confirmed Grade 4 local reaction, the investigatormust immediately notify the sponsor and, if it is determined to be related to theadministration of the study intervention, further vaccinations will be discontinued in thatparticipant.
Table 2.

Local Reaction Grading Scale
Mild(Grade 1)

Pain at the
injection site

Does not interferewith activity

Redness

2.5 cm to 5.0 cm(5 to 10 measuring
device units)
2.5 cm to 5.0 cm(5 to 10 measuring
device units)

Swelling

Moderate(Grade 2)

Severe(Grade 3)

Potentially Life
Threatening(Grade 4)
Interferes with activity Prevents daily activity Emergency room visit
or hospitalization forsevere pain
>5.0 cm to 10.0 cm>10 cmNecrosis or exfoliative(11 to 20 measuring(≥21 measuring
dermatitis
device units)device units)>5.0 cm to 10.0 cm>10 cmNecrosis(11 to 20 measuring(≥21 measuring
device units)device units)

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8.2.2.3. Systemic Events
During the e-diary reporting period, participants will be asked to assess vomiting, diarrhea,
headache, fatigue, chills, new or worsened muscle pain, and new or worsened joint pain andto record the symptoms in the e-diary. The symptoms will be assessed by the participant as
absent, mild, moderate, or severe according to the grading scale in Table 3.
If a Grade 3 systemic event is reported in the e-diary, a telephone contact should occur toascertain further details and determine whether a site visit is clinically indicated. Only an
investigator or medically qualified person is able to classify a participant’s systemic event as
Grade 4. If a participant experiences a confirmed Grade 4 systemic event, the investigatormust immediately notify the sponsor and, if it is determined to be related to theadministration of the study intervention, further vaccinations will be discontinued in thatparticipant.
Table 3.

Systemic Event Grading Scale

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Mild(Grade 1)

Moderate(Grade 2)

Severe(Grade 3)

Vomiting

1-2 times in
24 hours>2 times in 24 hours Requires IV
hydration

Diarrhea

2 to 3 loose stools
in 24 hours

4 to 5 loose stools in 6 or more loose
24 hours
stools in 24 hours

Headache

Does not interferewith activity

Some interferencewith activity

Prevents daily
routine activity

Fatigue/tiredness

Does not interferewith activity

Some interferencewith activity

Prevents daily
routine activity

Chills

Does not interferewith activity

Some interferencewith activity

Prevents daily
routine activity

New or
Does not interfere
worsenedwith activity
muscle pain
New or
Does not interfere
worsened joint with activity
pain
Abbreviation: IV = intravenous.

Some interferencewith activity

Prevents daily
routine activity

Some interferencewith activity

Prevents daily
routine activity

Potentially Life
Threatening(Grade 4)
Emergency room visit or
hospitalization for
hypotensive shock
Emergency room visit or
hospitalization for severe
diarrhea
Emergency room visit or
hospitalization for severe
headache
Emergency room visit or
hospitalization for severe
fatigue
Emergency room visit or
hospitalization for severe
chillsEmergency room visit or
hospitalization for severe newor worsened muscle pain
Emergency room visit or
hospitalization for severe newor worsened joint pain

8.2.2.4. Fever
In order to record information on fever, a thermometer will be given to participants with
instructions on how to measure oral temperature at home. Temperature will be collected in
the e-diary in the evening daily during the e-diary reporting period. It will also be collected
at any time during the e-diary data collection periods when fever is suspected. Fever is
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defined as an oral temperature of ≥38.0°C (100.4°F). The highest temperature for each day
will be recorded in the e-diary. Temperature will be measured and recorded to 1 decimal
place and then categorized during analysis according to the scale shown in Table 4.
If a fever of ≥39.0°C (102.1°F) is reported in the e-diary, a telephone contact should occur toascertain further details and determine whether a site visit is clinically indicated. Only an
investigator or medically qualified person is able to confirm a participant’s fever as >40.0°C(>104.0°F). If a participant experiences a confirmed fever >40.0°C (>104.0°F), theinvestigator must immediately notify the sponsor and, if it is determined to be related to theadministration of the study intervention, further vaccinations will be discontinued in thatparticipant.
Table 4.

Scale for Fever

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38.0-38.4°C (100.4-101.1°F)
38.5-38.9°C (101.2-102.0°F)
39.0-40.0°C (102.1-104.0°F)>40.0°C (>104.0°F)

8.2.2.5. Antipyretic Medication
The use of antipyretic medication to treat symptoms associated with study intervention
administration will be recorded in the e-diary daily during the reporting period (Day 1 to
Day 7).
8.2.3. Stopping Rules
The following stopping rules are in place for all Stage 1 sentinel-cohort participants, basedon review of AE data and e-diary reactogenicity data. These data will be monitored on an
ongoing basis by the investigator (or medically qualified designee) and sponsor in order topromptly identify and flag any event that potentially contributes to a stopping rule.
The sponsor study team will be unblinded during the Stage 1, so will be able to assess
whether or not a stopping rule has been met on the basis of a participant’s individual study
intervention allocation.
In the event that sponsor personnel confirm that a stopping rule is met, the following actions
will commence:The IRC will review all appropriate data.

The stopping rule will PAUSE randomization and study intervention administration for
the impacted vaccine candidate all dose levels and age groups.



The DMC will review all appropriate data.
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ongoing data entry, reporting of AEs, participant e-diary completion, blood sample
collection, and participant follow-up, will continue during the pause.

A stopping rule is met if any of the following rules occur after administration of
investigational BNT162 vaccine; data from placebo recipients will not contribute to thestopping rules. E-diary data confirmed by the investigator as being entered by the participant
in error will not contribute toward a stopping rule.
BNT162 vaccine candidates will be evaluated for contribution to stopping rules individually;
vaccine candidate dose levels and age groups will contribute to stopping rules together.
However, it is possible that the recommendations may include halting or continuing
randomization with any of the BNT162 vaccine candidates.
Stopping Rule Criteria for Each BNT162 Vaccine Candidate:

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1. If any participant vaccinated with the BNT162 candidate (at any dose level) develops an
SAE that is assessed by the investigator as possibly related, or for which there is noalternative, plausible, attributable cause.
2. If any participant vaccinated with the BNT162 candidate (at any dose level) develops a
Grade 4 local reaction or systemic event within 7 days after vaccination that is assessedas possibly related by the investigator, or for which there is no alternative, plausible,
attributable cause.
3. If any participant vaccinated with the BNT162 candidate (at any dose level) develops afever >40.0°C (>104.0°F) for at least 1 daily measurement within 7 days after
vaccination that is assessed as possibly related by the investigator, or for which there is
no alternative, plausible, attributable cause.
4. If any 2 participants vaccinated with the BNT162 candidate (at any dose level) report thesame or similar severe (Grade 3) AE (including laboratory abnormalities) within 21 days
after vaccination, assessed as possibly related by the investigator, or for which there is noalternative, plausible, attributable cause.
5. If any participant dies or requires ICU admission due to SARS-CoV-2 infection; if thisstopping rule is met, all available clinical and preclinical safety and immunogenicity data
should be reviewed to evaluate for enhanced COVID-19 disease.
8.2.3.1. Randomization and Vaccination After a Stopping Rule Is Met
Once the IRC and DMC have reviewed the safety data and provided guidance, a notification
will be sent from the sponsor to the sites with guidance on how to proceed.

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8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19 Disease
As this is a sponsor open-label study during Stages 1 and 2, the sponsor will conduct
unblinded reviews of the data during the course of the study, including for the purpose ofsafety assessment.
Participants in all stages of the study will be surveilled for potential COVID-19 illness from
Visit 1 onwards (see Section 8.13). All NAAT-confirmed cases will be reviewed
contemporaneously by the IRC and the DMC (see Section 9.6). In addition, instances ofsymptomatic and asymptomatic seroconversion to SARS-CoV-2 (see Section 8.1) will be
reviewed.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)The purpose of these reviews will be to identify whether any features of each case appear
unusual, in particular greater severity, compared to available information at the time ofreview. Indicators of severity may include accelerated deterioration, need for hospitalization,need for ventilation, or death. Observed rates of these indicators will be compared with what
could be expected in a similar population to the study participants based upon available
information at the time of review. Since the DMC is able to review unblinded information, it
will also be able to compare cases in active vaccine and placebo recipients in Stage 3 (whensponsor staff will be blinded).
8.2.5. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA,
immediately before the administration of each vaccine dose. A negative pregnancy test result
will be required prior to the participant’s receiving the study intervention. Pregnancy tests
may also be repeated if requested by IRBs/ECs or if required by local regulations. In thecase of a positive confirmed pregnancy, the participant will be withdrawn fromadministration of study intervention but may remain in the study.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or
the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, andrecording events that meet the definition of an AE or SAE and remain responsible to pursue
and obtain adequate information both to determine the outcome and to assess whether the
event meets the criteria for classification as an SAE or caused the participant to discontinue
the study intervention (see Section 7.1).
Each participant will be questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up
information in an expedited fashion.
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8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection
period”) for each participant begins from the time the participant provides informed consent,
which is obtained before the participant’s participation in the study (ie, before undergoing
any study-related procedure and/or receiving study intervention), through and including
Visit 7 for Stage 1 sentinel-cohort participants, Visit 4 for Stage 1 nonsentinel participants
and Stage 2 participants, and Visit 3 for Stage 3 participants. In addition, any AEs occurring
up to 48 hours after each subsequent blood draw must be recorded on the CRF.
SAEs will be collected from the time the participant provides informed consent toapproximately 6 months after the last dose of study intervention (Visit 8 for Stage 1 sentinelcohort participants, Visit 5 for Stage 1 nonsentinel cohort participants and Stage 2
participants, and Visit 4 for Stage 3 participants).

