A PHASE 1/2, PLACEBO-CONTROLLED, RANDOMIZED, AND OBSERVER-BLIND STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND IMMUNOGENICITY OF A SARS-COV-2 RNA VACCINE CANDIDATE AGAINST COVID-19 IN HEALTHY JAPANESE ADULTS
Phase: PHASE4
Conditions: SARS-CoV-2 Infection, COVID-19
Sponsor: BioNTech SE

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591005
Final Protocol Amendment 3, 17 March 2021
PFIZER CONFIDENTIAL
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A PHASE 1/2, PLACEBO-CONTROLLED, RANDOMIZED, AND 
OBSERVER-BLIND STUDY TO EVALUATE THE SAFETY, TOLERABILITY, 
AND IMMUNOGENICITY OF A SARS-COV-2 RNA VACCINE CANDIDATE 
AGAINST COVID-19 IN HEALTHY JAPANESE ADULTS
Study Sponsor:
BioNTech SE
Study Conducted By:
Pfizer Japan Inc
Study Intervention Number:
PF-07302048
Study Intervention Name:
RNA-Based COVID-19 Vaccine
US IND Number:
N/A
EudraCT Number:
N/A
Protocol Number:
C4591005
Phase:
1/2
Short Title: A Phase 1/2 Study to Evaluate the Safety, Tolerability, and Immunogenicity 
of an RNA Vaccine Candidate Against COVID-19 in Healthy Japanese Adults
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise 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 for unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591005
Final Protocol Amendment 3, 17 March 2021
PFIZER CONFIDENTIAL
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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Amendment 3
17 March 2021

Transitioned this study to a postmarketing study 
according to the Japanese regulation.

Added the possibility of administering BNT162b2 
to participants who originally received placebo.

Included the possibility, due to local circumstances 
related to the COVID-19 pandemic, that study 
procedures that do not require in-person participant 
contact may be performed by telehealth.

Incorporated the PACL dated 20 November 2020.
Amendment 2
22 October 2020

Removed S1-binding IgG assay and 
immunogenicity assessment from 
Sections 1.1, 3, 8.1, 9.2, 9.4.1, and 9.4.3, because 
these will not be included in analysis.

Added in Section 6.3.3 that blinding can apply not 
just to designated CRAs but also to designated 
study managers to prevent potential risk of 
breaking the blind.
Amendment 1
17 September 2020
Following regulatory feedback:

Extended the SAE reporting period to 12 months 
after the last dose of study intervention.

Consolidated the reasons for discontinuation of 
study intervention.

Revised an estimand of the primary safety objective 
to be consistent with the change in the SAE 
reporting period.

Extended the period for collecting pregnancy 
details to be consistent with the change in the SAE 
reporting period.
In addition:

Reflected the change in the SAE reporting period in 
other relevant sections.

Added the number of participants in 
Section 4.1, because this was considered key 
information for the study design.
Original protocol
07 August 2020
N/A
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs.

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Final Protocol Amendment 3, 17 March 2021
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................9
1. PROTOCOL SUMMARY...................................................................................................10
1.1. Synopsis ..................................................................................................................10
1.2. Schema ....................................................................................................................14
1.3. Schedule of Activities .............................................................................................15
1.3.1. Clinical Laboratory Subset: ........................................................................16
1.3.2. Standard Participants ..................................................................................21
1.3.3. Administration of BNT162b2 to Those Originally Assigned to 
Placebo.............................................................................................................24
2. INTRODUCTION ...............................................................................................................26
2.1. Study Rationale .......................................................................................................26
2.2. Background .............................................................................................................26
2.2.1. Clinical Overview.......................................................................................27
2.3. Benefit/Risk Assessment.........................................................................................27
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
4.2. Scientific Rationale for Study Design.....................................................................32
4.3. Justification for Dose ..............................................................................................32
4.4. End of Study Definition ..........................................................................................32
5. STUDY POPULATION......................................................................................................32
5.1. Inclusion Criteria.....................................................................................................33
5.2. Exclusion Criteria....................................................................................................33
5.3. Lifestyle Considerations..........................................................................................35
5.3.1. Contraception..............................................................................................35
5.4. Screen Failures ........................................................................................................35
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study 
Intervention Administration ......................................................................................35

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Final Protocol Amendment 3, 17 March 2021
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6. STUDY INTERVENTION..................................................................................................36
6.1. Study Intervention(s) Administered........................................................................36
6.1.1. Administration............................................................................................37
6.2. Preparation/Handling/Storage/Accountability ........................................................37
6.2.1. Preparation and Dispensing........................................................................38
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................38
6.3.1. Allocation to Study Intervention ................................................................38
6.3.2. Blinding of Site Personnel..........................................................................39
6.3.3. Blinding of the Sponsor..............................................................................39
6.3.4. Breaking the Blind......................................................................................40
6.4. Study Intervention Compliance...............................................................................40
6.5. Concomitant Therapy..............................................................................................40
6.5.1. Prohibited During the Study.......................................................................40
6.5.2. Permitted During the Study ........................................................................41
6.6. Dose Modification...................................................................................................41
6.7. Intervention After the End of the Study..................................................................41
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................42
7.1. Discontinuation of Study Intervention ....................................................................42
7.2. Participant Discontinuation/Withdrawal From the Study.......................................42
7.2.1. Withdrawal of Consent...............................................................................43
7.3. Lost to Follow-up....................................................................................................43
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................44
8.1. Efficacy and/or Immunogenicity Assessments .......................................................45
8.1.1. Biological Samples.....................................................................................45
8.2. Safety Assessments .................................................................................................45
8.2.1. Clinical Safety Laboratory Assessments (Clinical Laboratory Subset 
Only) ................................................................................................................46
8.2.2. Electronic Diary..........................................................................................46
8.2.2.1. Grading Scales...........................................................................47
8.2.2.2. Local Reactions.........................................................................47
8.2.2.3. Systemic Events ........................................................................48

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Final Protocol Amendment 3, 17 March 2021
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8.2.2.4. Fever..........................................................................................49
8.2.2.5. Antipyretic Medication .............................................................50
8.2.3. Surveillance of Events That Could Represent Enhanced COVID-19 
Disease.............................................................................................................50
8.2.4. Pregnancy Testing ......................................................................................50
8.3. Adverse Events and Serious Adverse Events..........................................................50
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......51
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................52
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................52
8.3.2. Method of Detecting AEs and SAEs ..........................................................52
8.3.3. Follow-up of AEs and SAEs.......................................................................52
8.3.4. Regulatory Reporting Requirements for SAEs...........................................52
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................53
8.3.5.1. Exposure During Pregnancy......................................................53
8.3.5.2. Exposure During Breastfeeding ................................................54
8.3.5.3. Occupational Exposure .............................................................55
8.3.6. Cardiovascular and Death Events...............................................................55
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................55
8.3.8. Adverse Events of Special Interest.............................................................56
8.3.8.1. Lack of Efficacy........................................................................56
8.3.9. Medical Device Deficiencies......................................................................56
8.3.10. Medication Errors.....................................................................................56
8.4. Treatment of Overdose............................................................................................57
8.5. Pharmacokinetics ....................................................................................................57
8.6. Pharmacodynamics..................................................................................................57
8.7. Genetics...................................................................................................................57
8.8. Biomarkers ..............................................................................................................58
8.9. Immunogenicity Assessments.................................................................................58
8.10. Health Economics .................................................................................................58
8.11. Study Procedures...................................................................................................58

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8.11.1. Clinical Laboratory Subset .......................................................................58
8.11.1.1. Screening (0 to 28 Days Before Visit 1) .................................58
8.11.1.2. Visit 1 – Vaccination 1 (Day 1) ..............................................59
8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1) (1 to 
3 Days After Visit 1) .........................................................................61
8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1) (6 to 8 
Days After Visit 1) ............................................................................62
8.11.1.5. Visit 4 – Vaccination 2 (19 to 23 Days After Visit 1).............63
8.11.1.6. Visit 5 – 1-Week Follow-up Visit (6 to 8 Days After 
Visit 4)...............................................................................................65
8.11.1.7. Visit 6 – 2-Week Follow-up Visit (12 to 16 Days After 
Visit 4)...............................................................................................66
8.11.1.8. Visit 7 – 1-Month Follow-up Visit (28 to 35 Days After 
Visit 4)...............................................................................................67
8.11.1.9. Between Visits 7 and 8............................................................67
8.11.1.10. Visit 8 – 6-Month Follow-up Visit (154 to 168 Days 
After Visit 4): Only for Those Participants Who Originally 
Received BNT162b2 or Placebo Recipients Who Decline 
BNT162b2 .........................................................................................68
8.11.1.11. Visit 9 – 12-Month Follow-up Visit (350 to 378 Days 
After Visit 4): Only for Those Participants Who Originally 
Received BNT162b2 or Placebo Recipients Who Decline 
BNT162b2 .........................................................................................68
8.11.2. Standard Participants ................................................................................69
8.11.2.1. Visit 1 – Vaccination 1 (Day 1) ..............................................69
8.11.2.2. Visit 2 – Vaccination 2 (19 to 23 Days After Visit 1).............71
8.11.2.3. Visit 3 – 1-Week Follow-up Visit (6 to 8 Days After 
Visit 2)...............................................................................................73
8.11.2.4. Visit 4 – 2-Week Follow-up Visit (12 to 16 Days After 
Visit 2)...............................................................................................73
8.11.2.5. Visit 5 – 1-Month Follow-up Visit (28 to 35 Days After 
Visit 2)...............................................................................................74
8.11.2.6. Between Visits 5 and 6............................................................75
8.11.2.7. Visit 6 – 6-Month Follow-up Visit (154 to 168 Days 
After Visit 2): Only for Those Participants Who Originally 
Received BNT162b2 or Placebo Recipients Who Decline 
BNT162b2 .........................................................................................75

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Final Protocol Amendment 3, 17 March 2021
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8.11.2.8. Visit 7 – 12-Month Follow-up Visit (350 to 378 Days 
After Visit 2): Only for Those Participants Who Originally 
Received BNT162b2 or Placebo Recipients Who Decline 
BNT162b2 .........................................................................................75
8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction ........................76
8.13. COVID-19 Disease Surveillance ..........................................................................77
8.13.1. Potential COVID-19 Illness Visit (Optimally Within 3 Days After 
Potential COVID-19 Illness Onset) .................................................................78
8.13.2. Potential COVID-19 Convalescent Visit (28 to 35 Days After 
Potential COVID-19 Illness Visit)...................................................................78
8.14. Communication and Use of Technology...............................................................78
8.15. SARS-CoV-2 NAAT Results From Vaccination 1 and Vaccination 2 Visits ......79
8.16. Procedures for Administration of BNT162b2 to Those Originally Assigned 
to Placebo After Approval of Protocol Amendment 3..............................................79
8.16.1. Visit 101 – Vaccination 3 (After Protocol Amendment 3 is 
Approved by the IRB)......................................................................................80
8.16.2. Visit 102 – Vaccination 4 (19 to 23 Days After Visit 101)......................81
8.16.3. Visit 103 – 1-Month After Vaccination 4 Follow-up Telephone 
Contact (28 to 35 Days After Visit 102)..........................................................82
8.16.4. Visit 104 – 6-Months After Vaccination 4 Follow-up Telephone 
Contact (175 to 189 Days After Visit 102)......................................................83
9. STATISTICAL CONSIDERATIONS ................................................................................83
9.1. Estimands and Statistical Hypotheses.....................................................................83
9.1.1. Estimands....................................................................................................83
9.1.2. Statistical Hypotheses.................................................................................84
9.2. Sample Size Determination.....................................................................................84
9.3. Analysis Sets ...........................................................................................................85
9.4. Statistical Analyses .................................................................................................85
9.4.1. Immunogenicity Analyses ..........................................................................86
9.4.2. Safety Analyses ..........................................................................................88
9.5. Interim Analyses .....................................................................................................89
9.5.1. Analysis Timing..........................................................................................89
9.6. Data Monitoring Committee or Other Independent Oversight Committee.............90

