A PHASE 1/2/3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLIND, DOSE-FINDING STUDY TO EVALUATE THE SAFETY, TOLERABILITY, IMMUNOGENICITY, AND EFFICACY OF SARS-COV-2 RNA VACCINE CANDIDATES AGAINST COVID-19 IN HEALTHY INDIVIDUALS
Phase: PHASE2
Conditions: SARS-CoV-2 Infection, COVID-19
Sponsor: BioNTech SE

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
Page 1
A PHASE 1/2/3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLIND, 
DOSE-FINDING STUDY TO EVALUATE THE SAFETY, TOLERABILITY, 
IMMUNOGENICITY, AND EFFICACY OF SARS-COV-2 RNA VACCINE 
CANDIDATES AGAINST COVID-19 IN HEALTHY INDIVIDUALS
Study Sponsor:
BioNTech
Study Conducted By:
Pfizer
Study Intervention Number:
PF-07302048
Study Intervention Name:
RNA-Based COVID-19 Vaccines
US IND Number:
19736
EudraCT Number:
2020-002641-42
Protocol Number:
C4591001
Phase:
1/2/3
Short Title: A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, and 
Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Individuals
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.

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Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Protocol amendment 20
15 September 2022

Added language pertaining to early completion of 
this clinical trial as agreed with FDA and EMA.

Updated schedules of assessments and 
protocol text to identify study visits that no 
longer need to be completed.

Updated Study Procedures to describe site 
actions following approval of protocol 
amendment 20.

Removed the objective to describe the safety and 
immunogenicity of prophylactic BNT162b2 in 
individuals 16 to 55 years of age vaccinated with 
study intervention produced by manufacturing 
“Process 1” or “Process 2” because of the volume 
of BNT162b2 now distributed and administered 
globally using manufacturing “Process 2,” making 
this comparison unwarranted.

Removed corresponding endpoints.

Removed corresponding wording throughout 
the protocol text.

Added rationale for removal of this objective.

Added wording regarding return of e-diary devices 
or removal of application from participants’
personal devices at the end of the study.
Protocol amendment 19
21 March 2022

Inclusion of an additional 30-µg dose of BNT162b2
for eligible participants from protocol amendments 
13-15 who received at least 3 doses of BNT162 in 
the study.

Added corresponding objectives, estimands, 
and endpoints.

Added corresponding SoA and procedures.

Added details in the statistical methods
sections.

Added language to permit early discontinuation of 
participants for reasons including but not limited to 
the increased access and availability of BNT162b2
in the real world, reducing the value of participant 
involvement and observation in this clinical trial.

Updated the eligibility window for participants to 
receive the third (booster) dose under protocol 
amendment 18 from at least 6 months after Dose 2 
to at least 3 months after Dose 2 to provide 
maximum opportunity to all participants to receive 
the third dose.

Updated the existing objectives, estimands, and 
endpoints in line with the revised schedule and 
study duration, and where applicable, removed
what is no longer relevant.

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Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
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Document History
Document
Version Date
Summary and Rationale for Changes

Clarified AE/SAE collection requirements for 
participants enrolled under protocol amendments
18 and 19.

Updated risk assessment as BNT162b2 is no longer 
a novel vaccine and there are extensive data 
available from both clinical trial and real-world 
settings.
Protocol amendment 18
07 September 2021

Addition of procedures for monitoring potential 
myocarditis or pericarditis.

Addition of a third dose of BNT162b2 for 
participants who meet specified recommendations 
and have not yet received a third dose.

Added corresponding objectives, estimands, 
and endpoints.

Added corresponding SoA and procedures.

Added details in the statistical methods
sections.

Added the instruction that participants who receive 
COVID-19 vaccines outside of the study from 
protocol amendment 18 onwards should be 
withdrawn.
Protocol amendment 17
20 July 2021

Changed the analysis method for the within-group 
comparison of seroresponse rates for Phase 3 
booster and VOC immunogenicity assessment from 
the Miettinen and Nurminen method to the adjusted 
Wald interval to provide tighter CI and higher 
power for NI in most cases.

Clarified that any nonstudy coronavirus vaccines 
are to be recorded at any time they are given during 
study participation.

Clarified that participants who are randomized in 
the C4591031 study should be withdrawn from this 
study.
Protocol amendment 16
28 May 2021

Removed the requirement to conduct a potential 
COVID-19 convalescent visit following each 
potential COVID-19 illness visit.

Clarified that only non-Pfizer interventional studies 
for prevention of COVID-19 are prohibited 
throughout study participation.

Clarified that during the 7 days following each 
vaccination (either as part of this study, co-enrolled 
C459 studies, or the B7471026 [20vPnC] study), 
potential COVID-19 symptoms that overlap with 
specific systemic events (ie, fever, chills, new or 
increased muscle pain, diarrhea, vomiting) should 
not trigger a potential COVID-19 illness visit 
unless, in the investigator’s opinion, the clinical 
picture is more indicative of a possible COVID-19 
illness than vaccine reactogenicity.

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Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
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Document
Version Date
Summary and Rationale for Changes

Revised the noninferiority margin from 2-fold to 
1.5-fold and added a minimum GMR point estimate 
of ≥0.8 as another success criterion for Phase 3 
booster and VOC immunogenicity assessment. 
Noninferiority is met if the lower limit of the alpha-
adjusted CI for the GMR is >0.67 and the point 
estimate of the GMR is ≥0.8.

Added Phase 1 booster participants to the Dose 3 
booster immunogenicity population definitions.

Included a booster safety population definition.

Clarified that the interim analyses for booster 
immunogenicity will be conducted when serology 
data for the reference strain or for the SA strain are 
available.
Protocol amendment 15
25 March 2021

In order to further characterize booster responses 
induced by BNT162b2, 2 additional lower-dose 
booster groups have been added to the subset for 
evaluation of boostability and protection against 
emerging VOCs. An additional 5-µg or 10-µg dose 
of BNT162b2 will be given to approximately 144 
Phase 3 participants approximately 5 to 7 months 
after their second dose of BNT162b2.

To further describe cell-mediated immune 
responses following isolations of PBMCs in a 
subset of both the Phase 3 participants who receive 
a single booster vaccination and the 
BNT162b2-naïve group who receive BNT162b2SA, 
additional genetic testing may also be performed; 
corresponding details and an appendix have been 
added.

An exploratory objective was added for Phase 3 
participants to describe the immune response to a 
third dose of BNT162b2 or a third or fourth dose of 
BNT162b2SA at later time points to align with 
analyses and corresponding changes detailed in the 
statistical section.

Removed the lower age limit for eligibility for 
administration of BNT162b2 to those originally 
assigned to placebo: this will now be covered in the 
recommendations detailed separately, and available 
in the electronic study reference portal.

Allowed administration of BNT162b2 at Visits 101 
and 102 to pregnant participants in certain 
circumstances.

To align with contraception requirements, reduced 
the EDP reporting period to 28 days after the last 
dose of study intervention.

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Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
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Document
Version Date
Summary and Rationale for Changes
Protocol amendment 14
02 March 2021

In order to further describe duration of protection,
and heterologous/homologous protection against 
the emerging VOCs, an additional dose of 
BNT162b2 or BNT162b2SA will be given to 
approximately 600 Phase 3 participants 
approximately 5 to 7 months after their second dose 
of BNT162b2; a further dose of BNT162b2SA will 
be given to approximately 30 of those participants 
who receive BNT162b2SA: 

Added corresponding objectives, estimands, 
and endpoints

Added corresponding SoA and procedures

Added details in the statistical methods 
sections.

Approximately 300 BNT162b2-naïve participants 
will be enrolled and receive 2 doses of 
BNT162b2SA to describe heterologous/homologous 
protection against the emerging VOCs and 
reference strains:

Added corresponding objectives, estimands, 
and endpoints

Added corresponding SoA and procedures

Added details in the statistical methods 
sections.

Cell-mediated immune responses will also be 
described following isolations of PBMCs in a 
subset of both the Phase 3 participants who receive 
a single booster vaccination and the 
BNT162b2-naïve group who receive BNT162b2SA

Added the asymptomatic case definitions in Section 
8.1 and further clarified the secondary definition for 
asymptomatic case based on seroconversion of N-
binding antibody.

Defined the analysis populations used for 
evaluation of asymptomatic infection based on 
seroconversion of N-binding antibody and based on 
NAAT from participants who consent to active 
surveillance.

Clarified that unblinding for a nonemergency 
reason should be conducted outside of the IRT 
system.

Clarified that if multiple visits occur on the same 
day, all procedures for all visits must be conducted 
(including collection of all blood samples).

Clarified the plan for stepwise unblinding of the 
sponsor in the study.

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
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Version Date
Summary and Rationale for Changes
Protocol amendment 13
12 February 2021

In order to describe the boostability of BNT162, an 
additional dose of BNT162b2 at 30 µg will be 
given to Phase 1 participants approximately 6 to 12 
months after their second dose of BNT162b1 or 
BNT162b2: 

Added corresponding objectives, estimands, 
and endpoints

Added corresponding SoA and procedures

Added details in the statistical methods
sections.

Clarified the population used for analysis of 
reactogenicity endpoints.

To align with current recommendations, 
investigators may exercise judgment on review of
inclusion and exclusion criteria ahead of 
vaccination with BNT162b2 for participants who 
originally received placebo.

Clarified that if a participant has previously 
withdrawn consent and wishes to receive a 
COVID-19 vaccine outside the study, they may 
request to know which study intervention they 
received for Vaccination(s) 1/2 without needing to 
reconsent.

Participants who provide biweekly swabs for 
surveillance of asymptomatic infection should now 
continue to swab even after unblinding if they 
originally received BNT162b2, to maximize the 
numbers of swabs to be collected.

Clarified the procedures for unscheduled visits to 
administer a second dose in the event a participant 
received only 1 dose of BNT162b2.
Protocol amendment 12
14 January 2021

Because of a formatting error in protocol 
amendment 11, exclusion criterion 4 was 
inadvertently added to exclusion criterion 3 and the 
subsequent criteria renumbered. This amendment 
corrects that error.

Because of a change in the pace with which 
participants ≥16 years of age who originally 
received placebo will become eligible for receipt 
of BNT162b2, text was updated throughout the 
protocol to reflect that this will happen in a phased 
manner, with recommendations detailed separately 
and available in the electronic study reference 
portal.

Clarified that participants who are unblinded 
because they become potentially eligible for 
receipt of BNT162b2 will not participate in 
surveillance for asymptomatic SARS CoV-2 
infection.

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Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
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Document History
Document
Version Date
Summary and Rationale for Changes

Corrected the exploratory objective to describe 
non-S seroconversion to SARS-CoV-2 to clarify 
that this will only include participants who 
received BNT162b2 at initial randomization (since 
those who received it subsequently do not have 
blood drawn).

In line with current recommendations, removed the 
requirement to discontinue study intervention 
because of a diagnosis of COVID-19 during the 
study.
Protocol amendment 11 
04 January 2021

Added approaches to evaluate efficacy against 
asymptomatic SARS-CoV-2 infection:
Added objectives, estimands, and endpoints, 
and statistical methods, for assessment via 
N-binding antibody seroconversion;
Added a potential intensive surveillance period 
for nasal swabbing, for assessment via NAAT:

Corresponding objectives, estimands, and 
endpoints added

Corresponding SoA and procedures added

Details added in the statistical methods
sections.

Added the possibility of assessing full-length 
S-binding, instead of S1-binding, IgG levels in 
Phase 2/3.

Clarified in Section 4.1.1 that any Phase 1 placebo 
recipient who has not already been offered the 
opportunity to receive BNT162b2 will be given 
this opportunity at the approximate time 
participants in Phase 2/3 reach Visit 4, for 
consistency with other sections.

Added a sentence to reflect that assent is obtained 
from participants <18 years of age.
Protocol amendment 10
01 December 2020

Added the possibility of administering BNT162b2 
to participants who originally received placebo, 
following any local or national recommendations.

Added the possibility of administering BNT162b2 
to participants who originally received placebo, 
following completion of the active safety 
surveillance period.

Added corresponding exploratory objectives and 
statistical analysis details.

Removed immunogenicity analyses of titers 
greater than defined threshold(s).

Removed the need for blinded COVID-19 case 
review after the final efficacy analysis.

Included the possibility, due to local circumstances 
related to the COVID-19 pandemic, that study 

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Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
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Summary and Rationale for Changes
procedures that do not require in-person participant 
contact may be performed by telehealth.

In light of additional information to better estimate 
the standard deviation of SARS-CoV-2 
neutralizing titers, increased the sample size for the 
noninferiority immunogenicity analysis in 
adolescents 12 to 15 years of age.
Protocol amendment 9
29 October 2020

To better align with the natural history of 
SARS-CoV-2 infection, added Phase 2/3 
secondary efficacy objectives, estimands, and 
endpoints to include COVID-19 cases that occur 
from 14 days after the second dose; also modified 
the existing secondary efficacy objectives, 
estimands, and endpoints to include COVID-19 
cases that occur from 14 days, as well as 7 days, 
after the second dose;

Made corresponding changes to the study 
design, study assessments and procedures, and 
statistical analysis sections.

For operational reasons, removed the interim 
analysis planned after accrual of 32 cases.

Clarified that interim analyses will be conducted 
after accrual of at least 62, 92, and 120 cases.

Included any participants 16 through 17 years of 
age enrolled under this amendment in the 
reactogenicity subset.

Added an unblinded clinical scientist to support 
DMC activities.

Clarified that serology data after a postbaseline 
positive SARS-CoV-2 test result will not be 
included in the analysis based on the evaluable 
immunogenicity populations.
Protocol amendment 8
15 October 2020

Removed “N-binding antibody” and “SARS-CoV-
2 detection by NAAT” as endpoints from the third 
exploratory objective, as these results are used for 
the determination of the population, and are not 
endpoints.

Clarified that the “Process 1” participants included 
in the descriptive analysis of “Process 1”- and 
“Process 2”-manufactured study interventions will 
be selected randomly.

Clarified that surveillance of potential COVID-19 
symptoms should continue even if a participant has 
a positive SARS-CoV-2 test earlier in the study.

Further modified the circumstances in which a 
local NAAT result may be used in the COVID-19 
case definition.

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Final Protocol Amendment 20, 15 September 2022
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
Clarified that for participants who are not in the 
reactogenicity subset, local reactions and systemic 
events following vaccination should be detected
and reported as AEs.

Clarified that premenarchal females are not 
WOCBP.

Made various editorial changes.
Protocol amendment 7
06 October 2020

Reduced the lower age range to include 
adolescents 12 to 15 years of age and added 
corresponding objectives.

Removed reference to COVID-19 antibody testing 
in Section 2.3.2.

Clarified with efficacy estimands and endpoints 
that last dose refers to second dose.

Added an additional exploratory objective to 
describe safety and immunogenicity in participants 
16 to 55 years of age vaccinated with study 
intervention produced by manufacturing “Process 
1” or “Process 2.”

Clarified exclusion criterion 5.

Added Section 6.1.1 to describe manufacturing 
“Process 1” and “Process 2.”

Clarified the degree of unblinding on the unblinded 
submissions team in Section 6.3.3.

Made provision for a second dose of BNT162b2 in 
participants who were affected by a medication 
error at Visit 2 in Section 6.6.

Provided further clarification regarding 
discontinuation of study intervention in 
Section 7.1.

Modified the circumstances in which a local 
NAAT result may be used in the COVID-19 case 
definition.

Added that 2 periods of potential COVID-19 
symptoms within 4 days will be considered as a 
single illness.

Provided guidance in Section 8.13 regarding 
circumstances in which a SARS-CoV-2 test might 
be required even if symptoms within 7 days 
following each vaccination are considered more 
likely due to vaccine reactogenicity.

Made allowance in Section 8.13 for a second 
SARS-CoV-2 test to be performed within the same 
potential COVID-19 illness if it is in accordance 
with routine practice.

Added Section 8.15 to describe the reporting of 
SARS-CoV-2 test results and their implications for 
participants receiving a second vaccine dose.

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Version Date
Summary and Rationale for Changes

Added statistical hypothesis and power analysis for 
evaluation of noninferiority of the immune 
response to BNT162b2 in participants 12 to 15 
years of age to the response in participants 16 to 25 
years of age.

Amended scope of analyses of safety data in 
Section 9.5.1.

Made various editorial changes.
Protocol amendment 6 
(Germany-specific)
23 September 2020

According to regulatory request, inclusion criterion 
1 now specifies that participants less than 18 years 
of age will not be enrolled in the EU.
Protocol amendment 6
08 September 2020

Reordered some procedures in the Phase 2/3 
schedule of activities for consistency with the main 
body of the protocol.

Corrected the window for the 6-month follow-up 
visit to be approximately 6 months after 
Vaccination 2.

Reduced the volume of blood draws to ~20 mL.

Removed the need to have safety data reported for 
participants to be included in the safety objective 
assessment.

Added an exploratory objective to describe safety, 
immunogenicity, and efficacy in participants with 
stable HIV disease.

Increased the sample size for Phase 2/3 to ~43,998.

Clarified that inclusion criterion 4 (ie, participants 
at higher risk for acquiring COVID-19) is 
applicable for Phase 2/3 only, and provided some 
examples.

Removed exclusion criterion 2 (ie, known 
infection with HIV, HCV, or HBV) for Phase 3 
and added criteria for HIV-positive participants.

Decreased the lower age limit and removed the 
upper age limit for inclusion in Phase 2/3 in order 
to evaluate BNT162b2 30 µg in older adolescents 
and those over 85 years of age; updated the title 
and other references to adults to align with this 
change.

Renamed the immunological assays to align with 
other program-level documents.

Removed reference to the SARS-CoV-2 full-
length, P2 mutant, prefusion spike glycoprotein
(P2 S) being “heads up.”

Clarified that a positive SARS-CoV-2 NAAT 
result without symptoms should not result in 
discontinuation of study intervention.

Added clarification that potential COVID-19 
illnesses that are consistent with the clinical 
endpoint definition should not be recorded as AEs.

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
Updated the analysis population descriptions to 
align with the study SAP.
Protocol amendment 5
24 July 2020
Following regulatory feedback:

Renamed Stage 1 to Phase 1, removed Stage 2, and 
renamed Stage 3 to Phase 2/3.

Clarified that a single vaccine candidate, 
administered as 2 doses 21 days apart, will be 
studied in Phase 2/3.

Stated that the vaccine candidate selected for Phase 
2/3 evaluation is BNT162b2 at a dose of 30 µg.

Removed the potential to study BNT162b3.

Immunogenicity data will be summarized for the 
first 360 participants through 1 month after Dose 2, 
rather than through 21 days after Dose 1.

Provided further details of sponsor staff that will 
be unblinded in Phase 2/3.

Clarified which stopping rules apply to which 
phase of the study.
In addition:

Clarified the AE reporting requirements for 
potential COVID-19 illnesses.

Updated that Visit 1 may be conducted across 2 
consecutive days in Phase 2/3.

Moved the immunogenicity objectives in Phase 2/3 
to become exploratory.

Added an additional inclusion criterion to enroll 
participants who, in the judgment of the 
investigator, are at risk for acquiring COVID-19.

Modified exclusion criterion 5, so that participants
with a previous clinical or microbiological 
diagnosis of COVID-19 are excluded from all 
phases of the study.

Clarified that there will be 2 all-available efficacy 
populations.

Clarified that immunogenicity samples will be 
drawn for all participants; analyses will be based 
upon results from subsets of samples, according to 
the purpose.

Updated that the 3-tier approach to summarizing 
AEs will only be performed in Phase 2/3.

Updated that at each interim analysis for efficacy, 
only the first primary objective will be evaluated.

Changed to use the same posterior probability 
(99.5%) for all interim analyses, resulting in case 
split changes in Tables 5, 6, and 7.

Updated the stopping and alert rule parameters for 
enhanced COVID-19.

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Protocol amendment 4
30 June 2020
Given the rapidly evolving pandemic situation, and the 
need to demonstrate VE as soon as possible, the 
protocol has been amended to be powered to meet new 
efficacy objectives. These new efficacy objectives and 
corresponding endpoints have been added to Section 3.
Further nonclinical data are available to support the 
study of the BNT162b3 candidate in humans, and the 
candidate has been added to the protocol.
The 6-month safety follow-up telephone contact has 
been changed to an in-person visit for Stage 3 
participants, to allow collection of an immunogenicity 
blood sample.
The COVID-19 illness visit has now added flexibility 
to permit a remote or in-person visit.
The COVID-19 illness symptoms have been updated to 
align with the FDA-accepted definitions; this change is 
also reflected in the criteria for temporary delay of 
enrollment.
AEs that occur between consent and dosing will now 
be reported on the AE (rather than Medical History) 
CRF, to align with the latest Pfizer protocol template.
Changes have been made to the headings to align with 
the latest Pfizer protocol template.
Clarified that only an unblinded site staff member may 
obtain the participant’s randomization number and 
study intervention allocation.
Additional interim analyses have been added to 
evaluate VE and futility during the study.
As a result of regulatory feedback, an appendix has 
been added to outline the stopping and alert rules to 
monitor for potential enhanced COVID-19.
Protocol amendment 3
10 June 2020
As data have become available from this study and the 
BNT162-01 study in Germany, the following decisions 
were made:

Not to study the BNT162a1 and BNT162c2 
vaccine candidates at this time.  Therefore, these 
candidates have been removed from the protocol.

To study further lower dose levels of the modRNA 
candidates.  Therefore, a 20-µg dose level is 
formally included for BNT162b1 and BNT162b2.

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
To permit individual and group dosing alterations 
for the second dose of study intervention.
Following regulatory feedback, the BNT162b3 vaccine 
candidate has been removed from the protocol until 
further nonclinical data are available to support study in 
humans.
Given the rapidly evolving pandemic situation, 
additional blood draws for exploratory COVID-19 
research, intended to establish an immunological 
surrogate of protection, will be taken from selected 
participants who consent.
In order to increase flexibility enrolling participants, an 
extended screening window (increased from 14 to 28 
days) for sentinel participants in Stage 1 has been 
added.  This is considered acceptable since eligible 
participants are expected to be either healthy or have 
stable medical conditions.
To increase the number of doses that can be obtained 
from available vaccine vials, not all dose levels will 
result in a dosing volume of 0.5 mL.  Precise dosing 
instructions will be provided in the IP manual.
To facilitate the reporting of COVID-19 illness 
diagnoses and potential symptoms to the investigator, 
participants may utilize a COVID-19 illness e-diary.
Protocol amendment 2
27 May 2020
Given the urgent nature of the pandemic situation, the 
following changes allow determination of the 
appropriate human dose level for both younger and 
older adults to move speedily into the next phase of 
clinical evaluation:

Added a new vaccine candidate, BNT162b3, 
modRNA encoding a membrane-anchored RBD

Added a 50-µg dose level for vaccine candidates 
based on the modRNA platform (ie, BNT162b1, 
BNT162b2, and BNT162b3)

Modified the criteria required for the IRC to 
determine dose escalation in the 18- to 55-year age 
cohort and advancement to groups of participants 
65 to 85 years of age
In addition:

Removed hemoglobin change-from-baseline 
abnormalities from the laboratory abnormality 
grading scale as abnormalities should be graded 
based upon absolute values

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Document History
Document
Version Date
Summary and Rationale for Changes
Protocol amendment 1
13 May 2020

Following regulatory feedback:

Modified exclusion criteria and prohibited 
inhaled/nebulized corticosteroids for sentinel 
participants in Stage 1

Clarified that the rapid test for prior COVID-19 
infection for sentinel participants in Stage 1 will be 
used only for screening purposes

Removed time frames for stopping rules

Stated that data supporting the selection of vaccine 
candidate(s)/dose level(s) and schedule(s) for 
Stages 2 and 3 will be submitted to the FDA for 
review

Following preliminary experience in the BioNTech 
study conducted in Germany (BNT162-01):

Decreased the dose levels for BNT162a1 and 
BNT162c2
Additionally:

Clarified the roles of BioNTech and Pfizer

Amended text so that the IRC decision to progress 
group(s) into Stages 2 and 3 can be based upon 
safety and immunogenicity data after Dose 1 or 2

Clarified safety data requirements to permit dose 
escalation

Amended text so that the progression to 
participants 65 to 85 years of age can be based 
upon data from the same RNA platform

Incorporated a protocol administrative change to 
correct the variant designation and the encoded 
antigen to BNT162c2

Clarified that the SARS-CoV-2 neutralizing assay 
does not employ wild-type virus

Clarified that the SARS-CoV-2 spike protein–
binding antibody assay is specific for the S1 
subunit

Clarified that efficacy against COVID-19 is based 
upon illness (not infection) rate ratio

Incorporated a protocol administrative change to 
state that the study placebo may be supplied in a 
glass or plastic vial

Corrected a typographical error in Section 6.5.1 
regarding the time frame for prior receipt of 
blood/plasma products or immunoglobulins

Corrected a typographical error in Table 2 
regarding the lower limit of diameter (cm) for mild 
redness and swelling

Updated the °C fever scale in Table 4 to ensure 
that all potential °F values are correctly assigned

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Document History
Document
Version Date
Summary and Rationale for Changes

Incorporated a protocol administrative change to 
clarify that a rapid test for prior COVID-19 
infection will be performed for sentinel 
participants in Stage 1, and a serum sample will be 
drawn for potential future assessment

Clarified that, after screening, physical 
examinations in sentinel participants in Stage 1
will be directed

Clarified the descriptions of the populations for 
analysis to align with the statistical analysis plan

Added a complete safety and immunogenicity 
analysis approximately 6 months after Dose 2 for 
all participants in Stage 3

Amended text so that the stopping rules apply to an 
RNA platform rather than a specific vaccine 
candidate
Original protocol
15 April 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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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................24
LIST OF FIGURES .................................................................................................................25
1. PROTOCOL SUMMARY...................................................................................................26
1.1. Synopsis ..................................................................................................................26
1.2. Schema ....................................................................................................................40
1.3. Schedule of Activities .............................................................................................41
1.3.1. Phase 1........................................................................................................41
1.3.2. Phase 2/3.....................................................................................................48
1.3.3. Administration of BNT162b2 to Those Originally Assigned to 
Placebo.............................................................................................................52
1.3.4. Administration of an Additional Dose of BNT162b2 (5, 10, or 
30 µg) or BNT162b2SA (30 µg) (Subset for Evaluation of Boostability 
and Protection Against Emerging VOCs)........................................................54
1.3.5. Administration of BNT162b2SA to BNT162b2-Naïve Participants ...........57
1.3.6. Surveillance for Asymptomatic SARS-CoV-2 Infection ...........................60
1.3.7. Administration of a Third Dose of BNT162b2 to Participants Who 
Have Not Previously Received a Third Dose ..................................................61
1.3.8. Administration of a Fourth (or Fifth) Dose of BNT162b2 to Eligible 
Participants From Protocol Amendments 13, 14, and 15 ................................63
2. INTRODUCTION ...............................................................................................................66
2.1. Study Rationale .......................................................................................................66
2.2. Background .............................................................................................................66
2.3. Clinical Overview ...................................................................................................69
2.4. Benefit/Risk Assessment.........................................................................................69
2.4.1. Risk Assessment.........................................................................................70
2.4.2. Benefit Assessment.....................................................................................71
2.4.3. Overall Benefit/Risk Conclusion................................................................71
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................72
3.1. For Phase 1..............................................................................................................72
3.2. For Phase 2/3...........................................................................................................74
4. STUDY DESIGN.................................................................................................................80
4.1. Overall Design.........................................................................................................80

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4.1.1. Phase 1........................................................................................................81
4.1.2. Phase 2/3.....................................................................................................83
4.2. Scientific Rationale for Study Design.....................................................................86
4.3. Justification for Dose ..............................................................................................87
4.4. End of Study Definition ..........................................................................................88
5. STUDY POPULATION......................................................................................................88
5.1. Inclusion Criteria.....................................................................................................88
5.2. Exclusion Criteria....................................................................................................89
5.3. Lifestyle Considerations..........................................................................................92
5.3.1. Contraception..............................................................................................92
5.4. Screen Failures ........................................................................................................92
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study 
Intervention Administration ......................................................................................93
6. STUDY INTERVENTION..................................................................................................93
6.1. Study Intervention(s) Administered........................................................................94
6.1.1. Manufacturing Process ...............................................................................95
6.1.2. Administration............................................................................................95
6.2. Preparation/Handling/Storage/Accountability ........................................................96
6.2.1. Preparation and Dispensing........................................................................97
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................98
6.3.1. Allocation to Study Intervention ................................................................98
6.3.2. Blinding of Site Personnel..........................................................................98
6.3.3. Blinding of the Sponsor..............................................................................99
6.3.4. Breaking the Blind....................................................................................100
6.4. Study Intervention Compliance.............................................................................101
6.5. Concomitant Therapy............................................................................................101
6.5.1. Prohibited During the Study.....................................................................102
6.5.2. Permitted During the Study ......................................................................103
6.6. Dose Modification.................................................................................................103
6.7. Intervention After the End of the Study................................................................104
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.........................................................................104

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7.1. Discontinuation of Study Intervention ..................................................................104
7.2. Participant Discontinuation/Withdrawal From the Study.....................................104
7.2.1. Withdrawal of Consent.............................................................................106
7.3. Lost to Follow-up..................................................................................................106
8. STUDY ASSESSMENTS AND PROCEDURES.............................................................106
8.1. Efficacy and/or Immunogenicity Assessments .....................................................108
8.1.1. Efficacy Against COVID-19 ....................................................................108
8.1.2. Efficacy Against Asymptomatic SARS-CoV-2 Infection........................110
8.1.2.1. Seroconversion of N-Binding Antibody .................................110
8.1.2.2. NAAT-Confirmed SARS-CoV-2 Infection ............................111
8.1.3. Vaccine-Induced Immunogenicity............................................................111
8.1.4. Biological Samples...................................................................................111
8.1.5. Surveillance for Asymptomatic SARS-CoV-2 Infection .........................112
8.2. Safety Assessments ...............................................................................................112
8.2.1. Clinical Safety Laboratory Assessments (Phase 1 Participants Only) .....113
8.2.2. Electronic Diary........................................................................................113
8.2.2.1. Grading Scales.........................................................................114
8.2.2.2. Local Reactions.......................................................................114
8.2.2.3. Systemic Events ......................................................................115
8.2.2.4. Fever........................................................................................116
8.2.2.5. Antipyretic Medication ...........................................................117
8.2.3. Phase 1 Stopping Rules ............................................................................117
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19 
and Phase 2/3 Stopping Rule .........................................................................118
8.2.5. Randomization and Vaccination After a Stopping Rule Is Met ...............119
8.2.6. Pregnancy Testing ....................................................................................119
8.3. Adverse Events and Serious Adverse Events........................................................119
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.....120
8.3.1.1. Reporting SAEs to Pfizer Safety.............................................121
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF.................122
8.3.2. Method of Detecting AEs and SAEs ........................................................122
8.3.3. Follow-up of AEs and SAEs.....................................................................122