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Follow-up by the investigator continues throughout and after the active collection period anduntil the AE or SAE or its sequelae resolve or stabilize at a level acceptable to theinvestigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervention
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE
reported using the Vaccines SAE Report Form.
Investigators are not obligated to actively seek AEs or SAEs after the participant has
concluded study participation. However, if the investigator learns of any SAE, including adeath, at any time after a participant has completed the study, and he/she considers the event
to be reasonably related to the study intervention, the investigator must promptly report the
SAE to Pfizer using the Vaccines SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in
Section 8.3.1 are reported to Pfizer Safety on the Vaccines SAE Report Form immediately
upon awareness and under no circumstance should this exceed 24 hours, as indicated inAppendix 3. The investigator will submit any updated SAE data to the sponsor within
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period as
described in Section 8.3.1 are recorded on the CRF. AEs and SAEs that begin after obtaining
informed consent but before the start of study intervention will be recorded on the Medical
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History/Current Medical Conditions section of the CRF, not the AE section. AEs and SAEs
that begin after the start of study intervention are recorded on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and theprocedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended andnonleading verbal questioning of the participant is the preferred method to inquire about
AE occurrences.
8.3.3. Follow-up of AEs and SAEs

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After the initial AE/SAE report, the investigator is required to proactively follow eachparticipant at subsequent visits/contacts. For each event, the investigator must pursue andobtain adequate information until resolution, stabilization, the event is otherwise explained,or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail toallow for a complete medical assessment of the case and independent determination of
possible causality. Any information relevant to the event, such as concomitant medications
and illnesses, must be provided. In the case of a participant death, a summary of available
autopsy findings must be submitted as soon as possible to Pfizer Safety.
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal
obligations and ethical responsibilities towards the safety of participants and the safety of astudy intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and otherregulatory agencies about the safety of a study intervention under clinical investigation. The
sponsor will comply with country-specific regulatory requirements relating to safety
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the
study and will notify the IRB/EC, if appropriate according to local requirements.

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8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding andoccupational exposure are reportable to Pfizer Safety within 24 hours of investigatorawareness.
8.3.5.1. Exposure During Pregnancy

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)An EDP occurs if:A female participant is found to be pregnant while receiving or after discontinuing study
intervention.



A male participant who is receiving or has discontinued study intervention exposes afemale partner prior to or around the time of conception.



A female is found to be pregnant while being exposed or having been exposed to study
intervention due to environmental exposure. Below are examples of environmental
exposure during pregnancy:

A female family member or healthcare provider reports that she is pregnant after
having been exposed to the study intervention by inhalation or skin contact.

A male family member or healthcare provider who has been exposed to the study
intervention by inhalation or skin contact then exposes his female partner prior to or
around the time of conception.

The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s
awareness, irrespective of whether an SAE has occurred. The initial information submitted
should include the anticipated date of delivery (see below for information related totermination of pregnancy).


If EDP occurs in a participant or a participant’s partner, the investigator must report thisinformation to Pfizer Safety on the Vaccines SAE Report Form and an EDP
Supplemental Form, regardless of whether an SAE has occurred. Details of thepregnancy will be collected after the start of study intervention and until 6 months after
the last dose of study intervention.



If EDP occurs in the setting of environmental exposure, the investigator must report
information to Pfizer Safety using the Vaccines SAE Report Form and EDP
Supplemental Form. Since the exposure information does not pertain to the participant
enrolled in the study, the information is not recorded on a CRF; however, a copy of thecompleted Vaccines SAE Report Form is maintained in the investigator site file.

Follow-up is conducted to obtain general information on the pregnancy and its outcome for
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a
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follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural
integrity of the neonate can be assessed at the time of birth. In the event of a termination, thereason(s) for termination should be specified and, if clinically possible, the structural
integrity of the terminated fetus should be assessed by gross visual inspection (unlesspreprocedure test findings are conclusive for a congenital anomaly and the findings arereported).

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Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meetsthe criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal
demise, neonatal death, or congenital anomaly), the investigator should follow the procedures
for reporting SAEs. Additional information about pregnancy outcomes that are reported to
Pfizer Safety as SAEs follows:

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard tocausality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs
when the investigator assesses the infant death as related or possibly related to exposure
to the study intervention.

Additional information regarding the EDP may be requested by the sponsor. Further
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on
preterm infants to identify developmental delays). In the case of paternal exposure, theinvestigator will provide the participant with the Pregnant Partner Release of Information
Form to deliver to his partner. The investigator must document in the source documents thatthe participant was given the Pregnant Partner Release of Information Form to provide to his
partner.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if:A female participant is found to be breastfeeding while receiving or after discontinuing
study intervention.



A female is found to be breastfeeding while being exposed or having been exposed to
study intervention (ie, environmental exposure). An example of environmental exposure
during breastfeeding is a female family member or healthcare provider who reports that
she is breastfeeding after having been exposed to the study intervention by inhalation orskin contact.

The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hoursof the investigator’s awareness, irrespective of whether an SAE has occurred. The
information must be reported using the Vaccines SAE Report Form. When exposure during
breastfeeding occurs in the setting of environmental exposure, the exposure information does
not pertain to the participant enrolled in the study, so the information is not recorded on a
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CRF. However, a copy of the completed Vaccines SAE Report Form is maintained in theinvestigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specificallyapproved for use in breastfeeding women (eg, vitamins) is administered in accord withauthorized use. However, if the infant experiences an SAE associated with such a drug, theSAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure

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An occupational exposure occurs when a person receives unplanned direct contact with thestudy intervention, which may or may not lead to the occurrence of an AE. Such persons
may include healthcare providers, family members, and other roles that are involved in thetrial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of theinvestigator’s awareness, regardless of whether there is an associated SAE. The informationmust be reported using the Vaccines SAE Report Form. Since the information does not
pertain to a participant enrolled in the study, the information is not recorded on a CRF;
however, a copy of the completed Vaccines SAE Report Form is maintained in theinvestigator site file.
8.3.6. Medication Errors
Medication errors may result from the administration or consumption of the study
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as
medication errors.
Safety Event

Recorded on the CRF

Reported on the Vaccines SAE Report
Form to Pfizer Safety Within 24 Hours
of Awareness

Medication errors

All (regardless of whether
associated with an AE)

Only if associated with an SAE

Medication errors include:Medication errors involving participant exposure to the study intervention;Potential medication errors or uses outside of what is foreseen in the protocol that do or
do not involve the study participant;The administration of expired study intervention;

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The administration of an incorrect study intervention;

The administration of an incorrect dosage;The administration of study intervention that has undergone temperature excursion fromthe specified storage range, unless it is determined by the sponsor that the study
intervention under question is acceptable for use.

Such medication errors occurring to a study participant are to be captured on the medication
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by theinvestigator, the medication error is recorded on the medication error page of the CRF and, if
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of theCRF.

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Medication errors should be reported to Pfizer Safety within 24 hours on a Vaccines SAE
Report Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of study intervention greater than 1 dose of study intervention within
a 24-hour time period will be considered an overdose.
Pfizer does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the medical monitor immediately.
2. Closely monitor the participant for any AEs/SAEs.
3. Document the quantity of the excess dose as well as the duration of the overdose in the
CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.

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8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7. Genetics
Genetics (specified analyses) are not evaluated in this study.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.9. Immunogenicity Assessments
Immunogenicity assessments are described in Section 8.1.
8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are notevaluated in this study.

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8.11. Study Procedures
8.11.1. Stage 1 Sentinel Cohorts
8.11.1.1. Screening: (0 to 14 Days Before Visit 1)
Before enrollment and before any study-related procedures are performed, voluntary, written
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.
It is anticipated that the procedures below will be conducted in a stepwise manner; however,the visit can occur over more than 1 day.
Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance.

Obtain details of any medications currently taken.

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Perform physical examination including vital signs (weight, height, body temperature,pulse rate, and seated blood pressure), evaluating any clinically significant abnormalities
within the following body systems: general appearance; skin; head, eyes, ears, nose, andthroat; heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph
nodes.



Collect a blood sample (approximately 20 mL) for serological assessment of prior
COVID-19 infection.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.

Collect a blood sample (approximately 10 mL) for HIV, HBsAg, HBc Ab, and HCV Ab
tests.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Record AEs as described in Section 8.3. AEs that occur prior to dosing should be notedon the Medical History CRF.



Ask the participant to contact the site staff or investigator immediately if any significant
illness or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

Complete the CRF.

8.11.1.2. Visit 1 – Vaccination 1: (Day 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.
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Perform physical examination including vital signs (body temperature, pulse rate, andseated blood pressure), evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Review screening laboratory results (hematology and chemistry, and HIV, HBsAg,
HBc Ab, and HCV Ab tests).

Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested(if possible at the site, otherwise at the central laboratory) within 24 hours andvaccination will proceed only if it is NAAT-negative for SARS-CoV-2 genomes.
The second will be sent to the central laboratory for potential later testing.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Obtain the participant’s randomization number and study intervention allocation using
the IRT system. Either blinded site staff or unblinded site staff member may obtain thisinformation.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.



The first 5 participants vaccinated in each Stage 1 sentinel group must be observed byblinded site staff for any acute reactions for at least 4 hours after vaccination. For
participants enrolled thereafter, blinded site staff must observe the participant for at least
30 minutes after study intervention administration for any acute reactions. Record any
acute reactions (including time of onset) in the participant’s source documents and on the
AE page of the CRF, and on an SAE form as applicable.

Issue a measuring device to measure local reactions at the injection site and athermometer for recording daily temperatures and provide instructions on their use.

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Explain the e-diary technologies available for this study, and assist the participant indownloading the study application onto the participant’s own device or issue aprovisioned device if required. Provide instructions on e-diary completion and ask theparticipant to complete the e-diary from Day 1 to Day 7, with Day 1 being the day of
vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the e-diary data online
following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1 to 3 Days After Visit 1)

Record AEs as described in Section 8.3.

Perform physical examination including vital signs (body temperature, pulse rate, andseated blood pressure), evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.
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

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the e-diary data online
following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to 8 Days After Visit 1)

Record AEs as described in Section 8.3.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.
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Perform physical examination including vital signs (body temperature, pulse rate, andseated blood pressure), evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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The investigator or appropriately qualified designee reviews the e-diary data online
following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1)

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It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



Review the participant’s e-diary data. Collect stop dates of any e-diary events ongoingon the last day that the e-diary was completed and record stop dates in the CRF if
required.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Perform physical examination including vital signs (body temperature, pulse rate, andseated blood pressure), evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested (ifpossible at the site, otherwise at the central laboratory) within 24 hours and vaccination
will only proceed if it is NAAT-negative for SARS-CoV-2 genomes. The second will besent to the central laboratory for potential later testing.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met. If not, the participant should not receive further study intervention but willremain in the study to be evaluated for safety, immunogenicity, and potential efficacy(see Section 7.1).

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

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

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection
site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and ask the participant to complete the ediary from Day 1 to Day 7, with Day 1 being the day of vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.