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Final Protocol Amendment 3, 17 March 2021
PFIZER CONFIDENTIAL
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................91
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............91
10.1.1. Regulatory and Ethical Considerations ....................................................91
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................91
10.1.2. Financial Disclosure .................................................................................92
10.1.3. Informed Consent Process ........................................................................92
10.1.4. Data Protection .........................................................................................93
10.1.5. Dissemination of Clinical Study Data ......................................................93
10.1.6. Data Quality Assurance ............................................................................95
10.1.7. Source Documents....................................................................................96
10.1.8. Study and Site Start and Closure ..............................................................96
10.1.9. Publication Policy.....................................................................................97
10.1.10. Sponsor’s Qualified Medical Personnel .................................................98
10.2. Appendix 2: Clinical Laboratory Tests .................................................................99
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ....................................................................101
10.3.1. Definition of AE .....................................................................................101
10.3.2. Definition of SAE...................................................................................102
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.....................104
10.3.4. Reporting of SAEs..................................................................................108
10.4. Appendix 4: Contraceptive Guidance .................................................................109
10.4.1. Male Participant Reproductive Inclusion Criteria..................................109
10.4.2. Female Participant Reproductive Inclusion Criteria...............................109
10.4.3. Woman of Childbearing Potential ..........................................................110
10.4.4. Contraception Methods...........................................................................111
10.5. Appendix 5: Genetics..........................................................................................113
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ......113
10.7. Appendix 7: Abbreviations .................................................................................115
11. REFERENCES ................................................................................................................118

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LIST OF TABLES
Table 1.
Local Reaction Grading Scale ..................................................................48
Table 2.
Systemic Event Grading Scale..................................................................49
Table 3.
Scale for Fever..........................................................................................50
Table 4.
Probability of Observing at Least 1 AE by Assumed True Event 
Rates .........................................................................................................84
Table 5.
Precision of Each SARS-CoV-2 Assay....................................................85
Table 6.
Laboratory Abnormality Grading Scale ...................................................99

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Protocol C4591005
Final Protocol Amendment 3, 17 March 2021
PFIZER CONFIDENTIAL
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1. PROTOCOL SUMMARY 
1.1. Synopsis
Short Title: A Phase 1/2 Study to Evaluate the Safety, Tolerability, and Immunogenicity of 
an RNA Vaccine Candidate Against COVID-19 in Healthy Japanese Adults
Rationale
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 a novel 
coronavirus.  The outbreak was declared a Public Health Emergency of International 
Concern on 30 January 2020.  On 12 February 2020, the virus was officially named as 
SARS-CoV-2, and the WHO officially named the disease caused by SARS-CoV-2 as 
COVID-19.  On 11 March 2020, the WHO upgraded the status of the COVID-19 outbreak 
from 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 globally, 
including Japan, the rapid development of an effective vaccine is of utmost importance.
BioNTech has developed RNA-based vaccine candidates using a platform approach that 
enables 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) 
(BNT162b2 [variant RBP020.2]: a modRNA encoding P2 S) or a trimerized SARS-CoV-2 
spike glycoprotein receptor-binding domain (RBD) (version 5) (BNT162b1 [variant 
RBP020.3]: a modRNA encoding the RBD).
A Phase 1/2/3 study (C4591001) conducted in the United States in adults 18 to 85 years of 
age is intended to investigate the safety, immunogenicity, and efficacy of these prophylactic 
BNT162 vaccines against COVID-19.  The 2 vaccine candidates (BNT162b1 and 
BNT162b2) at several dose levels were studied in the C4591001 study, and the vaccine 
candidate selected for Phase 2/3 evaluation in the C4591001 study is BNT162b2 at a dose of 
30 µg.
This study is a Phase 1/2 study to evaluate the safety, tolerability, and immunogenicity of the 
BNT162b2 vaccine candidate selected based on the data from the C4591001 study, in 
Japanese adults 20 to 85 years of age.

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Objectives, Estimands, and Endpoints
Objectives
Estimands
Endpoints
Primary Safety:
To describe the safety and 
tolerability profiles of a 
prophylactic BNT162 
vaccine in healthy Japanese 
adults after 2 doses
In participants receiving at least 1 dose 
of study intervention, the percentage 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 month after 
Dose 2

SAEs from Dose 1 to 12 months 
after Dose 2

Local reactions (pain at the 
injection site, redness, and 
swelling)

Systemic events (fever, fatigue, 
headache, chills, vomiting, 
diarrhea, new or worsened 
muscle pain, and new or 
worsened joint pain)

AEs

SAEs
In addition, in a clinical laboratory 
subset, the percentage of participants 
with:

Abnormal hematology and 
chemistry laboratory values 1 and 
7 days after Dose 1; and 7 days 
after Dose 2

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

Hematology and chemistry 
laboratory parameters detailed in 
Section 10.2
Primary Immunogenicity:
To describe the immune 
responses elicited by a 
prophylactic BNT162 
vaccine in healthy Japanese 
adults
In participants complying with the key 
protocol criteria (evaluable 
participants):

GMTs 1 month after Dose 2

GMFR from before vaccination to 
1 month after Dose 2

SARS-CoV-2 serum neutralizing 
titers
Secondary Immunogenicity:
To describe the immune 
responses elicited by a 
prophylactic BNT162 
vaccine in healthy Japanese 
adults
In the evaluable participants, at 
baseline, 21 days after Dose 1; 7 and 
14 days and 6 and 12 months after 
Dose 2:

GMTs at each time point

GMFR from before vaccination to 
each subsequent time point after 
vaccination

SARS-CoV-2 serum neutralizing 
titers

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Objectives
Estimands
Endpoints
To describe the immune 
responses elicited by a 
prophylactic BNT162 
vaccine in participants 
with/without confirmed 
COVID-19 before Dose 2
In the evaluable participants, at 
baseline, 21 days after Dose 1; 7 and 
14 days and 1, 6, and 12 months after 
Dose 2:

GMTs at each time point

GMFR from before vaccination to 
each subsequent time point after 
vaccination

SARS-CoV-2 serum neutralizing 
titers
Exploratory Immunogenicity:
To describe the immune 
responses elicited by a 
prophylactic BNT162 
vaccine in participants 
with/without confirmed 
COVID-19 during the 
study
In the evaluable participants, at 
baseline, 21 days after Dose 1; 7 and 
14 days and 1, 6, and 12 months after 
Dose 2:

GMTs at each time point

GMFR from before vaccination to 
each subsequent time point after 
vaccination

SARS-CoV-2 serum neutralizing 
titers
To evaluate the immune 
response (non-S) to 
SARS-CoV-2 in 
participants with/without 
confirmed COVID-19 
during the study

SARS-CoV-2 N-binding 
antibody
Overall Design
This is a Phase 1/2, randomized, placebo-controlled, and observer-blind study in healthy 
Japanese adults.
The study will evaluate the safety, tolerability, and immunogenicity of the SARS-CoV-2 
RNA vaccine candidate against COVID-19 (BNT162b2), which was the same as the vaccine 
candidate selected for Phase 2/3 evaluation in the C4591001 study:

As 2 doses, separated by 21 days

At a 30-µg dose level

In adults 20 to 85 years of age
Local reactions (redness, swelling, and pain at the injection site), systemic events (fever, 
vomiting, diarrhea, headache, fatigue, chills, new or worsened muscle pain, and new or 
worsened joint pain), and use of antipyretic medication will be prompted for and collected by 
all participants in an e-diary from Day 1 through Day 7 after each administration of study 
intervention.  AEs will be collected from the time the participant provides informed consent 

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through 1 month after Dose 2, and SAEs will be collected from the time of informed consent 
through 12 months after Dose 2.
As this study is the first study conducted in Japan, clinical laboratory tests will be performed 
in the first 24 participants (12 participants 20 to 64 years of age and 12 participants 65 to 
85 years of age) (clinical laboratory subset).  After randomization of all participants in the 
clinical laboratory subset is completed, the other participants (standard participants) will be 
enrolled.
Blood will be collected prior to Dose 1, prior to Dose 2, and 7 and 14 days and 1, 6, and 
12 months after Dose 2 to assess immunogenicity.
The study is observer-blinded, as the physical appearance of the investigational vaccine 
candidates and the placebo may differ.  The participant, investigator, study coordinator, and 
other 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.
From protocol amendment 3, this study is transitioned from a clinical trial to a postmarketing 
study according to the Japanese regulation, because BNT162b2 was approved by the MHLW 
on 14 February 2021.
All participants who originally received placebo will be offered the opportunity to receive 
BNT162b2 at their earliest convenience as part of the study (administration of BNT162b2 
before the 6-month follow-up visit [Visit 8 for the clinical laboratory subset or Visit 6 for 
standard participants] is allowed).
Number of Participants
One hundred sixty participants will be randomly assigned in a 3:1 ratio to study intervention 
(candidate vaccine: 120, placebo: 40) such that approximately 144 evaluable participants 
(candidate vaccine: 108, placebo: 36) will be evaluated. 
Intervention Groups and Duration
The study will evaluate a 2-dose (separated by 21 days) schedule of 30 µg of the 
investigational RNA vaccine candidate for active immunization against COVID-19, which is 
the same as that selected for Stage 3 of the C4591001 study.  The vaccine candidate or 
placebo (normal saline) will be administered to a study participant.
Participants are expected to participate for up to a maximum of approximately 14 months.

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Data Monitoring Committee or Other Independent Oversight Committee: Yes
An external DMC will be utilized for this study and will review cumulative unblinded safety 
data throughout the study in accordance with the charter.
Statistical Methods
The study sample size is not based on any statistical hypothesis testing.  All statistical 
analyses of safety and immunogenicity will be descriptive.
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 (clinical laboratory subset only), for each vaccine group.  A 3-tier approach will 
be used to summarize AEs.
The primary immunogenicity objectives will be evaluated descriptively by GMT, GMFR, 
and the associated 95% CIs for SARS-CoV-2 serum neutralizing titers at 1 month after 
Dose 2.
Additionally, the RCDCs of SARS-CoV-2 serum neutralizing titers and SARS-CoV-2 
N-binding antibody will be provided for the specified time points to provide further 
characterization of the immune response.
1.2. Schema
Not applicable.

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1.3. Schedule of Activities
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 the protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA 
table, in order to conduct evaluations or assessments required to protect the well-being of the 
participant.
Administration of BNT162b2 to Those Originally Assigned to Placebo: All participants 
will be informed of their original study intervention allocation (BNT162b2 or placebo) by the 
site staff.  All participants who originally received placebo will be offered the opportunity to 
receive BNT162b2 at their earliest convenience as part of the study (administration of 
BNT162b2 before the 6-month follow-up visit [Visit 8 for the clinical laboratory subset or 
Visit 6 for the standard participants] is allowed).  If they want to receive BNT162b2, they 
will move to the SoA in Section 1.3.3 for their remaining visits.  All participants who 
originally received BNT162b2 and placebo recipients who decline BNT162b2 vaccination 
will continue in the study as originally planned.

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1.3.1. Clinical Laboratory Subset:
Visit Number
Screening
1
2
3
4
5
6
7
8
9
Unplanned
Unplanned
Visit Description
Screening
Vax 1
Next-Day 
Follow-
up Visit 
(Vax 1) 
1-Week
Follow-
up Visit 
(Vax 1)
Vax 2
1-Week
Follow-
up Visit 
(Vax 2)
2-Week
Follow-
up Visit 
(Vax 2) 
1-Month 
Follow-
up Visit
6-Month
Follow-
up Visit
12-
Month 
Follow-
up Visit
Potential 
COVID-19 
Illness 
Visita
Potential 
COVID-19 
Convalescent 
Visita
Visit Window (Days)
0 to 28 
Days 
Before 
Visit 1
Day 1
1 to 3 
Days 
After 
Visit 1
6 to 8 
Days 
After 
Visit 1
19 to 23 
Days 
After 
Visit 1
6 to 8 
Days 
After 
Visit 4
12 to 16 
Days 
After 
Visit 4 
28 to 35 
Days 
After 
Visit 4
154 to 
168 Days 
After 
Visit 4
350 to 
378 Days 
After 
Visit 4
Optimally 
Within 3 
Days After 
Potential 
COVID-19 
Illness 
Onset
28 to 35 Days 
After 
Potential 
COVID-19 
Illness Visit
ONLY FOR 
THOSE 
PARTICIPANTS
ORIGINALLY 
ASSIGNED TO 
BNT162b2 OR
PLACEBO 
RECIPIENTS 
WHO DECLINE 
BNT162b2
Obtain informed consent
X
Assign participant number 
X
Obtain demography and medical 
history data
X
Perform clinical assessmentb
X
X
X
X
X
Measure height and weight
X
Collect blood sample for 
hematology and chemistry 
laboratory testsc
~10 mL
~10 mL
~10 mL
~10 mL
~10 mL
Perform urine pregnancy test (if 
appropriate)d
X
X
X
Collect nonstudy vaccine 
information 
X
X
X
X
X
X
X
X
X