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8.3.4. Regulatory Reporting Requirements for SAEs.........................................122
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ........................................................................................................123
8.3.5.1. Exposure During Pregnancy....................................................123
8.3.6. Exposure During Breastfeeding................................................................124
8.3.6.1. Occupational Exposure ...........................................................125
8.3.7. Cardiovascular and Death Events.............................................................125
8.3.8. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs............................................................................125
8.3.9. Adverse Events of Special Interest...........................................................126
8.3.9.1. Lack of Efficacy......................................................................126
8.3.10. Medical Device Deficiencies..................................................................126
8.3.11. Medication Errors...................................................................................126
8.4. Treatment of Overdose..........................................................................................127
8.5. Pharmacokinetics ..................................................................................................128
8.6. Pharmacodynamics................................................................................................128
8.7. Genetics.................................................................................................................128
8.8. Biomarkers ............................................................................................................128
8.9. Immunogenicity Assessments...............................................................................128
8.10. Health Economics ...............................................................................................128
8.11. Study Procedures.................................................................................................128
8.11.1. Phase 1....................................................................................................129
8.11.1.1. Screening: (0 to 28 Days Before Visit 1) ..............................129
8.11.1.2. Visit 1 – Vaccination 1: (Day 1) ...........................................130
8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1 
to 3 Days After Visit 1) ...................................................................132
8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to 
8 Days After Visit 1) .......................................................................133
8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1) .........135
8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to 
8 Days After Visit 4) .......................................................................137
8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to 
16 Days After Visit 4) .....................................................................138

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8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After 
Visit 4).............................................................................................139
8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (175 to 189 Days 
After Visit 4)....................................................................................140
8.11.1.10. Between Visits 8 and 9........................................................140
8.11.1.11. Visit 8a – Vaccination 3: (175 to 315 Days After 
Vaccination 2) .................................................................................140
8.11.1.12. Visit 8b – 1-Week Follow-up Visit (After Vaccination 
3): (6 to 8 Days After Visit 8a)........................................................142
8.11.1.13. Visit 8c – 1-Month Follow-up Visit (After Vaccination 
3): (28 to 35 Days After Visit 8a)....................................................143
8.11.1.14. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days 
After Visit 4): Only for Those Participants Who Originally 
Received BNT162b1 or BNT162b2 or Placebo Recipients Who 
Decline BNT162b2..........................................................................144
8.11.1.15. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days 
After Visit 4):  Only for Those Participants Who Originally 
Received BNT162b1 or BNT162b2 or Placebo Recipients Who 
Decline BNT162b2..........................................................................144
8.11.2. Phase 2/3.................................................................................................144
8.11.2.1. Visit 1 – Vaccination 1: (Day 1) ...........................................144
8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days After Visit 1) .........147
8.11.2.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2): 
(28 to 35 Days After Visit 2)...........................................................149
8.11.2.4. Visit 4 – 6-Month Follow-up Visit: (175 to 189 Days 
After Visit 2)....................................................................................150
8.11.2.5. Visit 5 – 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 .......................................................................................151
8.11.2.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days 
After Visit 2) ): Only for Those Participants Who Originally 
Received BNT162b2 or Placebo Recipients Who Decline 
BNT162b2 .......................................................................................151
8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction ......................152
8.13. COVID-19 Surveillance (All Participants) .........................................................153
8.13.1. Potential COVID-19 Illness Visit: (Optimally Within 3 Days After 
Potential COVID-19 Illness Onset) ...............................................................154

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8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After 
Potential  COVID-19 Illness Visit)................................................................156
8.14. Communication and Use of Technology.............................................................156
8.15. SARS-CoV-2 NAAT Results..............................................................................156
8.16. Procedures for Administration of BNT162b2 to Those Originally Assigned 
to Placebo ................................................................................................................157
8.16.1. Visit 101 – Vaccination 3: (From Recommendation or at Least 175 
Days After Vaccination 2) .............................................................................157
8.16.2. Visit 102 – Vaccination 4: (19 to 23 Days After Visit 101)...................159
8.16.3. Visit 103 – 1-Month Follow-up Telephone Contact (After 
Vaccination 4): (28 to 35 Days After Visit 102)............................................160
8.16.4. Visit 104 – 6-Month Follow-up Telephone Contact (After 
Vaccination 4): (175 to 189 Days After Visit 102)........................................160
8.16.5. Visit 105 – 18-Month Follow-up Telephone Contact (After 
Vaccination 4): (532 to 560 Days After Visit 102)........................................161
8.17. Administration of an Additional Dose of BNT162b2 (5, 10, or 30 µg) or 
BNT162b2SA (30 µg) (Subset for Evaluation of Boostability and Protection 
Against Emerging VOCs)........................................................................................162
8.17.1. Visit 301 – Vaccination 3: (150 to 210 Days After Visit 2)...................162
8.17.2. Visit 302 – 1-Week Follow-up Visit (After Vaccination 3): (6 to 8 
Days After Visit 301).....................................................................................164
8.17.3. Visit 303 – 1-Month Follow-up Visit (After Vaccination 3): (28 to 
35 Days After Visit 301)................................................................................165
8.17.4. Visit 304 – 1-Week Follow-up Visit (Vaccination 4): (6 to 8 Days 
After Visit 303): Only for Those Participants Who Received a fourth 
dose of BNT162b2SA .....................................................................................166
8.17.5. Visit 305 – 1-Month Follow-up Visit (Vaccination 4): (28 to 35 
Days After Visit 303): Only for Those Participants Who Received a 
fourth dose of BNT162b2SA...........................................................................167
8.17.6. Visit 306 – 6-Month Follow-up Visit: (175 to 189 Days After Visit 
301) ................................................................................................................168
8.17.7. Visit 307 – 18-Month Follow-up Visit: (532 to 560 Days After 
Visit 301) .......................................................................................................168
8.18. Administration of BNT162b2SA to BNT162b2-Naïve Participants....................169
8.18.1. Visit 401 – Vaccination 1: (Day 1).........................................................169
8.18.2. Visit 402 – Vaccination 2: (19 to 23 Days After Visit 401)...................171

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8.18.3. Visit 403 – 1-Week Follow-up Visit (After Vaccination 2): (6 to 8 
Days After Visit 402).....................................................................................173
8.18.4. Visit 404 – 1-Month Follow-up Visit (After Vaccination 2): (28 to 
35 Days After Visit 402)................................................................................174
8.18.5. Visit 405 – 6-Month Follow-up Visit: (175 to 189 Days After Visit 
402) ................................................................................................................174
8.18.6. Visit 406 – 18-Month Follow-up Visit: (532 to 560 Days After 
Visit 402) .......................................................................................................175
8.19. Surveillance for Asymptomatic SARS-CoV-2 Infection....................................175
8.19.1. Visit 201– Asymptomatic SARS-CoV-2 Infection Surveillance 
Consent: From Approval of Protocol Amendment 11...................................176
8.19.2. Visit 202 Onward – Asymptomatic SARS-CoV-2 Infection 
Surveillance Swab: Repeating Every 10 to 18 Days After Each Previous 
Surveillance Swab Collection........................................................................177
8.20. Administration of a Third Dose of BNT162b2 to Participants Who Have 
Not Previously Received a Third Dose ...................................................................177
8.20.1. Visit 501 – Third Dose of BNT162b2....................................................178
8.20.2. Visit 502 – 1-Month Follow-up Telephone Contact: (28 to 35 Days 
After Visit 501)..............................................................................................179
8.20.3. Visit 503 – 6-Month Follow-up Telephone Contact: (175 to 189 
Days After Visit 501).....................................................................................180
8.20.4. Visit 504 – 12-Month Follow-up Visit: (350 to 378 Days After 
Visit 501): ......................................................................................................180
8.21. Administration of a Fourth (or Fifth) Dose of BNT162b2 to Eligible 
Participants From Protocol Amendments 13, 14, and 15........................................181
8.21.1. Visit 601 – Dose 4: (At Least 175 Days After Visit 301 or Visit 8a): 
Only For Those Participants Who Received Dose 3 at Visit 8a or Visit 
301..................................................................................................................181
8.21.2. Visit 602 – 1-Month Follow-up Telephone Contact: (28 to 35 Days 
After Visit 601)..............................................................................................183
8.21.3. Visit 603 – 6-Month Follow-up Telephone Contact: (175 to 189 
Days After Visit 601).....................................................................................183
8.21.4. Visit 604 – Dose 5: (At Least 175 Days After Visit 303): Only for 
the Subset of Participants Who Receive Dose 4 at Visit 303 ........................184
8.21.5. Visit 605 – 1-Month Follow-up Telephone Contact: (28 to 35 Days 
After Visit 604)..............................................................................................185

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8.21.6. Visit 606 – 6-Month Follow-up Telephone Contact: (175 to 189 
Days After Visit 601).....................................................................................186
8.22. Additional Procedures for Monitoring of Potential Myocarditis or 
Pericarditis...............................................................................................................186
9. STATISTICAL CONSIDERATIONS ..............................................................................187
9.1. Estimands and Statistical Hypotheses...................................................................187
9.1.1. Estimands..................................................................................................187
9.1.2. Statistical Hypotheses...............................................................................187
9.1.2.1. Statistical Hypothesis Evaluation for Efficacy........................187
9.1.2.2. Statistical Hypothesis Evaluation for Immunogenicity...........188
9.2. Sample Size Determination...................................................................................189
9.2.1. Phase 1......................................................................................................189
9.2.2. Efficacy Against COVID-19 ....................................................................190
9.2.3. Efficacy Against Asymptomatic Infection ...............................................190
9.2.4. Immunogenicity Bridging of 12 to 15 Years to 16 to 25 Years ...............190
9.2.5. Boostability and Protection Against Emerging SARS-CoV-2 VOCs ......191
9.2.6. Safety........................................................................................................192
9.3. Analysis Sets .........................................................................................................193
9.4. Statistical Analyses ...............................................................................................195
9.4.1. Immunogenicity Analyses ........................................................................195
9.4.2. Efficacy Analyses .....................................................................................206
9.4.3. Safety Analyses ........................................................................................210
9.4.4. Other Analyses..........................................................................................213
9.5. Interim Analyses ...................................................................................................213
9.5.1. Analysis Timing........................................................................................216
9.6. Data Monitoring Committee or Other Independent Oversight Committee...........217
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS........................................................................................................219
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations.............219
10.1.1. Regulatory and Ethical Considerations ..................................................219
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.......................................................................219
10.1.2. Informed Consent Process ......................................................................220

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10.1.3. Data Protection .......................................................................................221
10.1.4. Dissemination of Clinical Study Data ....................................................221
10.1.5. Data Quality Assurance ..........................................................................222
10.1.6. Source Documents..................................................................................224
10.1.7. Study and Site Start and Closure ............................................................224
10.1.8. Sponsor’s Qualified Medical Personnel .................................................225
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................226
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ....................................................................228
10.3.1. Definition of AE .....................................................................................228
10.3.2. Definition of SAE...................................................................................229
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.....................231
10.3.4. Reporting of SAEs..................................................................................234
10.4. Appendix 4: Contraceptive Guidance .................................................................235
10.4.1. Male Participant Reproductive Inclusion Criteria..................................235
10.4.2. Female Participant Reproductive Inclusion Criteria...............................235
10.4.3. Woman of Childbearing Potential ..........................................................236
10.4.4. Contraception Methods...........................................................................237
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ......239
10.6. Appendix 6: Abbreviations .................................................................................241
10.7. Appendix 7: Stopping and Alert Rules for Enhanced COVID-19......................245
10.8. Appendix 8: Criteria for Allowing Inclusion of Participants With Chronic 
Stable HIV, HCV, or HBV Infection ......................................................................248
10.9. Appendix 9: Genetics..........................................................................................249
11. REFERENCES ................................................................................................................250
LIST OF TABLES
Table 1.
Local Reaction Grading Scale ................................................................115
Table 2.
Systemic Event Grading Scale................................................................116
Table 3.
Scale for Fever........................................................................................117
Table 4.
Power Analysis for Noninferiority Assessment .....................................191

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Table 5.
Probability of Observing at Least 1 AE by Assumed True Event 
Rates With Different Sample Sizes ........................................................192
Table 6.
Interim Analysis Plan and Boundaries for Efficacy and Futility............214
Table 7.
Statistical Design Operating Characteristics: Probability of Success 
or Failure for Interim Analyses...............................................................215
Table 8.
Statistical Design Operating Characteristics: Probability of Success 
for Final Analysis and Overall................................................................215
Table 9.
Laboratory Abnormality Grading Scale .................................................226
Table 10.
Stopping Rule: Enrollment Is Stopped if the Number of Severe 
Cases in the Vaccine Group Is Greater Than or Equal to the 
Prespecified Stopping Rule Value (S) ....................................................246
Table 11.
Alert Rule: Further Action Is Taken if the Number of Severe Cases 
in the Vaccine Group Is Greater Than or Equal to the Prespecified 
Alert Rule Value (A) ..............................................................................247
LIST OF FIGURES
Figure 1.
Multiplicity Schema................................................................................189

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1. PROTOCOL SUMMARY
1.1. Synopsis
Short Title: A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, and 
Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Individuals
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 2019. 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 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the WHO 
officially named the disease caused by SARS-CoV-2 as coronavirus disease 2019 
(COVID-19). On 11 March 2020, the WHO upgraded the status of the COVID-19 outbreak 
from epidemic to pandemic, which continues to spread globally at high speed. To date, more 
than 392 million people have been infected with SARS-CoV-2 and >5.7 million have died, 
demonstrating an urgent need for efficacious vaccines.
Numerous COVID-19 vaccines are currently in development globally, and several candidate 
COVID-19 vaccines (eg, mRNA vaccines and adenovirus-vectored vaccines expressing the 
S protein) have been shown to be efficacious in the prevention of COVID-19 in clinical 
studies and are now available under temporary or emergency authorizations. BNT162b2, an 
RNA-based COVID-19 vaccine given as a 2-dose series administered 21 days apart, was 
shown to be safe and effective in a Phase 1/2/3 study and has received authorizations for 
temporary or emergency use or marketing authorizations in multiple countries and has been 
fully licensed for use in individuals 16 years of age and above in the US as of 23 Aug 2021.
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 3 antigens:
BNT162b1 (variant RBP020.3): a modRNA encoding the trimerized SARS-CoV-2 spike 
glycoprotein receptor-binding domain (RBD) (version 5);
BNT162b2 (variant RBP020.2): a modRNA encoding the SARS-CoV-2 full-length, P2 
mutant, prefusion spike glycoprotein (P2 S) (version 9);
BNT162b2s01 (variant RBP020.11): a modRNA encoding the P2 S containing South Africa 
B.1.351 variant–specific mutations, hereafter referred to as BNT162b2SA, as a representative 
variant of concern (VOC).
All candidates are formulated in the same lipid nanoparticle (LNP) composition. This study 
is intended to investigate the safety, immunogenicity, and/or efficacy of these prophylactic 
BNT162 vaccines against COVID-19.

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
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Objectives, Estimands, and Endpoints
For Phase 1
Objectives
Estimands
Endpoints
Primary: 
Primary:
Primary: 
To describe the safety and tolerability 
profiles of prophylactic BNT162 
vaccines in healthy adults after 1 or 
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

Adverse events (AEs) from Dose 1 
to 1 month after the last dose

Serious AEs (SAEs) from Dose 1 
to 6 months after the last dose

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, 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
Secondary: 
Secondary:
Secondary: 
To describe the immune responses 
elicited by prophylactic BNT162 
vaccines in healthy adults after 1 or 
2 doses
In participants complying with the key 
protocol criteria (evaluable participants)
at the following time points after receipt
of study intervention:
7 and 21 days after Dose 1; 7 and 
14 days and 1 and 6 months after Dose 2

Geometric mean titers (GMTs) at 
each time point

Geometric mean fold rise (GMFR) 
from before vaccination to each 
subsequent time point after 
vaccination

Proportion of participants 
achieving ≥4-fold rise from before 
vaccination to each subsequent 
time point after vaccination
SARS-CoV-2 neutralizing titers

Geometric mean concentrations 
(GMCs) at each time point

GMFR from before vaccination to 
each subsequent time point after 
vaccination

Proportion of participants 
achieving ≥4-fold rise from before 
vaccination to each subsequent 
time point after vaccination
S1-binding IgG levels and 
RBD-binding IgG levels

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
Page 28
Objectives
Estimands
Endpoints

Geometric mean ratio (GMR), 
estimated by the ratio of the 
geometric mean of SARS-CoV-2
neutralizing titers to the geometric 
mean of binding IgG levels at each 
time point

SARS-CoV-2 neutralizing titers

S1-binding IgG levels

RBD-binding IgG levels
Exploratory: 
Exploratory:
Exploratory: 
To describe the immune responses 
elicited by a third dose of prophylactic 
BNT162b2 administered to healthy 
adults at least 6 months after the second 
dose of either BNT162b1 or BNT162b2

GMCs/GMTs at the time of 
Dose 3, 7 days and 1 month after 
Dose 3, and 12 months after 
Dose 2

GMFRs from before Dose 3 to 
7 days and 1 month after Dose 3
and 12 months after Dose 2

SARS-CoV-2 reference-strain 
neutralizing titers

SARS-CoV-2 SA-variant
neutralizing titers

Full-length S-binding or 
S1-binding IgG levels

GMR of SARS-CoV-2 reference-
strain neutralizing titers 1 month 
after Dose 3 to 1 month after 
Dose 2

SARS-CoV-2 reference-strain 
neutralizing titers

GMR of SARS-CoV-2 SA-variant
neutralizing titers 1 month after 
Dose 3 to SARS-CoV-2 reference-
strain neutralizing titers 1 month 
after Dose 2

SARS-CoV-2 reference-strain 
neutralizing titers

SARS-CoV-2 SA-variant
neutralizing titers
To describe the safety profile of a third 
dose of prophylactic BNT162b2
administered to healthy adults 6 to 
12 months after the second dose of 
either BNT162b1 or BNT162b2
In participants receiving a third dose of 
BNT162b2, the percentage of 
participants reporting:

Local reactions for up to 7 days 
after Dose 3

Systemic events for up to 7 days 
after Dose 3

AEs and SAEs from Dose 3 to 
1 month after Dose 3

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
To describe the safety and tolerability 
profile of BNT162b2 given as a fourth 
dose at least 6 months after the third 
dose of BNT162b2 for participants who 
received a fourth dose as part of 
protocol amendment 19
In participants receiving a fourth dose of 
study intervention, the percentage of 
participants reporting:

AEs and SAEs from Dose 4 to 
1 month after Dose 4

AEs

SAEs

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
Page 29
For Phase 2/3
Objectivesa
Estimands
Endpoints
Primary Efficacy
To evaluate the efficacy of 
prophylactic BNT162b2 against 
confirmed COVID-19 occurring from 
7 days after the second dose in 
participants without evidence of 
infection before vaccination
In participants complying with the 
key protocol criteria (evaluable 
participants) at least 7 days after 
receipt of the second dose of study 
intervention:
100 × (1 – IRR) [ratio of active 
vaccine to placebo]
COVID-19 incidence per 1000 
person-years of follow-up based on 
central laboratory or locally 
confirmed NAAT in participants with 
no serological or virological evidence 
(up to 7 days after receipt of the 
second dose) of past SARS-CoV-2 
infection
To evaluate the efficacy of 
prophylactic BNT162b2 against 
confirmed COVID-19 occurring from 
7 days after the second dose in 
participants with and without 
evidence of infection before 
vaccination
In participants complying with the 
key protocol criteria (evaluable 
participants) at least 7 days after 
receipt of the second dose of study 
intervention:
100 × (1 – IRR) [ratio of active 
vaccine to placebo]
COVID-19 incidence per 1000 
person-years of follow-up based on 
central laboratory or locally 
confirmed NAAT
Primary Safety
To define the safety profile of 
prophylactic BNT162b2 in the first 
360 participants randomized (Phase 2)
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 7 days after 
the second dose

SAEs from Dose 1 to 7 days
after the second dose

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
To define the safety profile of 
prophylactic BNT162b2 in all 
participants randomized in Phase 2/3
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 the second dose

SAEs from Dose 1 to 6 months 
after the second dose

AEs

SAEs

In a subset of at least 
6000 participants:
o
Local reactions (pain at the 
injection site, redness, and 
swelling)
o
Systemic events (fever, 
fatigue, headache, chills, 
vomiting, diarrhea, new or 
worsened muscle pain, and 
new or worsened joint pain)
To define the safety profile of 
prophylactic BNT162b2 in 
participants 12 to 15 years of age in 
Phase 3
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 the second dose

SAEs from Dose 1 to 6 months 
after the second dose

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

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
Page 30
Objectivesa
Estimands
Endpoints
To describe the safety and tolerability 
profile of BNT162b2SA given as 1 or 
2 doses to BNT162b2-experienced 
participants, or as 2 doses to 
BNT162b2-naïve participants
To describe the safety and tolerability 
profile of BNT162b2 given as a third
dose to BNT162b2-experienced 
participants in the subset for 
evaluation of boostability and 
protection against emerging VOCs
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 
the last dose

SAEs from Dose 1 to 5 or 
6 months after the last dose

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
To describe the safety and tolerability 
profile of BNT162b2 given as a third 
dose at least 3 months after the second 
dose of BNT162b2 (or BNT162b2SA) 
for participants who received a third 
dose as part of protocol 
amendment 18
In participants receiving at least 
1 dose of study intervention, the 
percentage of participants reporting:

AEs and SAEs from Dose 3 to 
1 month after Dose 3

AEs

SAEs
To describe the safety and tolerability 
profile of BNT162b2 given as a fourth
(or fifth) dose at least 6 months after 
the third (or fourth) dose of 
BNT162b2 (or BNT162b2SA) for 
participants who received a fourth (or 
fifth) dose as part of protocol 
amendment 19
In participants receiving a fourth (or 
fifth) dose of study intervention, the 
percentage of participants reporting:

AEs and SAEs from Dose 4
(or Dose 5) to 1 month after Dose 
4 (or Dose 5)

AEs

SAEs
Primary Immunogenicity
BNT162b2-experienced participants
To demonstrate the noninferiority of 
the anti–reference strain immune 
response after a third dose of 
BNT162b2 at 30 µg compared to after 
2 doses of BNT162b2, in the same 
individuals
GMR of reference strain NT 1 month 
after the third dose of BNT162b2 at 
30 µg to 1 month after the second
dose of BNT162b2
The difference in percentages of 
participants with seroresponse to the 
reference strain at 1 month after the 
third dose of BNT162b2 at 30 µg and 
1 month after the second dose of 
BNT162b2
SARS-CoV-2 reference strain NTs in 
participants with no serological or 
virological evidence (up to 1 month
after receipt of the third dose of 
BNT162b2 at 30 µg) of past SARS-
CoV-2 infection
To demonstrate the noninferiority of 
the anti-SA immune response after 
1 dose of BNT162b2SA compared to 
the anti–reference strain immune 
response after 2 doses of BNT162b2, 
in the same individuals
GMR of SA NT 1 month after 1 dose 
of BNT162b2SA to the reference strain 
NT 1 month after the second dose of 
BNT162b2
The difference in percentages of 
participants with seroresponse to the 
SA strain at 1 month after 1 dose of 
BNT162b2SA and seroresponse to the 
reference strain at 1 month after the 
second dose of BNT162b2
SARS-CoV-2 SA and reference strain 
NTs in participants with no 
serological or virological evidence 
(up to 1 month after receipt of 1 dose 
of BNT162b2SA) of past SARS-CoV-
2 infection

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
Page 31
Objectivesa
Estimands
Endpoints
BNT162b2-naïve participants 
To demonstrate the noninferiority of 
the anti-SA immune response after 
2 doses of BNT162b2SA compared to 
the anti–reference strain immune 
response after 2 doses of BNT162b2 
GMR of SA NT 1 month after the 
second dose of BNT162b2SA to the 
reference strain NT 1 month after the 
second dose of BNT162b2
The difference in percentages of 
participants with seroresponse to the
SA strain at 1 month after the second 
dose of BNT162b2SA and 
seroresponse to the reference strain at 
1 month after the second dose of 
BNT162b2
SARS-CoV-2 SA and reference strain 
NTs in participants with no 
serological or virological evidence 
(up to 1 month after receipt of the 
second dose of BNT162b2SA or 
BNT162b2 as appropriate) of past 
SARS-CoV-2 infection
Secondary Efficacy
To evaluate the efficacy of 
prophylactic BNT162b2 against 
confirmed COVID-19 occurring from 
14 days after the second dose in 
participants without evidence of 
infection before vaccination
In participants complying with the 
key protocol criteria (evaluable 
participants) at least 14 days after 
receipt of the second dose of study 
intervention:
100 × (1 – IRR) [ratio of active 
vaccine to placebo]
COVID-19 incidence per 1000 
person-years of follow-up based on 
central laboratory or locally 
confirmed NAAT in participants with 
no serological or virological evidence 
(up to 14 days after receipt of the 
second dose) of past SARS-CoV-2 
infection
To evaluate the efficacy of 
prophylactic BNT162b2 against 
confirmed COVID-19 occurring from 
14 days after the second dose in 
participants with and without 
evidence of infection before 
vaccination
In participants complying with the 
key protocol criteria (evaluable 
participants) at least 14 days after 
receipt of the second dose of study 
intervention:
100 × (1 – IRR) [ratio of active 
vaccine to placebo]
COVID-19 incidence per 1000 
person-years of follow-up based on 
central laboratory or locally 
confirmed NAAT
To evaluate the efficacy of 
prophylactic BNT162b2 against 
confirmed severe COVID-19
occurring from 7 days and from 
14 days after the second dose in 
participants without evidence of 
infection before vaccination
In participants complying with the 
key protocol criteria (evaluable 
participants) 

at least 7 days 
and

at least 14 days
after receipt of the second dose of 
study intervention:
100 × (1 – IRR) [ratio of active 
vaccine to placebo]
Confirmed severe COVID-19 
incidence per 1000 person-years of 
follow-up in participants with no 
serological or virological evidence (up 
to 7 days and up to 14 days after 
receipt of the second dose) of past 
SARS-CoV-2 infection
To evaluate the efficacy of 
prophylactic BNT162b2 against 
confirmed severe COVID-19
occurring from 7 days and from 
14 days after the second dose in 
participants with and without 
evidence of infection before 
vaccination
In participants complying with the 
key protocol criteria (evaluable 
participants) 

at least 7 days 
and

at least 14 days
after receipt of the second dose of 
study intervention:
100 × (1 – IRR) [ratio of active 
vaccine to placebo]
Confirmed severe COVID-19 
incidence per 1000 person-years of 
follow-up

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
Page 32
Objectivesa
Estimands
Endpoints
To describe the efficacy of 
prophylactic BNT162b2 against 
confirmed COVID-19 (according to 
the CDC-defined symptoms) 
occurring from 7 days and from 
14 days after the second dose in 
participants without evidence of 
infection before vaccination
In participants complying with the 
key protocol criteria (evaluable 
participants) 

at least 7 days 
and

at least 14 days
after receipt of the second dose of 
study intervention:
100 × (1 – IRR) [ratio of active 
vaccine to placebo]
COVID-19 incidence per 1000 
person-years of follow-up based on 
central laboratory or locally 
confirmed NAAT in participants with
no serological or virological evidence 
(up to 7 days and up to 14 days after 
receipt of the second dose) of past 
SARS-CoV-2 infection
To describe the efficacy of 
prophylactic BNT162b2 against 
confirmed COVID-19 (according to 
the CDC-defined symptoms) 
occurring from 7 days and from 
14 days after the second dose in 
participants with and without 
evidence of infection before 
vaccination
In participants complying with the 
key protocol criteria (evaluable 
participants) 

at least 7 days 
and

at least 14 days
after receipt of the second dose of 
study intervention:
100 × (1 – IRR) [ratio of active 
vaccine to placebo]
COVID-19 incidence per 1000 
person-years of follow-up based on 
central laboratory or locally 
confirmed NAAT
To evaluate the efficacy of 
prophylactic BNT162b2 against 
non-S seroconversion to 
SARS-CoV-2 in participants without 
evidence of infection or confirmed 
COVID-19
In participants complying with the 
key protocol criteria (evaluable 
participants):
100 × (1 – IRR) [ratio of active 
vaccine to placebo]
Incidence of asymptomatic 
SARS-CoV-2 infection per 1000 
person-years of follow-up based on 
N-binding antibody seroconversion in 
participants with no serological or 
virological evidence of past 
SARS-CoV-2 infection or confirmed 
COVID-19 
To evaluate the efficacy of 
prophylactic BNT162b2 against 
asymptomatic SARS-CoV-2 infection 
in participants without evidence of 
infection up to the start of the
asymptomatic surveillance period
In participants complying with the 
key protocol criteria (evaluable 
participants):
100 × (1 – IRR) [ratio of active 
vaccine to placebo]
Incidence of asymptomatic 
SARS-CoV-2 infection per 1000 
person-years of follow-up based on 
central laboratory–confirmed NAAT 
in participants with no serological or 
virological evidence (up to the start of 
the asymptomatic surveillance period) 
of past SARS-CoV-2 infection
Secondary Immunogenicity
To demonstrate the noninferiority of 
the immune response to prophylactic 
BNT162b2 in participants 12 to 15 
years of age compared to participants 
16 to 25 years of age
GMR, estimated by the ratio of the 
geometric mean of SARS-CoV-2 
neutralizing titers in the 2 age groups 
(12-15 years of age to 16-25 years of 
age) 1 month after completion of 
vaccination
SARS-CoV-2 neutralizing titers in 
participants with no serological or 
virological evidence (up to 1 month
after receipt of the second dose) of 
past SARS-CoV-2 infection
BNT162b2-experienced participants
To demonstrate the noninferiority of 
the anti-SA immune response after a 
third dose of BNT162b2 at 30 µg 
compared to the anti–reference strain 
immune response after 2 doses of 
BNT162b2, in the same individuals 
GMR of SA NT 1 month after the 
third dose of BNT162b2 at 30 µg to 
the reference strain NT 1 month after 
the second dose of BNT162b2
The difference in percentages of 
participants with seroresponse to the
SA strain at 1 month after the third 
dose of BNT162b2 at 30 µg and 
seroresponse to the reference strain at 
1 month after the second dose of 
BNT162b2
SARS-CoV-2 SA and reference strain 
NTs in participants with no 
serological or virological evidence 
(up to 1 month after receipt of the 
third dose of BNT162b2 at 30 µg) of 
past SARS-CoV-2 infection