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The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the e-diary data online
following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

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8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to 8 Days After Visit 4)

Record AEs as described in Section 8.3.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Perform physical examination including vital signs (body temperature, pulse rate, andseated blood pressure), evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory
tests as described in Section 10.2.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.

Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.
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

Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



The investigator or appropriately qualified designee reviews the e-diary data online
following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

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8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to 16 Days After Visit 4)

Record AEs as described in Section 8.3.



Review the participant’s e-diary data. Collect stop dates of any e-diary events ongoingon the last day that the e-diary was completed and record stop dates in the CRF if
required.



Review hematology and chemistry laboratory results and record any AEs in accordancewith Appendix 2.

Perform physical examination including vital signs (body temperature, pulse rate, andseated blood pressure), evaluating any clinically significant abnormalities within thefollowing body systems: general appearance; skin; head, eyes, ears, nose, and throat;heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

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Final Protocol, 15 April 2020

Schedule an appointment for the participant to return for the next study visit.

Collect the participant’s e-diary or assist the participant to remove the study applicationfrom his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)

8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After Visit 4)

Record AEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (154 to 168 Days After Visit 4)

Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.
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

Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)

8.11.1.10. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 4)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.1.11. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 4)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

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8.11.2. Stage 1 Nonsentinel Cohorts and Stage 2 Cohorts
8.11.2.1. Visit 1 – Vaccination 1: (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written,
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)

It is anticipated that the procedures below will be conducted in a stepwise manner.
Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance.



Perform physical examination including vital signs (weight, height, body temperature,pulse rate, and seated blood pressure), evaluating any clinically significant abnormalities
within the following body systems: general appearance; skin; head, eyes, ears, nose, andthroat; heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph
nodes.



Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.



Record AEs as described in Section 8.3.

Obtain the participant’s randomization number and study intervention allocation using
the IRT system. Either blinded site staff or unblinded site staff member may obtain thisinformation.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

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Protocol C4591001
Final Protocol, 15 April 2020

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Issue a measuring device to measure local reactions at the injection site and athermometer for recording daily temperatures and provide instructions on their use.



Explain the e-diary technologies available for this study, and assist the participant indownloading the study application onto the participant’s own device or issue aprovisioned device if required. Provide instructions on e-diary completion and ask theparticipant to complete the e-diary from Day 1 to Day 7, with Day 1 being the day of
vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.

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The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the e-diary data online
following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days or 56 to 70 Days After Visit 1)
The window for Visit 2 is dependent on the dosing schedule for the assigned group.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)

It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



Review the participant’s e-diary data. Collect stop dates of any e-diary events ongoingon the last day that the e-diary was completed and record stop dates in the CRF if
required.

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met. If not, the participant should not receive further study intervention but willremain in the study to be evaluated for safety, immunogenicity, and potential efficacy(see Section 7.1).

Measure the participant’s body temperature.

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.
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Final Protocol, 15 April 2020

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection
site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and ask the participant to complete the
e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.



The investigator or appropriately qualified designee reviews the e-diary data online
following vaccination to evaluate participant compliance and as part of the ongoingsafety review. Daily review is optimal during the active diary period.

CONFIDENTIAL
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8.11.2.3. Visit 3 – 2-Week Follow-up Visit: (12 to 16 Days After Visit 2)

Record AEs as described in Section 8.3.



Review the participant’s e-diary data. Collect stop dates of any e-diary events ongoingon the last day that the e-diary was completed and record stop dates in the CRF if
required.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Collect the participant’s e-diary or assist the participant to remove the study applicationfrom his or her own personal device.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.11.2.4. Visit 4 – 1-Month Follow-up Visit: (28 to 35 Days After Visit 2)

Record AEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.
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

Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)

8.11.2.5. Visit 5 – 6-Month Follow-up Visit: (154 to 168 Days After Visit 2)

Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.2.6. Visit 6 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 2)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

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Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)

8.11.2.7. Visit 7 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 2)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.3. Stage 3 Cohort(s)8.11.3.1. Visit 1 – Vaccination 1: (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written,
study-specific informed consent will be obtained from the participant. Each signature on the
ICD must be personally dated by the signatory. The investigator or his or her designee will
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The
source data must reflect that the informed consent was obtained before participation in the
study.
It is anticipated that the procedures below will be conducted in a stepwise manner.
Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).
The full date of birth will be collected to critically evaluate the immune response andsafety profile by age.

Obtain any medical history of clinical significance.



Perform physical examination including vital signs (weight, height, body temperature,pulse rate, and seated blood pressure), evaluating any clinically significant abnormalities
within the following body systems: general appearance; skin; head, eyes, ears, nose, andthroat; heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph
nodes.
CONFIDENTIAL
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Protocol C4591001
Final Protocol, 15 April 2020

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.



Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.



Record AEs as described in Section 8.3.

Obtain the participant’s randomization number and study intervention allocation number
using the IRT system. Either blinded site staff or unblinded site staff member may obtain
this information.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Issue a measuring device to measure local reactions at the injection site and athermometer for recording daily temperatures and provide instructions on their use.



Explain the e-diary technologies available for this study, and assist the participant indownloading the study application onto the participant’s own device or issue aprovisioned device if required. Provide instructions on e-diary completion and ask theparticipant to complete the e-diary from Day 1 to Day 7, with Day 1 being the day of
vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).
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Final Protocol, 15 April 2020

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.

The investigator or appropriately qualified designee reviews the e-diary data online following
vaccination to evaluate participant compliance and as part of the ongoing safety review.
Daily review is optimal during the active diary period.
8.11.3.2. Visit 2 – Vaccination 2: (19 to 23 Days or 56 to 70 Days After Visit 1)
The window for Visit 2 is dependent on the dosing schedule(s) selected for Stage 3.
It is anticipated that the procedures below will be conducted in a stepwise manner; ensurethat procedures listed prior to administration of the vaccine are conducted prior tovaccination.


Record AEs as described in Section 8.3.



Review the participant’s e-diary data. Collect stop dates of any e-diary events ongoingon the last day that the e-diary was completed and record stop dates in the CRF if
required.

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 10.4.



Record nonstudy vaccinations as described in Section 6.5.

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Final Protocol, 15 April 2020



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met. If not, the participant should not receive further study intervention but willremain in the study to be evaluated for safety, immunogenicity, and potential efficacy(see Section 7.1).

Measure the participant’s body temperature.

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual forfurther instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study
intervention administration for any acute reactions. Record any acute reactions(including time of onset) in the participant’s source documents and on the AE page of the
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection
site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with his or her chosen e-diary platform,
confirm instructions on e-diary completion, and ask the participant to complete the
e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 isthe day of vaccination) to determine if an unscheduled reactogenicity visit is required:Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm(>20 measuring device units).



Severe pain at the injection site.



Any severe systemic event.

Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.
CONFIDENTIAL
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

Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs and an unblindeddispenser/administrator updates the study intervention accountability records.

The investigator or appropriately qualified designee reviews the e-diary data online following
vaccination to evaluate participant compliance and as part of the ongoing safety review.
Daily review is optimal during the active diary period.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)

8.11.3.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2): (28 to 35 Days After
Visit 2)


Record AEs as described in Section 8.3.



Review the participant’s e-diary data. Collect stop dates of any e-diary events ongoingon the last day that the e-diary was completed and record stop dates in the CRF if
required.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Ask the participant to contact the site staff or investigator if a medically attended event(eg, doctor’s visit, emergency room visit) or hospitalization occurs.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Collect the participant’s e-diary or assist the participant to remove the study applicationfrom his or her own personal device.

Complete the source documents.
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The investigator or an authorized designee completes the CRFs.

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8.11.3.4. Visit 4 – 6-Month Safety Telephone Contact: (154 to 168 Days After Visit 2)Contact the participant by telephone in order to obtain the following information.



Record SAEs as described in Section 8.3.



Record nonstudy vaccinations as described in Section 6.5.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.3.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

8.11.3.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 2)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.



Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.11.3.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 2)Collect a blood sample (approximately 50 mL) for immunogenicity testing.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.
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Complete the source documents.



The investigator or an authorized designee completes the CRFs.



Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.

8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction
If a Grade 3 local reaction (Section 8.2.2.2), systemic event (Section 8.2.2.3), or fever(Section 8.2.2.4) is reported in the e-diary, a telephone contact should occur to ascertain
further details and determine whether a site visit is clinically indicated. If suspected Grade 4
local reaction (Section 8.2.2.2), systemic event (Section 8.2.2.3), or fever (Section 8.2.2.4) isreported in the e-diary, a telephone contact or site visit should occur to confirm whether the
event meets the criteria for Grade 4.

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A site visit must be scheduled as soon as possible to assess the participant unless any of thefollowing is true:The participant is unable to attend the unscheduled visit.

The local reaction/systemic event is no longer present at the time of the telephone
contact.



The participant recorded an incorrect value in the e-diary (confirmation of an e-diary data
entry error).



The PI or authorized designee determined it was not needed.

This telephone contact will be recorded in the participant’s source documentation and theCRF.
If the participant is unable to attend the unscheduled visit, or the PI or authorized designee
determined it was not needed, any ongoing local reactions/systemic events must be assessedat the next study visit.
During the unscheduled visit, the reactions should be assessed by the investigator or a
medically qualified member of the study staff such as a study physician or a study nurse, asapplicable to the investigator’s local practice, who will:Measure body temperature (°F/°C).

Measure minimum and maximum diameters of redness (if present).

Measure minimum and maximum diameters of swelling (if present).

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Assess injection site pain (if present) in accordance with the grades provided in
Section 8.2.2.2.

Assess systemic events (if present) in accordance with the grades provided in
Section 8.2.2.3.

Assess for other findings associated with the reaction and record on the AE page of the
CRF, if appropriate.

The investigator or an authorized designee will complete the unscheduled visit assessment
page of the CRF.
8.13. COVID-19 Disease Surveillance (All Participants)

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If a participant experiences any of the following, he or she is instructed to contact the site
immediately, and if confirmed, participate in a telehealth visit as soon as possible, optimallywithin 3 days of symptom onset. Note that this does not substitute for a participant’s routine
medical care. Therefore participants should be encouraged to seek care, if appropriate, fromtheir usual provider.