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Visit Number
Screening
1
2
3
4
5
6
7
8
9
Unplanned
Unplanned
Visit Description
Screening
Vax 1
Next-Day 
Follow-
up Visit 
(Vax 1) 
1-Week
Follow-
up Visit 
(Vax 1)
Vax 2
1-Week
Follow-
up Visit 
(Vax 2)
2-Week
Follow-
up Visit 
(Vax 2) 
1-Month 
Follow-
up Visit
6-Month
Follow-
up Visit
12-
Month 
Follow-
up Visit
Potential 
COVID-19 
Illness 
Visita
Potential 
COVID-19 
Convalescent 
Visita
Visit Window (Days)
0 to 28 
Days 
Before 
Visit 1
Day 1
1 to 3 
Days 
After 
Visit 1
6 to 8 
Days 
After 
Visit 1
19 to 23 
Days 
After 
Visit 1
6 to 8 
Days 
After 
Visit 4
12 to 16 
Days 
After 
Visit 4 
28 to 35 
Days 
After 
Visit 4
154 to 
168 Days 
After 
Visit 4
350 to 
378 Days 
After 
Visit 4
Optimally 
Within 3 
Days After 
Potential 
COVID-19 
Illness 
Onset
28 to 35 Days 
After 
Potential 
COVID-19 
Illness Visit
ONLY FOR 
THOSE 
PARTICIPANTS
ORIGINALLY 
ASSIGNED TO 
BNT162b2 OR
PLACEBO 
RECIPIENTS 
WHO DECLINE 
BNT162b2
Confirm prohibited medication 
use
X
X
X
X
X
X
X
X
X
X
Confirm eligibility
X
X
X
Review hematology and chemistry 
results
X
X
X
X
X
Measure temperature (axillary)
X
X
Review temporary delay criteria
X
X
Confirm use of contraceptives 
(if appropriate)
X
X
X
X
X
X
X
X
Obtain randomization number and 
study intervention allocation
X
Collect blood sample for 
immunogenicity assessmentd
~25 mL
~25 mL
~25 mL
~25 mL
~25 mL
~25 mL
~25 mL
Obtain nasal (midturbinate) swabd
X
X

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Visit Number
Screening
1
2
3
4
5
6
7
8
9
Unplanned
Unplanned
Visit Description
Screening
Vax 1
Next-Day 
Follow-
up Visit 
(Vax 1) 
1-Week
Follow-
up Visit 
(Vax 1)
Vax 2
1-Week
Follow-
up Visit 
(Vax 2)
2-Week
Follow-
up Visit 
(Vax 2) 
1-Month 
Follow-
up Visit
6-Month
Follow-
up Visit
12-
Month 
Follow-
up Visit
Potential 
COVID-19 
Illness 
Visita
Potential 
COVID-19 
Convalescent 
Visita
Visit Window (Days)
0 to 28 
Days 
Before 
Visit 1
Day 1
1 to 3 
Days 
After 
Visit 1
6 to 8 
Days 
After 
Visit 1
19 to 23 
Days 
After 
Visit 1
6 to 8 
Days 
After 
Visit 4
12 to 16 
Days 
After 
Visit 4 
28 to 35 
Days 
After 
Visit 4
154 to 
168 Days 
After 
Visit 4
350 to 
378 Days 
After 
Visit 4
Optimally 
Within 3 
Days After 
Potential 
COVID-19 
Illness 
Onset
28 to 35 Days 
After 
Potential 
COVID-19 
Illness Visit
ONLY FOR 
THOSE 
PARTICIPANTS
ORIGINALLY 
ASSIGNED TO 
BNT162b2 OR
PLACEBO 
RECIPIENTS 
WHO DECLINE 
BNT162b2
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 the participant with 
downloading the app, or issue 
provisioned device, if required
X
Provide thermometer and 
measuring device
X
X
Review reactogenicity e-diary 
data (daily review is optimal 
during the active diary period)

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Visit Number
Screening
1
2
3
4
5
6
7
8
9
Unplanned
Unplanned
Visit Description
Screening
Vax 1
Next-Day 
Follow-
up Visit 
(Vax 1) 
1-Week
Follow-
up Visit 
(Vax 1)
Vax 2
1-Week
Follow-
up Visit 
(Vax 2)
2-Week
Follow-
up Visit 
(Vax 2) 
1-Month 
Follow-
up Visit
6-Month
Follow-
up Visit
12-
Month 
Follow-
up Visit
Potential 
COVID-19 
Illness 
Visita
Potential 
COVID-19 
Convalescent 
Visita
Visit Window (Days)
0 to 28 
Days 
Before 
Visit 1
Day 1
1 to 3 
Days 
After 
Visit 1
6 to 8 
Days 
After 
Visit 1
19 to 23 
Days 
After 
Visit 1
6 to 8 
Days 
After 
Visit 4
12 to 16 
Days 
After 
Visit 4 
28 to 35 
Days 
After 
Visit 4
154 to 
168 Days 
After 
Visit 4
350 to 
378 Days 
After 
Visit 4
Optimally 
Within 3 
Days After 
Potential 
COVID-19 
Illness 
Onset
28 to 35 Days 
After 
Potential 
COVID-19 
Illness Visit
ONLY FOR 
THOSE 
PARTICIPANTS
ORIGINALLY 
ASSIGNED TO 
BNT162b2 OR
PLACEBO 
RECIPIENTS 
WHO DECLINE 
BNT162b2
Review ongoing reactogenicity 
e-diary symptoms and obtain stop 
dates 
X
X
X
Collect AEs and SAEs as 
appropriatee
X
X
X
X
X
X
X
X
X
X
X
X
Collect e-diary or assist the 
participant to delete application
X

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Visit Number
Screening
1
2
3
4
5
6
7
8
9
Unplanned
Unplanned
Visit Description
Screening
Vax 1
Next-Day 
Follow-
up Visit 
(Vax 1) 
1-Week
Follow-
up Visit 
(Vax 1)
Vax 2
1-Week
Follow-
up Visit 
(Vax 2)
2-Week
Follow-
up Visit 
(Vax 2) 
1-Month 
Follow-
up Visit
6-Month
Follow-
up Visit
12-
Month 
Follow-
up Visit
Potential 
COVID-19 
Illness 
Visita
Potential 
COVID-19 
Convalescent 
Visita
Visit Window (Days)
0 to 28 
Days 
Before 
Visit 1
Day 1
1 to 3 
Days 
After 
Visit 1
6 to 8 
Days 
After 
Visit 1
19 to 23 
Days 
After 
Visit 1
6 to 8 
Days 
After 
Visit 4
12 to 16 
Days 
After 
Visit 4 
28 to 35 
Days 
After 
Visit 4
154 to 
168 Days 
After 
Visit 4
350 to 
378 Days 
After 
Visit 4
Optimally 
Within 3 
Days After 
Potential 
COVID-19 
Illness 
Onset
28 to 35 Days 
After 
Potential 
COVID-19 
Illness Visit
ONLY FOR 
THOSE 
PARTICIPANTS
ORIGINALLY 
ASSIGNED TO 
BNT162b2 OR
PLACEBO 
RECIPIENTS 
WHO DECLINE 
BNT162b2
Collection of local test result of 
COVID-19 and local diagnosis of 
COVID-19
X
Abbreviation: vax = vaccination.
a.
The COVID-19 illness visit may be conducted as a telehealth visit.
b.
Including, if indicated, a physical examination.
c.
Hematology: hemoglobin, hematocrit, 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.
d.
Prior to vaccination, if at a vaccination visit.
e.
Details of AE and SAE reporting are described in Section 8.3.1.

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1.3.2. Standard Participants
Visit Number
1
2
3
4
5
6
7
Unplanned
Unplanned
Visit Description
Vaccination 
1
Vaccination 
2
1-Week
Follow-up 
Visit
2-Week
Follow-up 
Visit
1-Month
Follow-up 
Visit
6-Month
Follow-up 
Visit
12-Month 
Follow-up 
Visit
Potential 
COVID-19 
Illness Visita
Potential 
COVID-19 
Convalescent 
Visita
Visit Window (Days)
Day 1
19 to 23 
Days After 
Visit 1
6 to 8 Days 
After Visit 2
12 to 16 
Days After 
Visit 2
28 to 35 
Days After 
Visit 2
154 to 168 
Days After 
Visit 2
350 to 378 
Days After 
Visit 2
Optimally 
Within 3 
Days After 
Potential 
COVID-19 
Illness Onset
28 to 35 
Days After 
Potential 
COVID-19 
Illness Visit
ONLY FOR THOSE 
PARTICIPANTS 
ORIGINALLY 
ASSIGNED TO 
BNT162b2 OR PLACEBO 
RECIPIENTS WHO 
DECLINE BNT162b2
Obtain informed consent
X
Assign participant number 
X
Obtain demography and medical history 
data
X
Perform clinical assessmentb
X
Measure height and weight
X
Perform urine pregnancy test (if 
appropriate)c
X
X
Collect nonstudy vaccine information 
X
X
X
X
X
X
Confirm prohibited medication use
X
X
X
X
X
X
X
X
Confirm eligibility
X
X
Measure temperature (axillary)
X
X
Review temporary delay criteria
X
X
Confirm use of contraceptives 
(if appropriate)
X
X
X
X
X
Obtain randomization number and study 
intervention allocation
X

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Final Protocol Amendment 3, 17 March 2021
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Visit Number
1
2
3
4
5
6
7
Unplanned
Unplanned
Visit Description
Vaccination 
1
Vaccination 
2
1-Week
Follow-up 
Visit
2-Week
Follow-up 
Visit
1-Month
Follow-up 
Visit
6-Month
Follow-up 
Visit
12-Month 
Follow-up 
Visit
Potential 
COVID-19 
Illness Visita
Potential 
COVID-19 
Convalescent 
Visita
Visit Window (Days)
Day 1
19 to 23 
Days After 
Visit 1
6 to 8 Days 
After Visit 2
12 to 16 
Days After 
Visit 2
28 to 35 
Days After 
Visit 2
154 to 168 
Days After 
Visit 2
350 to 378 
Days After 
Visit 2
Optimally 
Within 3 
Days After 
Potential 
COVID-19 
Illness Onset
28 to 35 
Days After 
Potential 
COVID-19 
Illness Visit
ONLY FOR THOSE 
PARTICIPANTS 
ORIGINALLY 
ASSIGNED TO 
BNT162b2 OR PLACEBO 
RECIPIENTS WHO 
DECLINE BNT162b2
Collect blood sample for immunogenicity 
assessmentc
~25 mL
~25 mL
~25 mL
~25 mL
~25 mL
~25 mL
~25 mL
Obtain nasal (midturbinate) swabc
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-diary completion), assist the 
participant with downloading the app, or 
issue provisioned device, if required
X
Provide a thermometer (all participants) and 
measuring 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
X
X
X
Collect AEs and SAEs as appropriated
X
X
X
X
X
X
X
X
X

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Final Protocol Amendment 3, 17 March 2021
PFIZER CONFIDENTIAL
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Visit Number
1
2
3
4
5
6
7
Unplanned
Unplanned
Visit Description
Vaccination 
1
Vaccination 
2
1-Week
Follow-up 
Visit
2-Week
Follow-up 
Visit
1-Month
Follow-up 
Visit
6-Month
Follow-up 
Visit
12-Month 
Follow-up 
Visit
Potential 
COVID-19 
Illness Visita
Potential 
COVID-19 
Convalescent 
Visita
Visit Window (Days)
Day 1
19 to 23 
Days After 
Visit 1
6 to 8 Days 
After Visit 2
12 to 16 
Days After 
Visit 2
28 to 35 
Days After 
Visit 2
154 to 168 
Days After 
Visit 2
350 to 378 
Days After 
Visit 2
Optimally 
Within 3 
Days After 
Potential 
COVID-19 
Illness Onset
28 to 35 
Days After 
Potential 
COVID-19 
Illness Visit
ONLY FOR THOSE 
PARTICIPANTS 
ORIGINALLY 
ASSIGNED TO 
BNT162b2 OR PLACEBO 
RECIPIENTS WHO 
DECLINE BNT162b2
Collect e-diary or assist the participant to 
delete application
X
Collection of local test result of COVID-19 
and local diagnosis of COVID-19
X
a.
The COVID-19 illness visit may be conducted as a telehealth visit.
b.
Including, if indicated, a physical examination.
c.
Prior to vaccination, if at a vaccination visit.
d.
Details of AE and SAE reporting are described in Section 8.3.1.