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
Page 33
Objectivesa
Estimands
Endpoints
To demonstrate the noninferiority of 
the anti–reference strain immune 
response after 1 dose of BNT162b2SA
compared to after 2 doses of 
BNT162b2, in the same individuals 
GMR of reference strain NT 1 month 
after 1 dose of BNT162b2SA to 
1 month after the second dose of 
BNT162b2
The difference in percentages of 
participants with seroresponse to the 
reference strain at 1 month after 
1 dose of BNT162b2SA and 1 month 
after the second dose of BNT162b2
SARS-CoV-2 reference strain NTs in 
participants with no serological or 
virological evidence (up to 1 month 
after receipt of 1 dose of 
BNT162b2SA) of past SARS-CoV-2 
infection
To descriptively compare the anti-SA 
immune response after 1 dose of 
BNT162b2SA and a third dose of 
BNT162b2 at 30 µg
GMR of SA NT 1 month after 1 dose 
of BNT162b2SA to 1 month after the 
third dose of BNT162b2 at 30 µg
The difference in percentages of 
participants with seroresponse to the 
SA strain at 1 month after 1 dose of 
BNT162b2SA and 1 month after the 
third dose of BNT162b2 at 30 µg
SARS-CoV-2 SA NT in participants 
with no serological or virological 
evidence (up to 1 month after receipt 
of 1 dose of BNT162b2SA or the third
dose of BNT162b2 at 30 µg) of past 
SARS-CoV-2 infection
To descriptively compare the anti-SA 
immune response after 2 doses of 
BNT162b2SA and the anti–reference 
strain immune response after 2 doses 
of BNT162b2, in the same individuals 
GMR of SA NT 1 month after the 
second dose of BNT162b2SA to the 
reference strain NT 1 month after the 
second dose of BNT162b2
The difference in percentages of 
participants with seroresponse to the 
SA strain at 1 month after the second 
dose of BNT162b2SA and 
seroresponse to the reference strain at 
1 month after the second dose of 
BNT162b2
SARS-CoV-2 SA and reference strain 
NTs in participants with no 
serological or virological evidence 
(up to 1 month after receipt of the 
second dose of BNT162b2SA) of past 
SARS-CoV-2 infection
BNT162b2-naïve participants
To demonstrate a statistically greater 
anti-SA immune response after 
2 doses of BNT162b2SA compared to 
after 2 doses of BNT162b2 
GMR of SA NT 1 month after the 
second dose of BNT162b2SA to 
1 month after the second dose of 
BNT162b2
The difference in percentages of 
participants with seroresponse to the 
SA strain at 1 month after the second 
dose of BNT162b2SA and 1 month 
after the second dose of BNT162b2
SARS-CoV-2 SA NTs in participants 
with no serological or virological 
evidence (up to 1 month after receipt 
of the second dose of BNT162b2SA or 
BNT162b2 as appropriate) of past 
SARS-CoV-2 infection
To descriptively compare the 
anti–reference strain immune 
response after 2 doses of 
BNT162b2SA and after 2 doses of 
BNT162b2 
GMR of reference strain NT 1 month 
after the second dose of BNT162b2SA
to 1 month after the second dose of 
BNT162b2
The difference in percentages of 
participants with seroresponse to the 
reference strain at 1 month after the 
second dose of BNT162b2SA and 
1 month after the second dose of 
BNT162b2
SARS-CoV-2 reference strain NTs in 
participants with no serological or 
virological evidence (up to 1 month 
after receipt of the second dose of 
BNT162b2SA or BNT162b2 as 
appropriate) of past SARS-CoV-2 
infection

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
Page 34
Objectivesa
Estimands
Endpoints
Exploratory
To describe the efficacy of 
prophylactic BNT162b2 against 
confirmed COVID-19 occurring from 
7 days after the second dose through 
the blinded follow-up period in 
participants without, and with and 
without, evidence of infection before 
vaccination
In participants complying with the 
key protocol criteria (evaluable 
participants) after receipt of the 
second dose of study intervention:
100 × (1 – IRR) [ratio of active 
vaccine to placebo]
COVID-19 incidence per 1000 
person-years of blinded follow-up 
based on central laboratory or locally 
confirmed NAAT
To describe the incidence of 
confirmed COVID-19 through the 
entire study follow-up period in 
participants who received BNT162b2 
at initial randomization or 
subsequently
In participants after receipt of each 
dose of BNT162b2:
Incidence per 1000 person-years of 
follow-up
COVID-19 incidence per 1000 
person-years of follow-up based on 
central laboratory or locally 
confirmed NAAT
To evaluate the immune response 
over time to prophylactic BNT162b2
and persistence of immune response 
in participants with and without 
serological or virological evidence of 
SARS-CoV-2 infection before 
vaccination
GMC/GMT at baseline and 1 and 
6 months after Dose 2 and GMFR 
from baseline to 1 and 6 months after
Dose 2

Full-length S-binding or 
S1-binding IgG levels

SARS-CoV-2 neutralizing titers
To describe the efficacy of 
prophylactic BNT162b2 against 
asymptomatic SARS-CoV-2 infection 
in participants with evidence of 
infection up to the start of the 
asymptomatic surveillance period
In participants complying with the 
key protocol criteria (evaluable 
participants):
100 × (1 – IRR) [ratio of active 
vaccine to placebo]
Incidence of asymptomatic 
SARS-CoV-2 infection per 1000 
person-years of follow-up based on 
central laboratory–confirmed NAAT
in participants with serological or 
virological evidence (up to the start of 
the asymptomatic surveillance period) 
of past SARS-CoV-2 infection
To describe the serological responses 
to the BNT vaccine candidate and 
characterize the SARS-CoV-2 isolate 
in cases of:

Confirmed COVID-19 cases that 
occur through approximately 
6 months after the second dose

Confirmed severe COVID-19
cases that occur through 
approximately 6 months after the 
second dose

SARS-CoV-2 neutralizing titers

Identification of SARS-CoV-2 
variant(s)
To describe the safety, 
immunogenicity, and efficacy of 
prophylactic BNT162b2 in 
individuals with confirmed stable HIV 
disease

All safety, immunogenicity, and 
efficacy endpoints described 
above
To describe the immune response to 
any VOCs not already specified
Geometric mean NT for any VOCs
not already specified, after any dose 
of BNT162b2SA or BNT162b2

SARS-CoV-2 NTs for any VOCs
not already specified
To describe the immune response to a 
third dose of BNT162b2 (at 30 µg or 
a lower dose of 5 µg or 10 µg) or a
third or fourth dose of BNT162b2SA

GMTs at Dose 3 and subsequent 
time points

GMFRs from Dose 3 to 
subsequent time points

SARS-CoV-2 reference strain 
NTs 

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Objectivesa
Estimands
Endpoints
To describe the cell-mediated immune 
response, and additional humoral 
immune response parameters, to the 
reference strain and SA in a subset of 
participants:

7 Days and 1 and 6 months after 
BNT162b2SA given as 1 or 
2 doses to BNT162b2-
experienced participants

7 Days and 1 and 6 months after 
BNT162b2SA given as 2 doses to 
BNT162b2-naïve participants

7 Days and 1 and 6 months after 
BNT162b2 given as a third dose 
to BNT162b2-experienced 
participants
a.
HIV-positive participants in Phase 3 will not be included in analyses of the objectives, with the 
exception of the specific exploratory objective.
Overall Design
This is a Phase 1/2/3, multicenter, multinational, randomized, placebo-controlled, 
observer-blind, dose-finding, vaccine candidate–selection, and efficacy study in healthy 
individuals.
The study consists of 2 parts: Phase 1: to identify preferred vaccine candidate(s) and dose 
level(s); Phase 2/3: an expanded cohort and efficacy part.  These parts, and the progression 
between them, are detailed in the schema (Section 1.2).
The study will evaluate the safety, tolerability, and immunogenicity of 3 different 
SARS-CoV-2 RNA vaccine candidates against COVID-19 and the efficacy of 1 candidate:

As a 2-dose (separated by 21 days) schedule;

At various different dose levels in Phase 1;

As a booster;

In 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; 
Phase 2/3: ≥12 years of age [stratified as 12-15, 16-55, or >55 years of age]).
Dependent upon safety and/or immunogenicity data generated during the course of this 
study, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups 
in Phase 1 may be started at the next highest dose, groups may not be started, groups may be 
terminated early, and/or groups may be added with dose levels below the lowest stated dose 
or intermediate between the lowest and highest stated doses.
The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.

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Participants who originally received placebo will be offered the opportunity to receive 
BNT162b2 at defined points as part of the study.
An intensive period of surveillance to evaluate the efficacy of BNT162b2 against
asymptomatic SARS-CoV-2 infection may be conducted at selected sites among Phase 2/3 
participants following approval of protocol amendment 11. After an initial in-person visit 
where a blood sample will be collected and a nasal (midturbinate) swab obtained, nasal 
swabs will be obtained from consented participants every 2 weeks until Visit 4, or a 
sufficient number of cases of SARS-CoV-2 infection have accrued to evaluate this objective, 
whichever is sooner. The swabs will be tested at a central laboratory using NAAT to detect 
SARS-CoV-2. Participants who originally received placebo and become eligible for receipt 
of BNT162b2 according to local or national recommendations and then receive BNT162b2 
as part of the study will not participate in surveillance for asymptomatic SARS-CoV-2
infection; if they become eligible during the surveillance period, the swabbing every 2 weeks 
will cease.
In order to describe the boostability of BNT162, and potential heterologous protection 
against emerging SARS-CoV-2 VOCs, an additional dose of BNT162b2 at 30 µg will be 
given to Phase 1 participants approximately 6 to 12 months after their second dose of 
BNT162b1 or BNT162b2. This will provide an early assessment of the safety of a third dose 
of BNT162, as well as its immunogenicity.  The assessment of boostability will be further 
expanded in a subset of Phase 3 participants at selected sites in the US who will receive a 
third dose of BNT162b2 at 30 µg or a third and potentially a fourth dose of prototype 
BNT162b2VOC at 30 µg (based upon the South African variant and hereafter referred to as 
BNT162b2SA). A further subset of Phase 3 participants will receive a third, lower, dose of 
BNT162b2 at 5 or 10 µg.
To further describe potential homologous and heterologous protection against emerging 
SARS-CoV-2 VOCs, a new cohort of participants will be enrolled who are COVID-19 
vaccine–naïve (ie, BNT162b2-naïve) and have not experienced COVID-19. They will 
receive BNT162b2SA given as a 2-dose series, separated by 21 days.
As part of protocol amendment 18, to reflect current and anticipated recommendations for 
COVID-19 vaccine boosters, participants in C4591001 who meet specified recommendations 
(detailed separately and available in the electronic study portal) and have not already 
received one, will be offered a third dose of BNT162b2 after their second dose of BNT162. 
This opportunity is only for those participants who received their first 2 doses of BNT162
(including BNT162b1, BNT162b2, or BNT162b2SA) as part of the study.
As part of protocol amendment 19, eligible participants who received a third dose of 
BNT162b2 (or BNT162b2SA) or a third and fourth dose of BNT162b2SA under protocol 
amendments 13 to 15 will be offered an additional 30-µg dose of BNT162b2. BNT162-naïve 
participants who received 2 primary doses of 30 µg BNT162b2SA under protocol 
amendment 14 and were enrolled to receive a booster dose at Visit 501 under protocol 
amendment 18 are not eligible to receive an additional dose.

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As part of protocol amendment 19, the study may be terminated early for reasons including 
but not limited to the increased access and availability of BNT162b2 in the real world, 
reducing the value of participant involvement and observation in this clinical trial. Further to 
this, participants who are offered the possibility to participate in a future study within the 
Pfizer/BioNTech COVID-19 vaccine development program will be discontinued from this 
study.
As of protocol amendment 20, because the study is now being fully unblinded with no 
control arm, making it observational in nature, and with the active safety surveillance period 
for the majority of participants completed, following agreement with the FDA and EMA, the 
study will be concluded early. Following approval of protocol amendment 20, active study 
participants will be informed of the early completion of the study and further data collection 
will be ceased.
Number of Participants
Each group in Phase 1 will comprise 15 participants (12 receiving active vaccine and 
3 receiving placebo). In this phase, 13 groups will be studied, corresponding to a total of 
195 participants.
The vaccine candidate selected for Phase 2/3, BNT162b2 at a dose of 30 µg, will comprise 
21,999 vaccine recipients. The 12- to 15-year stratum will comprise up to approximately
2000 participants (1000 vaccine recipients) enrolled at selected investigational sites. It is 
intended that a minimum of 40% of participants will be in the >55-year stratum. An equal 
number of participants will receive placebo, ie, randomized in a 1:1 ratio.
For evaluation of boostability and protection against emerging VOCs, 600 existing Phase 3 
participants 18 to 55 years of age will be rerandomized in a 1:1 ratio to receive either a third 
dose of BNT162b2 at 30 µg or a third dose of BNT162b2SA.
An additional group of 30 existing Phase 3 participants 18 to 55 years of age will be enrolled 
to receive a third and fourth dose of BNT162b2SA. For these 30 participants, through 1 
month after their first dose of BNT162b2SA the participants will be blinded to their vaccine 
allocation, but the investigator and sponsor will not be. Serum samples from these 
participants may be used for assay development purposes and, except for objectives relating 
to response to a fourth dose, their results will be analyzed separately from the main 
immunogenicity analyses.
A further group of approximately 144 existing Phase 3 participants 18 years of age and older
will be enrolled to receive a third, lower, dose of BNT162b2 of either 5 or 10 µg.
Approximately 24 participants 18 to 55 years of age and 48 participants >55 years of age will 
be enrolled in each dose group.
Three hundred participants 18 to 55 years of age who are COVID-19 vaccine–naïve 
(ie, BNT162b2-naïve) and have not experienced COVID-19 will be enrolled as a new cohort 
of participants to receive BNT162b2SA given as a 2-dose series.

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Intervention Groups and Duration
The study will evaluate a 2-dose (separated by 21 days) schedule of various different dose 
levels of 3 investigational RNA vaccine candidates for active immunization against 
COVID-19 in 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3:
≥12 years of age [stratified as 12-15, 16-55, or >55 years of age]):

BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD): 
10 µg, 20 µg, 30 µg, 100 µg

BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S): 
5 µg, 10 µg, 20 µg, 30 µg

BNT162b2SA (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S 
containing South Africa B.1.351 variant–specific mutations): 30 µg
The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.
Participants are expected to participate for up to a maximum of approximately 26 months. 
The duration of study follow-up may be shorter among participants enrolled in Phase 1 
dosing arms that are not evaluated in Phase 2/3 or among participants that are offered the 
possibility of participating in another study within the Pfizer/BioNTech COVID-19 vaccine 
development program.
Phase 1 participants who originally received BNT162b1 or BNT162b2 at dose levels of 10, 
20, or 30 µg at Doses 1 and 2 will be offered an additional dose of BNT162b2 at 30 µg 
approximately 6 to 12 months after their second dose of BNT162.
Phase 1/2/3 participants who received a third dose of BNT162b2 (or BNT162b2SA) or a third 
and fourth dose of BNT162b2SA under protocol amendments 13 to 15 will be offered an 
additional dose of BNT162b2 at 30 µg at least 6 months after their last dose of BNT162b2
(or BNT162b2SA).
Data Monitoring Committee or Other Independent Oversight Committee
The study will utilize an IRC, an internal Pfizer committee that will review data to allow 
dose escalation or changes to continuation of specific groups.
An external data monitoring committee (DMC) will be formed and will review cumulative 
unblinded data throughout the study.
Statistical Methods
The sample size for Phase 1 of the study is not based on any statistical hypothesis testing.
For Phase 2/3, the VE evaluation will be the primary objective. The VE is defined as 
VE = 100 × (1 – IRR), where IRR is calculated as the ratio of the first confirmed COVID-19 

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illness rate in the vaccine group to the corresponding illness rate in the placebo group. With 
assumptions of a true VE of 60% and 4 IAs planned, 164 COVID-19 cases will provide 90% 
power to conclude true VE >30%. This would be achieved with a total 43,998 participants 
(21,999 vaccine recipients), based on the assumption of a 1.3% per year incidence in the 
placebo group, accrual of 164 primary-endpoint cases within 6 months, and 20% of the 
participants being nonevaluable.  If the attack rate is much higher, case accrual would be 
expected to be more rapid, enabling the study’s primary endpoint to be evaluated much 
sooner. The total number of participants enrolled in Phase 2/3 may vary depending on the 
incidence of COVID-19 at the time of the enrollment, the true underlying VE, and a potential 
early stop for efficacy or futility.
VE will be evaluated using a beta-binomial model and the posterior probability of VE being 
>30% will be assessed.
The secondary objectives regarding VE against asymptomatic SARS-CoV-2 (determined by 
asymptomatic seroconversion of N-binding antibody and/or asymptomatic SARS-CoV-2 
infection based on central laboratory–confirmed NAAT) will be evaluated. VE will be
demonstrated if the lower bound of the 95% CI for VE is >20%.
In Phase 3, up to approximately 2000 participants are anticipated to be 12 to 15 years of age. 
Noninferiority of immune response to prophylactic BNT162b2 in participants 12 to 15 years 
of age to response in participants 16 to 25 years of age will be assessed based on the GMR of 
SARS-CoV-2 neutralizing titers using a 1.5-fold margin. A sample size of 225 evaluable 
participants (or 280 vaccine recipients) per age group will provide a power of 90.4% to 
declare the noninferiority in terms of GMR (lower limit of 95% CI for GMR >0.67).
The boostability and protection against emerging VOCs for BNT162b2-experienced 
participants and BNT162b2-naïve participants will be assessed based on GMRs of 
SARS-CoV-2 SA-neutralizing and/or reference strain–neutralizing titers using a 1.5-fold 
noninferiority margin and the difference in percentages of participants with seroresponse 
using a 10% noninferiority margin.
The primary safety objective will be evaluated by descriptive summary statistics for local 
reactions, systemic events, AEs/SAEs, and abnormal hematology and chemistry laboratory 
parameters (Phase 1 only), for each vaccine group. A 3-tier approach will be used to 
summarize AEs in Phase 2/3.
Except for the objectives to assess the noninferiority of immune response in participants 
12 to 15 years of age compared to participants 16 to 25 years of age and evaluation of 
boostability and protection against emerging VOCs by BNT162b2 and BNT162b2SA in 
Phase 3, the other immunogenicity objectives will be evaluated descriptively by GMT, GMC, 
GMFR, percentage of participants with ≥4-fold rise, and GMR, and the associated 95% CIs, 
for SARS-CoV-2 neutralizing titers, full-length S-binding or S1-binding IgG levels, and/or
RBD-binding IgG levels (Phase 1 only) at the various time points.

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1.2. Schema
Phase 1
For each vaccine candidate
(4:1 randomization active:placebo)
Age: 18-55 y
Age: 65-85 y
Low-dose-level 2-dose group (n=15)
IRC (safety)
IRC (safety
Low-dose-level 2-dose group (n=15)
after Dose 1)
Mid-dose-level 2-dose group (n=15)
IRC (safety)
IRC (safety
Mid-dose-level 2-dose group (n=15)
after Dose 1)
High-dose-level 2-dose group (n=15)
IRC (safety
High-dose-level 2-dose group (n=15)
after Dose 1)
IRC choice of group(s) for Phase 2/3
(safety & immunogenicity after Doses 1 and 2)
Phase 2/3
Single vaccine candidate
(1:1 randomization active:placebo)
Safety and immunogenicity analysis of 
Phase 2 data (first 360 participants) 
by unblinded team (these participants
will also be included in Phase 3 
analyses)
Age: ≥12
(Stratified 12-15, 16-55, or >55)
BNT162b2 30 µg or placebo 2 doses
(n~21,999 per group, total n~43.998)
Abbreviation: IRC = internal review committee.
Note: Participants who originally received placebo will be offered the opportunity to receive BNT162b2 at 
defined points as part of the study.

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1.3. Schedule of Activities
The SoA tables provide 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.
1.3.1. Phase 1
An unplanned potential COVID-19 illness visit is required at any time between Visit 1 
(Vaccination 1) and Visit 10 (24-month follow-up visit) that COVID-19 is suspected. Prior 
to protocol amendment 16, a COVID-19 convalescent visit was required 28 to 35 days after 
each potential COVID-19 illness visit. Sufficient data have now been accrued from these 
visits, so the requirement has been removed from the protocol.
Administration of BNT162b2 to Those Originally Assigned to Placebo: If a participant 
becomes eligible for receipt of BNT162b2 or another COVID-19 vaccine according to 
recommendations detailed separately, and available in the electronic study reference portal, 
the participant will be advised to contact the site to determine whether he or she can receive 
BNT162b2 in a phased manner as part of the study. When contacted, the site will conduct a 
phone visit to confirm eligibility and, if eligible and wanting to receive BNT162b2 if the
participant originally received placebo, will unblind study intervention allocation to 
determine whether the participant received BNT162b1, BNT162b2, or placebo. If he or she
originally received placebo and wants to receive BNT162b2, the participant will move to the 
SoA in Section 1.3.3 for his or her remaining visits. Participants who received BNT162b1 or 
BNT162b2 (at any dose level) will continue in the study as originally planned.
All other participants will be advised to contact the site to determine whether they can 
receive BNT162b2 as part of the study no later than at the approximate time participants in 
Phase 2/3 reach Visit 4. When contacted, the site will unblind study intervention allocation 
to determine whether the participant received BNT162b1, BNT162b2, or placebo. If he or 
she originally received placebo and wants to receive BNT162b2, the participant will move to 
the SoA in Section 1.3.3 for his or her remaining visits.

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Visit Number
Screening
1
2
3
4
5
6
7
Study 
procedures 
for Visit 8 
onwards 
continue 
on the next 
table
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
Potential COVID-
19 Illness 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
Optimally Within 
3 Days After 
Potential COVID-
19 Illness Onset
Obtain informed consent
X
Continued on table below
Assign participant number 
X
Obtain demography and medical history 
data
X
Obtain details of medications currently 
taken
X
Perform physical examination
X
X
X
X
X
X
X
Measure vital signs 
(including body temperature)
X
X
X
X
X
X
X
Collect blood sample for hematology and 
chemistry laboratory testsb
~10 mL
~10 mL
~10 mL
~10 mL
~10 mL
Collect screening blood sample for HIV, 
HBsAg, HBc Ab, and HCV Ab tests
~10 mL
Serological test for prior COVID-19 
infection
~20 mL
Perform urine pregnancy test 
(if appropriate)
X
X
X
Obtain nasal (midturbinate) swab(s)c
X
X
X
Collect nonstudy vaccine information 
X
X
X
X
X
X
X
X
Confirm eligibility
X
X
X
Collect prohibited medication use
X
X
X
X
X
X
X

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Visit Number
Screening
1
2
3
4
5
6
7
Study 
procedures 
for Visit 8 
onwards 
continue 
on the next 
table
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
Potential COVID-
19 Illness 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
Optimally Within 
3 Days After 
Potential COVID-
19 Illness Onset
Review hematology and chemistry
results
X
X
X
X
X
Continued on table below
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 assessment 
~50 mL
~50 mL
~50 mL
~50 mL
+ optionald
~170 mL
~50 mL
+ optionald
~170 mL
~50 mL
+ optionald
~170 mL
Administer study intervention
X
X
Assess acute reactions for at least 
30 minutes after study intervention 
administratione
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
Study 
procedures 
for Visit 8 
onwards 
continue 
on the next 
table
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
Potential COVID-
19 Illness 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
Optimally Within 
3 Days After 
Potential COVID-
19 Illness Onset
Review ongoing reactogenicity e-diary 
symptoms and obtain stop dates 
X
X
Continued on table 
below
Collect AEs and SAEs as appropriate
X
X
X
X
X
X
X
X
X
Collect e-diary or assist the participant to 
delete application
Collection of 
COVID-19–related clinical and 
laboratory information (including local 
diagnosis)
X
Abbreviations: e-diary = electronic diary; HBc Ab = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HCV Ab = hepatitis C virus antibody; 
HIV = human immunodeficiency virus; NAAT = nucleic acid amplification test; vax = vaccination.
a.
The COVID-19 illness visit may be conducted as an in-person or telehealth visit. This visit should not be performed if protocol amendment 20 is approved 
and participants are informed of early study completion prior to potential COVID-19 illness onset.
b.
Hematology: hemoglobin, complete blood count with differential, and platelets.  Blood chemistry: alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), and creatinine.
c.
Two swabs will be taken at Visits 1 and 4. One will be tested (if possible at the site, otherwise at the central laboratory) within 24 hours and vaccination 
will only proceed if it is NAAT-negative for SARS-CoV-2 genomes. The second will be sent to the central laboratory for potential later testing.
d.
An optional blood draw of ~170 mL will be taken at 1 of the visits (from selected participants who consent) for exploratory COVID-19 research.
e.
The first 5 participants in in each group will be observed at the site for at least 4 hours after study intervention administration. Further vaccination will 
commence no sooner than 24 hours after the fifth participant received his or her vaccination.

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Visit Number
8
8a
8b
8c
9
10
Unplanned
Visit Description
6-Month
Follow-up Visit
Vax 3
1-Week
Follow-up Visit 
(After Vax 3)
1-Month Follow-
up Visit (After 
Vax 3)
12-Month 
Follow-up 
Visit
24-Month 
Follow-up 
Visita
Potential 
COVID-19 Illness 
Visitb
Visit Window (Days)
175 to 189
Days After 
Visit 4
175 to 315 Days 
After Visit 4
6 to 8 Days 
After Visit 8a
28 to 35 Days 
After Visit 8a
350 to 378 
Days After 
Visit 4
714 to 742 Days 
After Visit 4
Optimally Within 
3 Days After 
Potential 
COVID-19 Illness 
Onset
ONLY FOR THOSE PARTICIPANTS 
ORIGINALLY ASSIGNED TO BNT162 at 10 µg, 
20 µg, or 30 µg 
Those participants who decline to receive a third 
dose of BNT162 move directly from Visit 8 to Visit 9
ONLY FOR THOSE 
PARTICIPANTS 
ORIGINALLY ASSIGNED 
TO BNT162 OR PLACEBO 
RECIPIENTS WHO 
DECLINE BNT162b2 (ie, 
those participants who do not
transition from placebo to 
BNT162b2)
Obtain informed consent
X
Confirm participant originally received 10 to 
30 µg of BNT162b1 or BNT162b2
X
Perform urine pregnancy test (if appropriate)
X
Confirm use of contraceptives (if appropriate)
X
X
X
Collect prohibited medication use
X
X
X
X
X
X
X
Collect nonstudy vaccine information 
X
X
X
X
Measure body temperature
X
Confirm eligibility
X
Review temporary delay criteria
X
Collect blood sample for immunogenicity 
assessment 
~20 mL
~20 mL
~20 mL
~20 mL
~20 mL
Obtain nasal (midturbinate) swab(s)
X
X
Obtain the participant’s vaccine vial allocation 
using the IRT system
X
Administer 30-µg dose of BNT162b2
X

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Visit Number
8
8a
8b
8c
9
10
Unplanned
Visit Description
6-Month
Follow-up Visit
Vax 3
1-Week
Follow-up Visit 
(After Vax 3)
1-Month Follow-
up Visit (After 
Vax 3)
12-Month 
Follow-up 
Visit
24-Month 
Follow-up 
Visita
Potential 
COVID-19 Illness 
Visitb
Visit Window (Days)
175 to 189
Days After 
Visit 4
175 to 315 Days 
After Visit 4
6 to 8 Days 
After Visit 8a
28 to 35 Days 
After Visit 8a
350 to 378 
Days After 
Visit 4
714 to 742 Days 
After Visit 4
Optimally Within 
3 Days After 
Potential 
COVID-19 Illness 
Onset
ONLY FOR THOSE PARTICIPANTS 
ORIGINALLY ASSIGNED TO BNT162 at 10 µg, 
20 µg, or 30 µg 
Those participants who decline to receive a third 
dose of BNT162 move directly from Visit 8 to Visit 9
ONLY FOR THOSE 
PARTICIPANTS 
ORIGINALLY ASSIGNED 
TO BNT162 OR PLACEBO 
RECIPIENTS WHO 
DECLINE BNT162b2 (ie, 
those participants who do not
transition from placebo to 
BNT162b2)
Assess acute reactions for at least 30 minutes 
after study intervention administration
X
Provide thermometer and measuring device
X
Remind participant of e-diary technologies
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
Collect AEs and SAEs as appropriate
X
X
X
X
Xc
X
Collect e-diary or assist the participant to delete 
application
Xd

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Visit Number
8
8a
8b
8c
9
10
Unplanned
Visit Description
6-Month
Follow-up Visit
Vax 3
1-Week
Follow-up Visit 
(After Vax 3)
1-Month Follow-
up Visit (After 
Vax 3)
12-Month 
Follow-up 
Visit
24-Month 
Follow-up 
Visita
Potential 
COVID-19 Illness 
Visitb
Visit Window (Days)
175 to 189
Days After 
Visit 4
175 to 315 Days 
After Visit 4
6 to 8 Days 
After Visit 8a
28 to 35 Days 
After Visit 8a
350 to 378 
Days After 
Visit 4
714 to 742 Days 
After Visit 4
Optimally Within 
3 Days After 
Potential 
COVID-19 Illness 
Onset
ONLY FOR THOSE PARTICIPANTS 
ORIGINALLY ASSIGNED TO BNT162 at 10 µg, 
20 µg, or 30 µg 
Those participants who decline to receive a third 
dose of BNT162 move directly from Visit 8 to Visit 9
ONLY FOR THOSE 
PARTICIPANTS 
ORIGINALLY ASSIGNED 
TO BNT162 OR PLACEBO 
RECIPIENTS WHO 
DECLINE BNT162b2 (ie, 
those participants who do not
transition from placebo to 
BNT162b2)
Collection of 
COVID-19–related clinical and laboratory 
information (including local diagnosis)
X
Abbreviations: IRT = interactive response technology; vax = vaccination.
a.
This visit should not be performed if protocol amendment 20 is approved and participants are informed of early study completion prior to reaching this time
point.
b.
The COVID-19 illness visit may be conducted as an in-person or telehealth visit. This visit should not be performed if protocol amendment 20 is approved 
and participants are informed of early study completion prior to potential COVID-19 illness onset.
c.
Any AEs occurring up to 48 hours after the blood draw must be recorded (see Section 8.3.1).
d.
If protocol amendment 20 is approved and participants are informed of early study completion, e-diary device return should be arranged by the site.