A diagnosis of COVID-19;



Fever;

New or increased cough;

New or increased shortness of breath;New or increased sore throat;

New or increased wheezing;New or increased sputum production;New or increased nasal congestion;New or increased nasal discharge;



Loss of taste/smell.

8.13.1. Potential COVID-19 Illness Telehealth Visit: (Optimally Within 3 Days After
Potential COVID-19 Illness Onset)
This telehealth visit is expected to involve the sharing of healthcare information and services
via telecommunication technologies (eg, audio, video, video-conferencing software)remotely, thus allowing the participant and investigator to communicate on aspects of clinicalcare.
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be required to obtain the following information:


Record AEs, as appropriate as described in Section 8.3.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Instruct the participant to self-collect a nasal (midturbinate) swab and ship for assessment
at the central laboratory. The result from this swab will be provided to the site once it isavailable, but this will not be in real time, and cannot be relied upon to direct clinicalcare. Therefore, the participant should be encouraged to seek care, if appropriate, fromhis or her usual provider.

Collect COVID-19–related standard-of-care clinical and laboratory information. This
includes, but is not limited to:Symptoms

Clinical diagnosis

Local laboratory COVID-19 test resultFull blood countC-reactive protein

Number and type of any healthcare contact; duration of hospitalization and intensive
care unit stay

Need for oxygen therapy



Need for ventilation



Schedule an appointment for the participant to return for the potential COVID-19
convalescent visit once he or she has recovered.

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After Potential
COVID-19 Illness Visit)

Record AEs, as appropriate as described in Section 8.3.



Record details of any of the prohibited medications specified in Section 6.5.1 received by
the participant if required for his or her clinical care.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Collect/update COVID-19–related clinical and laboratory information (detailed in
Section 8.13.1).

Complete the source documents.



The investigator or an authorized designee completes the CRFs.

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9. STATISTICAL CONSIDERATIONS
Methodology for summary and statistical analyses of the data collected in this study is
described here and further detailed in a statistical analysis plan (SAP), which will bemaintained by the sponsor. The SAP may modify what is outlined in the protocol whereappropriate; however, any major modifications of the primary endpoint definitions or theiranalyses will also be reflected in a protocol amendment.
9.1. Estimands and Statistical Hypotheses
9.1.1. Estimands
The estimand corresponding to each primary, secondary, and tertiary/exploratory objective is
described in the table in Section 3.
In the primary safety objective evaluations, missing e-diary data will not be imputed.
Missing AE dates will be imputed according to Pfizer safety rules. No other missing
information will be imputed in the safety analysis.
The estimands to evaluate the immunogenicity objectives are based on evaluable populations
for immunogenicity (Section 9.3). These estimands estimate the vaccine effect in the
hypothetical setting where participants follow the study schedules and protocol requirements
as directed. Missing antibody results will not be imputed. Immunogenicity results that are
below the LLOQ will be set to 0.5 × LLOQ in the analysis.
The estimands to evaluate the efficacy objectives are based on evaluable populations for
efficacy (Section 9.3). These estimands estimate the vaccine effect in the hypotheticalsetting where participants follow the study schedules and protocol requirements as directed.
Missing laboratory results will not be imputed for the primary analysis, but missing data
imputation for the efficacy endpoint may be performed as a sensitivity analysis.

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9.1.2. Statistical Hypotheses
At the end of Stage 3, the vaccine efficacy (VE) will be evaluated. VE is defined as
VE = 100 × (1 – IRR), where IRR is the infection rate ratio, the calculated ratio of the
COVID-19 infection rate in the active vaccine group to the incidence rate in the placebogroup. The efficacy hypothesis is:
H0: VE ≤20% vs Ha: VE >20%
where H0 and Ha represent null hypothesis and alternative hypothesis. For participants withmultiple infections, only the first infection will contribute to the VE calculation in the
hypothesis test.
The efficacy will be demonstrated if the null hypothesis VE ≤20% is rejected at the 0.025
significance level, that is, when the lower limit of the 2-sided 95% CI for VE is >20%, which
is derived using the Clopper-Pearson method as described by Agresti.9

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9.2. Sample Size Determination
The study sample size for the first 2 stages of the study is not based on any statistical
hypothesis testing. Stage 1 will comprise 15 participants (randomization ratio of 4:1 so that
12 receive active vaccine and 3 receive placebo) per group; up to 56 potential groups areforeseen; if all groups are fully enrolled, assuming 2 dose levels are selected following theinitial dose escalation, this corresponds to a total of 840 participants. Stage 2 will include 1 ormore vaccine groups selected from Stage 1, and 225 participants will be randomized per
selected vaccine candidate in a 4:1 ratio to receive active vaccine (180 participants) orplacebo (45 participants).
For Stage 3, for the selected vaccine candidate/dose level, with assumptions of a true vaccine
efficacy (VE) of 70%, 53 cases of COVID-19 will provide 90% power to conclude true
VE >20%. This would be achieved with 3000 participants per group (1:1 randomization
ratio), based on the assumption of a 1.7% incidence rate in the placebo group, and 20% of theparticipants being nonevaluable.
For safety outcomes, Table 5 shows the probability of observing at least 1 AE for a given
true event rate of a particular AE, for various sample sizes. For example, if the true AE rate
is 10%, with 12 participants in a vaccine group, there is 72% probability of observing at least
1 AE.

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Table 5.

Probability of Observing at Least 1 AE by Assumed True Event Rates With
Different Sample Sizes

Assumed True Event
Rate of an AE
0.10%
0.50%
1.00%
2.00%
3.00%
5.00%
7.00%
10.00%

N=12

N=45

N=180

N=3000

0.01
0.06
0.11
0.22
0.31
0.46
0.58
0.72

0.04
0.20
0.36
0.60
0.75
0.90
0.96
0.99

0.16
0.59
0.84
0.97
>0.99
>0.99
>0.99
>0.99

0.95
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99

9.3. Analysis Sets

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)For purposes of analysis, the following populations are defined:
Population
Enrolled
Randomized
Dose 1 evaluable
immunogenicity

Dose 2 evaluable
immunogenicity

Dose 1 all-available
immunogenicity
Dose 2 all-available
immunogenicity

Description
All participants who have a signed ICD.
All participants who are assigned a randomization number in
the IWR system.
All eligible randomized participants who are 18 to 85 years ofage (stratified by 18 to 55 and 56 to 85) (inclusive) on the dayof first vaccination, receive the vaccine to which they are
randomly assigned at the first dose, have at least 1 valid anddeterminate immunogenicity result 21 days after Dose 1, haveblood collection within an appropriate window after Dose 1,
and have no other major protocol deviations as determined by
the clinician.
All eligible randomized participants who are 18 to 85 years ofage (stratified by 18 to 55 and 56 to 85) (inclusive) on the dayof first vaccination, receive 2 randomized vaccinations within
the predefined window, have at least 1 valid and determinate
immunogenicity result after Dose 2, have blood collection
within an appropriate window after Dose 2, and have no othermajor protocol deviations as determined by the clinician.
All participants who receive at least 1 dose of the study
intervention with at least 1 valid and determinate
immunogenicity result 21 days after Dose 1.
All participants who receive at least 1 dose of the study
intervention with at least 1 valid and determinate
immunogenicity result 14 days after Dose 2.

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Population
Evaluable efficacy

All-available efficacy
SafetyDescription
All eligible randomized participants who are 18 to 85 years ofage (inclusive) on the day of first vaccination, receive
2 vaccinations as randomized within the predefined window,
have the efficacy measurement after Dose 2, and have no othermajor protocol deviations as determined by the clinician.
All eligible randomized participants who are 18 to 85 years ofage (inclusive) on the day of first vaccination, receive at least
1 vaccination, and have the efficacy measurement after Dose 2.
All randomized participants who receive at least 1 dose of thestudy intervention and have safety data assessed after any dose.

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9.4. Statistical Analyses
The SAP will be developed and finalized before database lock for any of the planned
analyses in Section 9.5.1. It will describe the participant populations to be included in theanalyses and the procedures for accounting for missing, unused, and spurious data. Thissection provides a summary of the planned statistical analyses of the primary, secondary, andtertiary/exploratory endpoints.
9.4.1. Immunogenicity Analyses
The statistical analysis of immunogenicity results will be primarily based on the evaluable
immunogenicity populations as defined in Section 9.3.
An additional analysis will be performed based on the all-available populations if there is alarge enough difference in sample size between the all-available immunogenicity populationand the evaluable immunogenicity population. Participants will be summarized according to
the vaccine group to which they were randomized.

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Endpoint
Secondaryimmunogenicity

Statistical Analysis Methods
Geometric mean titers/concentrations (GMTs/GMCs) of SARSCoV-2–specific WT serum neutralizing titers and SARS-CoV-2spike protein–specific binding antibody and RBD-specific binding
antibody

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)For SARS-CoV-2–specific WT serum neutralizing titers and SARSCoV-2-spike protein–specific binding antibody levels and RBD-specificbinding antibody levels, GMTs/GMCs and 2-sided 95% CIs will be
provided for each investigational product (active/placebo) within eachgroup before vaccination and at each of the following time points:
Stage 1 sentinel cohorts: 7 and 21 days after Dose 1; 7 and 14
days and 1, 6, 12 and 24 months after Dose 2

Stage 1 nonsentinel cohorts and Stage 2 cohorts: 21 days after
Dose 1; 14 days and 1, 6, 12, and 24 months after Dose 2

Stage 3 cohort(s): 1, 12, and 24 months after Dose 2

Geometric means and the associated 2-sided CIs will be derived by
calculating means and CIs on the natural log scale based on thet-distribution, and then exponentiating the results.
GMFRs of SARS-CoV-2–specific WT serum neutralizing titers and
SARS-CoV-2-spike protein–specific binding antibody and RBDspecific binding antibody
For SARS-CoV-2–specific WT serum neutralizing titers and SARSCoV-2-spike protein–specific antibody levels and RBD-specific binding
levels, the GMFRs and 2-sided 95% CIs will be provided for each
investigational product within each group at each of the following time
points:Stage 1 sentinel cohorts: 7 and 21 days after Dose 1; 7 and 14
days and 1, 6, 12, and 24 months after Dose 2

Stage 1 nonsentinel cohorts and Stage 2 cohorts: 21 days after
Dose 1; 14 days and 1, 6, 12, and 24 months after Dose 2