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Final Protocol Amendment 3, 17 March 2021
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1.3.3. Administration of BNT162b2 to Those Originally Assigned to Placebo
All participants who originally received placebo will be offered the opportunity to receive BNT162b2 at their earliest convenience as 
part of the study (administration of BNT162b2 before the 6-month follow-up visit [Visit 8 for the clinical laboratory subset or Visit 6 
for standard participants] is allowed).
Visit Number
101
102
103
104
Unplanned
Unplanned
Visit Description
Vaccination 3
Vaccination 4
1-Month
Telephone Contact
6-Month
Telephone Contact
Potential 
COVID-19 Illness 
Visita
Potential 
COVID-19 
Convalescent Visita
Visit Window (Days)
After This Protocol 
Amendment is 
Approved by the 
IRBb
19 to 23 Days After 
Visit 101
28 to 35 Days After 
Visit 102
175 to 189 Days 
After Visit 102
Optimally Within 
3 Days After 
Potential 
COVID-19 Illness 
Onset
28 to 35 Days After 
Potential 
COVID-19 Illness 
Visit
Obtain informed consent
X
Confirm participant originally received placebo
X
Perform urine pregnancy test (if appropriate)
X
X
Confirm use of contraceptives (if appropriate)
X
X
Collect nonstudy vaccine information
X
X
X
X
Confirm prohibited medication use
X
X
X
X
X
X
Confirm eligibility
X
X
Measure temperature (axillary)
X
X
Review temporary delay criteria
X
X
Collect blood sample for immunogenicity 
assessmentc
~25 mL
Obtain vaccine vial allocation via IRT
X
X
Administer BNT162b2
X
X
Assess acute reactions for at least 30 minutes 
after study intervention administration
X
X
Collect AEs and SAEs as appropriated
X
X
X
X
X
X
Contact the participant by telephonee
X
X
Request the participant return the e-diary or 
assist the participant to delete the application
X

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Final Protocol Amendment 3, 17 March 2021
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Visit Number
101
102
103
104
Unplanned
Unplanned
Visit Description
Vaccination 3
Vaccination 4
1-Month
Telephone Contact
6-Month
Telephone Contact
Potential 
COVID-19 Illness 
Visita
Potential 
COVID-19 
Convalescent Visita
Visit Window (Days)
After This Protocol 
Amendment is 
Approved by the 
IRBb
19 to 23 Days After 
Visit 101
28 to 35 Days After 
Visit 102
175 to 189 Days 
After Visit 102
Optimally Within 
3 Days After 
Potential 
COVID-19 Illness 
Onset
28 to 35 Days After 
Potential 
COVID-19 Illness 
Visit
Collection of local test result of COVID-19 and 
local diagnosis of COVID-19
X
Abbreviations: IRB = institutional review board; IRT = interactive response technology.
a. The COVID 19 illness visit may be conducted as a telehealth visit.
b. For all placebo recipients who wish to receive BNT162b2; may be combined with Visit 8 for the clinical laboratory subset or Visit 6 for the standard participants.
c. Only if the participant has no blood sample collected in the previous 7 days.
d. Nonserious AEs need only be recorded if the participant remains in the AE reporting period (see Section 8.3.1).
e. Visit is intended to be conducted by telephone but, if desired, may be conducted in person.

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2. INTRODUCTION
The BNT162 RNA-based COVID-19 vaccines are currently being investigated for 
prevention 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 
BNT162 RNA-based COVID-19 vaccine candidate against COVID-19 in healthy Japanese 
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 globally, 
including Japan, the rapid development of an effective vaccine is of utmost importance.
2.2. Background
In December 2019, a pneumonia outbreak of unknown cause occurred in Wuhan, China.  In 
January 2020, it became clear that a 2019-nCoV was the underlying cause.  Later in January, 
the genetic sequence of the 2019-nCoV became available to the World Health Organization 
(WHO) and public (MN908947.3), and the virus was categorized in the Betacoronavirus
subfamily.  By sequence analysis, the phylogenetic tree revealed a closer relationship to 
severe acute respiratory syndrome (SARS) virus isolates than to another coronavirus 
infecting humans, the Middle East respiratory syndrome (MERS) virus.
The outbreak was declared a Public Health Emergency of International Concern on 
30 January 2020.  On 12 February 2020, the virus was officially named as SARS-CoV-2, and 
the WHO officially named the disease caused by SARS-CoV-2 as coronavirus disease 2019 
(COVID-19).
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 cases with 
33,106 deaths globally, including 142,081 confirmed cases with 2457 deaths in the 
Americas.2  The number of confirmed cases continues to rise globally.  There are currently 
no licensed vaccines to prevent infection with SARS-CoV-2 or COVID-19.3
A prophylactic, RNA-based SARS-CoV-2 vaccine provides one of the most flexible and 
fastest approaches available to immunize against the emerging virus.4,5  BioNTech has 
developed RNA-based vaccine candidates using a platform approach that enables the rapid 
development of vaccines against emerging viral diseases, including SARS CoV-2.
The development of an RNA-based vaccine encoding a viral antigen, which is then expressed 
by 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 and 
immunocompromised persons).  RNA-based vaccines are manufactured via a cell-free 

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PFIZER CONFIDENTIAL
Page 27
in vitro 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 
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 a 
Phase 1/2/3 study (C4591001) conducted in the United States.  Each vaccine candidate 
expresses 1 of 2 antigens: the SARS-CoV-2 full-length, P2 mutant, prefusion spike 
glycoprotein (P2 S) (version 9) (BNT162b2 [variant RBP020.2]: a modRNA encoding P2 S) 
or a trimerized SARS-CoV-2 spike glycoprotein-receptor binding domain (RBD) (version 5) 
(BNT162b1 [variant RBP020.3]: a modRNA encoding the RBD).  The vaccine candidate 
selected for Phase 2/3 evaluation in the C4591001 study is BNT162b2.
This study will evaluate the safety, tolerability, and immunogenicity of a vaccine candidate 
(BNT162b2) in Japanese adults 20 to 85 years of age.
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 to 
have 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 the C4591001 
study and the BNT162-01 study conducted in Germany by BioNTech, at doses between 1 μg 
and 100 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 preventive or therapeutic options 
available.  There are accumulating data from ongoing human clinical trials of BNT162 
vaccines in the United States and Germany, with an acceptable safety and tolerability profile 
observed at the time of initiation of this study.  In addition, available nonclinical data with 
these vaccines, and data from nonclinical studies and clinical trials with the same or related 
RNA components, or antigens, supported a favorable risk/benefit profile.  Anticipated AEs 
after vaccination were expected to be manageable using routine symptom-driven standard of 
care as determined by the investigators and, as a result, the profile of these vaccine 
candidates supported initiation of this Phase 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 the IB, which is 
the SRSD for this study.

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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 CBER guidelines on toxicity 
grading scales for healthy adult 
volunteers enrolled in preventive vaccine 
clinical trials.8
The study employs the use of a reactogenicity e-diary to monitor local 
reactions and systemic events in real time.  Study clinicians will 
closely monitor for severe reactions.  In addition, investigators will 
contact participants and conduct unscheduled visits for any reported 
severe local reactions or systemic events.
Unknown AEs and laboratory 
abnormalities with a novel vaccine.
Accumulating safety data from ongoing 
clinical studies have shown an acceptable 
safety profile.  Known laboratory 
abnormalities from the clinical studies 
conducted in the United States and 
Germany include transient and 
self-limited reduction in lymphocyte 
counts.
The study design includes the use of a clinical laboratory subset to 
monitor participants for laboratory abnormalities.  Participants will be 
observed for 30 minutes after vaccination to assess for immediate 
AEs.
Potential for COVID-19 disease 
enhancement.
Disease enhancement has been seen 
following vaccination with respiratory 
syncytial virus (RSV), feline 
coronavirus, and Dengue virus vaccines.
Participants with likely previous or current COVID-19 will be 
excluded.  All participants will be 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 
healthcare facilities during the global 
SARS-CoV-2 pandemic.
Without appropriate social distancing 
and PPE, there is a potential for 
increased exposure to SARS-CoV-2.
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.
Venipuncture will be performed during 
the study.
There is the risk of bleeding, bruising, 
hematoma formation, and infection at the 
venipuncture site.
Only appropriately qualified personnel will 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 this 
study, 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
Objectives
Estimands
Endpoints
Primary Safety:
To describe the safety and 
tolerability profiles of a 
prophylactic BNT162 
vaccine in healthy Japanese 
adults after 2 doses
In participants receiving at least 1 dose 
of study intervention, the percentage 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 month after 
Dose 2

SAEs from Dose 1 to 12 months 
after Dose 2

Local reactions (pain at the 
injection site, redness, and 
swelling)

Systemic events (fever, fatigue, 
headache, chills, vomiting, 
diarrhea, new or worsened 
muscle pain, and new or 
worsened joint pain)

AEs

SAEs
In addition, in a clinical laboratory 
subset, the percentage of participants 
with:

Abnormal hematology and 
chemistry laboratory values 1 and 
7 days after Dose 1; and 7 days 
after Dose 2

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

Hematology and chemistry 
laboratory parameters detailed in 
Section 10.2

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Objectives
Estimands
Endpoints
Primary Immunogenicity:
To describe the immune 
responses elicited by a 
prophylactic BNT162 
vaccine in healthy Japanese 
adults
In participants complying with the key 
protocol criteria (evaluable 
participants):

GMTs 1 month after Dose 2

GMFR from before vaccination to 
1 month after Dose 2

SARS-CoV-2 serum neutralizing 
titers
Secondary Immunogenicity:
To describe the immune 
responses elicited by a 
prophylactic BNT162 
vaccine in healthy Japanese 
adults
In the evaluable participants, at 
baseline, 21 days after Dose 1; 7 and 
14 days and 6 and 12 months after 
Dose 2:

GMTs at each time point

GMFR from before vaccination to 
each subsequent time point after 
vaccination

SARS-CoV-2 serum neutralizing 
titers
To describe the immune 
responses elicited by a 
prophylactic BNT162 
vaccine in participants 
with/without confirmed 
COVID-19 before Dose 2
In the evaluable participants, at 
baseline, 21 days after Dose 1; 7 and 
14 days and 1, 6, and 12 months after 
Dose 2:

GMTs at each time point

GMFR from before vaccination to 
each subsequent time point after 
vaccination

SARS-CoV-2 serum neutralizing 
titers
Exploratory Immunogenicity:
To describe the immune 
responses elicited by 
prophylactic BNT162 
vaccine in participants 
with/without confirmed 
COVID-19 during the 
study
In the evaluable participants, at 
baseline, 21 days after Dose 1; 7 and 
14 days and 1, 6, and 12 months after 
Dose 2:

GMTs at each time point

GMFR from before vaccination to 
each subsequent time point after 
vaccination

SARS-CoV-2 serum neutralizing 
titers
To evaluate the immune 
response (non-S) to 
SARS-CoV-2 in 
participants with/without 
confirmed COVID-19 
during the study

SARS-CoV-2 N-binding 
antibody

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4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1/2, randomized, placebo-controlled, and observer-blind study in healthy 
Japanese adults.
The study will evaluate the safety, tolerability, and immunogenicity of the SARS-CoV-2 
RNA vaccine candidate against COVID-19 (BNT162b2), which is the same as the vaccine 
candidate selected for Phase 2/3 evaluation in the C4591001 study:

As 2 doses, separated by 21 days

At a 30-µg dose level 

In adults 20 to 85 years of age
Local reactions (redness, swelling, and pain at the injection site), systemic events (fever, 
vomiting, diarrhea, headache, fatigue, chills, new or worsened muscle pain, and new or 
worsened joint pain), and use of antipyretic medication will be prompted for and collected by 
all participants in an e-diary from Day 1 through Day 7 after each administration of study 
intervention.  AEs will be collected from the time the participant provides informed consent 
through 1 month after Dose 2, and SAEs will be collected from the time of informed consent 
through 12 months after Dose 2.
One hundred sixty participants will be randomly assigned in a 3:1 ratio to study intervention 
(candidate vaccine: 120, placebo: 40), such that approximately 144 evaluable participants 
(candidate vaccine: 108, placebo: 36) will be evaluated.
As this study is the first study conducted in Japan, clinical laboratory tests will be performed 
in the first 24 participants (12 participants 20 to 64 years of age and 12 participants 65 to 
85 years of age) (clinical laboratory subset).  After randomization of all participants in the 
clinical laboratory subset is completed, the standard participants will be enrolled.
Blood will be collected prior to Dose 1, prior to Dose 2, and 7 and 14 days and 1, 6, and 
12 months after Dose 2 to assess immunogenicity.
The study is observer-blinded, as the physical appearance of the investigational vaccine 
candidates and the placebo may differ.  The participant, investigator, study coordinator, and 
other 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.
Participants are expected to participate for up to a maximum of approximately 14 months.