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1.3.2. Phase 2/3
An unplanned potential COVID-19 illness visit is required at any time between Visit 1 
(Vaccination 1) and Visit 6 (24-month follow-up visit) that potential COVID-19 symptoms 
are reported, including MIS-C. Prior to protocol amendment 16, a COVID-19 convalescent 
visit was required 28 to 35 days after each potential COVID-19 illness visit. Sufficient data 
have now been accrued from these visits, so the requirement has been removed from the 
protocol.
Administration of BNT162b2 to Those Originally Assigned to Placebo: If a participant 
becomes eligible for receipt of BNT162b2 or another COVID-19 vaccine according to 
recommendations detailed separately, and available in the electronic study reference portal, 
the participant will be advised to contact the site to determine whether he or she can receive 
BNT162b2 in a phased manner as part of the study. When contacted, the site will conduct a
phone visit to confirm eligibility and, if eligible and wanting to receive BNT162b2 if the
participant originally received placebo, will unblind study intervention allocation to 
determine whether the participant received BNT162b2 or placebo. If he or she originally 
received placebo and wants to receive BNT162b2, the participant will move to the SoA in 
Section 1.3.3 for his or her remaining visits. Participants who received BNT162b2 will 
continue in the study as originally planned.
All other participants who have not already been offered the opportunity to receive 
BNT162b2 will be given this opportunity no later than 6 months after Vaccination 2 (at the 
time of the originally planned Visit 4). If they want to receive BNT162b2, they will be 
unblinded and those who did originally receive placebo will move to the SoA in 
Section 1.3.3 for their remaining visits.

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Visit Number
1
2
3
4
5
6
Unplanned
Visit Description
Vaccination 1
Vaccination 2
1-Month
Follow-up Visit
6-Month
Follow-up 
Visit
12-Month 
Follow-up Visit
24-Month 
Follow-up 
Visita
Potential 
COVID-19 
Illness Visitb
Visit Window (Days)
Day 1c
19 to 23 Days 
After Visit 1
28 to 35 Days 
After Visit 2
175 to 189
Days After 
Visit 2
350 to 378 Days 
After Visit 2
714 to 742 
Days After 
Visit 2
Optimally 
Within 3 Days 
After Potential 
COVID-19 
Illness Onset
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 assessmentd
X
For participants who are HIV-positive, record latest CD4 
count and HIV viral load
X
X
X
X
X
Measure height and weight
X
Measure temperature (body)
X
X
Perform urine pregnancy test (if appropriate)
X
X
Confirm use of contraceptives (if appropriate)
X
X
X
Collect nonstudy vaccine information 
X
X
X
X
Collect prohibited medication use
X
X
X
X
X
X
Confirm eligibility
X
X
Review temporary delay criteria
X
X
Collect blood sample for immunogenicity assessmente
~20 mL/
~10 mL
~20 mL/
~10 mL
~20 mL/
~10 mL
~20 mL/
~10 mL
~20 mL/
~10 mL
Obtain nasal (midturbinate) swab
X
X
X
Obtain randomization number and study intervention 
allocation
X

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Final Protocol Amendment 20, 15 September 2022
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Visit Number
1
2
3
4
5
6
Unplanned
Visit Description
Vaccination 1
Vaccination 2
1-Month
Follow-up Visit
6-Month
Follow-up 
Visit
12-Month 
Follow-up Visit
24-Month 
Follow-up 
Visita
Potential 
COVID-19 
Illness Visitb
Visit Window (Days)
Day 1c
19 to 23 Days 
After Visit 1
28 to 35 Days 
After Visit 2
175 to 189
Days After 
Visit 2
350 to 378 Days 
After Visit 2
714 to 742 
Days After 
Visit 2
Optimally 
Within 3 Days 
After Potential 
COVID-19 
Illness Onset
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/ensure the participant has a thermometer
(all participants) and measuring device (reactogenicity 
subset participants only)
X
X
Review reactogenicity e-diary data (daily review is 
optimal during the active diary period)f
Review ongoing reactogenicity e-diary symptoms and 
obtain stop datesf
X
X
Collect AEs and SAEs as appropriate
X
X
X
Xg
Xg
Xg
X
According to eligibility, ascertain willingness to receive 
BNT162b2 if originally received placebo; if willing, 
unblind the participant’s study intervention assignment 
(if not already done), and move placebo recipients to the 
SoA in Section 1.3.3
X
X

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Final Protocol Amendment 20, 15 September 2022
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Visit Number
1
2
3
4
5
6
Unplanned
Visit Description
Vaccination 1
Vaccination 2
1-Month
Follow-up Visit
6-Month
Follow-up 
Visit
12-Month 
Follow-up Visit
24-Month 
Follow-up 
Visita
Potential 
COVID-19 
Illness Visitb
Visit Window (Days)
Day 1c
19 to 23 Days 
After Visit 1
28 to 35 Days 
After Visit 2
175 to 189
Days After 
Visit 2
350 to 378 Days 
After Visit 2
714 to 742 
Days After 
Visit 2
Optimally 
Within 3 Days 
After Potential 
COVID-19 
Illness Onset
ONLY FOR THOSE 
PARTICIPANTS 
ORIGINALLY ASSIGNED TO 
BNT162b2 OR PLACEBO 
RECIPIENTS WHO 
DECLINE BNT162b2
Collect e-diary or assist the participant to delete 
application
Xh
Collection of COVID-19–related clinical and laboratory 
information (including local diagnosis)
X
Abbreviations: HIV = human immunodeficiency virus; e-diary = electronic diary.
a.
This visit should not be performed if protocol amendment 20 is approved and participants are informed of early study completion prior to reaching this time
point.
b.
The COVID-19 illness visit may be conducted as an in-person or telehealth visit. This visit should not be performed if protocol amendment 20 is approved 
and participants are informed of early study completion prior to potential COVID-19 illness onset.
c.
The visit may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and exclusion criteria onwards must be conducted on the 
same day.
d.
Including, if indicated, a physical examination.
e.
20 mL is to be collected from participants ≥16 years of age; 10 mL is to be collected from participants 12 to 15 years of age.
f.
Reactogenicity subset participants only.
g.
Any AEs occurring up to 48 hours after the blood draw must be recorded (see Section 8.3.1).
h.
If protocol amendment 20 is approved and participants are informed of early study completion, e-diary device return should be arranged by the site.

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Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
Page 52
1.3.3. Administration of BNT162b2 to Those Originally Assigned to Placebo
Participants who originally received placebo and become eligible for receipt of BNT162b2 according to recommendations detailed 
separately, and available in the electronic study reference portal, will have the opportunity to receive BNT162b2 in a phased manner 
as part of the study. Any placebo recipient who has not already been offered the opportunity to receive BNT162b2 will be given this 
opportunity no later than 6 months after Vaccination 2.
Visit Number
101
102
103
104
105
Unplanned
Visit Description
Vaccination 3
Vaccination 4
1-Month
Telephone 
Contact
6-Month
Telephone 
Contact
18-Month
Telephone 
Contacta
Potential 
COVID-19 
Illness Visitb
Visit Window (Days)
From 
Recommendationc
or
At Least 175 Days 
After Vaccination 2d
19 to 23 Days 
After Visit 101
28 to 35 Days 
After Visit 102
175 to 189 Days 
After Visit 102
532 to 560 Days 
After Visit 102
Optimally Within 
3 Days After 
Potential 
COVID-19 
Illness Onset
Confirm participant meets local/national 
recommending criteria or is at least 175 days after 
Vaccination 2 (Visit 4/Visit 2)
X
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 prohibited medication use
X
X
X
X
X
X
For participants who are HIV-positive, record latest 
CD4 count and HIV viral load
X
X
X
X
Review and consider eligibility
X
X
Review temporary delay criteria
X
X
Collect blood sample for immunogenicity 
assessmente
~20 mL
Obtain nasal (midturbinate) swab
X
X
X
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

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Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
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Visit Number
101
102
103
104
105
Unplanned
Visit Description
Vaccination 3
Vaccination 4
1-Month
Telephone 
Contact
6-Month
Telephone 
Contact
18-Month
Telephone 
Contacta
Potential 
COVID-19 
Illness Visitb
Visit Window (Days)
From 
Recommendationc
or
At Least 175 Days 
After Vaccination 2d
19 to 23 Days 
After Visit 101
28 to 35 Days 
After Visit 102
175 to 189 Days 
After Visit 102
532 to 560 Days 
After Visit 102
Optimally Within 
3 Days After 
Potential 
COVID-19 
Illness Onset
Collect AEs and SAEs as appropriate
X
X
X
X
Xf
Contact the participant by telephone
X
X
X
Request the participant return the e-diary or assist the 
participant to delete the application
Xg
Collection of COVID-19–related clinical and 
laboratory information (including local diagnosis)
X
Abbreviations: HIV = human immunodeficiency virus; IRT = interactive response technology.
a.
This visit should not be performed if protocol amendment 20 is approved and participants are informed of early study completion prior to reaching this 
time point.
b.
This visit should not be performed if protocol amendment 20 is approved and participants are informed of early study completion prior to potential 
COVID-19 illness onset.
c.
For participants who become eligible according to recommendations detailed separately and available in the electronic study reference portal.
d.
For any remaining Phase 2/3 placebo recipients who wish to receive BNT162b2; may be combined with Visit 4 for Phase 2/3 participants.
e.
Only if the participant has no blood sample collected in the previous 7 days.
f.
AEs need only be recorded if the participant remains in the AE reporting period (see Section 8.3.1).
g.
If protocol amendment 20 is approved and participants are informed of early study completion, e-diary device return should be arranged by the site.

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Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
Page 54
1.3.4. Administration of an Additional Dose of BNT162b2 (5, 10, or 30 µg) or BNT162b2SA (30 µg) (Subset for Evaluation of 
Boostability and Protection Against Emerging VOCs)
Select participants in Phase 3 at select sites who originally received 2 doses of BNT162b2 will be offered the opportunity to receive a 
third (and potentially fourth) dose of BNT162b2 or BNT162b2SA.
Visit Number
301
302
303
304
305
306
307
Unplanned
Visit Description
Vax 3a
1-Week
Follow-up Visit 
(After Vax 3)
1-Month 
Follow-up 
Visit
(After Vax 3)
1-Week
Follow-up Visit 
(After Vax 4)b
1-Month 
Follow-up Visit
(After Vax 4)b
6-Month 
Follow-up 
Visit
18-Month 
Follow-up Visitc
Potential 
COVID-19 
Illness Visitd
Visit Window (Days)
150 to 210 
Days After 
Visit 2
6 to 8 Days 
After Visit 301
28 to 35 Days 
After Visit 301
6 to 8 Days 
After Visit 303
28 to 35 Days 
After Visit 303
175 to 189 
Days After 
Visit 301
532 to 560 Days 
After Visit 301
Optimally 
Within 3 Days 
After Potential 
COVID-19 
Illness Onset
ONLY FOR SELECT PARTICIPANTS AT 
SELECT SITES WHO ORIGINALLY 
RECEIVED BNT162b2 AT DOSE 1 AND 
DOSE 2
ONLY FOR THE SUBSET OF 
PARTICIPANTS WHO 
RECEIVE DOSE 4
Obtain informed consent
X
Confirm participant originally 
received BNT162b2 at Dose 1 and 
Dose 2
X
Perform urine pregnancy test 
(if appropriate)
X
Xb
Confirm use of contraceptives 
(if appropriate)
X
X
X
X
X
Collect prohibited medication use
X
X
X
X
X
X
X
X
Collect nonstudy vaccine 
information 
X
X
X
X
X
X
For participants who are 
HIV-positive, record latest CD4 
count and HIV viral load
X
X
X
X
Measure body temperature
X
Xb
Confirm eligibility
X
Xb
Review temporary delay criteria
X
Xb

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
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Visit Number
301
302
303
304
305
306
307
Unplanned
Visit Description
Vax 3a
1-Week
Follow-up Visit 
(After Vax 3)
1-Month 
Follow-up 
Visit
(After Vax 3)
1-Week
Follow-up Visit 
(After Vax 4)b
1-Month 
Follow-up Visit
(After Vax 4)b
6-Month 
Follow-up 
Visit
18-Month 
Follow-up Visitc
Potential 
COVID-19 
Illness Visitd
Visit Window (Days)
150 to 210 
Days After 
Visit 2
6 to 8 Days 
After Visit 301
28 to 35 Days 
After Visit 301
6 to 8 Days 
After Visit 303
28 to 35 Days 
After Visit 303
175 to 189 
Days After 
Visit 301
532 to 560 Days 
After Visit 301
Optimally 
Within 3 Days 
After Potential 
COVID-19 
Illness Onset
ONLY FOR SELECT PARTICIPANTS AT 
SELECT SITES WHO ORIGINALLY 
RECEIVED BNT162b2 AT DOSE 1 AND 
DOSE 2
ONLY FOR THE SUBSET OF 
PARTICIPANTS WHO 
RECEIVE DOSE 4
Collect blood sample for 
immunogenicity assessment 
~50 mL
~50 mL
~50 mL
~50 mL
~50 mL
~50 mL
~50 mL
Collect blood sample for PBMC 
isolatione
~120 mL
~120 mL
~120 mL
~120 mL
Collect blood sample for HLA 
typinge
~5 mL
Obtain nasal (midturbinate) swab(s)
X
Xb
X
Obtain randomization number and 
study intervention allocation using 
the IRT system
X
Administer study intervention
X
Xb
Assess acute reactions for at least 
30 minutes after study intervention 
administration
X
Xb
Provide thermometer and 
measuring device
X
Remind participant of e-diary 
technologies
X
Xb
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

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
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Visit Number
301
302
303
304
305
306
307
Unplanned
Visit Description
Vax 3a
1-Week
Follow-up Visit 
(After Vax 3)
1-Month 
Follow-up 
Visit
(After Vax 3)
1-Week
Follow-up Visit 
(After Vax 4)b
1-Month 
Follow-up Visit
(After Vax 4)b
6-Month 
Follow-up 
Visit
18-Month 
Follow-up Visitc
Potential 
COVID-19 
Illness Visitd
Visit Window (Days)
150 to 210 
Days After 
Visit 2
6 to 8 Days 
After Visit 301
28 to 35 Days 
After Visit 301
6 to 8 Days 
After Visit 303
28 to 35 Days 
After Visit 303
175 to 189 
Days After 
Visit 301
532 to 560 Days 
After Visit 301
Optimally 
Within 3 Days 
After Potential 
COVID-19 
Illness Onset
ONLY FOR SELECT PARTICIPANTS AT 
SELECT SITES WHO ORIGINALLY 
RECEIVED BNT162b2 AT DOSE 1 AND 
DOSE 2
ONLY FOR THE SUBSET OF 
PARTICIPANTS WHO 
RECEIVE DOSE 4
Collect AEs and SAEs as 
appropriate
X
X
X
X
X
Xf
Xf
X
Collect e-diary or assist the 
participant to delete application
Xg
Collection of 
COVID-19–related clinical and 
laboratory information (including 
local diagnosis)
X
Abbreviations: e-diary = electronic diary; HIV = human immunodeficiency virus; HLA = human leukocyte antigen; IRT = interactive response technology; PBMC = peripheral 
blood mononuclear cell; vax = vaccination.
a.
Visit 301 can occur on the same day as Visit 4, but all procedures for both visits must be conducted (including collection of all blood samples).
b.
Only for those participants who will receive Dose 4.
c.
This visit should not be performed if protocol amendment 20 is approved and participants are informed of early study completion prior to reaching this 
time point.
d.
The COVID-19 illness visit may be conducted as an in-person or telehealth visit. This visit should not be performed if protocol amendment 20 is approved 
and participants are informed of early study completion prior to potential COVID-19 illness onset.
e.
Additional 120 mL for PBMC isolation and 5 mL for HLA typing is for select participants who will receive a third (but not fourth) dose of BNT162b2 at 
30 µg or BNT162b2SA at select sites only.
f.
Any AEs occurring up to 48 hours after the blood draw must be recorded (see Section 8.3.1).
g.
If protocol amendment 20 is approved and participants are informed of early study completion, e-diary device return should be arranged by the site.

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Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
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1.3.5. Administration of BNT162b2SA to BNT162b2-Naïve Participants
As part of Amendment 14, an additional cohort of BNT162b2-naïve participants will be enrolled to receive BNT162b2SA per the
following SoA.
Visit Number
401
402
403
404
405
406
Unplanned
Visit Description
Vaccination 1
Vaccination 2
1-Week
Follow-up Visit
1-Month
Follow-up Visit
6-Month
Follow-up Visit
18-Month 
Follow-up 
Visita
Potential 
COVID-19 
Illness Visitb
Visit Window (Days)
Day 1c
19 to 23 Days 
After Visit 401
6 to 8 Days 
After Visit 402
28 to 35 Days 
After Visit 402
175 to 189 Days 
After Visit 402
532 to 560 Days 
After Visit 402
Optimally 
Within 3 Days 
After Potential 
COVID-19 
Illness Onset
Obtain informed consent
X
Assign participant number 
X
Obtain demography and medical history data
X
Perform clinical assessmentd
X
Measure height and weight
X
Measure temperature (body)
X
X
Perform urine pregnancy test (if appropriate)
X
X
Confirm use of contraceptives (if appropriate)
X
X
X
X
Collect nonstudy vaccine information 
X
X
X
X
X
Collect prohibited medication use
X
X
X
X
X
X
For participants who are HIV-positive, record latest 
CD4 count and HIV viral load
X
X
X
X
Confirm eligibility
X
X
Review temporary delay criteria
X
X
Collect blood sample for immunogenicity 
assessment
~50 mL
~50 mL
~50 mL
~50 mL
~50 mL
Collect blood sample for PBMC isolatione
~120 mL
~120 mL
~120 mL
~120 mL
Collect blood sample for HLA typinge
~5 mL
Obtain nasal (midturbinate) swab
X
X
X

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
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Visit Number
401
402
403
404
405
406
Unplanned
Visit Description
Vaccination 1
Vaccination 2
1-Week
Follow-up Visit
1-Month
Follow-up Visit
6-Month
Follow-up Visit
18-Month 
Follow-up 
Visita
Potential 
COVID-19 
Illness Visitb
Visit Window (Days)
Day 1c
19 to 23 Days 
After Visit 401
6 to 8 Days 
After Visit 402
28 to 35 Days 
After Visit 402
175 to 189 Days 
After Visit 402
532 to 560 Days 
After Visit 402
Optimally 
Within 3 Days 
After Potential 
COVID-19 
Illness Onset
Obtain the participant’s vaccine vial allocation using 
the IRT system
X
X
Administer BNT162b2SA
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/ensure the participant has a thermometer (all 
participants) and measuring device (reactogenicity 
subset participants only)
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
Collect AEs and SAEs as appropriate
X
X
X
X
Xf
Xf
X
Collect e-diary or assist the participant to delete 
application
Xg

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
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Visit Number
401
402
403
404
405
406
Unplanned
Visit Description
Vaccination 1
Vaccination 2
1-Week
Follow-up Visit
1-Month
Follow-up Visit
6-Month
Follow-up Visit
18-Month 
Follow-up 
Visita
Potential 
COVID-19 
Illness Visitb
Visit Window (Days)
Day 1c
19 to 23 Days 
After Visit 401
6 to 8 Days 
After Visit 402
28 to 35 Days 
After Visit 402
175 to 189 Days 
After Visit 402
532 to 560 Days 
After Visit 402
Optimally 
Within 3 Days 
After Potential 
COVID-19 
Illness Onset
Collection of COVID-19–related clinical and 
laboratory information (including local diagnosis)
X
Abbreviations: e-diary = electronic diary; HIV = human immunodeficiency virus; HLA = human leukocyte antigen; IRT = interactive response technology; PBMC = peripheral 
blood mononuclear cell; vax = vaccination.
a.
This visit should not be performed if protocol amendment 20 is approved and participants are informed of early study completion prior to reaching this 
time point.
b.
The COVID-19 illness visit may be conducted as an in-person or telehealth visit. This visit should not be performed if protocol amendment 20 is approved 
and participants are informed of early study completion prior to potential COVID-19 illness onset.
c.
The visit may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and exclusion criteria onwards must be conducted on the 
same day.
d.
Including, if indicated, a physical examination.
e.
Additional 120 mL for PBMC isolation and 5 mL for HLA typing is for select participants at select sites only.
f.
Any AEs occurring up to 48 hours after the blood draw must be recorded (see Section 8.3.1).
g.
If protocol amendment 20 is approved and participants are informed of early study completion, e-diary device return should be arranged by the site.

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1.3.6. Surveillance for Asymptomatic SARS-CoV-2 Infection
An intensive period of surveillance for asymptomatic SARS-CoV-2 infection may be conducted at selected sites among Phase 2/3 
participants following approval of protocol amendment 11. After an initial in-person visit where a blood sample will be collected and 
a nasal (midturbinate) swab obtained, nasal (midturbinate) swabs will be obtained from consented participants every 2 weeks until 
Visit 4 or a sufficient number of cases of SARS-CoV-2 infection have accrued to evaluate this objective, whichever is sooner.
Participants who are unblinded because they become potentially eligible for receipt of BNT162b2 according to recommendations 
detailed separately, and available in the electronic study reference portal, will not participate in surveillance for asymptomatic 
SARS-CoV-2 infection. However, participants who provided additional consent to conduct biweekly swabbing for surveillance of 
asymptomatic infection should continue to swab even after unblinding if they originally received BNT162b2.
Surveillance for asymptomatic SARS-CoV-2 infection (swabbing) should cease in participants enrolled into the subset of participants 
who will receive an additional dose of BNT162b2 or BNT162b2SA.
Visit Number
201
202 Onward
Visit Description
Asymptomatic SARS-CoV-2 
Infection Surveillance Consent
Asymptomatic SARS-CoV-2 
Infection 
Surveillance Swab
Visit Window (Days)
From Approval of Protocol 
Amendment 11 
Repeating Every 10 to 18 Days 
After Each Previous Surveillance 
Swab Collection
Obtain informed consent for asymptomatic SARS-CoV-2 infection surveillance
X
Collect prohibited medication use
X
Collect blood sample for immunogenicity assessmenta
~20 mL/~10 mL
Obtain nasal (midturbinate) swab (self-swab at home or by site staff at an 
in-person visit)
X
X
Collect AEs and SAEs as appropriateb
X
a.
Only if the participant has no blood sample collected in the previous 7 days. 20 mL is to be collected from participants ≥16 years of age; 10 mL is to be 
collected from participants 12 to 15 years of age.
b.
AEs need only be recorded if the participant remains in the AE reporting period (see Section 8.3.1).

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1.3.7. Administration of a Third Dose of BNT162b2 to Participants Who Have Not Previously Received a Third Dose
As part of protocol amendment 18, to reflect current and anticipated recommendations for COVID-19 vaccine boosters, participants in 
C4591001 who have not already received one, will be offered a third dose of BNT162b2 from at least 3 months (84 days) after their 
second dose of BNT162. The opportunity to receive a third dose of BNT162b2 will be offered as part of the study, according to 
recommendations detailed separately, and available in the electronic study reference portal. This opportunity is only for those 
participants who received their first 2 doses of BNT162 (including BNT162b1, BNT162b2, or BNT162b2SA) as part of the study.
Once a participant receives a vaccination at Visit 501, all remaining study visits will follow the SoA as set out below.
The additional information collected at Visits 501, 502, 503, and 504 will be collected in a supplementary database; further 
information on the recording of this information will be provided in the study CRF Completion Requirements document.
Visit Number
501
502
503
504
Unplanned
Visit Description
Third Dose of 
BNT162b2
1-Month
Telephone 
Contact
6-Month
Telephone 
Contacta
12-Month
Follow-up Visita
Potential COVID-19 
Illness Visitb
Visit Window (Days)
Per Recommendationc
28 to 35 Days 
After Visit 501
175 to 189 Days 
After Visit 501
350 to 378 Days 
After Visit 501
Optimally Within 3 Days 
After Potential 
COVID-19 Illness Onsetc
Confirm participant has only received 2 doses of BNT162 as 
part of the study and not outside the study
X
Obtain informed consent
X
Perform urine pregnancy test (if appropriate)
X
Confirm use of contraceptives (if appropriate)
X
Collect nonstudy vaccine informationd
X
X
X
Collect prohibited medication used
X
X
X
X
X
For participants who are HIV-positive, record latest CD4 count 
and HIV viral load
X
X
X
X
Review and consider eligibility
X
Review temporary delay criteria
X
Collect blood sample for immunogenicity assessment
~20 mL
~20 mL
Obtain nasal (midturbinate) swab
X
X
Obtain vaccine vial allocation via IRT
X

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Visit Number
501
502
503
504
Unplanned
Visit Description
Third Dose of 
BNT162b2
1-Month
Telephone 
Contact
6-Month
Telephone 
Contacta
12-Month
Follow-up Visita
Potential COVID-19 
Illness Visitb
Visit Window (Days)
Per Recommendationc
28 to 35 Days 
After Visit 501
175 to 189 Days 
After Visit 501
350 to 378 Days 
After Visit 501
Optimally Within 3 Days 
After Potential 
COVID-19 Illness Onsetc
Administer BNT162b2
X
Assess acute reactions for at least 30 minutes after study 
intervention administration
X
Collect AEs and SAEs as appropriated
X
X
X
Xe
Contact the participant by telephone
X
X
Request the participant return the e-diary device or assist the 
participant to delete the application
Xf
Collection of COVID-19–related clinical and laboratory 
information (including local diagnosis)
X
Abbreviations: HIV = human immunodeficiency virus; IRT = interactive response technology.
a.
This visit should not be performed if protocol amendment 20 is approved and participants are informed of early study completion prior to reaching this time
point.
b.
This visit should not be performed if protocol amendment 20 is approved and participants are informed of early study completion prior to potential 
COVID-19 illness onset.
c.
The opportunity to receive a third dose of BNT162b2 will be offered as part of the study, according to recommendations detailed separately, and available 
in the electronic study reference portal.
d.
AEs, nonstudy prohibited medications, and information relating to a potential COVID-19 illness will still be recorded in the original study database
(see Section 8.3.1).
e.
AEs need only be recorded if the participant remains in the AE reporting period (see Section 8.3.1).
f.
If protocol amendment 20 is approved and participants are informed of early study completion, e-diary device return should be arranged by the site.

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1.3.8. Administration of a Fourth (or Fifth) Dose of BNT162b2 to Eligible Participants From Protocol Amendments 13, 14, and
15
As part of protocol amendment 19, eligible participants who received a third dose of BNT162b2 (or BNT162b2SA) or a third and 
fourth dose of BNT162b2SA under protocol amendments 13 to 15 will be offered an additional 30-µg dose of BNT162b2. 
BNT162-naïve participants who received 2 primary doses of 30 µg BNT162b2SA under protocol amendment 14 and were enrolled to 
receive a booster dose at Visit 501 under protocol amendment 18 are not eligible to receive an additional dose.
The additional information collected at Visits 601, 602, 603, 604, 605, and 606 will be collected in a supplementary database, and on 
receipt of vaccination, participants will follow the schedule as set out below; further information on the recording of this information 
will be provided in the study CRF Completion Requirements document.
Visit Number
601
602
603
604
605
606
Unplanned
Visit Description
Dose 4a
1-Month
Telephone 
Contact
6-Month
Telephone 
Contactb
Dose 5a
1-Month
Telephone 
Contact
6-Month
Telephone 
Contactb
Potential COVID-19 
Illness Visitc
Visit Window (Days)
At Least
175 Days After 
Visit 8a OR 
Visit 301
28 to 35 Days 
After Visit 601
175 to 189 Days 
After Visit 601
At Least
175 Days After 
Visit 303
28 to 35 Days 
After Visit 604
175 to 189 Days 
After Visit 604
Optimally Within 3 
Days After Potential 
COVID-19 Illness 
Onset
ADDITIONAL DOSE ONLY FOR THOSE 
PARTICIPANTS WHO RECEIVED DOSE 3 AT VISIT 8a 
or VISIT 301; 
Participants who decline to receive a fourth dose of 
BNT162b2 will continue to follow schedule of assessments per 
Section 1.3.1 or 1.3.4 as appropriate.
ADDITIONAL DOSE ONLY FOR THOSE 
PARTICIPANTS WHO RECEIVED DOSE 4 at VISIT 
303; 
Participants who decline to receive a fifth dose of 
BNT162b2 will continue to follow schedule of assessments 
per Section 1.3.4.
Confirm participant has received at 
least 3 (or 4) prior doses as part of 
study and not outside and is eligible 
to receive fourth (or fifth) dose of 
BNT162b2
X
X
Obtain informed consent
X
X
Perform urine pregnancy test 
(if appropriate)
X
X

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Visit Number
601
602
603
604
605
606
Unplanned
Visit Description
Dose 4a
1-Month
Telephone 
Contact
6-Month
Telephone 
Contactb
Dose 5a
1-Month
Telephone 
Contact
6-Month
Telephone 
Contactb
Potential COVID-19 
Illness Visitc
Visit Window (Days)
At Least
175 Days After 
Visit 8a OR 
Visit 301
28 to 35 Days 
After Visit 601
175 to 189 Days 
After Visit 601
At Least
175 Days After 
Visit 303
28 to 35 Days 
After Visit 604
175 to 189 Days 
After Visit 604
Optimally Within 3 
Days After Potential 
COVID-19 Illness 
Onset
ADDITIONAL DOSE ONLY FOR THOSE 
PARTICIPANTS WHO RECEIVED DOSE 3 AT VISIT 8a 
or VISIT 301; 
Participants who decline to receive a fourth dose of 
BNT162b2 will continue to follow schedule of assessments per 
Section 1.3.1 or 1.3.4 as appropriate.
ADDITIONAL DOSE ONLY FOR THOSE 
PARTICIPANTS WHO RECEIVED DOSE 4 at VISIT 
303; 
Participants who decline to receive a fifth dose of 
BNT162b2 will continue to follow schedule of assessments 
per Section 1.3.4.
Confirm use of contraceptives 
(if appropriate)
X
X
Collect nonstudy vaccine 
informationd
X
X
X
X
Collect prohibited medication used
X
X
X
X
X
X
X
For participants who are HIV-
positive, record latest CD4 count and 
HIV viral loade
X
X
X
X
X
X
Review and consider eligibility
X
X
Review temporary delay criteria
X
X
Obtain nasal (midturbinate) swab
X
X
X
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
Xf
Contact the participant by telephone
X
X
X
X
Request the participant return the 
e-diary device or assist the participant 
to delete the application
X
X
Xg

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Visit Number
601
602
603
604
605
606
Unplanned
Visit Description
Dose 4a
1-Month
Telephone 
Contact
6-Month
Telephone 
Contactb
Dose 5a
1-Month
Telephone 
Contact
6-Month
Telephone 
Contactb
Potential COVID-19 
Illness Visitc
Visit Window (Days)
At Least
175 Days After 
Visit 8a OR 
Visit 301
28 to 35 Days 
After Visit 601
175 to 189 Days 
After Visit 601
At Least
175 Days After 
Visit 303
28 to 35 Days 
After Visit 604
175 to 189 Days 
After Visit 604
Optimally Within 3 
Days After Potential 
COVID-19 Illness 
Onset
ADDITIONAL DOSE ONLY FOR THOSE 
PARTICIPANTS WHO RECEIVED DOSE 3 AT VISIT 8a 
or VISIT 301; 
Participants who decline to receive a fourth dose of 
BNT162b2 will continue to follow schedule of assessments per 
Section 1.3.1 or 1.3.4 as appropriate.
ADDITIONAL DOSE ONLY FOR THOSE 
PARTICIPANTS WHO RECEIVED DOSE 4 at VISIT 
303; 
Participants who decline to receive a fifth dose of 
BNT162b2 will continue to follow schedule of assessments 
per Section 1.3.4.
Collection of COVID-19–related 
clinical and laboratory information 
(including local diagnosis)
X
Abbreviations: HIV = human immunodeficiency virus; IRT = interactive response technology; vax = vaccination.
a.
Applicable to those eligible participants per protocol amendments 13,14, and 15 who received Dose 3 at Visit 8a or 301 or Dose 4 at Visit 303.
b.
This visit should not be performed if protocol amendment 20 is approved and participants are informed of early study completion prior to reaching this time
point.
c.
The COVID-19 illness visit may be conducted as an in-person or telehealth visit. This visit should not be performed if protocol amendment 20 is approved 
and participants are informed of early study completion prior to potential COVID-19 illness onset.
d.
AEs and SAEs, nonstudy vaccines and prohibited medications, and information relating to a potential COVID-19 illness will still be recorded in the original 
study database.
e.
Not required to be recorded for Phase 1 participants who received Dose 3 at Visit 8a.
f.
AEs need only be recorded if the participant remains in the AE reporting period (see Section 8.3.1).
g.
If protocol amendment 20 is approved and participants are informed of early study completion, e-diary device return should be arranged by the site.