Stage 3 cohort(s): 1, 12, and 24 months after Dose 2

GMFRs will be limited to participants with nonmissing values prior to
the first dose and at the postvaccination time point. The GMFR will becalculated as the mean of the difference of logarithmically transformed
assay results (later time point – earlier time point) and transformed back
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Endpoint

Statistical Analysis Methods
to the original scale. Two-sided CIs will be obtained by calculating CIs
using Student’s t-distribution for the mean difference of thelogarithmically transformed assay results and transforming the limits
back to the original scale.
Percentage of participants with ≥4-fold rise in SARS-CoV-2–
specific WT serum neutralizing titers and SARS-CoV-2-spike
protein–specific binding antibody and RBD-specific binding
antibody

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)For SARS-CoV-2–specific WT serum neutralizing titers and SARSCoV-2-spike protein–specific antibody levels and RBD-specific binding
levels, percentages (and 2-sided 95% CIs) of participants with ≥4-foldrise will be provided for each investigational product within each groupat each of the following time points:
Stage 1 sentinel cohorts: 7 and 21 days after Dose 1; 7 and 14
days and 1, 6, 12, and 24 months after Dose 2

Stage 1 nonsentinel cohorts and Stage 2 cohorts: 21 days after
Dose 1; 14 days and 1, 6, 12, and 24 months after Dose 2

Stage 3 cohort(s): 1, 12, and 24 months after Dose 2

The Clopper-Pearson method will be used to calculate the CIs.
GMR of SARS-CoV-2–specific WT serum neutralizing titer foldrise to SARS-CoV-2-spike protein–specific antibody and
SARS-CoV-2 RBD–specific binding antibody
For SARS-CoV-2–specific WT serum neutralizing titers and
SARS-CoV-2-spike protein–specific binding antibody levels and RBDspecific binding antibody levels, the GMRs and 2-sided 95% CIs will be
provided for each investigational product within each group at each of
the following time points:
Stage 1 sentinel cohorts: 7 and 21 days after Dose 1; 7 and 14
days and 1, 6, 12, and 24 months after Dose 2

Stage 1 nonsentinel cohorts and Stage 2 cohorts: 21 days after
Dose 1; 14 days and 1, 6, 12, and 24 months after Dose 2

Stage 3 Cohort(s): 1, 12, and 24 months after Dose 2

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Endpoint

Statistical Analysis Methods
GMRs will be limited to participants with nonmissing values for both
SARS-CoV-2–specific WT serum neutralizing titers and SARS-CoV-2spike protein–specific antibody/SARS-CoV-2 RBD–specific binding
antibody at each time point. The GMR will be calculated as the mean ofthe difference of logarithmically transformed assay results (eg, SARSCoV-2–specific WT serum neutralizing titers minus SARS-CoV-2-spike
protein–specific antibody for each participant) and transformed back to
the original scale. Two-sided CIs will be obtained by calculating CIs
using Student’s t-distribution for the mean difference of thelogarithmically transformed assay results and transforming the limits
back to the original scale.
The same analysis methods will be applied to the immunogenicity
endpoints in Stages 2 and 3. For all the immunogenicity endpoints, theanalysis will be based on the Dose 1 and Dose 2 evaluable
immunogenicity populations. An additional analysis will be performed
based on the all-available immunogenicity populations if there is a large
enough difference in sample size between the all-available
immunogenicity populations and the evaluable immunogenicity
populations. Participants will be summarized according to the vaccine
group to which they were randomized. Missing serology data will not
be imputed.

Tertiary/
exploratory
immunogenicity

Correlation of an RT-PCR–confirmed COVID-19 infection andseropositivity/seroconversion measured by nonvaccine antigen
SARS-CoV-2 antibody
If sufficient data are collected, percentages (and 2-sided 95% CIs) ofparticipants with confirmed COVID-19 and nonvaccine antigen SARSCoV-2 antibody levels after Dose 1 and after Dose 2 will be provided.
RCDCs for immunogenicity results
Empirical RCDCs will be provided for SARS-CoV-2–specific WT
serum neutralizing titers, SARS-CoV-2-spike protein–specific antibody,and RBD-specific binding antibody after Dose 1 and after Dose 2.

9.4.2. Efficacy Analyses
The statistical analysis of efficacy will be based on the evaluable efficacy population(primary analysis) and the all-available efficacy population as defined in Section 9.3.

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Endpoint
Statistical Analysis Methods
Secondary efficacy Ratio of COVID-19 incidence per 1000 person-years of follow-up
for the active vaccine group to the placebo group
Vaccine efficacy will be estimated by 100 × (1 – IRR), where IRR is theinfection rate ratio, the calculated ratio of COVID-19 infection
incidence per 1000 person-years follow-up in the active vaccine groupto the corresponding incidence in the placebo group after 2 doses. The
2-sided 95% CI for VE will be derived using the Clopper-Pearson
method.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)The analysis will be based on the evaluable efficacy population and the
all-available efficacy population. For the primary analysis, missing
efficacy data will not be imputed. A sensitivity analysis may be
performed by imputing missing values; details will be provided in the
SAP.

9.4.3. Safety Analyses
Endpoint
PrimaryStatistical Analysis Methods
Descriptive statistics will be provided for each reactogenicity
endpoint for each dose and vaccine group. Local reactions andsystemic events from Day 1 through Day 7 after each vaccination
will be presented by severity cumulatively across severity levels.
Descriptive summary statistics will include counts and percentagesof participants with the indicated endpoint and the associatedClopper-Pearson 95% CIs.

For Stage 1 sentinel cohorts, descriptive statistics will be provided
for abnormal hematology and chemistry laboratory values at 1 and7 days after Dose 1 and 7 days after Dose 2, including grading shifts
in hematology and chemistry laboratory assessments between
baseline and 1 and 7 days after Dose 1, and before Dose 2 and7 days after Dose 2. Descriptive summary statistics will include
counts and percentages of participants with the indicated endpoint
and the associated Clopper-Pearson 2-sided 95% CIs.



AEs will be categorized according to the Medical Dictionary forRegulatory Activities (MedDRA) terms. A 3-tier approach will be
used to summarize AEs. Under this approach AEs are classified into
1 of 3 tiers: (1) Tier 1 events are prespecified events of clinicalimportance and are identified in a list in the product’s safety review
plan; (2) Tier 2 events are those that are not Tier 1 but areconsidered “relatively common”; a MedDRA preferred term is

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Endpoint

Statistical Analysis Methods
defined as a Tier 2 event if there are at least 1% of participants in atleast 1 vaccine group reporting the event; and (3) Tier 3 events arethose that are neither Tier 1 nor Tier 2 events. For both Tier 1 andTier 2 events, 2-sided 95% CIs for the difference between thevaccine and placebo groups in the percentage of participants
reporting the events based on the Miettinen and Nurminen method10
will be provided. In addition, for Tier 1 events, the asymptotic pvalues will also be presented for the difference between groups inthe percentage of participants reporting the events, based on thesame test statistic and under the assumption that the test statistic is
asymptotically normally distributed.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)Descriptive summary statistics (counts, percentages, andassociated Clopper-Pearson 95% CIs) will be provided for any
AE events for each vaccine group.



SAEs will be categorized according to MedDRA terms. Counts,
percentages, and the associated Clopper-Pearson 95% CIs of SAEs
from Dose 1 to 6 months after last dose will be provided for eachvaccine group.

The safety analyses are based on the safety population. Participants
will be summarized by vaccine group according to theinvestigational products they actually received. Missing e-diary data
will not be imputed; missing AE dates will be handled according to
the Pfizer safety rules.

Secondary

Not applicable (N/A)

Exploratory

N/A

9.4.4. Other Analyses
The ratios of (GMFR A to GMFR B) and (GMFR A to GMFR C) may be explored, where
GMFR A is the geometric mean of the ratio of the SARS-CoV-2–specific WT serum
neutralizing titer at the postvaccination time point to the corresponding titer at theprevaccination time point, GFMR B is the geometric mean of the ratio of the SARS-CoV-2
spike protein–specific binding antibody level at the postvaccination time point to thecorresponding antibody level at the prevaccination time point, and GMFR C is the geometricmean of the ratio of the SARS-CoV-2 RBD–specific binding antibody level at the
postvaccination time point to the corresponding antibody level at the prevaccination time
point.

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9.5. Interim Analyses
No formal interim analysis is planned in this study. As this is a sponsor open-label study
during Stages 1 and 2, the sponsor may conduct unblinded reviews of the data during thecourse of the study for the purpose of safety assessment, facilitating dose escalation
decisions, and/or supporting clinical development.
9.5.1. Analysis Timing
Statistical analyses will be carried out when the following data are available:Complete safety and immunogenicity analysis approximately 3 weeks after Dose 2 forStage 1.

Complete safety and immunogenicity analysis approximately 3 weeks after Dose 2 forStage 2.

Complete safety, immunogenicity, and efficacy analysis after complete data are available
for all participants for Stage 3.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will use an IRC and a DMC. The IRC is independent of the study team andincludes only internal members. The DMC is independent of the study team and includes
only external members. The IRC and DMC charters describe the role of the IRC and DMC
in more detail.
The responsibilities of the IRC will include:

Review of safety data to permit dose escalations



Review of safety data in the case of a stopping rule being met

Review of safety and immunogenicity data to:Allow groups of participants of 65 to 85 years of age to proceed

Select vaccine candidate(s)/dose level(s), and schedule(s) to proceed into Stage 2

Select vaccine candidate(s)/dose level(s), and schedule(s) to proceed into Stage 3

Review of any available safety and/or immunogenicity data generated during the courseof this study, or the BioNTech study conducted in Germany, to determine:Whether any groups may not be started



Whether any groups may be terminated early
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Whether any groups may be added with dose levels below the lowest stated dose orintermediate between the lowest and highest stated doses

Contemporaneous review of all NAAT-confirmed COVID-19 illnesses

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)The DMC will be responsible for ongoing monitoring of the safety of participants in the
study according to the charter. This may include, but is not limited to:Contemporaneous review of related AEs up to 1 month after completion of thevaccination scheduleContemporaneous review of all SAEs up to 6 months after completion of the vaccination
schedule

Contemporaneous review of all NAAT-confirmed COVID-19 illnesses

The recommendations made by the DMC to alter the conduct of the study will be forwarded
to the appropriate Pfizer personnel for final decision. Pfizer will forward such decisions,which may include summaries of aggregate analyses of safety data, to regulatory authorities,
as appropriate.