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From protocol amendment 3, this study is transitioned from a clinical trial to a postmarketing 
study according to the Japanese regulation, because BNT162b2 was approved by the MHLW 
on 14 February 2021.
All participants will be informed of their original study intervention allocation (BNT162b2 or 
placebo) by the site staff.  All participants who originally received placebo will be offered the 
opportunity to receive BNT162b2 at their earliest convenience as part of the study 
(administration of BNT162b2 before the 6-month follow-up visit [Visit 8 for the clinical 
laboratory subset or Visit 6 for the standard participants] is allowed).  If they want to receive 
BNT162b2, they will move to the SoA in Section 1.3.3 for their remaining visits.  
Participants who originally received BNT162b2 and placebo recipients who decline 
BNT162b2 vaccination will continue in the study as originally planned.
4.2. Scientific Rationale for Study Design
Additional surveillance for COVID-19 will be conducted as part of the study, given the 
potential 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 of 
these visits, local test results of COVID-19 and local diagnosis of COVID-19 as available 
will be confirmed.
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 mechanism 
of action of the compound.  Therefore, the use of a highly effective method of contraception 
is required (see Appendix 4).
4.3. Justification for Dose
The 2 vaccine candidates (BNT162b1 and BNT162b2) at several dose levels were studied in 
Phase 1 evaluation in the C4591001 study based on the preliminary experience in the 
C4591001 study and the BioNTech study (BNT162-01) conducted in Germany.  The vaccine 
candidate selected for Phase 2/3 evaluation in the C4591001 study is BNT162b2 at a dose of 
30 µg.
4.4. End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the study.
5. STUDY POPULATION
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 be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
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. Japanese male or female participants between the ages of 20 and 85 years, inclusive, 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, and 
clinical judgment of the investigator to be eligible for inclusion in the study.
Note: Healthy participants with preexisting stable disease, defined as disease not 
requiring significant change in therapy or hospitalization for worsening disease during 
the 6 weeks before enrollment, can be included.
Informed Consent:
4. Capable 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. 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 confirmed diagnosis of COVID-19 (refer to Section 8.15 for handling 
participants who have a positive SARS-CoV-2 NAAT result prior to the Vaccination 2 
visit).
6. Immunocompromised individuals with known or suspected immunodeficiency, as 
determined by history and/or laboratory/physical examination.
7. Bleeding diathesis or condition associated with prolonged bleeding that would, in the 
opinion of the investigator, contraindicate intramuscular injection.
8. Women who are pregnant or breastfeeding.
Prior/Concomitant Therapy:
9. Previous vaccination with any coronavirus vaccine.
10. 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 
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, intra-articular, intrabursal, or 
topical (skin or eyes) corticosteroids are permitted.
11. 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:
12. Participation in other studies involving study intervention within 28 days prior to study 
entry and/or during study participation.
13. Previous participation in other studies involving study intervention containing lipid 
nanoparticles.
Diagnostic Assessments:
14. Clinical laboratory subset 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 report 
of Grade 1 on an initial blood sample that remains ≤Grade 1 upon repeat testing on a
second sample from the same participant.)

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Other Exclusions:
15. 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 that 
the 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 in 
its consistent and correct use.  At time points indicated in the SoA, the investigator or 
designee 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 
of 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 to 
meet the CONSORT publishing requirements and to respond to queries from regulatory 
authorities.  Minimal information includes demography, screen failure details, eligibility 
criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened 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 
enrolled/randomized/vaccinated once the condition(s) has/have resolved and no other 
exclusion criteria are met.
1. Current febrile illness (axillary temperature ≥37.5°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;

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
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 other 
nonstudy 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 or 
eyes) 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 30 µg of the 
investigational RNA vaccine candidate for active immunization against COVID-19, which is 
the same as that selected for Phase 2/3 evaluation in the C4591001 study.  The vaccine 
candidate or placebo (normal saline) will be administered to a study participant.
6.1. Study Intervention(s) Administered
Intervention Name
BNT162b2 (BNT162 RNA-LNP Vaccine 
Utilizing modRNA)
Saline Placebo
Type
Vaccine
Placebo
Dose Formulation
modRNA
Normal saline (0.9% sodium chloride 
solution for injection)
Unit Dose Strength
250 µg/0.5 mL concentrate for solution
N/A
Dosage Level 
30-µg
N/A
Route of Administration
Intramuscular injection
Intramuscular injection
Use
Experimental
Placebo
IMP or NIMP
IMP
IMP
Sourcing
Provided centrally by the sponsor
Provided centrally by the sponsor

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Intervention Name
BNT162b2 (BNT162 RNA-LNP Vaccine 
Utilizing modRNA)
Saline Placebo
Packaging and Labeling
Study intervention will be provided in a glass 
vial as open-label supply.  Each vial will be 
labeled as required per country requirement
Study intervention will be provided in a glass 
or plastic vial as open-label supply.  Each vial 
will be labeled as required per country 
requirement
6.1.1. Administration
Participants will receive 1 dose of study intervention as randomized at each vaccination visit 
(Visits 1 and 4 for the clinical laboratory subset, Visits 1 and 2 for the standard participants) 
in accordance with the study’s SoA.  Participants who originally received placebo and accept 
the offer to receive BNT162b2 at defined points as part of the study, will receive 1 dose of 
BNT162b2 at each additional vaccination visit (Visits 101 and 102) in accordance with the 
study’s additional SoA (Section 1.3.3).  Full details are described in the IP manual.
Study intervention should be administered intramuscularly into the deltoid muscle, preferably 
of the nondominant arm, by an unblinded administrator.
Standard vaccination practices must be observed and vaccine must not be injected into blood 
vessels.  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 or nurse) 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 are 
reported 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 access 
limited to the investigator and authorized site staff.  At a minimum, daily minimum and 
maximum 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 to 
business.

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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 the 
labeling, 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 the 
site 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 
sponsor-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 ensure 
that 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 for 
administration.  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 to 
ensure 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 

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required to enter or select information including but not limited to the user’s ID and 
password, 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, and 
study 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 information 
and 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, and 
administering 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 will 
be 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 a 
manner that prevents the study participants from identifying the study intervention type based 
on its appearance.
The responsibility of the unblinded dispenser and administrator must be assigned to an 
individual or individuals who will not participate in the evaluation of any study participants.  
Contact between the unblinded dispenser/unblinded administrator and study participants 
should be kept to a minimum.  The remaining site personnel must not know study 
intervention assignments.
Site staff will be unblinded to all of the individual participants’ original study intervention 
allocations after IRB approval of protocol amendment 3 to inform all participants of the 
original study intervention allocation (BNT162b2 or placebo) and allow administration of 
BNT162b2 to participants who originally received placebo.
6.3.3. Blinding of the Sponsor
To facilitate rapid review of data in real time, the majority of sponsor staff will be unblinded 
to study intervention allocation for all participants.  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 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 
CRA).  CRAs and study managers not involved in ensuring that protocol requirements for 
study intervention preparation, handling, allocation, and administration are fulfilled at the site 
will remain blinded to study intervention assigned/received throughout the study.

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At the time when the original study intervention allocation for all participants will be 
unblinded by the site staff, all members of the study team including CRAs will become 
unblinded to the participant’s original study intervention allocation.
6.3.4. Breaking the Blind
The IRT will be programmed with blind-breaking instructions.  In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s study 
intervention assignment is warranted.  Participant safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 
warranted, 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 information 
and further details on the use of the IRT system.
Instructions on how to unblind participants ahead of administration of BNT162b2 to placebo 
recipients will be provided separately. This unblinding will NOT be performed in the IRT.
6.4. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator 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 the 
time of dosing by a member of the study site staff other than the person administering the 
study 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-month 
follow-up visit (Visit 8 for the clinical laboratory subset, Visit 6 for the standard 
participants).
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 the 
participant 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, or 
at least 14 days prior to, the administration of study intervention.
Receipt of chronic systemic treatment with known immunosuppressant medications, or 
radiotherapy, 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 8 for the clinical laboratory subset and 
Visit 6 for the standard 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 with 
study 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 of 
preexisting stable conditions or acute illness is permitted.
Inhaled, topical, or localized injections of corticosteroids (eg, intra-articular or intrabursal 
administration) are permitted.
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4).
6.6. Dose Modification 
Not applicable.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.  Participants 
who were originally assigned to placebo will be offered the opportunity to receive 
BNT162b2 as part of the study.

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7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/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; Grade 4 local reactions (Section 8.2.2.2), 
Grade 4 systemic events (Section 8.2.2.3), or fever >40.0°C (Section 8.2.2.4) that is 
confirmed and determined to be related to the administration of the study intervention; 
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 will 
remain in the study to be evaluated for safety and immunogenicity and for COVID-19 
disease surveillance.  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 the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, postvaccination 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 for 
discontinuation 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 during 

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contact 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 the 
site 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 data 
collected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed 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 this 
information.  Participants should notify the investigator in writing of the decision to 
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 the 
withdrawal is only from further receipt of study intervention or also from study procedures 
and/or postvaccination study follow-up, and entered on the appropriate CRF page.  In the 
event that 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 directed 
in 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 for 
scheduled 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 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, 

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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 have 
withdrawn from the study.
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated 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 or 
awareness 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 to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant.  When a protocol-required test cannot be performed, the 
investigator 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, and 
shipment 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 
225 mL for the clinical laboratory subset and 175 mL for the standard participants.  Other 
additional blood samples may be taken for safety assessments at times specified by Pfizer, 

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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
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

Roche Elecsys Anti-SARS-CoV-2, an electrochemiluminescence immunoassay (ECLIA) 
for the presence or absence of SARS-CoV-2 N-binding antibodies
Note that all immunogenicity analyses will be based upon samples analyzed at the central 
laboratory.  Additional exploratory assays to measure immune responses may be performed, 
with analyses described in the SAP.
8.1.1. Biological Samples
Blood samples for immunogenicity and nasal swab samples to be collected before Dose 1 
and before Dose 2 will be used only for scientific research.  Each sample will be labeled with 
a code so that the laboratory personnel testing the samples will not know the participant’s 
identity.  Samples for immunogenicity 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 requirements, the samples will be stored for up to 15 years after the end of the study 
and then destroyed.  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 the development 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 this 
research.  The biological samples may be shared with other researchers as long as 
confidentiality 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 clinical 
laboratory 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 from 
any physical examination, if performed, will be documented in the CRF.  Also, a clinical 
assessment will be performed on participants enrolled in the clinical laboratory subset at 
Visits 1 through 4.
AEs and SAEs are collected, recorded, and reported as defined in Section 8.3.

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Acute reactions within the first 30 minutes will be assessed and documented in the AE CRF.
The safety parameters also include reactogenicity e-diary reports of local reactions and 
systemic events (including fever), and use of antipyretic medication, that occur in the 7 days 
after administration of the study intervention.  These prospectively self-collected occurrences 
of local reactions and systemic events are graded as described in Section 8.2.2.
Clinical laboratory tests will be performed in the first 24 participants (12 participants 20 to 
64 years of age and 12 participants 65 to 85 years of age).
8.2.1. Clinical Safety Laboratory Assessments (Clinical Laboratory Subset 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 in 
Appendix 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 that are not associated 
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 Dose 2 of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant 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 6 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 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 will be asked to monitor and record local reactions, systemic events, 
and antipyretic medication usage for 7 days following administration of the study 
intervention.  All participants who originally received placebo and then received BNT162b2 
under protocol amendment 3 and onwards, will not complete a reactogenicity e-diary but will 
have their local reactions and systemic events collected and reported as AEs in accordance 
with Section 8.3.2.