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2. INTRODUCTION
The BNT162 RNA-based COVID-19 vaccines are currently being investigated for 
prevention of COVID-19 in healthy individuals.
2.1. Study Rationale
The purpose of the study is to rapidly describe the safety, tolerability, and immunogenicity of 
2 BNT162 RNA-based COVID-19 vaccine candidates against COVID-19, and the efficacy 
of 1 candidate, in healthy individuals. There are currently no licensed vaccines to prevent 
infection with SARS-CoV-2 or COVID-19. Given the global crisis of COVID-19 and fast 
expansion of the disease in the United States and elsewhere, the rapid development of 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 novel coronavirus (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.
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 United States currently has the most reported cases globally. At the time of 
this communication, the number of confirmed cases continues to rise globally. As of 
27 February 2022, over 433 million confirmed cases and over 5.9 million deaths have been 
reported globally, demonstrating an urgent need for efficacious vaccines.3
Numerous COVID-19 vaccines are currently in development globally, and several candidate 
COVID-19 vaccines (eg, mRNA vaccines and adenovirus-vectored vaccines expressing the 
S protein) have been shown to be efficacious in the prevention of COVID-19 in clinical 
studies and are now available under temporary or emergency authorizations. BNT162b2, an 
RNA-based COVID-19 vaccine given as a 2-dose series administered 21 days apart, was 
shown to be safe and effective in a Phase 1/2/3 study and has received authorizations for 
temporary or emergency use or marketing authorizations in multiple countries and has been 
fully licensed for use in individuals 16 years of age and above in the US as of 23 Aug 2021.
As more data about COVID-19 continue to accrue, the potential duration of protection 
afforded after a wild-type SARS-CoV-2 infection, and by vaccination, remains unknown. 
In addition, mutated SARS-CoV-2 VOCs have started to emerge, for example in the UK 

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(known as 20I/501Y.V1, VOC 202012/01, or B.1.1.7), SA (known as 20H/501Y.V2 or 
B.1.351), and Brazil (known as P.1).4
A prophylactic, RNA-based SARS-CoV-2 vaccine provides one of the most flexible and 
fastest approaches available to immunize against the emerging virus.5,6
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 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.
Three SARS-CoV-2–RNA lipid nanoparticle (RNA-LNP) vaccines based on a platform of
nucleoside-modified messenger RNA (modRNA, BNT162b) will be evaluated in this study. 
Each vaccine candidate expresses 1 of 3 antigens: 

BNT162b1 (variant RBP020.3): nucleoside-modified messenger RNA (modRNA) with 
blunted innate immune sensor–activating capacity and augmented expression encoding 
the trimerized SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) 
(version 5);

BNT162b2 (variant RBP020.2): nucleoside-modified messenger RNA (modRNA) as 
above, but encoding the SARS-CoV-2 full-length, P2 mutant, prefusion spike 
glycoprotein (P2 S) (version 9);

BNT162b2s01 (variant RBP020.11): nucleoside-modified messenger RNA (modRNA) 
as above, but encoding the P2 S containing South Africa B.1.351 variant–specific 
mutations, hereafter referred to as BNT162b2SA, as a representative variant of concern 
(VOC).
The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2.
In light of the unknowns regarding duration of protection, as well as the emerging VOCs, it is 
important to understand the boostability of BNT162, and potential heterologous protection 
against emerging VOC(s). A first step to address this will be to study an additional dose of 
BNT162b2 at 30 µg given to Phase 1 participants approximately 6 to 12 months after their 
second dose of BNT162b1 or BNT162b2. This will provide an early assessment of the safety 
of a third dose of BNT162, as well as its immunogenicity. The assessment of boostability 
will be further expanded in a subset of Phase 3 participants at selected sites in the US who 
will receive a third dose of BNT162b2 at 30 µg or a third and potentially a fourth dose of 
prototype BNT162b2VOC (based upon the South African variant and hereafter referred to as 

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BNT162b2SA). A further subset of Phase 3 participants will receive a third, lower, dose of 
BNT162b2 at 5 or 10 µg.
To further describe potential homologous and heterologous protection against emerging 
SARS-CoV-2 VOCs, a new cohort of participants will be enrolled who are COVID-19 
vaccine–naïve (ie, BNT162b2-naïve) and have not experienced COVID-19. They will 
receive BNT162b2SA given as a 2-dose series, separated by 21 days.
As part of protocol amendment 18, to reflect current and anticipated recommendations for 
COVID-19 vaccine boosters, participants in C4591001 who meet specified recommendations 
and have not already received one, will be offered a third dose of BNT162b2 after their 
second dose of BNT162b1, BNT162b2 or BNT162b2SA. The opportunity to receive a third
dose of BNT162b2 will be offered as part of the study, according to recommendations 
detailed separately, and available in the electronic study reference portal.
As part of protocol amendment 19, Phase 1/2/3 participants who received a third dose of 
BNT162b2 (or BNT162b2SA) or a third and fourth dose of BNT162b2SA under protocol 
amendments 13 to 15 will be offered an additional dose of BNT162b2 at 30 µg at least 
6 months after their last dose of BNT162b2 (or BNT162b2SA).
Since the initiation of this study, many protocol amendments have been implemented in order 
to adapt to expanding knowledge about COVID-19, the emergence of VOCs, and growing 
knowledge about duration of vaccine effectiveness. These amendments have included
unblinding and vaccination of initial placebo recipients and administration of booster doses, 
to ensure that participants have been protected in line with national and local guidelines as 
they have been determined. Therefore, the study is now fully unblinded with no control arm, 
making it observational in nature, and the active safety surveillance period for the majority of 
participants has completed. Real-world studies of both safety and effectiveness of 
BNT162b2 have contributed enormously, and continue to do so, to the knowledge about the 
vaccine beyond what is possible within the clinical trial setting. In view of this, and with 
agreement of the FDA and EMA, protocol amendment 20 will truncate participants’ study 
involvement to allow early completion of the study without the need to complete all study 
visits as per the SoA. Following the appropriate approvals of protocol amendment 20,
participants will be informed via the study sites that their participation in the study will be 
concluded with no further data collection required from that point onwards.
Protocol amendment 20 will also remove the objective to describe the safety and 
immunogenicity of prophylactic BNT162b2 in individuals 16 to 55 years of age vaccinated 
with study intervention produced by manufacturing “Process 1” or “Process 2.” As of 03 July 
2022, more than 3.6 billion doses of BNT162b2 have been distributed,7 with over 1.4 billion 
doses of BNT162b2 administered worldwide,8 which were manufactured via “Process 2.”
Given the number of doses now administered globally, the originally planned manufacturing 
process comparison is no longer warranted.

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2.3. Clinical Overview
Prior to this study, given clinical data from other similarly formulated uRNA liposomal 
vaccines from BioNTech in oncology trials9 and recent published results from clinical trials 
using modRNA influenza vaccines by Moderna,10 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 this 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.
2.4. Benefit/Risk Assessment
There is an ongoing global pandemic of COVID-19 with no preventative or therapeutic 
options available. While there were no data available from clinical trials on the use of 
BNT162 vaccines in humans at the outset of this study, available nonclinical data with 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 1/2/3 clinical study.
Updates as part of protocol amendment 6:

In order for the overall Phase 3 study population to be as representative and diverse as 
possible, the inclusion of participants with known chronic stable HIV, HCV, or HBV
infection is permitted. Individuals with chronic viral diseases are at increased risk for 
COVID-19 complications and severe disease. In addition, with the currently available 
therapies for their treatment, many individuals with chronic stable HIV, HCV, and HBV 
infections are unlikely to be at higher safety risk as a participant in this vaccine study 
than individuals with other chronic stable medical conditions.

All participants with chronic stable HIV disease will be included in the reactogenicity 
subset (see Section 8.2.2).
Updates as part of protocol amendment 7:

The minimum age for inclusion in Phase 3 is lowered to 12 years, therefore allowing the 
inclusion of participants 12 to 15 years of age.

For individuals 12 to 15 years of age, the immune responses in this age group may be 
higher and reactogenicity is expected to be similar to younger adults 18 to 25 years of 
age. Inclusion of individuals 12 to 15 years of age was based upon a satisfactory blinded 
safety profile in participants 18 to 25 years of age.

All participants 12 to 15 years of age will be included in the reactogenicity subset 
(see Section 8.2.2).

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More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of BNT162 RNA-based COVID-19 vaccines may be found in the IB, which is 
the SRSD for this study.
2.4.1. 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 Center for 
Biologics Evaluation and Research 
(CBER) guidelines on toxicity 
grading scales for healthy adult 
volunteers enrolled in preventive 
vaccine clinical trials.11
The Phase 1 study design includes 
the use of controlled vaccination
and dose escalation to closely 
monitor and limit the rate of 
enrollment to ensure participant
safety. The study employs the use 
of a reactogenicity e-diary to 
monitor local reactions and 
systemic events in real time. 
Stopping rules are also in place. 
The first 5 participants in each 
group in Phase 1 will be observed 
for 4 hours after vaccination to 
assess any immediate AEs. All 
other participants will be observed 
for at least 30 minutes after 
vaccination.
Potential for COVID-19
enhancement.
Disease enhancement has been seen 
following vaccination with 
respiratory syncytial virus (RSV),
feline coronavirus, and Dengue 
virus vaccines.
Phase 1 excludes participants 
with likely previous or current
COVID-19. In Phase 2/3, 
temporary delay criteria defer 
vaccination of participants with 
symptoms of potential COVID-19.
All participants are followed for 
any potential COVID-19 illness,
including markers of severity, and 
have blood samples taken for 
potential measurement of SARS-
CoV-2 antigen-specific antibody 
and SARS-CoV-2 neutralizing 
titers.
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.

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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
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 would obtain the blood 
draw.
Very rare cases of anaphylaxis, 
myocarditis, and pericarditis have 
been reported after authorization in 
recipients of BNT162b2.
Anaphylaxis: Frequency not 
known.
Myocarditis and pericarditis: Very 
rare cases of myocarditis and 
pericarditis have been reported 
following vaccination with mRNA 
COVID-19 vaccines. Typically, 
the cases have occurred more often 
in younger men and after the 
second dose of the vaccine and 
within 14 days after vaccination. 
These are generally mild cases, and 
individuals tend to recover within a 
short time following standard 
treatment and rest. Healthcare 
professionals should be alert to the 
signs and symptoms of myocarditis 
and pericarditis in vaccine 
recipients.
Specific reference to these risks is 
made within the ICD, with 
instruction to contact a healthcare 
professional if a case is suspected.
For anaphylaxis, there is an on-site 
30-minute observation period after 
vaccination.
Instructions for handling suspected 
cases of myocarditis and 
pericarditis are found in
Section 8.22.
2.4.2. Benefit Assessment
Benefits to individual participants may include:

Receipt of an efficacious COVID-19 vaccine during a global pandemic

Access to COVID-19 diagnostic testing

Contributing to research to help others in a time of global pandemic
2.4.3. 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.

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3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS
3.1. For Phase 1
Objectives
Estimands
Endpoints
Primary: 
Primary:
Primary: 
To describe the safety and tolerability 
profiles of prophylactic BNT162 
vaccines in healthy adults after 1 or 
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

Adverse events (AEs) from 
Dose 1 to 1 month after the last 
dose

Serious AEs (SAEs) from Dose 1 
to 6 months after the last dose

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, 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
Secondary: 
Secondary:
Secondary: 
To describe the immune responses 
elicited by prophylactic BNT162 
vaccines in healthy adults after 1 or 2 
doses
In participants complying with the key 
protocol criteria (evaluable 
participants) at the following time 
points after receipt of study 
intervention: 7 and 21 days after Dose 
1; 7 and 14 days and 1 and 6 months 
after Dose 2

Geometric mean titers (GMTs) at 
each time point

Geometric mean fold rise (GMFR) 
from before vaccination to each 
subsequent time point after 
vaccination

Proportion of participants 
achieving ≥4-fold rise from before 
vaccination to each subsequent 
time point after vaccination
SARS-CoV-2 neutralizing titers

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
Page 73
Objectives
Estimands
Endpoints

Geometric mean concentrations 
(GMCs) at each time point

GMFR from prior to first dose of 
study intervention to each 
subsequent time point

Proportion of participants 
achieving ≥4-fold rise from before 
vaccination to each subsequent 
time point after vaccination
S1-binding IgG levels and RBD-
binding IgG levels

Geometric mean ratio (GMR), 
estimated by the ratio of the
geometric mean of SARS-CoV-2
neutralizing titers to the geometric 
mean of binding IgG levels at each 
time point

SARS-CoV-2 neutralizing titers

S1-binding IgG levels

RBD-binding IgG levels
Exploratory: 
Exploratory:
Exploratory: 
To describe the immune responses 
elicited by a third dose of prophylactic 
BNT162b2 administered to healthy 
adults at least 6 months after the second 
dose of either BNT162b1 or 
BNT162b2

GMCs/GMTs at the time of 
Dose 3, 7 days and 1 month after 
Dose 3, and 12 months after 
Dose 2

GMFRs from before Dose 3 to 
7 days and 1 month after Dose 3
and 12 months after Dose 2 

SARS-CoV-2 reference-strain 
neutralizing titers

SARS-CoV-2 SA-variant
neutralizing titers

Full-length S-binding or 
S1-binding IgG levels

GMR of SARS-CoV-2 reference-
strain neutralizing titers 1 month 
after Dose 3 to 1 month after 
Dose 2

SARS-CoV-2 reference-strain 
neutralizing titers

GMR of SARS-CoV-2 SA-variant
neutralizing titers 1 month after 
Dose 3 to SARS-CoV-2 reference-
strain neutralizing titers 1 month 
after Dose 2

SARS-CoV-2 reference-strain 
neutralizing titers

SARS-CoV-2 SA-variant
neutralizing titers
To describe the safety profile of a third 
dose of prophylactic BNT162b2
administered to healthy adults 6 to 12 
months after the second dose of either 
BNT162b1 or BNT162b2
In participants receiving a third dose of 
BNT162b2, the percentage of 
participants reporting:

Local reactions for up to 7 days 
after Dose 3

Systemic events for up to 7 days 
after Dose 3

AEs and SAEs from Dose 3 to 
1 month after Dose 3

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
To describe the safety and tolerability
profile of BNT162b2 given as a fourth 
dose at least 6 months after the third 
dose of BNT162b2 for participants who 
received a fourth dose as part of 
protocol amendment 19
In participants receiving a fourth dose 
of study intervention, the percentage of 
participants reporting:

AEs and SAEs from Dose 4 to 
1 month after Dose 4

AEs

SAEs

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
Page 74
3.2. For Phase 2/3
Objectivesa
Estimands
Endpoints
Primary Efficacy
To evaluate the efficacy of prophylactic 
BNT162b2 against confirmed 
COVID-19 occurring from 7 days after 
the second dose in participants without 
evidence of infection before 
vaccination
In participants complying with the key 
protocol criteria (evaluable 
participants) at least 7 days after receipt 
of the second dose of study 
intervention:
100 × (1 – IRR) [ratio of active vaccine 
to placebo]
COVID-19 incidence per 1000 
person-years of follow-up based on 
central laboratory or locally confirmed 
NAAT in participants with no 
serological or virological evidence 
(up to 7 days after receipt of the second
dose) of past SARS-CoV-2 infection
To evaluate the efficacy of prophylactic 
BNT162b2 against confirmed 
COVID-19 occurring from 7 days after 
the second dose in participants with 
and without evidence of infection 
before vaccination
In participants complying with the key 
protocol criteria (evaluable 
participants) at least 7 days after receipt 
of the second dose of study 
intervention:
100 × (1 – IRR) [ratio of active vaccine 
to placebo]
COVID-19 incidence per 1000 
person-years of follow-up based on 
central laboratory or locally confirmed 
NAAT
Primary Safety
To define the safety profile of 
prophylactic BNT162b2 in the first 
360 participants randomized (Phase 2)
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 7 days after 
the second dose

SAEs from Dose 1 to 7 days after 
the second dose

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
To define the safety profile of 
prophylactic BNT162b2 in all 
participants randomized in Phase 2/3
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 
the second dose

SAEs from Dose 1 to 6 months
after the second dose

AEs

SAEs

In a subset of at least 
6000 participants:
o
Local reactions (pain at the 
injection site, redness, and 
swelling)
o
Systemic events (fever, 
fatigue, headache, chills, 
vomiting, diarrhea, new or 
worsened muscle pain, and 
new or worsened joint pain)
To define the safety profile of 
prophylactic BNT162b2 in participants
12 to 15 years of age in Phase 3
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 
the second dose

SAEs from Dose 1 to 6 months 
after the second dose

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

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
Page 75
Objectivesa
Estimands
Endpoints
To describe the safety and tolerability 
profile of BNT162b2SA given as 1 or 
2 doses to BNT162b2-experienced 
participants, or as 2 doses to 
BNT162b2-naïve participants
To describe the safety and tolerability 
profile of BNT162b2 given as a third
dose to BNT162b2-experienced 
participants in the subset for evaluation 
of boostability and protection against 
emerging VOCs
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 
the last dose

SAEs from Dose 1 to 5 or 6 months 
after the last dose

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
To describe the safety and tolerability 
profile of BNT162b2 given as a third 
dose at least 3 months after the second 
dose of BNT162b2 (or BNT162b2SA) 
for participants who received a third 
dose as part of protocol amendment 18
In participants receiving at least 1 dose 
of study intervention, the percentage of 
participants reporting:

AEs and SAEs from Dose 3 to 
1 month after Dose 3

AEs

SAEs
To describe the safety and tolerability 
profile of BNT162b2 given as a fourth 
(or fifth) dose at least 6 months after 
the third (or fourth) dose of BNT162b2 
(or BNT162b2SA) for participants who 
received a fourth (or fifth) dose as part 
of protocol amendment 19
In participants receiving a fourth
(or fifth) dose of study intervention, the 
percentage of participants reporting:

AEs and SAEs from Dose 4
(or Dose 5) to 1 month after 
Dose 4 (or Dose 5)

AEs

SAEs
Primary Immunogenicity
BNT162b2-experienced participants
To demonstrate the noninferiority of 
the anti–reference strain immune 
response after a third dose of 
BNT162b2 at 30 µg compared to after 
2 doses of BNT162b2, in the same 
individuals
GMR of reference strain NT 1 month 
after the third dose of BNT162b2 at 
30 µg to 1 month after the second dose 
of BNT162b2
The difference in percentages of 
participants with seroresponse to the 
reference strain at 1 month after the 
third dose of BNT162b2 at 30 µg and 
1 month after the second dose of 
BNT162b2
SARS-CoV-2 reference strain NTs in 
participants with no serological or 
virological evidence (up to 1 month
after receipt of the third dose of 
BNT162b2 at 30 µg) of past 
SARS-CoV-2 infection
To demonstrate the noninferiority of 
the anti-SA immune response after 
1 dose of BNT162b2SA compared to the 
anti–reference strain immune response 
after 2 doses of BNT162b2, in the same 
individuals
GMR of SA NT 1 month after 1 dose 
of BNT162b2SA to the reference strain 
NT 1 month after the second dose of 
BNT162b2
The difference in percentages of 
participants with seroresponse to the 
SA strain at 1 month after 1 dose of 
BNT162b2SA and seroresponse to the 
reference strain at 1 month after the 
second dose of BNT162b2
SARS-CoV-2 SA and reference strain 
NTs in participants with no serological 
or virological evidence (up to 1 month 
after receipt of 1 dose of BNT162b2SA) 
of past SARS-CoV-2 infection

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
Page 76
Objectivesa
Estimands
Endpoints
BNT162b2-naïve participants
To demonstrate the noninferiority of 
the anti-SA immune response after 
2 doses of BNT162b2SA compared to 
the anti–reference strain immune 
response after 2 doses of BNT162b2 
GMR of SA NT 1 month after the 
second dose of BNT162b2SA to the 
reference strain NT 1 month after the 
second dose of BNT162b2
The difference in percentages of 
participants with seroresponse to the 
SA strain at 1 month after the second 
dose of BNT162b2SA and seroresponse 
to the reference strain at 1 month after 
the second dose of BNT162b2
SARS-CoV-2 SA and reference strain 
NTs in participants with no serological 
or virological evidence (up to 1 month 
after receipt of the second dose of 
BNT162b2SA or BNT162b2 as 
appropriate) of past SARS-CoV-2 
infection
Secondary Efficacy
To evaluate the efficacy of prophylactic 
BNT162b2 against confirmed 
COVID-19 occurring from 14 days 
after the second dose in participants 
without evidence of infection before 
vaccination
In participants complying with the key 
protocol criteria (evaluable 
participants) at least 14 days after 
receipt of the second dose of study 
intervention:
100 × (1 – IRR) [ratio of active vaccine 
to placebo]
COVID-19 incidence per 1000 
person-years of follow-up based on 
central laboratory or locally confirmed 
NAAT in participants with no 
serological or virological evidence (up 
to 14 days after receipt of the second
dose) of past SARS-CoV-2 infection
To evaluate the efficacy of prophylactic
BNT162b2 against confirmed 
COVID-19 occurring from 14 days 
after the second dose in participants 
with and without evidence of infection 
before vaccination
In participants complying with the key 
protocol criteria (evaluable 
participants) at least 14 days after 
receipt of the second dose of study 
intervention:
100 × (1 – IRR) [ratio of active vaccine 
to placebo]
COVID-19 incidence per 1000 
person-years of follow-up based on 
central laboratory or locally confirmed 
NAAT
To evaluate the efficacy of prophylactic 
BNT162b2 against confirmed severe 
COVID-19 occurring from 7 days and 
from 14 days after the second dose in 
participants without evidence of 
infection before vaccination
In participants complying with the key 
protocol criteria (evaluable 
participants) 

at least 7 days 
and

at least 14 days after receipt of the 
second dose of study intervention:
100 × (1 – IRR) [ratio of active 
vaccine to placebo]
Confirmed severe COVID-19 incidence 
per 1000 person-years of follow-up in 
participants with no serological or 
virological evidence (up to 7 days and 
up to 14 days after receipt of the second 
dose) of past SARS-CoV-2 infection
To evaluate the efficacy of prophylactic 
BNT162b2 against confirmed severe 
COVID-19 occurring from 7 days and 
from 14 days after the second dose in 
participants with and without evidence 
of infection before vaccination
In participants complying with the key 
protocol criteria (evaluable 
participants) 

at least 7 days 
and

at least 14 days after receipt of the 
second dose of study intervention:
100 × (1 – IRR) [ratio of active 
vaccine to placebo]
Confirmed severe COVID-19 incidence 
per 1000 person-years of follow-up
To describe the efficacy of prophylactic 
BNT162b2 against confirmed 
COVID-19 (according to the 
CDC-defined symptoms) occurring 
from 7 days and from 14 days after the 
second dose in participants without 
evidence of infection before 
vaccination
In participants complying with the key 
protocol criteria (evaluable 
participants) 

at least 7 days 
and

at least 14 days after receipt of the 
second dose of study intervention:  
100 × (1 – IRR) [ratio of active 
vaccine to placebo]
COVID-19 incidence per 1000 
person-years of follow-up based on 
central laboratory or locally confirmed 
NAAT in participants with no 
serological or virological evidence 
(up to 7 days and up to 14 days after 
receipt of the second dose) of past 
SARS-CoV-2 infection

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
Page 77
Objectivesa
Estimands
Endpoints
To describe the efficacy of prophylactic 
BNT162b2 against confirmed 
COVID-19 (according to the 
CDC-defined symptoms) occurring 
from 7 days and from 14 days after the 
second dose in participants with and 
without evidence of infection before 
vaccination
In participants complying with the key 
protocol criteria (evaluable 
participants) 

at least 7 days 
and

at least 14 days after receipt of the 
second dose of study intervention:  
100 × (1 – IRR) [ratio of active 
vaccine to placebo]
COVID-19 incidence per 1000 
person-years of follow-up based on 
central laboratory or locally confirmed 
NAAT
To evaluate the efficacy of prophylactic 
BNT162b2 against non-S 
seroconversion to SARS-CoV-2 in 
participants without evidence of 
infection or confirmed COVID-19 
In participants complying with the key 
protocol criteria (evaluable 
participants):
100 × (1 – IRR) [ratio of active vaccine 
to placebo]
Incidence of asymptomatic 
SARS-CoV-2 infection per 1000 
person-years of follow-up based on 
N-binding antibody seroconversion in 
participants with no serological or 
virological evidence of past 
SARS-CoV-2 infection or confirmed 
COVID-19 
To evaluate the efficacy of prophylactic 
BNT162b2 against asymptomatic 
SARS-CoV-2 infection in participants 
without evidence of infection up to the 
start of the asymptomatic surveillance 
period
In participants complying with the key 
protocol criteria (evaluable 
participants):
100 × (1 – IRR) [ratio of active vaccine 
to placebo]
Incidence of asymptomatic 
SARS-CoV-2 infection per 1000 
person-years of follow-up based on 
central laboratory–confirmed NAAT in 
participants with no serological or 
virological evidence (up to the start of 
the asymptomatic surveillance period) 
of past SARS-CoV-2 infection
Secondary Immunogenicity
To demonstrate the noninferiority of 
the immune response to prophylactic 
BNT162b2 in participants 12 to 
15 years of age compared to 
participants 16 to 25 years of age
GMR, estimated by the ratio of the 
geometric mean of SARS-CoV-2
neutralizing titers in the 2 age groups 
(12-15 years of age to 16-25 years of 
age) 1 month after completion of 
vaccination
SARS-CoV-2 neutralizing titers in 
participants with no serological or 
virological evidence (up to 1 month
after receipt of the second dose) of past 
SARS-CoV-2 infection
BNT162b2-experienced participants
To demonstrate the noninferiority of 
the anti-SA immune response after a 
third dose of BNT162b2 at 30 µg 
compared to the anti–reference strain 
immune response after 2 doses of 
BNT162b2, in the same individuals 
GMR of SA NT 1 month after the third
dose of BNT162b2 at 30 µg to the 
reference strain NT 1 month after the 
second dose of BNT162b2
The difference in percentages of 
participants with seroresponse to the
SA strain at 1 month after the third 
dose of BNT162b2 at 30 µg and 
seroresponse to the reference strain at 
1 month after the second dose of 
BNT162b2
SARS-CoV-2 SA and reference strain 
NTs in participants with no serological 
or virological evidence (up to 1 month
after receipt of the third dose of 
BNT162b2 at 30 µg) of past 
SARS-CoV-2 infection
To demonstrate the noninferiority of 
the anti–reference strain immune 
response after 1 dose of BNT162b2SA
compared to after 2 doses of 
BNT162b2, in the same individuals 
GMR of reference strain NT 1 month 
after 1 dose of BNT162b2SA to 1 month 
after the second dose of BNT162b2
The difference in percentages of 
participants with seroresponse to the 
reference strain at 1 month after 1 dose 
of BNT162b2SA and 1 month after the 
second dose of BNT162b2
SARS-CoV-2 reference strain NTs in 
participants with no serological or 
virological evidence (up to 1 month 
after receipt of 1 dose of BNT162b2SA) 
of past SARS-CoV-2 infection

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
Page 78
Objectivesa
Estimands
Endpoints
To descriptively compare the anti-SA 
immune response after 1 dose of 
BNT162b2SA and a third dose of 
BNT162b2 at 30 µg
GMR of SA NT 1 month after 1 dose 
of BNT162b2SA to 1 month after the 
third dose of BNT162b2 at 30 µg
The difference in percentages of 
participants with seroresponse to the
SA strain at 1 month after 1 dose of 
BNT162b2SA and 1 month after the 
third dose of BNT162b2 at 30 µg
SARS-CoV-2 SA NT in participants 
with no serological or virological 
evidence (up to 1 month after receipt of 
1 dose of BNT162b2SA or the third
dose of BNT162b2 at 30 µg) of past 
SARS-CoV-2 infection
To descriptively compare the anti-SA 
immune response after 2 doses of 
BNT162b2SA and the anti–reference 
strain immune response after 2 doses of 
BNT162b2, in the same individuals 
GMR of SA NT 1 month after the 
second dose of BNT162b2SA to the 
reference strain NT 1 month after the 
second dose of BNT162b2
The difference in percentages of 
participants with seroresponse to the 
SA strain at 1 month after the second 
dose of BNT162b2SA and seroresponse 
to the reference strain at 1 month after 
the second dose of BNT162b2
SARS-CoV-2 SA and reference strain 
NTs in participants with no serological 
or virological evidence (up to 1 month 
after receipt of the second dose of 
BNT162b2SA) of past SARS-CoV-2 
infection
BNT162b2-naïve participants
To demonstrate a statistically greater 
anti-SA immune response after 2 doses 
of BNT162b2SA compared to after 
2 doses of BNT162b2 
GMR of SA NT 1 month after the 
second dose of BNT162b2SA to 
1 month after the second dose of 
BNT162b2
The difference in percentages of 
participants with seroresponse to the 
SA strain at 1 month after the second 
dose of BNT162b2SA and 1 month after 
the second dose of BNT162b2
SARS-CoV-2 SA NTs in participants 
with no serological or virological 
evidence (up to 1 month after receipt of 
the second dose of BNT162b2SA or 
BNT162b2 as appropriate) of past 
SARS-CoV-2 infection
To descriptively compare the anti–
reference strain immune response after 
2 doses of BNT162b2SA and after 
2 doses of BNT162b2 
GMR of reference strain NT 1 month 
after the second dose of BNT162b2SA
to 1 month after the second dose of 
BNT162b2
The difference in percentages of 
participants with seroresponse to 
reference strain at 1 month after the 
second dose of BNT162b2SA and 
1 month after the second dose of 
BNT162b2
SARS-CoV-2 reference strain NTs in 
participants with no serological or 
virological evidence (up to 1 month 
after receipt of the second dose of 
BNT162b2SA or BNT162b2 as 
appropriate) of past SARS-CoV-2 
infection
Exploratory
To describe the efficacy of prophylactic 
BNT162b2 against confirmed 
COVID-19 occurring from 7 days after 
the second dose through the blinded 
follow-up period in participants 
without, and with and without,
evidence of infection before 
vaccination
In participants complying with the key 
protocol criteria (evaluable 
participants) after receipt of the second 
dose of study intervention:
100 × (1 – IRR) [ratio of active vaccine 
to placebo]
COVID-19 incidence per 1000 
person-years of blinded follow-up 
based on central laboratory or locally 
confirmed NAAT
To describe the incidence of confirmed 
COVID-19 through the entire study 
follow-up period in participants who 
received BNT162b2 at initial 
randomization or subsequently
In participants after receipt of each 
dose of BNT162b2:
Incidence per 1000 person-years of 
follow-up
COVID-19 incidence per 1000 
person-years of follow-up based on 
central laboratory or locally confirmed 
NAAT

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
PFIZER CONFIDENTIAL
Page 79
Objectivesa
Estimands
Endpoints
To evaluate the immune response over 
time to prophylactic BNT162b2 and 
persistence of immune response in 
participants with and without 
serological or virological evidence of 
SARS-CoV-2 infection before 
vaccination
GMC/GMT at baseline and 1 and 
6 months after Dose 2 and GMFR from
baseline to 1 and 6 months after Dose 2

Full-length S-binding or 
S1-binding IgG levels

SARS-CoV-2 neutralizing titers
To describe the efficacy of prophylactic 
BNT162b2 against asymptomatic 
SARS-CoV-2 infection in participants 
with evidence of infection up to the 
start of the asymptomatic surveillance 
period
In participants complying with the key 
protocol criteria (evaluable 
participants):
100 × (1 – IRR) [ratio of active vaccine 
to placebo]
Incidence of asymptomatic 
SARS-CoV-2 infection per 1000 
person-years of follow-up based on 
central laboratory–confirmed NAAT in 
participants with serological or 
virological evidence (up to the start of 
the asymptomatic surveillance period) 
of past SARS-CoV-2 infection
To describe the serological responses to 
the BNT vaccine candidate and 
characterize the SARS-CoV-2 isolate 
in cases of:

Confirmed COVID-19 cases that 
occur through approximately 
6 months after the second dose

Confirmed severe COVID-19
cases that occur through 
approximately 6 months after the 
second dose

SARS-CoV-2 neutralizing titers

Identification of SARS-CoV-2 
variant(s) 
To describe the safety, 
immunogenicity, and efficacy of 
prophylactic BNT162b2 in individuals 
with confirmed stable HIV disease

All safety, immunogenicity, and 
efficacy endpoints described 
above
To describe the immune response to 
any VOCs not already specified
Geometric mean NT for any VOCs not 
already specified, after any dose of 
BNT162b2SA or BNT162b2

SARS-CoV-2 NTs for any VOCs
not already specified
To describe the immune response to a 
third dose of BNT162b2 (at 30 µg or a 
lower dose of 5 µg or 10 µg) or a third 
or fourth dose of BNT162b2SA

GMTs at Dose 3 and subsequent 
time points

GMFRs from Dose 3 to 
subsequent time points

SARS-CoV-2 reference strain NTs 
To describe the cell-mediated immune 
response, and additional humoral 
immune response parameters, to the 
reference strain and SA in a subset of 
participants:

7 Days and 1 and 6 months after 
BNT162b2SA given as 1 or 2 doses 
to BNT162b2-experienced 
participants

7 Days and 1 and 6 months after 
BNT162b2SA given as 2 doses to 
BNT162b2-naïve participants

7 Days and 1 and 6 months after 
BNT162b2 given as a third dose 
to BNT162b2-experienced 
participants
a.
HIV-positive participants in Phase 3 will not be included in analyses of the objectives, with the exception 
of the specific exploratory objective.