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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:Consensus ethical principles derived from international guidelines including the
Declaration of Helsinki and CIOMS International Ethical Guidelines;Applicable ICH GCP guidelines;Applicable laws and regulations, including applicable privacy laws.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents(eg, advertisements) must be reviewed and approved by the sponsor and submitted to an
IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study is
initiated.
Any amendments to the protocol will require IRB/EC approval before implementation ofchanges made to the study design, except for changes necessary to eliminate an immediate
hazard to study participants.
The investigator will be responsible for the following:Providing written summaries of the status of the study to the IRB/EC annually or more
frequently in accordance with the requirements, policies, and procedures established by
the IRB/EC;



Notifying the IRB/EC of SAEs or other significant safety findings as required by IRB/EC
procedures;Providing oversight of the conduct of the study at the site and adherence to requirementsof 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014 for clinicalstudies (if applicable), and all other applicable local regulations.

10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicableregulatory authority in any area of the world, or if the investigator is aware of any new
information that might influence the evaluation of the benefits and risks of the study
intervention, Pfizer should be informed immediately.
In addition, the investigator will inform Pfizer immediately of any urgent safety measurestaken by the investigator to protect the study participants against any immediate hazard, andof any serious breaches of this protocol or of ICH GCP that the investigator becomes awareof.
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10.1.2. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to theparticipant and answer all questions regarding the study. The participant should be given
sufficient time and opportunity to ask questions and to decide whether or not to participate in
the trial.
Participants must be informed that their participation is voluntary. Participants will be
required to sign a statement of informed consent that meets the requirements of 21 CFR 50,
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/EC
or study center.
The investigator must ensure that each study participant is fully informed about the natureand objectives of the study, the sharing of data related to the study, and possible risks
associated with participation, including the risks associated with the processing of theparticipant’s personal data.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)The participant must be informed that his/her personal study-related data will be used by thesponsor in accordance with local data protection law. The level of disclosure must also be
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical
Quality Assurance auditors or other authorized personnel appointed by the sponsor, byappropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or
her right to access and correct his or her personal data and to withdraw consent for theprocessing of his or her personal data.
The medical record must include a statement that written informed consent was obtained
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their
participation in the study.
A copy of the ICD(s) must be provided to the participant. Participants who are rescreened are
required to sign a new ICD.
Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate
section that addresses the use of samples for optional additional research. The optional
additional research does not require the collection of any further samples. The investigator
or authorized designee will explain to each participant the objectives of the additional
research. Participants will be told that they are free to refuse to participate and may
withdraw their consent at any time and for any reason during the storage period.

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10.1.3. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementationof organizational and technical measures to ensure protection of participant data.

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Participants’ personal data will be stored at the study site in encrypted electronic and/or paper
form and will be password protected or secured in a locked room to ensure that only
authorized study staff have access. The study site will implement appropriate technical andorganizational measures to ensure that the personal data can be recovered in the event ofdisaster. In the event of a potential personal data breach, the study site will be responsiblefor determining whether a personal data breach has in fact occurred and, if so, providing
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personaldata, participants will be assigned a single, participant-specific numerical code. Any
participant records or data sets that are transferred to the sponsor will contain the numericalcode; participant names will not be transferred. All other identifiable data transferred to thesponsor will be identified by this single, participant-specific code. The study site will
maintain a confidential list of participants who participated in the study, linking eachparticipant’s numerical code to his or her actual identity and medical record identification. In
case of data transfer, the sponsor will protect the confidentiality of participants’ personal dataconsistent with the clinical study agreement and applicable privacy laws.
10.1.4. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting theresults of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or
www.pfizer.com, and other public registries in accordance with applicable local
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, andcomplete manner and are reported regardless of the outcome of the study or the country inwhich the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional
studies (conducted in patients) that evaluate the safety and/or efficacy of a product,
regardless of the geographical location in which the study is conducted. These results are
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies inaccordance with the format and timelines set forth by EU requirements.

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www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used
to identify individual participants have been removed) on www.pfizer.com for
Pfizer-sponsored interventional studies at the same time the corresponding study results areposted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinicaldata to the EMA website. Clinical data, under Phase 1 of this policy, includes clinicaloverviews, clinical summaries, CSRs, and appendices containing the protocol and protocol
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of thispolicy, includes the publishing of individual participant data. Policy 0070 applies to newmarketing authorization applications submitted via the centralized procedure since
01 January 2015 and applications for line extensions and for new indications submitted via
the centralized procedure since 01 July 2015.

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Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposesof “bona-fide scientific research” that contributes to the scientific understanding of thedisease, target, or compound class. Pfizer will make available data from these trials
24 months after study completion. Patient-level data will be anonymized in accordance withapplicable privacy laws and regulations. CSRs will have personally identifiable information
redacted.
Data requests are considered from qualified researchers with the appropriate competencies toperform the proposed analyses. Research teams must include a biostatistician. Data will not
be provided to applicants with significant conflicts of interest, including individuals
requesting access for commercial/competitive or legal purposes.
10.1.5. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unlesstransmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is
responsible for verifying that data entries are accurate and correct by physically orelectronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports theinformation entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted
electronic and/or paper form and are password protected or secured in a locked room toprevent access by unauthorized third parties.

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The investigator must permit study-related monitoring, audits, IRB/EC review, andregulatory agency inspections and provide direct access to source data documents. This
verification may also occur after study completion. It is important that the investigator(s)and their relevant personnel are available during the monitoring visits and possible audits orinspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality
such as risk management and mitigation strategies and analytical risk-based monitoring),
methods, responsibilities, and requirements, including handling of noncompliance issues andmonitoring techniques (central, remote, or on-site monitoring), are provided in themonitoring plan.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)The sponsor or designee is responsible for the data management of this study, including
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data enteredinto the CRF by authorized site personnel are accurate, complete, and verifiable from source
documents; that the safety and rights of participants are being protected; and that the study is
being conducted in accordance with the currently approved protocol and any other study
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must
be retained by the investigator for 15 years after study completion unless local regulations or
institutional policies require a longer retention period. No records may be destroyed during
the retention period without the written approval of the sponsor. No records may betransferred to another location or party without written notification to the sponsor. The
investigator must ensure that the records continue to be stored securely for as long as they are
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of suchdata are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory
inspection notification in relation to the study. Furthermore, the investigator will cooperatewith the sponsor or its agents to prepare the investigator site for the inspection and will allow
the sponsor or its agent, whenever feasible, to be present during the inspection. The
investigator site and investigator will promptly resolve any discrepancies that are identified
between the study data and the participant's medical records. The investigator will promptly
provide copies of the inspection findings to the sponsor or its agent. Before response
submission to the regulatory authorities, the investigator will provide the sponsor or its
agents with an opportunity to review and comment on responses to any such findings.

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10.1.6. Source Documents
Source documents provide evidence for the existence of the participant and substantiate theintegrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be
consistent with the source documents or the discrepancies must be explained. The
investigator may need to request previous medical records or transfer records, depending on
the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the study monitoring plan.
Description of the use of computerized system is documented in the Data Management Plan.
10.1.7. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment ofparticipants.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)The first act of recruitment is the date of the first participant’s first visit and will be the study
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any
time for any reason at the sole discretion of the sponsor. Study sites will be closed uponstudy completion. A study site is considered closed when all required documents and study
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor
or designee if requested to do so by the responsible IRB/EC or if such termination is required
to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limitedto:

Failure of the investigator to comply with the protocol, the requirements of the IRB/EC
or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.

If the study is prematurely terminated or suspended, the sponsor shall promptly inform theinvestigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of
the reason for termination or suspension, as specified by the applicable regulatory
requirements. The investigator shall promptly inform the participant and should assure
appropriate participant therapy and/or follow-up.

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Study termination is also provided for in the clinical study agreement. If there is any conflict
between the contract and this protocol, the contract will control as to termination rights.
10.1.8. Sponsor’s Qualified Medical Personnel

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)The contact information for the sponsor's appropriately qualified medical personnel for the
study is documented in the study contact list located in the supporting study documentation.
To facilitate access to appropriately qualified medical personnel on study-related medical
questions or problems, participants are provided with a contact card at the time of informed
consent. The contact card contains, at a minimum, protocol and study intervention
identifiers, participant numbers, contact information for the investigator site, and contact
details for a contact center in the event that the investigator site staff cannot be reached toprovide advice on a medical question or problem originating from another healthcare
professional not involved in the participant’s participation in the study. The contact number
can also be used by investigator staff if they are seeking advice on medical questions or
problems; however, it should be used only in the event that the established communication
pathways between the investigator site and the study team are not available. It is therefore
intended to augment, but not replace, the established communication pathways between theinvestigator site and the study team for advice on medical questions or problems that may
arise during the study. The contact number is not intended for use by the participant directly,
and if a participant calls that number, he or she will be directed back to the investigator site.

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10.2. Appendix 2: Clinical Laboratory Tests

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)The following safety laboratory tests will be performed at times defined in the SoA section ofthis protocol. Additional laboratory results may be reported on these samples as a result of
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived
from calculated values. These additional tests would not require additional collection ofblood. Unscheduled clinical laboratory measurements may be obtained at any time during
the study to assess any perceived safety issues.
Hematology
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet countWBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)Basophils (Abs)
Lymphocytes (Abs)

Chemistry
BUN and creatinine
AST, ALT
Total bilirubin
Alkaline phosphatase

Other Urine pregnancy test (β-hCG)
At screening only: Hepatitis B core antibody
 Hepatitis B surface antigen
 Hepatitis C antibody
 Human immunodeficiency virus

Investigators must document their review of each laboratory safety report.
Clinically significant abnormal laboratory findings should be recorded in the AE CRF in
accordance with the following grading scale (Table 6).
Table 6.

Laboratory Abnormality Grading Scale

Hematology

Mild (Grade 1)

Moderate(Grade 2)

Severe (Grade 3)

Hemoglobin(Female) - g/dL
Hemoglobin(Female)change frombaselinevalue - g/dL
Hemoglobin(Male) - g/dL
Hemoglobin(Male)
change frombaselinevalue – g/dL

11.0 – 12.0

9.5 – 10.9

8.0 – 9.4

Potentially Life
Threatening(Grade 4)<8.0

Any decrease – 1.5

1.6 – 2.0

2.1 – 5.0

>5.0

12.5 – 13.5

10.5 – 12.4

8.5 – 10.4

<8.5

Any decrease – 1.5

1.6 – 2.0

2.1 – 5.0

>5.0

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Table 6.