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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 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 electronically 
into Pfizer's database for analysis and reporting.  These data do not need to be reported by the 
investigator in the CRF as AEs.
Investigators (or designee) will be required to review the reactogenicity e-diary data online at 
frequent 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 the 
reactogenicity 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 CBER guidelines on toxicity grading scales for 
healthy adult volunteers enrolled in preventive 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
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 to 
centimeters 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 to 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 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 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 1.
Local Reaction Grading Scale
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)
Pain at the 
injection site
Does not interfere 
with activity
Interferes with 
activity
Prevents daily activity Emergency room visit 
or hospitalization for 
severe pain
Redness
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)
>10 cm 
(≥21 measuring 
device units)
Necrosis or 
exfoliative dermatitis
Swelling
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)
>10 cm 
(≥21 measuring 
device units)
Necrosis
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 or 
worsened 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 the 
grading 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 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 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
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)
Vomiting
1-2 times in 
24 hours
>2 times in 
24 hours
Requires IV 
hydration
Emergency room visit or 
hospitalization for 
hypotensive shock
Diarrhea
2 to 3 loose stools 
in 24 hours
4 to 5 loose stools 
in 24 hours
6 or more loose 
stools in 24 hours
Emergency room visit or 
hospitalization for severe 
diarrhea
Headache
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room visit or 
hospitalization for severe 
headache
Fatigue/ 
tiredness
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room visit or 
hospitalization for severe 
fatigue
Chills
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room visit or 
hospitalization for severe 
chills
New or 
worsened 
muscle pain
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room visit or 
hospitalization for severe 
new or worsened muscle 
pain
New or 
worsened 
joint pain
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room visit or 
hospitalization for severe 
new or worsened joint pain
Abbreviation: IV = intravenous.
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 axillary 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 axillary temperature of ≥37.5°C.  
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 is reported in the reactogenicity e-diary, a telephone contact should 
occur to ascertain 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.  If a participant experiences a confirmed fever >40.0°C, 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.
Scale for Fever
≥37.5-38.4°C
>38.4-38.9°C
>38.9-40.0°C
>40.0°C
Note: Fever is defined as axillary temperature ≥37.5°C.
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. Surveillance of Events That Could Represent Enhanced COVID-19 Disease
As this is a sponsor open-label study, the sponsor will conduct unblinded reviews of the data 
during the course of the study, including for the purpose of safety assessment.
Participants will be surveilled for potential COVID-19 illness from Visit 1 onwards (see 
Section 8.13).
8.2.4. 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 the 
case of a positive confirmed pregnancy, the participant will be withdrawn from 
administration 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, and 
recording 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.

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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 (“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 the clinical 
laboratory subset and Visit 5 for the standard 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 to 
approximately 12 months after Dose 2 of study intervention (Visit 9 for the clinical 
laboratory subset, Visit 7 for the standard participants).
Confirmed COVID-19 diagnosis (SARS-CoV-2 positive test) will be collected as an AESI 
from the time the participant provides informed consent until study completion (Visit 9 for 
the clinical laboratory subset, Visit 7 for standard participants) (see Section 8.3.8).
Additionally, for those participants who originally received placebo but go on to receive 
BNT162b2 at Vaccinations 3 and 4, AEs will be collected from the time the participant 
provides informed consent (for receipt of Vaccinations 3 and 4) through and including 
Visit 103.  SAEs and confirmed COVID-19 diagnosis (SARS-CoV-2 positive test) will be 
collected from the time the participant provides informed consent (for receipt of 
Vaccinations 3 and 4) to approximately 6 months after Dose 2 of BNT162b2 (Visit 104).
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator 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 Vaccine SAE Reporting 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 
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 Vaccine SAE Reporting Form.

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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 Reporting Form immediately 
upon awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 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 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 the 
procedures 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 and 
nonleading 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 each 
participant at subsequent visits/contacts.  For each event, the investigator must pursue and 
obtain 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 to 
allow 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 a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation.  The 

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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 and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
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 a 
female 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 to 
termination 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 Reporting Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred.  Details of the 
pregnancy will be collected after the start of study intervention and until 12 months after 
Dose 2 of study intervention and until delivery.

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
If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the Vaccine SAE Reporting 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 the 
completed Vaccine SAE Reporting 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 
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, the 
reason(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 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs.  If the outcome of the pregnancy meets 
the 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, the 
investigator 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 that 
the 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.

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
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 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred.  The 
information must be reported using the Vaccine SAE Reporting 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 Reporting Form is 
maintained in the investigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use.  However, if the infant experiences an SAE associated with such a drug, the 
SAE 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 the 
study 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 the 
trial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness, regardless of whether there is an associated SAE.  The information 
must be reported using the Vaccine SAE Reporting 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 Reporting Form is maintained in the 
investigator 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
This section provides information on AESIs that may be detected during the study:

Confirmed COVID-19 diagnosis (positive SARS-CoV-2 test)
All AESIs must be reported as an AE or SAE following the procedures described in 
Sections 8.3.1 through 8.3.4.  An AESI is to be recorded as an AE or SAE on the CRF.  In 
addition, an AESI that is also an SAE must be reported using the Vaccine SAE Reporting 
Form.
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 Vaccine SAE 
Reporting 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 the 
investigator, 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 
Reporting 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.
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 not 
evaluated in this study.
8.11. Study Procedures
Unless stated otherwise, all study visits are intended to be conducted in person at the study 
site. If this is not possible because of local circumstances related to the COVID-19 
pandemic, study procedures that do not require in-person participant contact may be 
performed by telehealth. Telehealth includes the exchange of healthcare information and 
services via telecommunication technologies (eg, audio, video, and video-conferencing 
software) remotely, allowing the participant and the investigator to communicate on aspects 
of clinical care, including medical advice, reminders, education, and safety monitoring. 
Irrespective of the nature of the contact, all visit procedures are expected to be performed on 
the same day.
8.11.1. Clinical Laboratory Subset
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 and 
safety profile by age.

Obtain any medical history of clinical significance.

Perform a clinical assessment.  If the clinical assessment indicates that a physical 
examination is necessary to comprehensively evaluate the participant, perform a physical 

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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.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory 
tests as described in Section 10.2.

Perform urine pregnancy test on WOCBP as described in Section 8.2.4.

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 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; ensure 
that procedures listed prior to administration of the vaccine are conducted prior to 
vaccination.

Record AEs as described in Section 8.3.

Perform a clinical assessment.  If the clinical assessment indicates that a physical 
examination is necessary to comprehensively evaluate the participant, perform a physical 
examination and record any findings in the source documents and, if clinically 
significant, record on the AE CRF.

Perform urine pregnancy test on WOCBP as described in Section 8.2.4.

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
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 tests).

Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met.

Measure the participant’s body temperature (axillary).

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 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 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.

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.

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 is required:

Fever ≥39.0°C.

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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 (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any 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 unblinded 
dispenser/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.

Perform a clinical assessment.  If the clinical assessment indicates that a physical 
examination is necessary to comprehensively evaluate the participant, perform a physical 
examination and record any findings in the source documents and, if clinically 
significant, record on the AE CRF.

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.

Confirm 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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
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 is required:

Fever ≥39.0°C.

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 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.
8.11.1.4. 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 accordance 
with Appendix 2.

Perform a clinical assessment.  If the clinical assessment indicates that a physical 
examination is necessary to comprehensively evaluate the participant, perform a physical 
examination and record any findings in the source documents and, if clinically 
significant, record on the AE CRF.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory 
tests as described in Section 10.2.

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
Record nonstudy vaccinations as described in Section 6.5.

Confirm 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 is required:

Fever ≥39.0°C.

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 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.
8.11.1.5. 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; ensure 
that procedures listed prior to administration of the vaccine are conducted prior to 
vaccination.

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 was 
completed and record stop dates in the CRF if required.

Review hematology and chemistry laboratory results and record any AEs in accordance 
with Appendix 2.

Perform a clinical assessment.  If the clinical assessment indicates that a physical 
examination is necessary to comprehensively evaluate the participant, perform a physical 
examination and record any findings in the source documents and, if clinically 
significant, record on the AE CRF.

Perform urine pregnancy test on WOCBP as described in Section 8.2.4.

Discuss contraceptive use as described in Section 10.4.

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.

Confirm 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. Participants who have a positive SARS-CoV-2 NAAT result prior to the 
Vaccination 2 visit should be handled as described in Section 8.15.

Measure the participant’s body temperature (axillary).

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 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.

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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 the 
reactogenicity 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 is required:

Fever ≥39.0°C.

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 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.
8.11.1.6. Visit 5 – 1-Week Follow-up Visit (6 to 8 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.

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
Review hematology and chemistry laboratory results and record any AEs in accordance 
with Appendix 2.

Record nonstudy vaccinations as described in Section 6.5.

Confirm 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 10 mL) for hematology and chemistry laboratory 
tests as described in Section 10.2.

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 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.
8.11.1.7. Visit 6 – 2-Week Follow-up Visit (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 in accordance 
with Appendix 2.

Record nonstudy vaccinations as described in Section 6.5.

Confirm 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.

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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 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.

Confirm 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 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. Between Visits 7 and 8
All participants will be contacted by the site and unblinded to study intervention allocation to 
allow placebo recipients the opportunity to receive BNT162b2 as part of the study.  If the 
participant originally received placebo and wants to receive BNT162b2, he or she will follow
the procedures in Section 8.16 and the SoA in Section 1.3.3.

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8.11.1.10. Visit 8 – 6-Month Follow-up Visit (154 to 168 Days After Visit 4): Only for 
Those Participants Who Originally Received BNT162b2 or Placebo Recipients Who 
Decline BNT162b2

Record SAEs as described in Section 8.3.

Record nonstudy vaccinations as described in Section 6.5.

Confirm 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 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 9 – 12-Month Follow-up Visit (350 to 378 Days After Visit 4): Only for 
Those Participants Who Originally Received BNT162b2 or Placebo Recipients Who 
Decline BNT162b2

Record SAEs as described in Section 8.3.

Collect a blood sample (approximately 25 mL) for immunogenicity testing.

Confirm 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.

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
Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3.
8.11.2. Standard Participants
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 and 
safety profile by age.

Obtain any medical history of clinical significance.

Perform a clinical assessment.  If the clinical assessment indicates that a physical 
examination is necessary to comprehensively evaluate the participant, perform a physical 
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.

Perform urine pregnancy test on WOCBP as described in Section 8.2.4.

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.

Measure the participant’s body temperature (axillary).

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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
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 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.

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.

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 is required:

Fever ≥39.0°C.

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 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 and an unblinded 
dispenser/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.
8.11.2.2. 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; ensure 
that procedures listed prior to administration of the vaccine are conducted prior to 
vaccination.

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.

Perform urine pregnancy test on WOCBP as described in Section 8.2.4.

Discuss contraceptive use as described in Section 10.4.

Record nonstudy vaccinations as described in Section 6.5.

Confirm 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 
remain in the study to be evaluated for safety and immunogenicity (see Section 7.1). 
Participants who have a positive SARS-CoV-2 NAAT result prior to the Vaccination 2 
visit should be handled as described in Section 8.15.

Measure the participant’s body temperature (axillary).

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.

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
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 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 
reactogenicity 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 is required:

Fever ≥39.0°C.

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 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 unblinded 
dispenser/administrator updates the study intervention accountability records.

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
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.
8.11.2.3. Visit 3 – 1-Week Follow-up Visit (6 to 8 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 was 
completed and record stop dates in the CRF if required.

Record nonstudy vaccinations as described in Section 6.5.

Confirm 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 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 – 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 was 
completed and record stop dates in the CRF if required.

Record nonstudy vaccinations as described in Section 6.5.

Confirm 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 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 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 – 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.

Confirm 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 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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8.11.2.6. Between Visits 5 and 6
All participants will be contacted by the site and unblinded to study intervention allocation to 
allow placebo recipients the opportunity to receive BNT162b2 as part of the study.  If the 
participant originally received placebo and wants to receive BNT162b2, he or she will follow
the procedures in Section 8.16 and the SoA in Section 1.3.3.
8.11.2.7. Visit 6 – 6-Month Follow-up Visit (154 to 168 Days After Visit 2): Only for 
Those Participants Who Originally Received BNT162b2 or Placebo Recipients Who 
Decline BNT162b2

Record SAEs as described in Section 8.3.

Record nonstudy vaccinations as described in Section 6.5.

Confirm 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 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.
8.11.2.8. Visit 7 – 12-Month Follow-up Visit (350 to 378 Days After Visit 2): Only for 
Those Participants Who Originally Received BNT162b2 or Placebo Recipients Who 
Decline BNT162b2

Record SAEs as described in Section 8.3.

Collect a blood sample (approximately 25 mL) for immunogenicity testing.