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Up until the final efficacy analysis, this protocol will use a group of internal case reviewers 
to determine whether certain investigator-reported events meet the definition of 
disease-related efficacy endpoints, using predefined endpoint criteria.
For those AEs that are handled as disease-related efficacy endpoints (which may include 
death), a DMC will conduct unblinded reviews on a regular basis throughout the trial
(see Section 9.6).
Any AE that is determined by the internal case reviewers NOT to meet endpoint criteria is 
reported back to the investigator site of incidence.  Refer to Section 8.3.1.1 for instructions 
on how to report any such AE that meets the criteria for seriousness to Pfizer Safety.
4. STUDY DESIGN
4.1. Overall Design
This is a multicenter, multinational, Phase 1/2/3, randomized, placebo-controlled, 
observer-blind, dose-finding, vaccine candidate–selection, and efficacy study in healthy 
individuals.
The study consists of 2 parts. Phase 1: to identify preferred vaccine candidate(s) and dose 
level(s); Phase 2/3: an expanded cohort and efficacy part.  These parts, and the progression 
between them, are detailed in the schema (Section 1.2).
The study will evaluate the safety, tolerability, and immunogenicity of 3 different 
SARS-CoV-2 RNA vaccine candidates against COVID-19 and the efficacy of 1 candidate:

As a 2-dose (separated by 21 days) schedule;

At various different dose levels in Phase 1;

As a booster;

In 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3:
≥12 years of age [stratified as 12-15, 16-55, or >55 years of age]).
Dependent upon safety and/or immunogenicity data generated during the course of this 
study, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups 
in Phase 1 may be started at the next highest dose, groups may not be started, groups may be 
terminated early, and/or groups may be added with dose levels below the lowest stated dose 
or intermediate between the lowest and highest stated doses.
The study is observer-blinded, as the physical appearance of the investigational vaccine 
candidates and the placebo may differ. The participant, investigator, study coordinator, and 
other site staff will be blinded. At the study site, only the dispenser(s)/administrator(s) are 
unblinded.

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To facilitate rapid review of data in real time, sponsor staff will be unblinded to vaccine 
allocation for the participants in Phase 1.
In order to describe the boostability of BNT162, an additional dose of BNT162b2 at 30 µg 
will be given to Phase 1 participants approximately 6 to 12 months after their second dose of 
BNT162b1 or BNT162b2. This will provide an early assessment of the safety of a third dose 
of BNT162, as well as its immunogenicity. The assessment of boostability will be further 
expanded in a subset of Phase 3 participants at selected sites in the US who will receive a 
third dose of BNT162b2 at 30 µg or a third and potentially a fourth dose of prototype 
BNT162b2VOC at 30 µg (based upon the South African variant and hereafter referred to as 
BNT162b2SA). A further subset of Phase 3 participants will receive a third, lower, dose of 
BNT162b2 at 5 or 10 µg.
To further describe potential homologous and heterologous protection against emerging 
SARS-CoV-2 VOCs, a new cohort of participants will be enrolled who are COVID-19 
vaccine-naïve (ie, BNT162b2-naïve) and have not experienced COVID-19. They will 
receive BNT162b2SA given as a 2-dose series, separated by 21 days.
As part of protocol amendment 19, eligible participants who received a third dose of 
BNT162b2 (or BNT162b2SA) or a third and fourth dose of BNT162b2SA under protocol 
amendments 13 to 15 will be offered an additional 30-µg dose of BNT162b2. BNT162-naïve 
participants who received 2 primary doses of 30 µg BNT162b2SA under protocol amendment 
14 and were enrolled to receive a booster dose at Visit 501 under protocol amendment 18 are 
not eligible to receive an additional dose.
Protocol amendment 20 will truncate participants’ study involvement to allow early 
completion of the study without the need to complete all study visits as per the SoA.
4.1.1. Phase 1
Each group (vaccine candidate/dose level/age group) will comprise 15 participants; 
12 participants will be randomized to receive active vaccine and 3 to receive placebo.
For each vaccine candidate/dose level/age group, the following apply:

Additional safety assessments (see Section 8.2)

Controlled enrollment (required only for the first candidate and/or dose level studied):

No more than 5 participants (4 active, 1 placebo) can be vaccinated on the first day

The first 5 participants must be observed by blinded site staff for at least 4 hours after 
vaccination for any acute reactions

Vaccination of the remaining participants will commence no sooner than 24 hours 
after the fifth participant received his or her vaccination

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
Application of stopping rules

IRC review of safety data to determine escalation to the next dose level in the 18- to 
55-year age cohort:

Escalation between dose levels will be based on IRC review of at least 7-day 
post–Dose 1 safety data in this study and/or the BioNTech study conducted in 
Germany (BNT162-01)

Note that, since both candidates are based upon the same RNA platform, dose 
escalation for the second candidate studied may be based upon the safety profile of 
the first candidate studied being deemed acceptable at the same, or a higher, dose 
level by the IRC
Groups of participants 65 to 85 years of age will not be started until safety data for the RNA 
platform have been deemed acceptable at the same, or a higher, dose level in the 18- to 
55-year age cohort by the IRC.
In this phase, 13 groups will be studied, corresponding to a total of 195 participants.
The IRC will select 1 vaccine candidate that, in Phase 1, has an established dose level per age 
group based on induction of a post–Dose 2 immune response, including neutralizing 
antibodies, which is expected to be associated with protection against COVID-19, for
progression into Phase 2/3.
Participants who originally received placebo and become eligible for receipt of BNT162b2 or 
another COVID-19 vaccine according to recommendations detailed separately, and available 
in the electronic study reference portal, will have the opportunity to receive BNT162b2 in a 
phased manner as part of the study. The investigator will ensure the participant meets at least 
1 of the recommendation criteria.
Any Phase 1 placebo recipient who has not already been offered the opportunity to receive 
BNT162b2 will be given this opportunity no later than at the approximate time participants in 
Phase 2/3 reach Visit 4.
Any participant who originally received placebo but then goes on to receive BNT162b2 will 
move to a new visit schedule (Section 1.3.3).
In order to describe the boostability of BNT162, and potential heterologous protection 
against emerging SARS-CoV-2 VOCs, an additional dose of BNT162b2 at 30 µg will be 
given to Phase 1 participants approximately 6 to 12 months after their second dose of 
BNT162b1 or BNT162b2. This group of participants will also be offered a fourth dose of 
BNT162b2 at 30 µg at least 6 months after their third dose.
Phase 1 participants who originally received BNT162b1 or BNT162b2 at dose levels of 10, 
20, or 30 µg at Doses 1 and 2 will be offered an additional dose of BNT162b2 at 30 µg

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approximately 6 to 12 months after their second dose of BNT162. A further fourth dose of 
BNT162b2 at 30 µg will be offered to these participants at least 6 months after their third 
dose.
Participants are expected to participate for up to a maximum of approximately 26 months.
4.1.2. Phase 2/3
On the basis of safety and/or immunogenicity data generated during the course of this study, 
and/or the BioNTech study conducted in Germany (BNT162-01), 1 vaccine candidate was
selected to proceed into Phase 2/3. Participants in this phase will be ≥12 years of age, 
stratified as follows: 12 to 15 years, 16 to 55 years, or >55 years. The 12- to 15-year stratum 
will comprise up to approximately 2000 participants enrolled at selected investigational sites.
It is intended that a minimum of 40% of participants will be in the >55-year stratum.
Commencement of each age stratum will be based upon satisfactory post–Dose 2 safety and 
immunogenicity data from the 18- to 55-year and 65- to 85-year age groups in Phase 1, 
respectively.  The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose 
of 30 µg.
Phase 2/3 is event-driven. Under the assumption of a true VE rate of ≥60%, after the second
dose of investigational product, a target of 164 primary-endpoint cases of confirmed 
COVID-19 due to SARS-CoV-2 occurring at least 7 days following the second dose of the
primary series of the candidate vaccine will be sufficient to provide 90% power to conclude 
true VE >30% with high probability. The total number of participants enrolled in Phase 2/3 
may vary depending on the incidence of COVID-19 at the time of the enrollment, the true 
underlying VE, and a potential early stop for efficacy or futility.
Assuming a COVID-19 attack rate of 1.3% per year in the placebo group, accrual of 164 first
primary-endpoint cases within 6 months, an estimated 20% nonevaluable rate, and 1:1 
randomization, the BNT162b2 vaccine candidate selected for Phase 2/3 is expected to 
comprise approximately 21,999 vaccine recipients. This is the number of participants 
initially targeted for Phase 2/3 and may be adjusted based on advice from DMC analyses of 
case accumulation and the percentage of participants who are seropositive at baseline.
Dependent upon the evolution of the pandemic, it is possible that the COVID-19 attack rate 
may be much higher, in which case accrual would be expected to be more rapid, enabling the 
study’s primary endpoint to be evaluated much sooner.
The first 360 participants enrolled (180 to active vaccine and 180 to placebo, stratified 
equally between 18 to 55 years and >55 to 85 years) will comprise the “Phase 2” portion. 
Safety data through 7 days after Dose 2 and immunogenicity data through 1 month after 
Dose 2 from these 360 participants will be analyzed by the unblinded statistical team, 
reviewed by the DMC, and submitted to appropriate regulatory authorities for review. 
Enrollment may continue during this period and these participants would be included in the 
efficacy evaluation in the “Phase 3” portion of the study.

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In Phase 3, up to approximately 2000 participants, enrolled at selected sites, are anticipated 
to be 12 to 15 years of age. Noninferiority of immune response to prophylactic BNT162b2 
in participants 12 to 15 years of age to response in participants 16 to 25 years of age will be 
assessed based on the GMR of SARS-CoV-2 neutralizing titers using a 1.5-fold margin. 
A sample size of 225 evaluable participants (or 280 vaccine recipients) per age group will 
provide a power of 90.4% to declare the noninferiority in terms of GMR (lower limit of 95%
CI for GMR >0.67). A random sample of 280 participants from each of the 2 age groups
(12 to 15 years and 16 to 25 years) will be selected as an immunogenicity subset for the 
noninferiority assessment.
The initial BNT162b2 was manufactured using “Process 1”; however, “Process 2” was 
developed to support an increased scale of manufacture. In the study, each lot of
“Process 2”-manufactured BNT162b2 will be administered to approximately 250 participants
16 to 55 years of age. Protocol amendment 20 removes the objective to describe the safety 
and immunogenicity of prophylactic BNT162b2 in individuals 16 to 55 years of age 
vaccinated with study intervention produced by manufacturing “Process 1” or “Process 2”; 
considering the number of doses of BNT162b2 distributed and administered globally, this 
comparison is no longer warranted.
For evaluation of boostability and protection against emerging VOCs, 600 existing Phase 3 
participants 18 to 55 years of age will be rerandomized in a 1:1 ratio to receive either a third 
dose of BNT162b2 at 30 µg or a third dose of BNT162b2SA.
A further group of approximately 144 existing Phase 3 participants 18 years of age and older 
will be enrolled to receive a third, lower, dose of BNT162b2 of either 5 or 10 µg.  
Approximately 24 participants 18 to 55 years of age and 48 participants >55 years of age will 
be enrolled in each dose group. An additional group of 30 existing Phase 3 participants 18 to 
55 years of age will be enrolled to receive a third and fourth dose of BNT162b2SA. For these 
30 participants, through 1 month after their first dose of BNT162b2SA the participant will be 
blinded to their vaccine allocation but the investigator and Sponsor will not be. Serum 
samples from these participants may be used for assay development purposes and, except for 
objectives relating to response to a fourth dose, their results will be analyzed separately from 
the main immunogenicity analyses.
Three hundred participants 18 to 55 years of age who are COVID-19 vaccine–naïve 
(ie, BNT162b2-naïve) and have not experienced COVID-19 will be enrolled as a new cohort 
of participants to receive BNT162b2SA given as a 2-dose series.
Participants are expected to participate for up to a maximum of approximately 26 months. 
The duration of study follow-up may be shorter among participants enrolled in Phase 1 
dosing arms that are not evaluated in Phase 2/3.
Participants who originally received placebo and become eligible for receipt of BNT162b2 
according to recommendations detailed separately, and available in the electronic study 
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of the study. The investigator will ensure the participant meets at least 1 of the 
recommendation criteria.
Any Phase 2/3 placebo recipient who has not already been offered the opportunity to receive 
BNT162b2 will be given this opportunity no later than 6 months after Vaccination 2 (at the 
time of the originally planned Visit 4).
Any participant who originally received placebo but then goes on to receive BNT162b2 will 
move to a new visit schedule (Section 1.3.3).
The changes to the protocol as part of protocol amendment 14 to assess boostability and 
homologous/heterologous protection against emerging VOCs allow the evaluation of safety 
and immunogenicity of BNT162b2SA:

When given as a third dose to C4591001 Phase 3 participants who received a second dose 
of BNT162b2 approximately 6 months previously (ie, BNT162b2-experienced) and have 
not experienced COVID-19.

In a small separate group of individuals who previously received 2 doses of BNT162b2 
followed by 1 dose of BNT162b2SA, a second BNT162b2SA dose will also be given 
1 month after Dose 1 of BNT162b2SA.

When given as a 2-dose series, separated by 21 days, in newly recruited participants who 
are COVID-19 vaccine–naïve (ie, BNT162b2-naïve) and have not experienced 
COVID-19.
In addition, a group of C4591001 Phase 3 participants who received a second dose of 
BNT162b2 approximately 6 months previously will receive a third dose of BNT162b2.
This approach will allow an evaluation of immunogenicity against the reference ancestral 
SARS-CoV-2 strain (Wuhan-Hu-1/USA-WA1) and the selected South African VOC, using a 
noninferiority approach based on neutralizing antibody titers in prior BNT162b2 vaccinees 
who receive either a homologous boost (with BNT162b2) or a heterologous boost (with 
BNT162b2SA), as well as new vaccinees receiving 2 doses of BNT162b2SA.
As part of protocol amendment 18, to reflect current and anticipated recommendations for 
COVID-19 vaccine boosters, participants in C4591001 who meet specified recommendations 
(detailed separately and available in the electronic study portal) and have not already 
received one, will be offered a third dose of BNT162b2 after their second dose of BNT162.
The opportunity to receive a third dose of BNT162b2 will be offered as part of the study, 
according to recommendations detailed separately, and available in the electronic study 
reference portal. This opportunity is only for those participants who received their first 
2 doses of BNT162 (including BNT162b1, BNT162b2, or BNT162b2SA) as part of the study.
An intensive period of surveillance to evaluate the efficacy of BNT162b2 against 
asymptomatic SARS-CoV-2 infection may be conducted at selected sites among Phase 2/3 

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participants following approval of protocol amendment 11. After an initial in-person visit 
where a blood sample will be collected and a nasal (midturbinate) swab obtained, nasal 
(midturbinate) swabs will be obtained from consented participants every 2 weeks until 
Visit 4, or a sufficient number of cases of SARS-CoV-2 infection have accrued to evaluate 
this objective, whichever is sooner, per the SoA in Section 1.3.6. The swabs will be tested at 
a central laboratory using NAAT to detect SARS-CoV-2. Participants who are unblinded 
because they become potentially eligible for receipt of BNT162b2 according to 
recommendations detailed separately, and available in the electronic study reference portal, 
will not participate in surveillance for asymptomatic SARS-CoV-2 infection. However, 
participants who provided additional consent to conduct biweekly swabbing for surveillance 
of asymptomatic infection should continue to swab even after unblinding if they originally 
received BNT162b2.
Surveillance for asymptomatic SARS-CoV-2 infection (swabbing) should cease in 
participants enrolled into the subset of participants who will receive an additional dose of 
BNT162b2 or BNT162b2SA.
As part of protocol amendment 19, eligible participants who received a third dose of 
BNT162b2 (or BNT162b2SA) or a third and fourth dose of BNT162b2SA under protocol 
amendments 13 to 15 will be offered an additional 30-µg dose of BNT162b2. BNT162-naïve 
participants who received 2 primary doses of 30 µg BNT162b2SA under protocol amendment 
14 and were enrolled to receive a booster dose at Visit 501 under protocol amendment 18 are 
not eligible to receive an additional dose.
To provide maximum opportunity for all participants to receive the third dose of BNT162b2
under protocol amendment 18, protocol amendment 19 reduces the eligibility window from 
at least 6 months after Dose 2 to at least 3 months after Dose 2.
As part of protocol amendment 19, the study may be terminated early for reasons including 
but not limited to the increased access and availability of BNT162b2 in the real world, 
reducing the value of participant involvement and observation in this clinical trial.
Further to this, participants who are offered the possibility to participate in a future study 
within the Pfizer/BioNTech COVID-19 vaccine development program will be discontinued 
from this study.
Following the appropriate approvals of protocol amendment 20, participants will be informed 
via the study sites that their participation in the study will be concluded with no further data 
collection required from that point onwards, and there will be no requirement to complete 
any outstanding study visits or procedures.
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 visit will occur and, prior to protocol amendment 16, a 

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subsequent convalescent visit would occur. As part of these visits, samples (nasal
[midturbinate] swab and blood) will be taken for antigen and antibody assessment as well as 
recording of COVID-19–related clinical and laboratory information (including local 
diagnosis).
Human reproductive safety data are not available for BNT162 RNA-based COVID-19 
vaccines, but there is no suspicion of human teratogenicity based on the intended 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
Because of the requirement for a rapid response to the newly emerged COVID-19 pandemic, 
sufficient data were not available to experimentally validate the dose selection and initial 
starting dose. Therefore, the original planned starting dose of 10 µg (for both BNT162b1 and 
BNT162b2) in this study was based on nonclinical experience with the same RNAs encoding 
other viral antigens (such as influenza and HIV antigens). The general safety and 
effectiveness of uRNA and modRNA platforms have been demonstrated in oncological 
clinical trials with different administration routes (NCT02410733, NCT03871348). Doses of 
up to 400 µg total uRNA have been administered IV as RNA lipoplex (RNA-LPX) and doses 
of up to 1000 µg total naked modRNA have been administered intratumorally, both without 
signs of unpredictable overstimulation of the immune system.
Based on nonclinical data of the RNA components, with other liposomes or in conjunction 
with the lipid nanoparticles as will be tested clinically in this study, it was expected that 
doses in the 1- to 5-µg range would be immunogenic and induce neutralizing antibodies;
however, it was anticipated that 3- to 10-fold higher doses would likely be required to elicit a 
stronger antibody response. Based on previous clinical and nonclinical experience, it was 
expected that doses of up to 100 µg would be well tolerated.
Update as part of protocol amendment 2: preliminary experience in this study and the 
BioNTech study conducted in Germany (BNT162-01) suggests that, for vaccine candidates 
based on the modRNA platform, a dose level between 30 µg and 100 µg warrants 
consideration. Therefore, a 50-µg dose level is formally included for BNT162b1 and 
BNT162b2.
Update as part of protocol amendment 3: as data have become available from this study and 
the BNT162-01 study in Germany, it was decided:

To not study the BNT162a1 and BNT162c2 vaccine candidates at this time, so these 
candidates have been removed from the protocol; and

That lower dose levels of BNT162b1 and BNT162b2 warrant consideration.  Therefore, a 
20-µg dose level is formally included for both candidates.

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Update as part of protocol amendment 4: the 50-µg dose level for BNT162b1 and BNT162b2 
is removed and the 100-µg dose level for BNT162b2 is removed; similar dose levels of 
BNT162b3 may be studied as for BNT162b1 and BNT162b2.
Update as part of protocol amendment 5: the vaccine candidate selected for Phase 2/3 
evaluation is BNT162b2 at a dose of 30 µg. BNT162b3 will not be studied.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study, including the last visit. Note that participants enrolled in Phase 1 in groups that do 
not proceed to Phase 2/3 may be followed for fewer than 24 months (but no less than 
6 months after the last vaccination).
The end of the study is defined as the date of last visit of the last participant in the study.
Following the appropriate approvals of protocol amendment 20, participants will be informed 
via the study sites that their participation in the study will be concluded with no further data 
collection required from that point onwards. Therefore, as of protocol amendment 20, all 
active participants are considered to have reached the end of the study, without the need to 
complete any outstanding study visits or procedures as per the relevant SoA. Section 8
outlines the activities that should be performed after approval of protocol amendment 20.
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.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male or female participants between the ages of 18 and 55 years, inclusive, and 65 and 
85 years, inclusive (Phase 1), or ≥12 years (Phase 2/3), at randomization.
For the boostability and protection-against-VOCs subset:

Existing participants enrolled to receive a third dose of BNT162b2 at 30 µg or 
BNT162b2SA; male or female participants between the ages of 18 and 55 years, 
inclusive, at rerandomization.

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
Newly enrolled participants enrolled to receive 2 doses of BNT162b2SA; male or
female participants between the ages of 18 and 55 years, inclusive, at enrollment.

Existing participants enrolled to receive a third dose of BNT162b2 at 5 or 10 µg;
male or female participants ≥18 years at rerandomization.

Note that participants <18 years of age cannot be enrolled in the EU.

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, vaccination 
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Healthy participants who are determined by medical history, physical examination
(if required), and clinical judgment of the investigator to be eligible for inclusion in the 
study.
Note: Healthy participants with preexisting stable disease, defined as disease not 
requiring significant change in therapy or hospitalization for worsening disease during 
the 6 weeks before enrollment, can be included. Specific criteria for Phase 3 participants 
with known stable infection with human immunodeficiency virus (HIV), hepatitis C virus 
(HCV), or hepatitis B virus (HBV) can be found in Section 10.8.
4. Phase 2/3 only: Participants who, in the judgment of the investigator, are at higher risk 
for acquiring COVID-19 (including, but not limited to, use of mass transportation, 
relevant demographics, and frontline essential workers).
5. Boostability and protection-against-VOCs existing participant subset only:
Participants who provided a serum sample at Visit 3, with Visit 3 occurring within the 
protocol-specified window.
Informed Consent:
6. Capable of giving personal signed informed consent/have parent(s)/legal guardian 
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:

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Medical Conditions:
1. Other medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for the 
study.
2. Phases 1 and 2 only: Known infection with human immunodeficiency virus (HIV), 
hepatitis C virus (HCV), or hepatitis B virus (HBV).
3. History of severe adverse reaction associated with a vaccine and/or severe allergic 
reaction (eg, anaphylaxis) to any component of the study intervention(s).
4. Receipt of medications intended to prevent COVID-19.
5. Previous clinical (based on COVID-19 symptoms/signs alone, if a SARS-CoV-2 NAAT 
result was not available) or microbiological (based on COVID-19 symptoms/signs and a 
positive SARS-CoV-2 NAAT result) diagnosis of COVID-19.
6. Phase 1 only: Individuals at high risk for severe COVID-19, including those with any of 
the following risk factors:

Hypertension

Diabetes mellitus

Chronic pulmonary disease

Asthma

Current vaping or smoking

History of chronic smoking within the prior year

Chronic liver disease

Stage 3 or worse chronic kidney disease (glomerular filtration rate 
<60 mL/min/1.73 m2)

Resident in a long-term facility

BMI >30 kg/m2

Anticipating the need for immunosuppressive treatment within the next 6 months
7. Phase 1 only: Individuals currently working in occupations with high risk of exposure to 
SARS-CoV-2 (eg, healthcare worker, emergency response personnel).
8. Immunocompromised individuals with known or suspected immunodeficiency, as 
determined by history and/or laboratory/physical examination.

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9. Phase 1 only: Individuals with a history of autoimmune disease or an active autoimmune 
disease requiring therapeutic intervention, including but not limited to: systemic or 
cutaneous lupus erythematosus, autoimmune arthritis/rheumatoid arthritis, Guillain-Barré 
syndrome, multiple sclerosis, Sjögren’s syndrome, idiopathic thrombocytopenia purpura, 
glomerulonephritis, autoimmune thyroiditis, giant cell arteritis (temporal arteritis), 
psoriasis, and insulin-dependent diabetes mellitus (type 1).
10. Bleeding diathesis or condition associated with prolonged bleeding that would, in the 
opinion of the investigator, contraindicate intramuscular injection.
11. Women who are pregnant or breastfeeding.
Prior/Concomitant Therapy:
12. Previous vaccination with any coronavirus vaccine.
13. Individuals who receive treatment with immunosuppressive therapy, including cytotoxic 
agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned 
receipt throughout the study.  If systemic corticosteroids have been administered short 
term (<14 days) for treatment of an acute illness, participants should not be enrolled into 
the study until corticosteroid therapy has been discontinued for at least 28 days before 
study intervention administration.  Inhaled/nebulized (except for participants in 
Phase 1 – see exclusion criterion 14), intra-articular, intrabursal, or topical (skin or eyes) 
corticosteroids are permitted.
14. Phase 1 only: Regular receipt of inhaled/nebulized corticosteroids.
15. Receipt of blood/plasma products or immunoglobulin, from 60 days before study 
intervention administration or planned receipt throughout the study.
Prior/Concurrent Clinical Study Experience:
16. Participation in other studies involving study intervention within 28 days prior to study 
entry through and including 28 days after the last dose of study intervention, with the 
exception of non-Pfizer interventional studies for prevention of COVID-19, which are
prohibited throughout study participation.
17. Previous participation in other studies involving study intervention containing lipid 
nanoparticles.
Diagnostic Assessments:
18. Phase 1 only: Positive serological test for SARS-CoV-2 IgM and/or IgG antibodies at 
the screening visit.
19. Phase 1 only: Any screening hematology and/or blood chemistry laboratory value that 
meets the definition of a ≥Grade 1 abnormality.

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Note: With the exception of bilirubin, participants with any stable Grade 1 abnormalities 
(according to the toxicity grading scale) may be considered eligible at the discretion of 
the investigator.  (Note: A “stable” Grade 1 laboratory abnormality is defined as a report 
of Grade 1 on an initial blood sample that remains ≤Grade 1 upon repeat testing on a 
second sample from the same participant.)
20. Phase 1 only: Positive test for HIV, hepatitis B surface antigen (HBsAg), hepatitis B 
core antibodies (HBc Abs), or hepatitis C virus antibodies (HCV Abs) at the screening 
visit.
21. Phase 1 only: SARS-CoV-2 NAAT-positive nasal swab within 24 hours before receipt of 
study intervention.
Other Exclusions:
22. Investigator site staff or Pfizer/BioNTech employees directly involved in the conduct of 
the study, site staff otherwise supervised by the investigator, and their respective family 
members.
5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm 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 SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened under a different participant number.