Laboratory Abnormality Grading Scale

Hematology

Mild (Grade 1)

Moderate(Grade 2)

Severe (Grade 3)

WBC increase cells/mm3
WBC decrease cells/mm3
Lymphocytes
decrease - cells/mm3
Neutrophils decrease- cells/mm3
Eosinophils cells/mm3
Platelets decreased cells/mm3
Chemistry

10,800 – 15,000

15,001 – 20,000

20,001 – 25, 000

Potentially Life
Threatening(Grade 4)>25,000

2,500 – 3,500

1,500 – 2,499

1,000 – 1,499<1,000750 – 1,000

500 – 749

250 – 499

<250

1,500 – 2,000

1,000 – 1,499

500 – 999

<500

650 – 1500

1501 - 5000

>5000

Hypereosinophilic

125,000 – 140,000

100,000 – 124,000

25,000 – 99,000<25,000

Mild (Grade 1)

Moderate(Grade 2)

Severe(Grade 3)

BUN - mg/dL
Creatinine – mg/dL

23 – 26
1.5 – 1.7

27 – 31
1.8 – 2.0> 31
2.1 – 2.5

2.1 – 3.0 x ULN

3.1 – 10 x ULN

Potentially Life
Threatening(Grade 4)
Requires dialysis> 2.5 or requires
dialysis>10 x ULN

2.6 – 5.0 x ULN

5.1 – 10 x ULN>10 x ULN

1.26 – 1.5 x ULN

1.51 – 1.75 x ULN>1.75 x ULN

1.6 – 2.0 x ULN

2.0 – 3.0 x ULN>3.0 x ULN

Alkaline phosphate – 1.1 – 2.0 x ULN
increase by factor
Liver function tests – 1.1 – 2.5 x ULN
ALT, AST
increase by factor
Bilirubin – when
1.1 – 1.25 x ULN
accompanied
by any increase inliver function test increase by factor
Bilirubin – when
1.1 – 1.5 x ULN
liver function test is
normal - increase byfactorAbbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen;
ULN = upper limit of normal; WBC = white blood cell.

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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition


An AE is any untoward medical occurrence in a patient or clinical study participant,temporally associated with the use of study intervention, whether or not consideredrelated to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including anabnormal laboratory finding), symptom, or disease (new or exacerbated) temporally
associated with the use of study intervention.

Events Meeting the AE Definition

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) orother safety assessments (eg, ECG, radiological scans, vital sign measurements),
including those that worsen from baseline, considered clinically significant in the
medical and scientific judgment of the investigator Any abnormal laboratory test
results that meet any of the conditions below must be recorded as an AE:
Is associated with accompanying symptoms.



Requires additional diagnostic testing or medical/surgical intervention.



Leads to a change in study dosing (outside of any protocol-specified dose
adjustments) or discontinuation from the study, significant additional concomitantdrug treatment, or other therapy.



Exacerbation of a chronic or intermittent preexisting condition including either anincrease in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration eventhough it may have been present before the start of the study.



Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.



Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
intervention or a concomitant medication. Overdose per se will not be reported as an
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming
intent. Such overdoses should be reported regardless of sequelae.

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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safetyassessments which are associated with the underlying disease, unless judged by theinvestigator to be more severe than expected for the participant’s condition.



The disease/disorder being studied or expected progression, signs, or symptoms of thedisease/disorder being studied, unless more severe than expected for the participant’scondition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).



Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present
or detected at the start of the study that do not worsen.

10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:a. Results in deathb. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which theparticipant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.

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In general, hospitalization signifies that the participant has been detained (usually involving
at least an overnight stay) at the hospital or emergency ward for observation and/or treatmentthat would not have been appropriate in the physician’s office or outpatient setting.
Complications that occur during hospitalization are AEs. If a complication prolongs
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as towhether “hospitalization” occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen frombaseline is not considered an AE.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)d. Results in persistent disability/incapacity


The term disability means a substantial disruption of a person’s ability to conduct
normal life functions.

This definition is not intended to include experiences of relatively minor medicalsignificance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza,
and accidental trauma (eg, sprained ankle) which may interfere with or prevent
everyday life functions but do not constitute a substantial disruption.

e. Is a congenital anomaly/birth defectf. Other situations:Medical or scientific judgment should be exercised in deciding whether SAE
reporting is appropriate in other situations such as important medical events that may
not be immediately life-threatening or result in death or hospitalization but may
jeopardize the participant or may require medical or surgical intervention to prevent
one of the other outcomes listed in the above definition. These events should usually
be considered serious.



Examples of such events include invasive or malignant cancers, intensive treatment inan emergency room or at home for allergic bronchospasm, blood dyscrasias or
convulsions that do not result in hospitalization, or development of drug dependency
or drug abuse.

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10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF andfor reporting serious adverse events on the Vaccines SAE Report Form to Pfizer Safety.
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious adverse
events (AEs); and (3) exposure to the study intervention under study during pregnancy orbreastfeeding, and occupational exposure.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)It should be noted that the Vaccines SAE Report Form for reporting of SAE information is
not the same as the AE page of the CRF. When the same data are collected, the forms must
be completed in a consistent manner. AEs should be recorded using concise medical
terminology and the same AE term should be used on both the CRF and the Vaccines SAE
Report Form for reporting of SAE information.
Safety Event

Recorded on the CRF

Reported on the Vaccines
SAE Report Form to
Pfizer Safety Within 24
Hours of Awareness

SAE
Nonserious AE
Exposure to the study
intervention under study
during pregnancy orbreastfeeding, andoccupational exposure

All
All
None

All
None
All (and EDP supplemental
form for EDP)When an AE/SAE occurs, it is the responsibility of the investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostic reports)
related to the event.



The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s
medical records to Pfizer Safety in lieu of completion of the Vaccines SAE Report
Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases arerequested by Pfizer Safety. In this case, all participant identifiers, with the exceptionof the participant number, will be redacted on the copies of the medical records
before submission to Pfizer Safety.
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The investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. Whenever possible, the diagnosis(not the individual signs/symptoms) will be documented as the AE/SAE.

Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during
the study and assign it to 1 of the following categories:

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)GRADE If required on the AE page of the CRF, the investigator will use the adjectives
MILD, MODERATE, SEVERE, or LIFE-THREATENING to describe themaximum intensity of the AE. For purposes of consistency, these intensity
grades are defined as follows:
1

MILD

Does not interfere with participant's usual function.

2

MODERATE

Interferes to some extent with participant's usualfunction.

3

SEVEREInterferes significantly with participant's usualfunction.

4

LIFE-THREATENING Life-threatening consequences; urgent intervention
indicated.

Assessment of Causality

The investigator is obligated to assess the relationship between study intervention andeach occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence,
and/or arguments to suggest a causal relationship, rather than a relationship cannot be
ruled out.

The investigator will use clinical judgment to determine the relationship.



Alternative causes, such as underlying disease(s), concomitant therapy, and other risk
factors, as well as the temporal relationship of the event to study intervention
administration, will be considered and investigated.



The investigator will also consult the IB and/or product information, for marketed
products, in his/her assessment.

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has reviewed the AE/SAE and has provided an assessment of causality.



There may be situations in which an SAE has occurred and the investigator has
minimal information to include in the initial report to the sponsor. However, it isvery important that the investigator always make an assessment of causality forevery event before the initial transmission of the SAE data to the sponsor.



The investigator may change his/her opinion of causality in light of follow-up
information and send an SAE follow-up report with the updated causality assessment.



The causality assessment is one of the criteria used when determining regulatory
reporting requirements.



If the investigator does not know whether or not the study intervention caused theevent, then the event will be handled as “related to study intervention” for reporting
purposes, as defined by the sponsor. In addition, if the investigator determines that an
SAE is associated with study procedures, the investigator must record this causal
relationship in the source documents and CRF, and report such an assessment in the
dedicated section of the Vaccines SAE Report Form and in accordance with the SAE
reporting requirements.

Follow-up of AEs and SAEs


The investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by thesponsor to elucidate the nature and/or causality of the AE or SAE as fully as possible.
This may include additional laboratory tests or investigations, histopathologicalexaminations, or consultation with other healthcare providers.



If a participant dies during participation in the study or during a recognized follow-up
period, the investigator will provide Pfizer Safety with a copy of any postmortem
findings including histopathology.



New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours ofreceipt of the information.

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10.3.4. Reporting of SAEs

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SAE Reporting to Pfizer Safety via Vaccines SAE Report Form

Facsimile transmission of the Vaccines SAE Report Form is the preferred method totransmit this information to Pfizer Safety.



In circumstances when the facsimile is not working, notification by telephone isacceptable with a copy of the Vaccines SAE Report Form sent by overnight mail orcourier service.

Initial notification via telephone does not replace the need for the investigator tocomplete and sign the Vaccines SAE Report Form pages within the designatedreporting time frames.

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10.4. Appendix 4: Contraceptive Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during
the intervention period and for at least 28 days after the last dose of study intervention, whichcorresponds to the time needed to eliminate reproductive safety risk of the study
intervention(s):Refrain from donating sperm.

PLUS either:Be abstinent from heterosexual intercourse with a female of childbearing potential as
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) andagree to remain abstinent.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)OR

Must agree to use a male condom when engaging in any activity that allows for passageof ejaculate to another person.



In addition to male condom use, a highly effective method of contraception may beconsidered in WOCBP partners of male participants (refer to the list of highly effective
methods below in Section 10.4.4).

10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using an acceptable contraceptive method as described below during
the intervention period (for a minimum of 28 days after the last dose of study
intervention). The investigator should evaluate the effectiveness of the contraceptive
method in relationship to the first dose of study intervention.

The investigator is responsible for review of medical history, menstrual history, and recent
sexual activity to decrease the risk for inclusion of a woman with an early undetected
pregnancy.
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal
unless permanently sterile (see below).
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If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot
be confirmed before the first dose of study intervention, additional evaluation should beconsidered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.

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For individuals with permanent infertility due to an alternate medical cause other than theabove, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should beapplied to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s
review of the participant’s medical records, medical examination, or medical history
interview. The method of documentation should be recorded in the participant’s medical
record for the study.
2. Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause. In addition, ahigh FSH level in the postmenopausal range must be used to confirm apostmenopausal state in women under 60 years of age and not using hormonal
contraception or HRT.