Confirm 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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
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 to 
ascertain further details and determine whether a site visit is clinically indicated.  If a 
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 the 
following 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 of 
a 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 the 
CRF.
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 assessed 
at the next study visit.
During the unscheduled visit, the reactions/events should be assessed by the investigator or a 
medically qualified member of the study staff such as a study physician or a study nurse, as 
applicable to the investigator’s local practice, who will:

Measure body temperature (°C) (axillary).

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 Disease Surveillance
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, optimally 
within 3 days of symptom onset.  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’s opinion, the clinical picture is more indicative of a possible 
COVID-19 illness than vaccine reactogenicity.  Participants may utilize a COVID-19 illness 
e-diary via 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, 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.

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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, videoconferencing software) remotely, 
thus allowing the participant and investigator 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.

Confirm 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 local test results of COVID-19 and local diagnosis of COVID-19 as available.

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)
This visit is expected to involve the sharing of healthcare information and services via 
telecommunication technologies (eg, audio, video, videoconferencing software) remotely, 
thus allowing the participant and investigator to communicate on aspects of clinical care.

Record AEs, as appropriate as described in Section 8.3.

Confirm 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.
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 
established.  The participant 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:

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
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.
8.15. SARS-CoV-2 NAAT Results From Vaccination 1 and Vaccination 2 Visits
Nasal (midturbinate) swabs for SARS-CoV-2 NAAT are obtained at Visits 1 and 4 (clinical 
laboratory subset) or Visits 1 and 2 (standard participants) to describe the immune responses 
elicited by a prophylactic BNT162b2 vaccine in participants with or without confirmed 
COVID-19 before Dose 2 and during the study (the secondary and exploratory objectives).
Research laboratory–generated positive results from the Vaccination 1 and Vaccination 2 
visit swabs will be provided to the site once available, but this will not be in real time. The 
investigator must report the positive result to the community health center according to the 
local regulation in Japan.
Participants who have a positive SARS-CoV-2 NAAT result prior to the Vaccination 2 visit 
(Visit 2 for standard participants, Visit 4 for the clinical laboratory subset) should be handled 
as follows:

Positive SARS-CoV-2 test with no symptoms, either at Visit 1 or any time between 
Visit 1 and the Vaccination 2 visit: 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.
8.16. Procedures for Administration of BNT162b2 to Those Originally Assigned to 
Placebo After Approval of Protocol Amendment 3
All participants will be contacted by the site and unblinded to study intervention allocation to 
allow placebo recipients the opportunity to receive BNT162b2 as part of the study.  Visit 101 
could occur at the same time as the original Visit 8 for the clinical laboratory subset or 

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Visit 6 for the standard participants, if the participants originally received placebo and want 
to receive BNT162b2.
8.16.1. Visit 101 – Vaccination 3 (After Protocol Amendment 3 is Approved by the IRB)
Before vaccination and before any study-related procedures are performed, voluntary, 
written, informed consent (via an ICD addendum) will be obtained from the participant.  
Each signature on the ICD addendum must be personally dated by the signatory.  The 
investigator or his or her designee will also sign the ICD addendum.  A copy of the signed 
and dated ICD addendum must be given to the participant.

Confirm the participant originally received only placebo at Vaccinations 1 and 2.  
Secondary confirmation by another site staff member is required.

Perform a urine pregnancy test on WOCBP as described in Section 8.2.4.

Discuss contraceptive use as described in Section 10.4.

Record nonstudy vaccinations as described in Section 6.5.

Confirm 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 inclusion criteria 2, 3, and 4 are met and exclusion criteria 1, 3, 
6, 7, 8, 9, 10, 12, 13, and 15 are not met.  If, in the investigator’s judgment, vaccination is 
in the best interests of the participant, vaccination may proceed, even if inclusion criteria 
are not met and exclusion criteria are met.  Such exceptions should be recorded in the 
participant’s source documents.

Measure the participant’s body temperature (axillary).

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.  If a sample 
for this purpose has already been collected in the previous 7 days (eg, per the procedures 
at Visit 8 for the clinical laboratory subset or Visit 6 for the standard participants), a 
second sample need not be collected.

Obtain the participant’s vaccine vial allocation using the IRT system.

Site staff member(s) will dispense/administer 1 dose of BNT162b2 into the deltoid 
muscle of the preferably nondominant arm.

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
Site staff must observe the participant for at least 30 minutes after BNT162b2 
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.

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 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 and the 
dispenser/administrator updates the study intervention accountability records.
8.16.2. Visit 102 – Vaccination 4 (19 to 23 Days After Visit 101)
It is anticipated that the procedures below will be conducted in a stepwise manner.

Record AEs as described in Section 8.3.

Perform a urine pregnancy test on WOCBP as described in Section 8.2.4.

Discuss contraceptive use as described in Section 10.4.

Record nonstudy vaccinations as described in Section 6.5.

Confirm 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 inclusion criteria 2, 3, and 4 are met and exclusion criteria 1, 3, 
6, 7, 8, 9, 10, 12, 13, and 15 are not met.  If, in the investigator’s judgment, vaccination is 
in the best interests of the participant, vaccination may proceed, even if inclusion criteria 
are not met and exclusion criteria are met.  Such exceptions should be recorded in the 
participant’s source documents.

Measure the participant’s body temperature (axillary).

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Obtain the participant’s vaccine vial allocation using the IRT system.

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
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.

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.

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 the participant experiences any respiratory 
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study contact.

Complete the source documents.

The investigator or an authorized designee completes the CRFs and the 
dispenser/administrator updates the study intervention accountability records.
8.16.3. Visit 103 – 1-Month After Vaccination 4 Follow-up Telephone Contact (28 to 
35 Days After Visit 102)

Contact the participant by telephone but, if desired, may be conducted in person.

Record AEs as described in Section 8.3.

Record nonstudy vaccinations as described in Section 6.5.

Confirm 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 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 the participant experiences any respiratory 
symptoms as detailed in Section 8.13.

Schedule an appointment to call the participant by telephone for the next study contact.

Complete the source documents.

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
The investigator or an authorized designee completes the CRFs.
8.16.4. Visit 104 – 6-Months After Vaccination 4 Follow-up Telephone Contact (175 to 
189 Days After Visit 102)

Contact the participant by telephone but, if desired, may be conducted in person.

Record SAEs as described in Section 8.3.

Record nonstudy vaccinations as described in Section 6.5.

Confirm 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.

Inform the participant that his or her study participation has completed.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a SAP, which will be maintained by the sponsor.  The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses 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 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 other 
missing information will be imputed in the safety analysis.

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The estimands to evaluate the immunogenicity objectives are based on the evaluable 
population 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. Laboratory 
results will not be imputed for the primary analysis.
9.1.2. Statistical Hypotheses
There are no statistical hypotheses in the study.
9.2. Sample Size Determination
The study size of the study is not based on any formal hypothesis test for a safety or 
immunogenicity endpoint. All statistical analyses of safety and immunogenicity will be 
descriptive.
One hundred sixty participants will be randomized in a 3:1 ratio to receive active vaccine 
(120 participants) or placebo (40 participants).  The evaluable immunogenicity population is 
expected to comprise 144 participants (108: active vaccine, 36: placebo) 1 month after 
Dose 2 by assuming a nonevaluable rate of about 10%.
Safety Endpoints
For safety outcomes, Table 4 shows the probability of observing at least 1 AE for a given 
true event rate of a particular AE.  Administration of BNT162b2 to 120 participants provides 
about 70%, 91%, or more than 99% probability of observing at least 1 occurrence of any AE 
with a true incidence rate of 1.0%, 2.0%, or 5.0%, respectively.
Table 4.
Probability of Observing at Least 1 AE by Assumed True Event Rates
Assumed True Event Rate of an AE
N=120
1.0%
0.701
1.5%
0.837
2.0%
0.911
3.0%
0.974
5.0%
0.998
Immunogenicity Endpoints
To assess precision for the immunogenicity results of the primary immunogenicity endpoints, 
a precision measure for GMT of a given SARS-CoV-2 serum neutralizing titer is defined as 
the relative distance from the lower limit of the 2-sided 95% CI for the GMT to the GMT, 
calculated as (lower limit of CI/[GMT]) × 100%.  A precision measure of 80% means that 
the lower 2-sided 95% confidence limit of the GMT is 20% lower than the GMT for that 
serotype.

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Currently, immunogenicity data up to 14 days after Dose 2 for the BNT162b1 30-µg group 
(18-55 years of age) for the C4591001 study are available. Standard deviations (on the 
natural log scale) obtained from the data are used in the calculations of the confidence limits 
of GM (Table 5).
With 108 evaluable participants in the active vaccine group, the lower 95% confidence limits 
of the GMTs would be about 10% lower than the corresponding GMTs.
Table 5.
Precision of Each SARS-CoV-2 Assay
Assay
Assumed Standard Deviation
(Natural Log)
Evaluable Participants = 108
SARS-CoV-2 serum neutralizing titer
0.58
90%
Note: Standard deviations were derived at 14 days after Dose 2 for the C4591001 study. 
9.3. Analysis Sets
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who have a signed ICD.
Randomized
All participants who are assigned a randomization number in 
the IWR system.
Evaluable immunogenicity
(primary analysis 
population)
All eligible randomized participants who receive 2 doses of 
the vaccine to which they are randomly assigned, with Dose 2 
received 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 other major protocol deviations as determined by 
the clinician.
All-available 
immunogenicity
All randomized participants who receive at least 1 dose of the 
study intervention with at least 1 valid and determinate 
immunogenicity result after Dose 2.
Safety
All randomized participants who receive at least 1 dose of the 
study 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 the 
analyses and the procedures for accounting for missing, unused, and spurious data.  This 
section provides a summary of the planned statistical analyses of the primary, secondary, and 
exploratory endpoints.

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9.4.1. Immunogenicity Analyses
The statistical analysis of immunogenicity results will be primarily based on the evaluable 
immunogenicity population as defined in Section 9.3.
An additional analysis will be performed based on the all-available population if there is a 
large enough difference in sample size between the all-available immunogenicity population 
and the evaluable immunogenicity population.  Participants will be summarized according to 
the vaccine group to which they were randomized.
Endpoint
Statistical Analysis Methods
Primary 
immunogenicity 
GMTs of SARS-CoV-2 serum neutralizing titers
For SARS-CoV-2 serum neutralizing titers, the GMTs and 2-sided 
95% CIs will be provided for each group at the following time point:

1 Month after Dose 2 
Geometric means will be calculated as the mean of the assay results 
after making the logarithm transformation and then exponentiating the 
mean to express results on the original scale.  Two-sided 95% CIs will 
be obtained by taking natural log transforms of titers, calculating the 
95% CI with reference to the t-distribution, and then exponentiating the 
confidence limits.
GMFRs of SARS-CoV-2 serum neutralizing titers
For SARS-CoV-2 serum neutralizing titers, the GMFRs and 2-sided 
95% CIs will be provided for each group at the following time point:

To 1 month after Dose 2 from the prevaccination time point
GMFRs will be limited to participants with nonmissing values prior to 
the first dose and at the postvaccination time point.  The GMFR will be 
calculated 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 the 
logarithmically transformed assay results and exponentiating the 
confidence limits.

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Endpoint
Statistical Analysis Methods
Secondary 
immunogenicity
GMTs of SARS-CoV-2 serum neutralizing titers
For SARS-CoV-2 serum neutralizing titers, GMTs and 2-sided 95% 
CIs will be provided for each group at each of the following time 
points:

Baseline, 21 days after Dose 1; 7 and 14  days and 6 and 
12 months after Dose 2
GMTs will be calculated using the same methodology as described for 
the primary endpoints.
GMFRs of SARS-CoV-2 serum neutralizing titers
For SARS-CoV-2 serum neutralizing titers, the GMFRs and 2-sided 
95% CIs will be provided for each group at each of the following time 
points:

To 21 days after Dose 1, and 7 and 14 days and 6 and 
12 months after Dose 2, from the prevaccination time point
GMFRs will be calculated using the same methodology as described 
for the primary endpoints.
GMTs and GMFRs of SARS-CoV-2 serum neutralizing titers for 
participants with/without confirmed COVID-19 before Dose 2
GMTs, GMFRs, and their 2-sided 95% CIs will be provided for each 
group at each of the time points for participants with and without 
confirmed COVID-19 before Dose 2.
GMTs and GMFRs will be calculated using the same methodology as 
described for the primary endpoints.
Exploratory 
immunogenicity
GMTs and GMFRs of SARS-CoV-2 serum neutralizing titers for 
participants with/without confirmed COVID-19 during the study
GMTs, GMFRs, and their 2-sided 95% CIs will be provided for each 
group at each of the time points for participants with and without 
confirmed COVID-19 during the study.
GMTs and GMFRs will be calculated using the same methodology as 
described for the primary endpoints.