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5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention 
Administration
The following conditions are temporary or self-limiting and a participant may be vaccinated 
once the condition(s) has/have resolved and no other exclusion criteria are met.
1. Current febrile illness (body temperature ≥100.4°F [≥38°C]) or other acute illness within 
48 hours before study intervention administration. This includes current symptoms that 
could represent a potential COVID-19 illness:

New or increased cough; 

New or increased shortness of breath;

Chills;

New or increased muscle pain;

New loss of taste/smell;

Sore throat;

Diarrhea;

Vomiting.
2. Receipt of any seasonal or pandemic influenza vaccine within 14 days (not applicable for 
the third, fourth, or fifth dose of BNT162b2 at Visits 501, 601, or 604, respectively), 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 (not 
applicable for the third, fourth, or fifth dose of BNT162b2 at Visits 501, 601, or 604, 
respectively, 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.

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The study will evaluate a 2-dose (separated by 21 days) schedule of various different dose 
levels of 3 investigational RNA vaccine candidates for active immunization against 
COVID-19 in 3 age groups (18 to 55 years of age, 65 to 85 years of age, and ≥12 years of 
age [stratified as 12-15, 16-55, or >55 years of age]).
These 3 investigational RNA vaccine candidates, with the addition of saline placebo, are the 
4 potential study interventions that may be administered to a study participant:

BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD): 
10 µg, 20 µg, 30 µg, 100 µg

BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S): 
5 µg, 10 µg, 20 µg, 30 µg

BNT162b2SA (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S 
containing South Africa B.1.351 variant–specific mutations): 30 µg

Normal saline (0.9% sodium chloride solution for injection)
The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.
6.1. Study Intervention(s) Administered
Intervention Name
BNT162b1 
(BNT162 
RNA-LNP vaccine 
utilizing modRNA)
BNT162b2 
(BNT162 
RNA-LNP vaccine 
utilizing modRNA)
BNT162b2SA
(BNT162 
RNA-LNP vaccine 
utilizing modRNA)
Saline Placebo
Type
Vaccine
Vaccine
Vaccine
Placebo
Dose Formulation
modRNA
modRNA
modRNA
Normal saline 
(0.9% sodium 
chloride solution for 
injection)
Unit Dose 
Strength(s)
250 µg/0.5 mL
250 µg/0.5 mL
250 µg/0.5 mL
N/A
Dosage Level(s)a
10-, 20-, 30-, 100-µg 5-, 10-, 20-, 30-µg
30-µg
N/A
Route of 
Administration
Intramuscular 
injection
Intramuscular 
injection
Intramuscular 
injection
Intramuscular 
injection
Use
Experimental
Experimental
Experimental
Placebo
IMP or NIMP
IMP
IMP
IMP
IMP
Sourcing
Provided centrally 
by the sponsor
Provided centrally 
by the sponsor
Provided centrally 
by the sponsor
Provided centrally 
by the sponsor

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Intervention Name
BNT162b1 
(BNT162 
RNA-LNP vaccine 
utilizing modRNA)
BNT162b2 
(BNT162 
RNA-LNP vaccine 
utilizing modRNA)
BNT162b2SA
(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 vial as open-
label supply. Each 
vial will be labeled 
as required per 
country requirement
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
a.
Dependent upon safety and/or immunogenicity data generated during the course of this study, or the 
BioNTech study conducted in Germany (BNT162-01), it is possible that groups may be started at the next 
highest dose, groups may not be started, groups may be terminated early, and/or groups may be added 
with dose levels below the lowest stated dose or intermediate between the lowest and highest stated doses.
6.1.1. Manufacturing Process
The scale of the BNT162b2 manufacturing has been increased to support future supply.  
BNT162b2 generated using the manufacturing process supporting an increased supply 
(“Process 2”) will be administered to approximately 250 participants 16 to 55 years of age, 
per lot, in the study.
In brief, the process changes relate to the method of production for the DNA template that 
RNA drug substance is transcribed from, and the RNA drug substance purification method.  
The BNT162b2 drug product is then produced using a scaled-up LNP manufacturing process.
Protocol amendment 20 will also remove the objective to describe the safety and 
immunogenicity of prophylactic BNT162b2 in individuals 16 to 55 years of age vaccinated 
with study intervention produced by manufacturing “Process 1” or “Process 2.” As of 
03 July 2022, more than 3.6 billion doses of BNT162b2 have been distributed, with over 
620 million doses of BNT162b2 administered worldwide, which were manufactured via 
“Process 2.” Given the number of doses now administered globally, the originally planned 
manufacturing process comparison is no longer warranted.
6.1.2. Administration
Participants will receive 1 dose of study intervention as randomized at each vaccination visit 
(Visits 1 and 4 for Phase 1 participants, Visits 1 and 2 for Phase 2/3 participants) 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). The volume to be administered may vary by vaccine 
candidate and dose level; full details are described in the IP manual.

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Phase 1 participants who originally received BNT162b1 or BNT162b2 at dose levels of 10, 
20, or 30 µg at Doses 1 and 2 will be offered an additional dose of BNT162b2 at 30 µg 
approximately 6 to 12 months after their second dose of BNT162 at Visit 8a.
Participants in the subset for evaluation of boostability and protection against emerging 
VOCs will receive either a third dose of BNT162b2 or BNT162b2SA approximately 5 to 
7 months after their second dose of BNT162 at Visit 301. Of those who receive 
BNT162b2SA at Visit 301, a subset will receive a further dose of BNT162b2SA at Visit 303.
BNT162b2-naïve participants who are enrolled under protocol amendment 14 to receive 
BNT162b2SA will receive 1 dose of study intervention at each vaccination visit, Visits 401 
and 402.
Study intervention should be administered intramuscularly into the deltoid muscle, preferably 
of the nondominant arm, by an unblinded administrator.
As part of protocol amendment 18, participants who have not yet received a third dose of 
BNT162b2 may receive one at Visit 501, at least 3 months (84 days) after their second dose 
of BNT162. The administration of a third dose of BNT162b2 at Visit 501 will be conducted 
in an open-label manner; therefore, the requirement for an unblinded dispenser/administrator 
does not apply to this vaccination.
As part of protocol amendment 19, eligible participants who received a third dose of 
BNT162b2 (or BNT162b2SA) or a third and fourth dose of BNT162b2SA under protocol 
amendments 13 to 15 may receive an additional dose of 30 µg BNT162b2 at Visit 601
or 604, at least 6 months after their last dose of BNT162. The administration of a fourth 
(or fifth) dose of BNT162b2 at Visit 601 or 604 will be conducted in an open-label manner;
therefore, the requirement for an unblinded preparer, dispenser, and administrator does not 
apply to this vaccination.
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, nurse, 
physician’s assistant, nurse practitioner, pharmacist, or medical assistant) as allowed by 
local, state, and institutional guidance.
Study intervention administration details will be recorded on the CRF.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study interventions received and any discrepancies are 
reported and resolved before use of the study intervention.

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2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study interventions
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated recording) area in accordance with the labeled storage conditions with 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.
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.
9. 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 

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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.  The visits added in protocol amendment 19 
(Visits 601 through 606) will be conducted in an open-label manner; therefore, the 
requirement for an unblinded preparer, dispenser, and administrator does not apply to this 
vaccination.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
Allocation (randomization) of participants to vaccine groups will proceed through the use of 
an IRT system (IWR).  The site personnel (study coordinator or specified designee) will be 
required to enter or select information including but not limited to the user’s ID 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 and study participants and unblinded administrator 
and study participants should be kept to a minimum.  The remaining site personnel must not 
know study intervention assignments.
To allow administration of BNT162b2 to participants who originally received placebo, site 
staff will be unblinded to individual participants’ original study intervention allocation as the
participants become eligible for vaccination under local/national recommendations or from 
6 months after the second dose.

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For the group of 30 existing Phase 3 participants 18 to 55 years of age who will be enrolled 
to receive a third and fourth dose of BNT162b2SA, through 1 month after their first dose of 
BNT162b2SA the participants will be blinded to their vaccine allocation, but the investigator 
will not be.
The administration of the third and fourth (or fifth) dose of BNT162b2 at Visits 501 and 601
(or 604), respectively, will be conducted in an open-label manner.
6.3.3. Blinding of the Sponsor
To facilitate rapid review of data in real time, sponsor staff will be unblinded to study 
intervention allocation for the participants in Phase 1. The majority of sponsor staff will be 
blinded to study intervention allocation in Phase 2/3. All laboratory testing personnel 
performing serology assays will remain blinded to study intervention assigned/received 
throughout the study. The following sponsor staff, who will have no part in the blinded 
conduct of the study, will be unblinded in Phase 2/3 (further details will be provided in a data 
blinding plan):

Those study team members who are involved in ensuring that protocol requirements for 
study intervention preparation, handling, allocation, and administration are fulfilled at the 
site will be unblinded for the duration of the study (eg, unblinded study manager, 
unblinded clinical research associate).

Unblinded clinician(s), who are not direct members of the study team and will not 
participate in any other study-related activities, will review unblinded protocol 
deviations.

An unblinded team supporting interactions with, and analyses for, the DMC 
(see Section 9.6). This will comprise a statistician, programmer(s), a clinical scientist, 
and a medical monitor who will review cases of severe COVID-19 as they are received,
and will review AEs at least weekly for additional potential cases of severe COVID-19
(see Section 8.2.3).

An unblinded submissions team will be responsible for preparing unblinded analyses and 
documents to support regulatory activities that may be required while the study is 
ongoing. This team will only be unblinded at the group level and not have access to 
individual participant assignments. The programs that produce the summary tables will 
be developed and validated by the blinded study team, and these programs will be run by 
the unblinded DMC team. The submissions team will not have access to unblinded 
COVID-19 cases unless efficacy is achieved in either an interim analysis or the final 
analysis, as determined by the DMC.

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
After the formal data release of the final efficacy analysis of at least 164 cases, which is 
considered the primary completion of the study efficacy objectives, additional 
statisticians and programmers will become unblinded at the participant level to prepare 
unblinded analyses and other regulatory activities. A group of statisticians and 
programmers will remain blinded and continue supporting the blinded conduct of the 
study.

After the study data used for submission become public, the blinded study team will also 
have access to those data, and become unblinded at a group level.

When a participant is unblinded for potential receipt of BNT162b2 (if he or she originally 
received placebo) per Section 8.16, the study team will become unblinded to the
participant’s original study intervention allocation.
For the group of 30 existing Phase 3 participants 18 to 55 years of age who will be enrolled 
to receive a third and fourth dose of BNT162b2SA, through 1 month after their first dose of 
BNT162b2SA the participants will be blinded to their vaccine allocation, but the sponsor will 
not be.
The study will be unblinded in stages once all ongoing participants either have been 
individually unblinded or have concluded their 6-month post–Dose 2 or post–Dose 3 study 
visit, as follows:

Phase 1 (after Visit 8).

Phase 2/3, ≥16 years (after Visit 4).

Phase 3, 12 to 15 years (after Visit 4).

Original Phase 3 participants rerandomized to assess boostability and protection against 
emerging VOCs (after Visit 306).
The administration of the third and fourth (or fifth) dose of BNT162b2 at Visits 501 and 601
(or 604), respectively, will be conducted in an open-label manner.
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.

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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, or for other, nonemergency reasons, will be provided separately: this unblinding 
will NOT be performed in the IRT. The date (that the participant becomes aware of study 
intervention allocation) and reason that the blind was broken must be recorded in the source 
documentation and CRF.
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 Phase 1 participants, and Visit 4 for Phase 2/3 participants).
In addition, for Phase 1 participants who go on to receive a third dose of BNT162, 
concomitant vaccinations will be collected from the time the participant provides 
informed consent (for receipt of Vaccination 3) through and including Visit 8c (1 month 
after the third dose). For BNT162-experienced participants in the subset for evaluation of 
boostability and protection against emerging VOCs, all vaccinations received will be 
recorded from 28 days prior to the time the participant provides informed consent 
(for participation in the subset) through and including Visit 306. For BNT162b2-naïve 
participants, the subset for evaluation of protection against emerging VOCs, all 
vaccinations received will be recorded from 28 days prior to study enrollment through 
and including Visit 405. For participants who receive a third dose of BNT162b2 at 
Visit 501, all vaccinations received will be recorded from 28 days prior to the time the 
participant provides informed consent (for receipt of the third dose) through Visit 503.
For participants who receive a fourth (or fifth) dose of BNT162b2 at Visit 601 or 604 all 
vaccinations received will be recorded from 28 days prior to the time the participant 
provides informed consent for receipt of the fourth (or fifth) dose through 1 month after 
vaccination (Visit 602 or 605.

Nonstudy coronavirus vaccines are listed in Section 6.5.1 as prohibited throughout the 
study and should therefore be recorded at any time they are given during study 
participation. This includes blinded BNT162b2 vaccine/placebo given in the B7471026 
study.

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
Prohibited medications listed in Section 6.5.1 will be recorded, to include start and stop 
dates, name of the medication, dose, unit, route, and frequency.

In addition, for participants enrolled in Phase 1, all current medication at baseline will be 
recorded, to include start date, name of the medication, dose, unit, route, and frequency.
6.5.1. Prohibited During the Study
Receipt of the following vaccines and medications during the time periods listed below may 
exclude a participant from the per-protocol analysis from that point onwards, and may 
require vaccinations to be discontinued in that participant; however, it is anticipated that 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.
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. For participants receiving 
the third dose of BNT162b2 at Visit 501, or the fourth (or fifth) dose of BNT162b2 at 
Visit 601 (or 604), the administration of the seasonal and pandemic influenza vaccine is not 
prohibited.
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 7 and from 28 days prior to Visit 8a to 
Visit 8c for Phase 1 participants, and from 28 days prior to enrollment to Visit 3 for 
Phase 2/3 participants). Use is also prohibited for participants in the subset for evaluation of 
boostability and protection against emerging VOCs, from 28 days prior to Visit 301 to 
Visit 303/305 and the BNT162b2-naïve participants from 28 days prior to enrollment to 
Visit 404.
Receipt of inhaled/nebulized corticosteroids from 28 days prior to enrollment to Visit 7 
(1-month follow-up visit) for Phase 1 participants.
Receipt of blood/plasma products or immunoglobulins within 60 days before enrollment 
through conclusion of the study.
Receipt of any other (nonstudy) coronavirus vaccine at any time prior to or during study 
participation is prohibited.
Prophylactic antipyretics and other pain medication to prevent symptoms associated 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.

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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 is permitted.
Inhaled (except in Phase 1 participants – see Section 6.5.1), topical, or localized injections of 
corticosteroids (eg, intra-articular or intrabursal administration) are permitted.
6.6. Dose Modification
This protocol allows some alteration of vaccine dose for individual participants and/or dose 
groups from the currently outlined dosing schedule. For reasons of reactogenicity, 
tolerability, or safety, the IRC may recommend to reduce the second dose of study 
intervention and/or increase the interval between doses.
If, for whatever reason, a participant receives only 1 dose of BNT162b2, the participant 
should be offered the possibility to receive a second dose of BNT162b2 at an unscheduled 
visit. This opportunity also extends to the third, fourth, and fifth doses of BNT162b2, in the 
event of an issue with the planned administration. For example, because of a medication 
error a participant receives only 1 dose of BNT162b2 at Visit 1 and 1 dose of placebo at 
Visit 2 (or vice versa); the participant can return at a later date for the unscheduled visit. In 
this situation:

Obtain informed consent.

Measure the participant’s body temperature (only in the event the unscheduled visit is to 
administer a second, not third, fourth, or fifth dose).

Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Unblinded or blinded (depending on time point in the study) 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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
The participant should continue to adhere to the normal visit schedule but must be 
followed for nonserious AEs for 1 month and SAEs for 6 months after the second dose of 
BNT162b2. This will require AEs to be elicited either by unscheduled telephone 
contact(s) and/or in-person visit(s). Following protocol amendment 19, the mandatory 
follow-up period for SAE collection will be at least 1 month after the third dose for all 
participants enrolled under protocol amendment 18.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND 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; participant request; investigator request; 
pregnancy; protocol deviation (including no longer meeting all the inclusion criteria, or 
meeting 1 or more exclusion criteria). In general, unless the investigator considers it unsafe 
to administer the second dose, or the participant does not wish to receive it, it is preferred 
that the second dose be administered. Note that a positive SARS-CoV-2 NAAT result 
without symptoms or a COVID-19 diagnosis (signs/symptoms only or signs/symptoms and a 
positive SARS-CoV-2 NAAT result) should not result in discontinuation of study 
intervention.
Note that discontinuation of study intervention does not represent withdrawal from the study.
Per the study estimands, if study intervention is definitively discontinued, the participant will 
remain in the study to be evaluated for safety, immunogenicity, and efficacy. See the SoA
for data to be collected at the time of discontinuation of study intervention and follow-up for 
any further evaluations that need to be completed.
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request.  Reasons for 
discontinuation from the study may include the following:

Refused further follow-up;

Lost to follow-up;

Death;

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
Study terminated by sponsor;

AEs;

Participant request; 

Investigator request;

Protocol deviation.
Note: Participants who are randomized in the C4591031 or the BNT162-17 study should be 
withdrawn from this study.
From protocol amendment 18 onwards, participants who receive COVID-19 vaccines outside 
of the study should be withdrawn. This does not apply if the nonstudy COVID-19 vaccine 
was administered prior to site receipt of IRB/EC approval of protocol amendment 18.
As part of protocol amendment 19, the study may be terminated early for reasons including 
but not limited to the increased access and availability of BNT162b2 in the real world, 
reducing the value of participant involvement and observation in this clinical trial. As part of 
protocol amendment 20, following agreement with the FDA and EMA, all outstanding study 
visits for all active study participants will not be required to be completed. Once protocol 
amendment 20 has been approved, participants will be informed of early study completion 
and no further data will be collected.
Further to this, participants who are offered the possibility to participate in a future study 
within the Pfizer/BioNTech COVID-19 vaccine development program will be discontinued 
from this study.
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 
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.

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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 posttreatment 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.
If a participant has previously withdrawn consent and wishes to receive a COVID-19 vaccine 
outside the study, they may request to know which study intervention they received for 
Vaccination(s) 1/2 without needing to reconsent.
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, 
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.

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The full date of birth will be collected to critically evaluate the immune response and safety 
profile by age.
Study procedures and their timing are summarized in the SoA. Protocol waivers or
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence 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. Following the appropriate approvals of protocol amendment 
20, all active participants will be contacted by the site by telephone to inform them of the 
changes brought about by protocol amendment 20. At this telephone contact participants 
within the mandatory AE reporting period will have up-to-date AE data collected and all 
participants will have their final disposition CRF completed to conclude their study 
participation; the date of study completion in the final disposition CRF will be the date of the 
telephone contact. No further data will be collected after that point, and no further study 
visits or procedures should be completed. If participants cannot be contacted via telephone,
all steps outlined in Section 7.3 should be followed to confirm the participant is lost to 
follow-up.
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 up 
to: 500 mL for participants in Phase 1, 150 mL for Phase 2/3 participants ≥16 years of age,
and 50 mL for participants in the 12- to 15-year age stratum.

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Select participants in Phase 1 will also be asked to provide an additional blood sample of 
approximately 170 mL at either Visit 5, 6, or 7.  These participants would therefore have a 
total blood sampling volume of 670 mL during the 24-month study period.
For those Phase 3 participants enrolled in the subset to receive an additional dose of 
BNT162b2 or BNT162b2SA, the total blood sampling volume for individual participants in 
this study is approximately up to 310 mL for those who receive 3 doses and 410 mL for those 
who receive 4 doses. Those participants in the subset who consent to additional blood 
collection for isolation of PBMCs will have a total blood sampling volume of approximately 
up to 795 mL.
For those participants enrolled into the additional cohort (added as part of protocol 
amendment 14) of BNT162b2-naïve participants who will receive 2 doses of BNT162b2SA, 
the total blood sampling volume for individual participants is approximately up to 250 mL.
Those participants in the cohort who consent to additional blood collection for isolation of 
PBMCs will have a total blood sampling volume of approximately up to 735 mL.
For all participants, other additional blood samples may be taken for safety assessments at 
times specified by Pfizer, provided the total volume taken during the study does not exceed 
550 mL during any period of 60 consecutive days.
8.1. Efficacy and/or Immunogenicity Assessments
8.1.1. Efficacy Against COVID-19
Efficacy will be assessed throughout a participant’s involvement in the study through 
surveillance for potential cases of COVID-19. If, at any time, a participant develops acute 
respiratory illness (see Section 8.13), for the purposes of the study he or she will be 
considered to potentially have COVID-19 illness.12 In this circumstance, the participant 
should contact the site, an in-person or telehealth visit should occur, and assessments should 
be conducted as specified in the SoA. The assessments will include a nasal (midturbinate) 
swab, which will be tested at a central laboratory using a reverse transcription–polymerase 
chain reaction (RT-PCR) test (Cepheid; FDA approved under EUA and Pfizer validated), or
other equivalent nucleic acid amplification–based test (ie, NAAT), to detect SARS-CoV-2. 
In addition, clinical information and results from local standard-of-care tests (as detailed in 
Section 8.13) will be assessed. The central laboratory NAAT result will be used for the case 
definition, unless no result is available from the central laboratory, in which case a local 
NAAT result may be used if it was obtained using 1 of the following assays:

Cepheid Xpert Xpress SARS-CoV-2

Roche cobas SARS-CoV-2 real-time RT-PCR test (EUA200009/A001)

Abbott Molecular/RealTime SARS-CoV-2 assay (EUA200023/A001)

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Two definitions of SARS-CoV-2–related cases, and SARS-CoV-2–related severe cases, will 
be considered (for both, the onset date of the case will be the date that symptoms were first 
experienced by the participant; if new symptoms are reported within 4 days after resolution 
of all previous symptoms, they will be considered as part of a single illness):

Confirmed COVID-19: presence of at least 1 of the following symptoms and 
SARS-CoV-2 NAAT-positive during, or within 4 days before or after, the symptomatic 
period, either at the central laboratory or at a local testing facility (using an acceptable
test):

Fever; 

New or increased cough; 

New or increased shortness of breath; 

Chills; 

New or increased muscle pain; 

New loss of taste or smell;

Sore throat;

Diarrhea;

Vomiting.
The second definition, which may be updated as more is learned about COVID-19, will 
include the following additional symptoms defined by the CDC (listed at 
https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html):

Fatigue;

Headache;

Nasal congestion or runny nose;

Nausea.

Confirmed severe COVID-19: confirmed COVID-19 and presence of at least 1 of the 
following:

Clinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per minute, 
HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or PaO2/FiO2
<300 mm Hg);

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
Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation, 
mechanical ventilation, or ECMO);

Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiring vasopressors);

Significant acute renal, hepatic, or neurologic dysfunction*;

Admission to an ICU;

Death.
The DMC may recommend modification of the definition of severe disease according to 
emerging information.
* Three blinded case reviewers (medically qualified Pfizer staff members) will review all 
potential COVID-19 illness events. If a NAAT-confirmed case in Phase 2/3 may be 
considered severe, or not, solely on the basis of this criterion, the blinded data will be 
reviewed by the case reviewers to assess whether the criterion is met; the majority opinion 
will prevail.
8.1.2. Efficacy Against Asymptomatic SARS-CoV-2 Infection
VE against asymptomatic SARS-CoV-2 infection will be evaluated in 2 ways, through 
impact on seroconversion of N-binding antibody and impact on NAAT-confirmed 
SARS-CoV-2 infection, in originally enrolled Phase 2/3 participants not suffering from 
COVID-19. Data from participants who receive more than 2 doses of BNT162b2 will not be 
included after they receive a third dose.
8.1.2.1. Seroconversion of N-Binding Antibody
Blood samples for assessment of N-binding antibodies are drawn at multiple scheduled visits. 
An asymptomatic case of SARS-CoV-2 infection based on seroconversion of N-binding 
antibody is defined as positive N-binding antibody at a post–Dose 2 visit in participants 
without serological evidence of infection (determined by negative N-binding antibody) at 
Visit 1 or virological evidence of infection (determined by negative NAAT result at Visit 1 
and Visit 2, and at the time of a potential COVID-19 illness). The requirement for a negative 
NAAT result at Visit 2 is to focus on assessment of protection against asymptomatic 
infection after 2 doses of vaccine, to the extent possible in an analysis based on 
seroconversion of N-binding antibody, recognizing that it is not possible to identify and 
exclude all asymptomatic infections that occur after Dose 1 and prior to Dose 2.
A secondary definition will be applied without the requirement for a negative NAAT result at 
Visit 2 to allow assessment of protection after 1 dose of vaccine. A positive N-binding 
antibody at a postvaccination visit in participants with negative N-binding antibody at Visit 1 
and negative NAAT results at Visit 1 and at the time of a potential COVID-19 illness is 
considered an asymptomatic case.

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8.1.2.2. NAAT-Confirmed SARS-CoV-2 Infection
For participants who consent to participate in an intensive period of surveillance, nasal swabs 
will be obtained to assess SARS-CoV-2 infection by NAAT (see Section 8.1.5).
An asymptomatic case of NAAT-confirmed SARS-CoV-2 infection is defined as a positive 
NAAT result on a nasal swab collected during the surveillance period from participants 
without COVID-19 symptoms at the time the nasal swab was taken, or within 14 days after 
it. The onset date of the asymptomatic case is the collection date of the first nasal swab that 
tested positive.
8.1.3. Vaccine-Induced Immunogenicity
Serum samples will be obtained for immunogenicity testing at the visits specified in the SoA.
The following assays will be performed:

SARS-CoV-2 neutralization assay (reference strain and SA variant)

Full-length S-binding or S1-binding IgG level assay

RBD-binding IgG level assay (Phase 1 only)
Note that all immunogenicity analyses will be based upon samples analyzed at the central 
laboratory; the rapid test will only be performed at screening by all sites recruiting 
participants in Phase 1 (see Section 8.11.1.1) to determine eligibility.
Serum obtained from the additional ~170-mL blood sample from select participants in 
Phase 1 at either Visit 5, 6, or 7 will be used for exploratory COVID-19 research, intended to 
establish a surrogate endpoint that is reasonably likely to predict clinical benefit.
Additional whole blood samples of ~120 mL will be obtained from a group of up to 
approximately 30 participants in each 30-µg group in the subset for evaluation of boostability 
and protection against emerging VOCs (both BNT162b2-experienced and BNT162b2-naïve)
at select sites for isolation of PBMCs. These samples will be used to describe T-cell 
responses to emerging VOCs and reference strains. Some of the sample may be used for 
sequencing of participants’ antibody and/or BCR heavy- and light-chain genes, TCR genes,
and/or mRNAs, for understanding the B-cell, T-cell, and antibody repertoires. A blood 
sample of ~5 mL for HLA typing will also be obtained. Some of the 5-mL blood sample 
collected for HLA typing may be used for DNA and/or RNA isolation to further characterize 
HLA type.
8.1.4. Biological Samples
Blood and nasal swab samples 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 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 

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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, with the exception of 
those participants who have provided specific consent to genetic testing of the blood samples 
for PBMC isolation and HLA typing.
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, with the 
exception of those participants who have provided specific consent to genetic testing of the 
blood samples for PBMC isolation and HLA typing.
8.1.5. Surveillance for Asymptomatic SARS-CoV-2 Infection
An intensive period of surveillance to evaluate the efficacy of BNT162b2 against
asymptomatic SARS-CoV-2 infection may be conducted at selected sites among Phase 2/3 
participants following approval of protocol amendment 11. After an initial in-person visit 
where a blood sample will be collected and a nasal (midturbinate) swab obtained, nasal 
(midturbinate) swabs will be obtained from consented participants every 2 weeks until 
Visit 4, or a sufficient number of cases of SARS-CoV-2 infection have accrued to evaluate 
this objective, whichever is sooner, per the SoA in Section 1.3.6.
The nasal swabs will be tested at a central laboratory using an RT-PCR test 
(Cepheid; FDA approved under EUA and Pfizer validated), or other equivalent nucleic acid 
amplification–based test (ie, NAAT), to detect SARS-CoV-2.
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.
AEs and SAEs are collected, recorded, and reported as defined in Section 8.3.
Acute reactions within the first 4 hours after administration of the study intervention (for the 
first 5 participants vaccinated in each Phase 1 group), and within the first 30 minutes (for the 
remainder of participants), will be assessed and documented in the AE CRF.
The safety parameters also include reactogenicity e-diary reports of local reactions and 
systemic events (including fever), and use of antipyretic medication that occur in the 7 days 
after administration of the study intervention in a subset of participants.  These prospectively 

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self-collected occurrences of local reactions and systemic events are graded as described in
Section 8.2.2. For participants who are not in the reactogenicity subset, these local reactions 
and systemic events should be detected and reported as AEs, in accordance with 
Section 8.3.2.
8.2.1. Clinical Safety Laboratory Assessments (Phase 1 Participants Only)
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined 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 which 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 the last dose 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 5 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury (DILI).
8.2.2. Electronic Diary
Certain participants will be required to complete a reactogenicity e-diary through an 
application (see Section 8.14) installed on a provisioned device or on the participant’s own 
personal device. All participants in Phase 1, and a subset of at least the first 6000
randomized in Phase 2/3, will be asked to monitor and record local reactions, systemic 
events, and antipyretic medication usage for 7 days following administration of the study 
intervention. All participants in Phase 3 who are HIV-positive or 12 to 15 years of age will 
be included in this subset. In addition, participants 16 through 17 years of age enrolled under 
protocol amendment 9 and onwards will be included in the reactogenicity subset. All other 
participants, including those who originally received placebo and then received BNT162b2 
under protocol amendment 10 and onwards, will not complete a reactogenicity e-diary but 
will have their local reactions and systemic events detected and reported as AEs in 
accordance with Section 8.3.2. Phase 1 participants who receive a third dose of BNT162b2 
will be asked to monitor and record local reactions, systemic events, and antipyretic 
medication usage in the reactogenicity e-diary for 7 days following administration of the 

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study intervention. Participants in the subset for evaluation of boostability and protection 
against emerging VOCs (both BNT162b2-experienced and BNT162b2-naïve) will be asked 
to monitor and record local reactions, systemic events, and antipyretic medication use in the 
reactogenicity e-diary for 7 days following each administration of the study intervention.
The participants receiving a third, fourth, or fifth dose of BNT162b2 at Visits 501, 601, or 
604 will not complete a reactogenicity e-diary following vaccination.
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.
Collect the participant’s e-diary or assist the participant to remove the study application from 
his or her own personal device upon approval of protocol amendment 20.
8.2.2.1. Grading Scales
The grading scales used in this study to assess local reactions and systemic events as 
described below are derived from the FDA Center for Biologics Evaluation and Research 
(CBER) guidelines on toxicity grading scales for healthy adult volunteers enrolled in 
preventive vaccine clinical trials.11
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 

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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 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.
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 oral temperature at home.  Temperature will be collected in 
the reactogenicity e-diary in the evening daily during the reactogenicity e-diary reporting 
period.  It will also be collected at any time during the reactogenicity e-diary data collection 
periods when fever is suspected.  Fever is defined as an oral temperature of ≥38.0°C 
(100.4°F).  The highest temperature for each day will be recorded in the reactogenicity 
e-diary.  Temperature will be measured and recorded to 1 decimal place and then categorized 
during analysis according to the scale shown in Table 3.
If a fever of ≥39.0°C (102.1°F) is reported in the reactogenicity e-diary, a telephone contact 
should occur to ascertain further details and determine whether a site visit is clinically 
indicated.  Only an investigator or medically qualified person is able to confirm a 
participant’s fever as >40.0°C (>104.0°F).  If a participant experiences a confirmed fever
>40.0°C (>104.0°F), 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
≥38.0-38.4°C (100.4-101.1°F)
>38.4-38.9°C (101.2-102.0°F)
>38.9-40.0°C (102.1-104.0°F)
>40.0°C (>104.0°F)
8.2.2.5. Antipyretic Medication
The use of antipyretic medication to treat symptoms associated with study intervention 
administration will be recorded in the reactogenicity e-diary daily during the reporting period 
(Day 1 to Day 7).
8.2.3. Phase 1 Stopping Rules
The following stopping rules are in place for all Phase 1 participants, based on review of AE 
data and e-diary reactogenicity data, until the start of Phase 2/3 or 30 days after the 
administration of the second dose of study intervention in Phase 1, whichever is later. These 
data will be monitored on an ongoing basis by the investigator (or medically qualified 
designee) and sponsor in order to promptly identify and flag any event that potentially 
contributes to a stopping rule.
The sponsor study team will be unblinded during Phase 1, so will be able to assess whether 
or not a stopping rule has been met on the basis of a participant’s individual study 
intervention allocation.
In the event that sponsor personnel confirm that a stopping rule is met, the following actions 
will commence:

The IRC will review all appropriate data.