Female on HRT and whose menopausal status is in doubt will be required to use
one of the nonestrogen hormonal highly effective contraception methods if theywish to continue their HRT during the study. Otherwise, they must discontinue
HRT to allow confirmation of postmenopausal status before study enrollment.

10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations
regarding the use of contraceptive methods for those participating in clinical trials.
1. Implantable progestogen-only hormone contraception associated with inhibition ofovulation.
2. Intrauterine device.

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3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner:


Vasectomized partner is a highly effective contraceptive method provided that thepartner is the sole sexual partner of the woman of childbearing potential and theabsence of sperm has been confirmed. If not, an additional highly effective methodof contraception should be used. The spermatogenesis cycle is approximately
90 days.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)

6. Combined (estrogen- and progestogen-containing) hormonal contraception associatedwith inhibition of ovulation:


Oral;



Intravaginal;Transdermal;



Injectable.

7. Progestogen-only hormone contraception associated with inhibition of ovulation:


Oral;



Injectable.

8. Sexual abstinence:Sexual abstinence is considered a highly effective method only if defined as
refraining from heterosexual intercourse during the entire period of risk associatedwith the study intervention. The reliability of sexual abstinence needs to be evaluatedin relation to the duration of the study and the preferred and usual lifestyle of theparticipant.

9. Progestogen-only oral hormonal contraception where inhibition of ovulation is not the
primary mode of action.
10. Male or female condom with or without spermicide.
11. Cervical cap, diaphragm, or sponge with spermicide.
12. A combination of male condom with either cervical cap, diaphragm, or sponge with
spermicide (double-barrier methods).
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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations intransaminases) are termed “tolerators,” while those who show transient liver injury, but adapt
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of amore serious potential outcome. These participants fail to adapt and therefore are"susceptible" to progressive and serious liver injury, commonly referred to as DILI.
Participants who experience a transaminase elevation above 3 × ULN should be monitored
more frequently to determine if they are an “adaptor” or are “susceptible.”

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LFTs are not required as a routine safety monitoring procedure for all participants in thisstudy. However, should an investigator deem it necessary to assess LFTs because aparticipant presents with clinical signs/symptoms, such LFT results should be managed andfollowed as described below.
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will beelevated within the same laboratory sample). In rare instances, by the time TBili elevations
are detected, AST/ALT values might have decreased. This occurrence is still regarded as apotential DILI. Therefore, abnormal elevations in either AST OR ALT in addition to TBili
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law
criteria) cases and should always be considered important medical events, even before allother possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on theparticipant’s individual baseline values and underlying conditions. Participants who present
with the following laboratory abnormalities should be evaluated further as potential DILI
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:Participants with AST/ALT and TBili baseline values within the normal range who
subsequently present with AST OR ALT values >3 × ULN AND a TBili value >2 × ULN
with no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or notavailable.

For participants with baseline AST OR ALT OR TBili values above the ULN, thefollowing threshold values are used in the definition mentioned above, as needed,
depending on which values are above the ULN at baseline:Preexisting AST or ALT baseline values above the normal range: AST or ALT values>2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is smaller).

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Rises in AST/ALT and TBili separated by more than a few weeks should be assessedindividually based on clinical judgment; any case where uncertainty remains as to whether it
represents a potential Hy’s law case should be reviewed with the sponsor.

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)The participant should return to the investigator site and be evaluated as soon as possible,
preferably within 48 hours from awareness of the abnormal results. This evaluation should
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili for suspected cases ofHy’s law, additional laboratory tests should include albumin, CK, direct and indirect
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should
also be given to drawing a separate tube of clotted blood and an anticoagulated tube of bloodfor further testing, as needed, for further contemporaneous analyses at the time of therecognized initial abnormalities to determine etiology. A detailed history, including relevant
information, such as review of ethanol, acetaminophen/paracetamol (either by itself or as a
coformulated product in prescription or over-the-counter medications), recreational drug,
supplement (herbal) use and consumption, family history, sexual history, travel history,
history of contact with a jaundiced person, surgery, blood transfusion, history of liver orallergic disease, and potential occupational exposure to chemicals, should be collected.
Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary
tract) and collection of serum samples for acetaminophen/paracetamol drug and/or protein
adduct levels may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if noother reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law)cases are to be reported as SAEs, irrespective of availability of all the results of theinvestigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results ofreasonable investigations have been received and have excluded an alternative etiology.

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10.6. Appendix 6: Abbreviations

090177e193424de3\Approved\Approved On: 17-Apr-2020 12:10 (GMT)The following is a list of abbreviations that may be used in the protocol.
Abbreviation
2019-nCoV
Abs
AE
ALT
AST
-hCG
BMI
BUN
CBER
CFR
CI
CIOMS
CONSORT
COVID-19
CRF
CRO
CSR
CT
DILI
DMC
DNA
DU
EC
ECG
eCRF
e-diary
EDP
EMA
EU
EUA
EudraCT
FDA
FSH
GCP
GGT
GMC
GMFR
GMR
GMT

Term
novel coronavirus 2019absolute (in Appendix 2)
adverse event
alanine aminotransferase
aspartate aminotransferase
beta-human chorionic gonadotropin
body mass index
blood urea nitrogen
Center for Biologics Evaluation and Research
Code of Federal Regulations
confidence interval
Council for International Organizations of Medical Sciences
Consolidated Standards of Reporting Trials
coronavirus disease 2019case report form
contract research organization
clinical study reportclinical trial
drug-induced liver injury
data monitoring committee
deoxyribonucleic aciddosing unit
ethics committee
electrocardiogram
electronic case report form
electronic diary
exposure during pregnancy
European Medicines Agency
European Union
emergency use application
European Clinical Trials Database
Food and Drug Administration
follicle-stimulating hormone
Good Clinical Practice
gamma-glutamyl transferase
geometric mean concentrationgeometric mean fold risegeometric mean ratio
geometric mean titer

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Abbreviation
HBc Ab
HBsAg
HBV
HCV
HCV Ab
HIPAA
HIV
HRT
IB
ICD
ICH
ICU
ID
Ig
IgG
IgM
IMP
IND
INR
IP manual
IPAL
IRB
IRC
IRR
IRT
IV
IWR
LFT
LLOQ
LNP
LPX
MCH
MCHC
MCV
MedDRAMERS
modRNA
N/A
NAAT
NVA
P2 S

Term
hepatitis B core antibody
hepatitis B surface antigen
hepatitis B virus
hepatitis C virus
hepatitis C virus antibody
Health Insurance Portability and Accountability Act
human immunodeficiency virus
hormone replacement therapy
investigator’s brochure
informed consent document
International Council for Harmonisation
intensive care unit
identification
immunoglobulin
immunoglobulin G
immunoglobulin M
investigational medicinal productinvestigational new druginternational normalized ratio
investigational product manual
Investigational Product Accountability Log
institutional review board
internal review committee
infection rate ratio
interactive response technology
intravenous(ly)interactive Web-based response
liver function test
lower limit of quantitation
lipid nanoparticle
lipoplexmean corpuscular hemoglobinmean corpuscular hemoglobin concentration
mean corpuscular volume
Medical Dictionary for Regulatory Activities
Middle East respiratory syndrome
nucleoside-modified messenger ribonucleic acidnot applicable
nucleic acid amplification test
nonvaccine antigen
SARS-CoV-2 full-length, P2 mutant, “heads up,” prefusion spikeglycoprotein

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Abbreviation
PCR
PI
PPE
PT
RBC
RBD
RCDC
RNA
RSV
RT-PCR
SAE
SAP
saRNA
SARS
SARS-CoV-2
SoA
SOP
SRSD
SUSAR
TBD
TBili
ULN
uRNA
US
vax
VE
WBC
WHO
WOCBP
WT

Term
polymerase chain reaction
principal investigatorpersonal protective equipment
prothrombin time
red blood cell
receptor-binding domain
reverse cumulative distribution curve
ribonucleic acidrespiratory syncytial virus
reverse transcription–polymerase chain reaction
serious adverse event
statistical analysis planself-amplifying messenger ribonucleic acidsevere acute respiratory syndrome
severe acute respiratory syndrome coronavirus 2schedule of activities
standard operating procedure
single reference safety document
suspected unexpected serious adverse reaction
to be determinedtotal bilirubin
upper limit of normal
uridine-containing messenger ribonucleic acid
United States
vaccination
vaccine efficacy
white blood cell
World Health Organization
woman/women of childbearing potential
wild type

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11. REFERENCES
1

World Health Organization. WHO Director-General's opening remarks at the media
briefing on COVID-19. Available from: https://www.who.int/dg/speeches/detail/whodirector-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march2020. Published: 11 March 2020. Accessed: 01 Apr 2020.

2

World Health Organization. Coronavirus disease 2019 (COVID-19) situation report - 70.
In: Data as reported by national authorities by 10:00 CET 30 March 2020. Geneva,
Switzerland: World Health Organization; 2020: 10 pages.

3

Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19):
therapeutic options. Available from: https://www.cdc.gov/coronavirus/2019ncov/hcp/therapeutic-options.html. Accessed: 12 Apr 2020.

4

Rauch S, Jasny E, Schmidt KE, et al. New vaccine technologies to combat outbreaksituations. Front Immunol 2018;9:1963.

5

Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics—developing a new class ofdrugs. Nat Rev Drug Discov 2014;13(10):759-80.

6

BioNTech RNA Pharmaceuticals GmbH. CorVAC/BNT162 Investigator’s Brochure.
Mainz, Germany: BioNTech RNA Pharmaceuticals GmbH; 25 March 2020.

7

Feldman RA, Fuhr R, Smolenov I, et al. mRNA vaccines against H10N8 and H7N9
influenza viruses of pandemic potential are immunogenic and well tolerated in healthy
adults in phase 1 randomized clinical trials. Vaccine. 2019;37(25):3326-34.

8

US Food and Drug Administration. Guidance for industry: toxicity grading scale forhealthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials.
Rockville, MD: Center for Biologics Evaluation and Research; September 2007.

9

Agresti A. Introduction: distributions and inference for categorical data. In: Agresti A,
editor. Categorical data analysis. 2nd ed. Hoboken, NJ: John Wiley & Sons; 2002:1-35.

10

Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med
1985;4(2):213-26.

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