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Endpoint
Statistical Analysis Methods
Percentage of participants with the immune response (non-S) to 
SARS-CoV-2 for N-binding antibody at the time points for 
participants with/without confirmed COVID-19 during the study 
when data are available
The Clopper-Pearson method will be used to calculate the CIs.
RCDCs for immunogenicity results
Empirical RCDCs will be provided for SARS-CoV-2 serum 
neutralizing titers after Dose 2.
9.4.2. Safety Analyses
Endpoint
Statistical Analysis Methods
Primary
Descriptive statistics will be provided for each reactogenicity endpoint 
for each vaccine group.  Local reactions and systemic 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 percentages of participants with the 
indicated endpoint and the associated Clopper-Pearson 95% CIs.
For the clinical laboratory subset, 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 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 indicated endpoint and the 
associated Clopper-Pearson 2-sided 95% CIs.
AEs will be categorized according to Medical Dictionary for 
Regulatory 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 clinical 
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 term is defined as a Tier 2 
event if there are at least 4 of participants 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 the difference between the vaccine and placebo groups in 
the percentage of participants reporting the events based on the 

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Endpoint
Statistical Analysis Methods
Miettinen and Nurminen method9 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 the assumption 
that the test statistic is asymptotically normally distributed.
Descriptive summary statistics (counts, percentages, and associated 
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 12 months after Dose 2 will be provided for each 
vaccine group.
AEs and SAEs reported only for participants originally assigned to 
placebo who accepted the opportunity to receive BNT162b2 after 
approval of protocol amendment 3 will be summarized separately.
The safety analyses are based on the safety population.  Participants 
will be summarized by vaccine group according to the investigational 
vaccine 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
9.5. Interim Analyses
No interim analysis is planned in this study.
9.5.1. Analysis Timing
Statistical analyses will be carried out when the following data are available:

Primary analysis: complete safety and immunogenicity data through 1 month after Dose 2 
from all participants
Interim summary at different time points may be considered to support internal decisions for 
additional visits and to support regulatory interactions.

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The study final analysis will be performed when all participants have completed the study 
and all immunogenicity and safety data are available.
9.6. Data Monitoring Committee or Other Independent Oversight Committee
An external DMC will be utilized for this study and will review cumulative unblinded safety 
data throughout the study in accordance with the charter.
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 and GPSP.
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 of 
changes 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 requirements 
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 applicable 
regulatory 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 measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.

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10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant 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 nature 
and 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 the 
participant’s personal data.
The participant must be informed that his/her personal study-related data will be used by the 
sponsor 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, by 
appropriate 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 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.  Participants who are rescreened 
are required to sign a new ICD.

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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.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
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 and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site will be responsible 
for 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 personal 
data, 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 numerical 
code; participant names will not be transferred.  All other identifiable data transferred to the 
sponsor 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 each 
participant’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 data 
consistent with the clinical study agreement and applicable privacy laws.
10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results 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, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which 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, 

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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 in 
accordance with the format and timelines set forth by EU requirements.
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 are 
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website.  Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods.  Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data.  Policy 0070 applies to new 
marketing 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.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, 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 with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform 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.

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10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information 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 to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory 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 or 
inspections 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 and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan.
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 entered 
into 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 be 
transferred 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 such 
data are promptly and irrevocably deleted from all systems.

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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 cooperate 
with 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.
10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity 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.
10.1.8. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
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 upon 
study 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 limited 
to:

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;

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
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 the 
investigators, 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.
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.
10.1.9. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission.  This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer 
intervention-related information necessary for the appropriate scientific presentation or 
understanding of the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites.  In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements.
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.

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10.1.10. Sponsor’s Qualified Medical Personnel
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 to 
provide 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 the 
investigator 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
The following safety laboratory tests will be performed at times defined in the SoA section of 
this 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 of 
blood.  Unscheduled clinical laboratory measurements may be obtained at any time during 
the study to assess any perceived safety issues.
Hematology
Chemistry
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN
Creatinine
AST
ALT
Total bilirubin
Alkaline phosphatase

Urine pregnancy test (β-hCG)
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) 
Potentially Life 
Threatening 
(Grade 4) 
Hemoglobin 
(Female) - g/dL 
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
<8.0 
Hemoglobin 
(Male) - g/dL 
12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
<8.5 
WBC increase -
cells/mm3
10,800 – 15,000 
15,001 – 20,000 
20,001 – 25, 000 
>25,000 
WBC decrease -
cells/mm3
2,500 – 3,500 
1,500 – 2,499 
1,000 – 1,499 
<1,000 
Lymphocytes 
decrease - cells/mm3
750 – 1,000 
500 – 749 
250 – 499 
<250 
Neutrophils decrease 
- cells/mm3
1,500 – 2,000 
1,000 – 1,499 
500 – 999 
<500 
Eosinophils -
cells/mm3
650 – 1500 
1501 - 5000 
>5000 
Hypereosinophilic 
Platelets decreased -
cells/mm3
125,000 – 140,000 
100,000 – 124,000 
25,000 – 99,000 
<25,000 

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Table 6.
Laboratory Abnormality Grading Scale
Chemistry
Mild (Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
BUN - mg/dL 
23 – 26 
27 – 31 
> 31 
Requires dialysis 
Creatinine – mg/dL 
1.5 – 1.7 
1.8 – 2.0 
2.1 – 2.5 
> 2.5 or requires 
dialysis 
Alkaline 
phosphate –
increase by factor 
1.1 – 2.0 x ULN 
2.1 – 3.0 x ULN 
3.1 – 10 x ULN 
>10 x ULN 
Liver function tests 
– ALT, AST 
increase by factor 
1.1 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10 x ULN 
>10 x ULN 
Bilirubin – when 
accompanied 
by any increase in 
liver function test -
increase by factor 
1.1 – 1.25 x ULN 
1.26 – 1.5 x ULN 
1.51 – 1.75 x ULN 
>1.75 x ULN 
Bilirubin – when 
liver function test is 
normal - increase by 
factor 
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 
considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

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 an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though 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 safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’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 death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant 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 
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 to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.

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An SAE is defined as any untoward medical occurrence that, at any dose:
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline 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 medical 
significance 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 defect
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 
non-pathogenic, is considered serious.  The event may be suspected from clinical 
symptoms or laboratory findings indicating an infection in a patient exposed to a 
Pfizer product.  The terms “suspected transmission” and “transmission” are 
considered synonymous.  These cases are considered unexpected and handled as 
serious 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
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data 
become available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF 
and for reporting serious adverse events on the Vaccine SAE Reporting 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 or breastfeeding, and occupational exposure. 
It should be noted that the Vaccine SAE Reporting 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 
Reporting Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the Vaccine 
SAE Reporting Form to 
Pfizer Safety Within 24 
Hours of Awareness
SAE
All
All
Nonserious AE
All
None

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AE and SAE Recording/Reporting
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding, and 
occupational exposure
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding
Occupational exposure is 
not recorded.
All (and EDP supplemental 
form for EDP)  
Note:  Include all SAEs 
associated with exposure 
during pregnancy or 
breastfeeding. Include all 
AEs/SAEs associated with 
occupational 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 
Reporting Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested 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.

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.

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AE and SAE Recording/Reporting
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: 
GRADE If required on the AE page of the CRF, the investigator will use the 
adjectives MILD, MODERATE, SEVERE, or LIFE-THREATENING to 
describe 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 usual 
function.
2
MODERATE
Interferes to some extent with participant's usual 
function.
3
SEVERE
Interferes significantly with participant's usual 
function.
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 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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Assessment of Causality

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 is 
very important that the investigator always make an assessment of causality 
for every 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 the 
event, 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 Vaccine SAE Reporting 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 the 
sponsor 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 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 
of receipt of the information.

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10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via Vaccine SAE Reporting Form

Facsimile transmission of the Vaccine SAE Reporting Form is the preferred 
method to transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the Vaccine SAE Reporting Form sent by overnight mail 
or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the Vaccine SAE Reporting Form pages within the designated 
reporting 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, which 
corresponds 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) and agree 
to remain abstinent. 
OR

Must agree to use a male condom when engaging in any activity that allows for passage 
of ejaculate to another person.

In addition to male condom use, a highly effective method of contraception may be 
considered 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 be 
considered.
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.
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied 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 a 
postmenopausal 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 they 
wish 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 of 
ovulation.a
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner:

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed.  If not, an additional highly effective method 
of contraception should be used.  The spermatogenesis cycle is approximately 
90 days.
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

Oral;

Intravaginala;

Transdermala;

Injectable.a
7. Progestogen-only hormone contraception associated with inhibition of ovulation:

Orala;

Injectable.a
                                                
a Unapproved in Japan.

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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 associated 
with the study intervention.  The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant.
9. Progestogen-only oral hormonal contraception where inhibition of ovulation is not the 
primary mode of action.a
10. Male or female condom with or without spermicide.
11. Cervical cap,a diaphragm,a or sponge with spermicide.a
12. A combination of male condom with either cervical cap,a diaphragm,a or sponge with 
spermicidea (double-barrier methods).
                                                
a Unapproved in Japan.

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10.5. Appendix 5: Genetics
Not applicable.
10.6. Appendix 6: 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 in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some participants, transaminase elevations are a harbinger of a 
more 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.”
LFTs are not required as a routine safety monitoring procedure in this study.  However, 
should an investigator deem it necessary to assess LFTs because a participant presents with 
clinical signs/symptoms, such LFT results should be managed and followed 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 be 
elevated 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 a 
potential 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 all 
other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’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, the 
following 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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
Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually 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.
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 of 
Hy’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 blood 
for further testing, as needed, for further contemporaneous analyses at the time of the 
recognized 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 or 
allergic 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 no 
other 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 the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.

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10.7. Appendix 7: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
2019-nCoV
novel coronavirus 2019
Abs
absolute
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
-hCG
beta-human chorionic gonadotropin
BUN
blood urea nitrogen
CBER
Center for Biologics Evaluation and Research
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSR
clinical study report
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
EC
ethics committee
ECG
electrocardiogram
ECLIA
electrochemiluminescence immunoassay
eCRF
electronic case report form
e-diary
electronic diary
EDP
exposure during pregnancy
EMA
European Medicines Agency
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration 
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GM
geometric mean
GMFR
geometric mean fold rise
GMT
geometric mean titer
GPSP
Good Postmarketing Study Practice

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Abbreviation
Term
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
investigator’s brochure
ICD
informed consent document
ICH
International Council for Harmonisation
ID
identification
IgG
immunoglobulin G
IMP
investigational medicinal product
IND
investigational new drug
INR
international normalized ratio
IP manual
investigational product manual
IPAL
Investigational Product Accountability Log
IRB
institutional review board
IRT
interactive response technology
IV
intravenous(ly)
IWR
interactive Web-based response
LFT
liver function test
LLOQ
lower limit of quantitation
LNP
lipid nanoparticle
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MERS
Middle East respiratory syndrome
MHLW
Ministry of Health, Labour and Welfare
modRNA
nucleoside-modified messenger ribonucleic acid
N
nucleoprotein
N/A
not applicable
NIMP
noninvestigational medicinal product
non-S
nonspike protein
P2 S
SARS-CoV-2 full-length, P2 mutant, prefusion spike glycoprotein
PI
principal investigator
PPE
personal protective equipment
PT
prothrombin time
RBC
red blood cell
RBD
receptor-binding domain
RCDC
reverse cumulative distribution curve
RNA
ribonucleic acid

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Abbreviation
Term
RSV
respiratory syncytial virus
S1
spike protein S1 subunit
SAE
serious adverse event
SAP
statistical analysis plan
SARS
severe acute respiratory syndrome
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
TBili
total bilirubin
ULN
upper limit of normal
uRNA
unmodified messenger ribonucleic acid
US
United States
vax
vaccination
WBC
white blood cell
WHO
World Health Organization
WOCBP
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/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/therapeutic-
options.html. Updated: 25 Apr 2020. Accessed: 26 Jun 2020.
4
Rauch S, Jasny E, Schmidt KE, et al. New vaccine technologies to combat outbreak 
situations. Front Immunol 2018;9:1963.
5
Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics—developing a new class of 
drugs. 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 for 
healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials. 
Rockville, MD: Center for Biologics Evaluation and Research; September 2007.
9
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 
1985;4(2):213-26.

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