The stopping rule will PAUSE randomization and study intervention administration for 
the impacted vaccine candidate all dose levels and age groups.

The DMC will review all appropriate data.

For all participants vaccinated, all other routine study conduct activities, including 
ongoing data entry, reporting of AEs, participant reactogenicity e-diary completion, 
blood sample collection, and participant follow-up, will continue during the pause.
A stopping rule is met if any of the following rules occur after administration of 
investigational BNT162 vaccine; data from placebo recipients will not contribute to the 
stopping rules. Reactogenicity e-diary data confirmed by the investigator as being entered by 
the participant in error will not contribute toward a stopping rule.

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The BNT162b RNA platform will be evaluated for contribution to stopping rules overall; 
vaccine candidate dose levels within the platform and age groups will contribute to stopping 
rules together.  However, it is possible that the recommendations may include halting or 
continuing randomization with any of the BNT162 vaccine candidates.
Stopping Rule Criteria for Each BNT162 Vaccine Candidate:
1. If any participant vaccinated with the BNT162 candidate (at any dose level) develops an 
SAE that is assessed by the investigator as possibly related, or for which there is no 
alternative, plausible, attributable cause.
2. If any participant vaccinated with the BNT162 candidate (at any dose level) develops a 
Grade 4 local reaction or systemic event after vaccination (see Section 8.2.2) that is 
assessed as possibly related by the investigator, or for which there is no alternative, 
plausible, attributable cause.
3. If any participant vaccinated with the BNT162 candidate (at any dose level) develops a 
fever >40.0°C (>104.0°F) for at least 1 daily measurement after vaccination 
(see Section 8.2.2.4) that is assessed as possibly related by the investigator, or for which 
there is no alternative, plausible, attributable cause.
4. If any 2 participants vaccinated with the BNT162 candidate (at any dose level) report the 
same or similar severe (Grade 3) AE (including laboratory abnormalities) after 
vaccination, assessed as possibly related by the investigator, or for which there is no 
alternative, plausible, attributable cause.
5. If any participant dies or requires ICU admission due to SARS-CoV-2 infection; if this 
stopping rule is met, all available clinical and preclinical safety and immunogenicity data 
should be reviewed to evaluate for enhanced COVID-19.
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19 and Phase 2/3
Stopping Rule
Participants in all phases of the study will be surveilled for potential COVID-19 illness from 
Visit 1 onwards (see Section 8.13).
As this is a sponsor open-label study during Phase 1, the sponsor will conduct unblinded 
reviews of the data during the course of the study, including for the purpose of safety 
assessment. All NAAT-confirmed cases in Phase 1 will be reviewed contemporaneously by 
the IRC and the DMC (see Section 9.6).
In Phase 2/3, the unblinded team supporting the DMC, including an unblinded medical 
monitor, will review cases of severe COVID-19 as they are received and will review AEs at 
least weekly for additional potential cases of severe COVID-19. At any point, the unblinded 
team may discuss with the DMC chair whether the DMC should review cases for an adverse 
imbalance of cases of COVID-19 and/or severe COVID-19 between the vaccine and placebo 
groups.

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The purpose of these reviews will be to identify whether any features of each case appear 
unusual, in particular greater in severity, compared to available information at the time of 
review.  Indicators of severity may include accelerated deterioration, need for hospitalization, 
need for ventilation, or death.  Observed rates of these indicators will be compared with what 
could be expected in a similar population to the study participants based upon available 
information at the time of review.
Stopping and alert rules will be applied as follows. The stopping rule will be triggered when 
the 1-sided probability of observing the same or a more extreme case split is 5% or less when 
the true incidence of severe disease is the same for vaccine and placebo participants, and alert 
criteria are triggered when this probability is less than 11%. In addition, when the total 
number of severe cases is low (15 or less), the unblinded team supporting the DMC will 
implement the alert rule when a reverse case split of 2:1 or worse is observed. For example, 
at 3 cases 2:1, at 4 cases 3:1, etc. Below 15 cases, this rule is more rigorous than requiring 
the probability of an observed adverse split or worse be <11%. Further details can be found 
in Section 10.7.
8.2.5. Randomization and Vaccination After a Stopping Rule Is Met
Once the IRC (if in Phase 1) and DMC (all phases) have reviewed the safety data and 
provided guidance, a notification will be sent from the sponsor to the sites with guidance on 
how to proceed.
8.2.6. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in WOCBP at the times listed in the SoA,
immediately before the administration of each vaccine dose.  A negative pregnancy test result 
will be required prior to the participant’s receiving the study intervention.  Pregnancy tests 
may also be repeated if requested by IRBs/ECs or if required by local regulations.  In the 
case of a positive confirmed pregnancy, the participant will be withdrawn from 
administration of study intervention but may remain in the study.
Administration of BNT162b2 to pregnant participants at Visits 101 and 102 (participants 
who originally received placebo and choose to be unblinded and receive BNT162b2) or at 
Visits 501, 601 and 604 may be considered if there are local or national recommendations for 
COVID-19 vaccination of pregnant women, and the investigator and participant are in 
agreement. This overrides the requirements stated in the previous paragraph, and will not be 
considered as a protocol deviation. However, the EDP should still be reported in accordance 
with Section 8.3.5.1.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's parent(s)/legal guardian).

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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/parent(s)/legal guardian will be questioned about the occurrence of AEs in a 
nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant/parent(s)/legal guardian
provides informed consent, which is obtained before the participant’s participation in the 
study (ie, before undergoing any study-related procedure and/or receiving study 
intervention), through and including Visit 7 for Phase 1 participants, and Visit 3 for Phase 
2/3 participants.  In addition, any AEs occurring up to 48 hours after each subsequent blood 
draw must be recorded on the CRF.
SAEs will be collected from the time the participant/parent(s)/legal guardian provides 
informed consent to approximately 6 months after the last dose of study intervention
(Visit 8 for Phase 1 participants, and Visit 4 for Phase 2/3 participants).
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 will be collected from the time the participant provides informed consent
(for receipt of Vaccinations 3 and 4) to approximately 6 months after the second dose of 
BNT162b2 (Visit 104).
For Phase 1 participants who go on to receive a third dose of BNT162, AEs and SAEs will be 
collected from the time the participant provides informed consent (for receipt of 
Vaccination 3) through and including Visit 8c (1 month after the third dose).
For BNT162b2-experienced participants in the subset for evaluation of boostability and 
protection against emerging VOCs, AEs will be collected from the time the participant
provides informed consent (for participation in the subset) through and including Visit 303 
for those receiving 1 additional dose and Visit 305 for those who receive 2 additional doses. 
For both schedules, this equates to collection for up to 1 month after the last dose. SAEs will 
be collected from the time the participant provides informed consent (for participation in the 
subset) through and including Visit 306 (5 or 6 months after the last dose, depending upon 
group).

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For BNT162b2-naïve participants, the subset for evaluation of protection against emerging 
VOCs, AEs will be collected from the time the participant provides informed consent
through and including Visit 404 (1 month after the second dose). SAEs will be collected 
from the time the participant provides informed consent through and including Visit 405 
(6 months after the second dose).
For participants who receive a third dose of BNT162b2 at Visit 501, AEs will be collected 
from the time the participant provides informed consent (for administration of the third dose 
of BNT162b2) through Visit 502 (1 month after the third dose of BNT162b2).  SAEs will be 
collected from the time the participant provides informed consent (for administration of the 
third dose of BNT162b2) through Visit 503 (6 months after the third dose of BNT162b2).
Under protocol amendment 19, the mandatory follow-up period for SAE collection will be at
least 1 month after the third dose for all participants enrolled under protocol amendment 18.
For participants who receive a fourth (or fifth) dose of BNT162b2 at Visit 601 (or 604), AEs 
and SAEs will be collected from the time the participant provides informed consent (for 
administration of the fourth [or fifth] dose of BNT162b2) through Visit 602 (or 605)
(1 month after the fourth [or fifth] dose of BNT162b2).
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 Report Form.
Investigators are not obligated to actively seek AEs or SAEs after the participant has 
concluded study participation.  However, if the investigator learns of any SAE, including a 
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 Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the Vaccine SAE Report Form immediately 
upon awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.

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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 
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.

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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 Report 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 28 days after the last dose of study 
intervention. Beyond 28 days after the last dose of study intervention, any pregnancy that 
occurs will not be considered EDP for this study.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the Vaccine SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in the 

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study, the information is not recorded on a CRF; however, a copy of the completed 
Vaccine SAE Report Form is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
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.
8.3.6. Exposure During Breastfeeding
An exposure during breastfeeding occurs if: 

A female participant is found to be breastfeeding while receiving or after discontinuing 
study intervention.

A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental exposure 
during breastfeeding is a female family member or healthcare provider who reports that 
she is breastfeeding after having been exposed to the study intervention by inhalation or 
skin contact.

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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 Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF. However, a copy of the completed Vaccine SAE Report Form is maintained in 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.
8.3.6.1. 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 Report Form.  Since the information does not 
pertain to a participant enrolled in the study, the information is not recorded on a CRF; 
however, a copy of the completed Vaccine SAE Report Form is maintained in the 
investigator site file.
8.3.7. Cardiovascular and Death Events
Not applicable.
8.3.8. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Potential COVID-19 illnesses and their sequelae that are consistent with the clinical endpoint 
definition should not be recorded as AEs. These data will be captured as efficacy assessment 
data only on the relevant pages of the CRF, as these are expected endpoints.
Potential COVID-19 illnesses and their sequelae will not be reported according to the 
standard process for expedited reporting of SAEs, even though the event may meet the 
definition of an SAE.  These events will be recorded on the COVID-19 illness pages in the 
participant’s CRF within 1 day.
NOTE: However, if either of the following conditions applies, then the event must be 
recorded and reported as an SAE (instead of a disease-related event):
The event is, in the investigator’s opinion, of greater intensity, frequency, or duration than 
expected for the individual participant.

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OR
The investigator considers that there is a reasonable possibility that the event was related to 
study intervention.
Potential COVID-19 illness events and their sequelae will be reviewed by a group of internal 
blinded case reviewers.  Any SAE that is determined by the internal case reviewers NOT to 
meet endpoint criteria is reported back to the investigator site of incidence.  The investigator 
must report the SAE to Pfizer Safety within 24 hours of being made aware that the SAE did 
not meet endpoint criteria.  The investigator’s SAE awareness date is the date on which the 
investigator site of incidence receives the SAE back from the internal case reviewers.
8.3.9. Adverse Events of Special Interest
The following events are considered AESIs:

A confirmed diagnosis of myocarditis or pericarditis. See Section 8.22 for additional 
procedures for monitoring of potential myocarditis or pericarditis.
8.3.9.1. Lack of Efficacy
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.
8.3.10. Medical Device Deficiencies
Not applicable.
8.3.11. 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 Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE

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Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do or 
do not involve the study participant;

The administration of expired study intervention;

The administration of an incorrect study intervention;

The administration of an incorrect dosage;

The administration of study intervention that has undergone temperature excursion from 
the specified storage range, unless it is determined by the sponsor that the study 
intervention under question is acceptable for use.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by 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 
Report Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of study intervention greater than 1 dose of study intervention within 
a 24-hour time period will be considered an overdose.
Pfizer does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs.
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF.
4. Overdose is reportable to Safety only when associated with an SAE.

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Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7. Genetics
Some of the blood samples collected for PBMC isolation and HLA typing may be used for 
DNA and/or RNA isolation. The DNA and/or RNA samples from the PBMC isolation may
be used for sequencing of participants’ antibody and/or BCR heavy- and light-chain genes,
TCR genes, and/or mRNAs, for understanding the B-cell, T-cell, and antibody repertoires.
The DNA and/or RNA samples from the blood sample for HLA typing may be used to 
further characterize HLA type.
See Appendix 9 for information regarding genetic research. Details on processes for 
collection and shipment of these samples will be provided separately.
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, 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.
As the protocol design includes visits of an unplanned nature, multiple visits may occur on 
the same day, but all procedures for all visits must be conducted (including collection of all 
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Following the appropriate approvals of protocol amendment 20, all active participants will be 
contacted by the study site by telephone to inform them of the changes brought about by 
protocol amendment 20. At this telephone contact participants within the mandatory AE
reporting period will have up-to-date AE data collected and all participants will have their 
final disposition CRF completed to conclude their study participation. AEs, concomitant 
medications, and potential COVID-19 illnesses that are ongoing at the end of the study 
should be marked as ongoing. No further data will be collected after that point, and no 
further study visits or procedures should be completed.
8.11.1. Phase 1
8.11.1.1. Screening: (0 to 28 Days Before Visit 1)
Before enrollment and before any study-related procedures are performed, voluntary, written 
study-specific informed consent will be obtained from the participant. Each signature on the 
ICD must be personally dated by the signatory. The investigator or his or her designee will 
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The 
source data must reflect that the informed consent was obtained before participation in the 
study.
It is anticipated that the procedures below will be conducted in a stepwise manner; however, 
the visit can occur over more than 1 day.

Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).  
The full date of birth will be collected to critically evaluate the immune response and 
safety profile by age.

Obtain any medical history of clinical significance.

Obtain details of any medications currently taken.

Perform physical examination including vital signs (weight, height, body temperature, 
pulse rate, and seated blood pressure), evaluating any clinically significant abnormalities 
within the following body systems: general appearance; skin; head, eyes, ears, nose, and 
throat; heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph 
nodes.

Collect a blood sample (approximately 20 mL) for potential future serological assessment 
and to perform a rapid test for prior COVID-19 infection.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory 
tests as described in Section 10.2.

Collect a blood sample (approximately 10 mL) for HIV, HBsAg, HBc Ab, and HCV Ab 
tests.

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
Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.

Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met.

Record AEs as described in Section 8.3. AEs that occur prior to dosing should be noted 
on the Medical History CRF.

Ask the participant to contact the site staff or investigator immediately if any significant 
illness or hospitalization occurs.

Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

Complete the CRF.
8.11.1.2. Visit 1 – Vaccination 1: (Day 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensure 
that procedures listed prior to administration of the vaccine are conducted prior to 
vaccination.

Record AEs as described in Section 8.3.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if 
indicated by any change in the participant’s health since the previous visit, perform a 
physical examination, evaluating any clinically significant abnormalities within the 
following body systems: general appearance; skin; head, eyes, ears, nose, and throat; 
heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.

Record nonstudy vaccinations as described in Section 6.5.

Review screening laboratory results (hematology and chemistry, and HIV, HBsAg, 
HBc Ab, and HCV Ab tests).

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
Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested 
(if possible at the site, otherwise at the central laboratory) within 24 hours and 
vaccination will proceed only if it is NAAT-negative for SARS-CoV-2 genomes. 
The second will be sent to the central laboratory for potential later testing.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Obtain the participant’s randomization number and study intervention allocation using 
the IRT system.  Only an unblinded site staff member may obtain this information.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into 
the deltoid muscle of the preferably nondominant arm.  Please refer to the IP manual for 
further instruction on this process.

The first 5 participants vaccinated in each group must be observed by blinded site staff 
for any acute reactions for at least 4 hours after vaccination.  For participants enrolled 
thereafter, blinded site staff must observe the participant for at least 30 minutes after 
study intervention administration for any acute reactions.  Record any acute reactions 
(including time of onset) in the participant’s source documents and on the AE page of the 
CRF, and on an SAE form as applicable.

Issue a measuring device to measure local reactions at the injection site and 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 (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units).

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
Severe pain at the injection site.

Any severe systemic event.

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs and an 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.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if 
indicated by any change in the participant’s health since the previous visit, perform a 
physical examination, evaluating any clinically significant abnormalities within the 
following body systems: general appearance; skin; head, eyes, ears, nose, and throat; 
heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory 
tests as described in Section 10.2.

Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

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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 (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units).

Severe pain at the injection site.

Any severe systemic event.

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

The investigator or appropriately qualified designee reviews the reactogenicity e-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.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if 
indicated by any change in the participant’s health since the previous visit, perform a 
physical examination, evaluating any clinically significant abnormalities within the 
following body systems: general appearance; skin; head, eyes, ears, nose, and throat; 
heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

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
Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory 
tests as described in Section 10.2.

Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Ask the participant to contact the site staff or investigator immediately if he or she 
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 is 
the day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units).

Severe pain at the injection site.

Any severe systemic event.

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

The investigator or appropriately qualified designee reviews the reactogenicity e-diary 
data online following vaccination to evaluate participant compliance and as part of the 
ongoing safety review.  Daily review is optimal during the active diary period.

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8.11.1.5. 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.

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.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if 
indicated by any change in the participant’s health since the previous visit, perform a 
physical examination, evaluating any clinically significant abnormalities within the 
following body systems: general appearance; skin; head, eyes, ears, nose, and throat; 
heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.

Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

Obtain 2 nasal (midturbinate) swabs (collected by site staff). One will be tested (if 
possible at the site, otherwise at the central laboratory) within 24 hours and vaccination 
will only proceed if it is NAAT-negative for SARS-CoV-2 genomes. The second will be 
sent to the central laboratory for potential later testing.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met. If not, the participant should not receive further study intervention but will 
remain in the study to be evaluated for safety, immunogenicity, and efficacy
(see Section 7.1).

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory 
tests as described in Section 10.2.

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
Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into 
the deltoid muscle of the preferably nondominant arm.  Please refer to the IP manual for 
further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study 
intervention administration for any acute reactions.  Record any acute reactions 
(including time of onset) in the participant’s source documents and on the AE page of the 
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection 
site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with his or her chosen e-diary platform, 
confirm instructions on e-diary completion, and ask the participant to complete 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 (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units).

Severe pain at the injection site.

Any severe systemic event.

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs and an 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.
8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to 8 Days After Visit 4)

Record AEs as described in Section 8.3.

Review hematology and chemistry laboratory results and record any AEs in accordance 
with Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if 
indicated by any change in the participant’s health since the previous visit, perform a 
physical examination, evaluating any clinically significant abnormalities within the 
following body systems: general appearance; skin; head, eyes, ears, nose, and throat; 
heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Collect a blood sample (approximately 10 mL) for hematology and chemistry laboratory 
tests as described in Section 10.2.

Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

If the participant (select participants only, details will be provided by the sponsor) 
consents, collect an additional 170 mL blood sample for exploratory COVID-19 research.

Ask the participant to contact the site staff or investigator immediately if he or she 
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 is 
the day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units).

Severe pain at the injection site.

Any severe systemic event.

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
Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator immediately if he or she
experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

The investigator or appropriately qualified designee reviews the reactogenicity e-diary 
data online following vaccination to evaluate participant compliance and as part of the 
ongoing safety review.  Daily review is optimal during the active diary period.
8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to 16 Days After Visit 4)

Record AEs as described in Section 8.3.

Review the participant’s reactogenicity e-diary data.  Collect stop dates of any 
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary was 
completed and record stop dates in the CRF if required.

Review hematology and chemistry laboratory results and record any AEs in accordance 
with Appendix 2.

Measure vital signs (body temperature, pulse rate, and seated blood pressure), and, if 
indicated by any change in the participant’s health since the previous visit, perform a 
physical examination, evaluating any clinically significant abnormalities within the 
following body systems: general appearance; skin; head, eyes, ears, nose, and throat; 
heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph nodes.

Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

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
If not collected at Visit 5, and the participant (select participants only, details will be 
provided by the sponsor) consents, collect an additional 170-mL blood sample for 
exploratory COVID-19 research.

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator immediately (this could be via 
the COVID-19 illness e-diary) if he or she experiences any respiratory symptoms as 
detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After Visit 4)

Record AEs as described in Section 8.3.

Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

If not collected at Visit 5 or 6, and the participant (select participants only, details will be 
provided by the sponsor) consents, collect an additional 170-mL blood sample for 
exploratory COVID-19 research.

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

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8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (175 to 189 Days After Visit 4)

Record SAEs as described in Section 8.3.

Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

Collect a blood sample (approximately 20 mL) for immunogenicity testing.

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.
8.11.1.10. Between Visits 8 and 9
All participants who have not already been unblinded, no later than at the approximate time 
participants in Phase 2/3 reach Visit 4, will be advised to contact the site to determine 
whether they can receive BNT162b2 as part of the study. When contacted, the site will 
unblind study intervention allocation to determine whether the participant received 
BNT162b1, BNT162b2, or placebo. If he or she originally received placebo and wants to 
receive BNT162b2, he or she will move to the procedures in Section 8.16.
8.11.1.11. Visit 8a – Vaccination 3: (175 to 315 Days After Vaccination 2)
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. If the participant does not consent 
to administration of a third dose of BNT162, his or her next visit should be Visit 9.

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
Confirm that the participant originally received 10-µg, 20-µg, or 30-µg doses of
BNT162b1 or BNT162b2 at Vaccinations 1 and 2. Secondary confirmation by another 
site staff member is required.

Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

Record nonstudy vaccinations as described in Section 6.5.

Measure the participant’s body temperature.

Ensure and document that inclusion criteria 2, 3, and 6 are met and exclusion criteria 1, 3, 
8, 10, 11, 12, 13, 16, 17, and 22 are not met prior to vaccination.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Record AEs as described in Section 8.3.

Collect a blood sample (approximately 20 mL) for immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Obtain the participant’s vaccine vial allocation using the IRT system.

Site staff member(s) will dispense/administer a 30-µg dose of BNT162b2 into the deltoid 
muscle of the preferably nondominant arm.

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.

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.

Remind the participant of the e-diary technologies available for this study (see 
Section 8.14).  Provide instructions on e-diary completion and ask the participant to 
complete the reactogenicity e-diary from Day 1 to Day 7, with Day 1 being the day of 
vaccination, and, if utilized, the COVID-19 illness e‑diary (to be completed if the 
participant is diagnosed with COVID-19 or has possible new or increased symptoms, 
and when he/she receives a reminder, at least weekly).

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
Ask the participant to contact the site staff or investigator immediately if he or she 
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 
is the day of vaccination) to determine if an unscheduled reactogenicity visit is 
required (see Section 8.12):

Fever ≥39.0°C (≥102.1°F)

Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units)

Severe pain at the injection site

Any severe systemic event

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if 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.

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.
8.11.1.12. Visit 8b – 1-Week Follow-up Visit (After Vaccination 3): (6 to 8 Days After 
Visit 8a)

Record AEs as described in Section 8.3.

Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample of approximately 20 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 the participant experiences any respiratory 
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
8.11.1.13. Visit 8c – 1-Month Follow-up Visit (After Vaccination 3): (28 to 35 Days After 
Visit 8a)

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.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample of approximately 20 mL for immunogenicity testing.

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

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8.11.1.14. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 4): Only for 
Those Participants Who Originally Received BNT162b1 or BNT162b2 or Placebo 
Recipients Who Decline BNT162b2

Collect a blood sample (approximately 20 mL) for immunogenicity testing.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.
8.11.1.15. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 4):  Only 
for Those Participants Who Originally Received BNT162b1 or BNT162b2 or Placebo 
Recipients Who Decline BNT162b2
This visit should not be performed if protocol amendment 20 is approved and participants are 
informed of early study completion prior to reaching this time point.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

Request the participant return the e-diary device or assist the participant to delete the 
application from his or her personal device.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
8.11.2. Phase 2/3
8.11.2.1. Visit 1 – Vaccination 1: (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written,
study-specific informed consent will be obtained from the participant or his/her 
parent(s)/legal guardian, as appropriate. Each signature on the ICD must be personally dated 
by the signatory. The investigator or his or her designee will also sign the ICD. A copy of 
the signed and dated ICD must be given to the participant/participant’s parent(s)/legal 

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guardian. The source data must reflect that the informed consent was obtained before 
participation in the study.
It is anticipated that the procedures below will be conducted in a stepwise manner. The visit 
may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and 
exclusion criteria onwards must be conducted on the same day.

Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).  
The full date of birth will be collected to critically evaluate the immune response and 
safety profile by age.

Obtain any medical history of clinical significance. For participants who are 
HIV-positive, record HIV viral load and CD4 count results from the most recent test 
performed in the previous 6 months.

Perform a clinical assessment. If the clinical assessment indicates that a 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.

Measure the participant’s body temperature.

Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.

Record nonstudy vaccinations as described in Section 6.5.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Record AEs as described in Section 8.3.

Collect a blood sample (approximately 20 mL for participants ≥16 years of age and 
approximately 10 mL for participants in the 12- to 15-year age stratum) for 
immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

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
Obtain the participant’s randomization number and study intervention allocation number 
using the IRT system.  Only an unblinded site staff member may obtain this information.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into 
the deltoid muscle of the preferably nondominant arm.  Please refer to the IP manual for 
further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study 
intervention administration for any acute reactions.  Record any acute reactions 
(including time of onset) in the participant’s source documents and on the AE page of the 
CRF, and on an SAE form as applicable.

For participants in the reactogenicity subset, issue a measuring device to measure local 
reactions at the injection site and a thermometer for recording daily temperatures and 
provide instructions on their use.

For participants not in the reactogenicity subset, issue a thermometer to monitor for fever 
(for COVID-19 surveillance) and provide instructions on its use.

Explain the e-diary technologies available for this study (see Section 8.14), and assist the 
participant or his/her parent(s)/legal guardian, as appropriate, in downloading the study 
application onto the participant’s own device or issue a provisioned device if required.

For participants in the reactogenicity subset, provide instructions on reactogenicity 
e-diary completion and ask the participant or his/her parent(s)/legal guardian, as 
appropriate, to complete the reactogenicity e-diary from Day 1 to Day 7, with Day 1 
being the day of vaccination.

For all participants, provide instructions on COVID-19 illness e-diary completion and 
ask the participant or his/her parent(s)/legal guardian, as appropriate, to complete the 
COVID-19 illness e-diary if the participant is diagnosed with COVID-19 or has 
possible new or increased symptoms, and when he/she receives a reminder, at least 
weekly. See Section 8.14 for further details.

If the participant is part of the reactogenicity subset, ask the participant or his/her 
parent(s)/legal guardian, as appropriate, to contact the site staff or investigator 
immediately if the participant experiences any of the following from Day 1 to Day 7 after 
vaccination (where Day 1 is the day of vaccination) to determine if an unscheduled 
reactogenicity visit is required: 

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units).

Severe pain at the injection site.

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
Any severe systemic event.

Ask the participant or his/her parent(s)/legal guardian, as appropriate, 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 or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator (this could be via the COVID-19 illness e-diary) immediately if he or 
she experiences any respiratory symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant or his/her parent(s)/legal guardian, as appropriate, 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.
If the participant is part of the reactogenicity subset, 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.

If the participant is part of the reactogenicity subset, review the participant’s
reactogenicity e-diary data.  Collect stop dates of any reactogenicity e-diary events 
ongoing on the last day that the reactogenicity e-diary was completed and record stop 
dates in the CRF if required.

Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.

Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

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
Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met. If not, the participant may not receive further study intervention but will remain 
in the study to be evaluated for safety, immunogenicity, and efficacy
(see Section 7.1).

Measure the participant’s body temperature.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into 
the deltoid muscle of the preferably nondominant arm.  Please refer to the IP manual for 
further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study 
intervention administration for any acute reactions.  Record any acute reactions 
(including time of onset) in the participant’s source documents and on the AE page of the 
CRF, and on an SAE form as applicable.

Ensure the participant or his/her parent(s)/legal guardian, as appropriate, has a measuring 
device to measure local reactions at the injection site and a thermometer for recording 
daily temperatures.

Ensure the participant or his/her parent(s)/legal guardian, as appropriate, remains 
comfortable with the chosen e-diary platform, confirm instructions on e-diary
completion, and, if the participant is part of the reactogenicity subset, ask the participant
or his/her parent(s)/legal guardian, as appropriate, to complete the reactogenicity e-diary 
from Day 1 to Day 7, with Day 1 being the day of vaccination.

If the participant is part of the reactogenicity subset, ask the participant or his/her 
parent(s)/legal guardian, as appropriate, to contact the site staff or investigator 
immediately if the participant experiences any of the following from Day 1 to Day 7 after 
vaccination (where Day 1 is the day of vaccination) to determine if an unscheduled 
reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units).

Severe pain at the injection site.

Any severe systemic event.

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
Ask the participant or his/her parent(s)/legal guardian, as appropriate, 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 or his/her parent(s)/legal guardian, as appropriate, 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.

Remind the participant or his/her parent(s)/legal guardian, as appropriate, 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.
If the participant is part of the reactogenicity subset, 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-Month Follow-up Visit (After Vaccination 2): (28 to 35 Days After 
Visit 2)

Record AEs as described in Section 8.3.

Review the participant’s reactogenicity e-diary data.  If the participant is part of the 
reactogenicity subset, review the participant’s reactogenicity e-diary data.  Collect stop 
dates of any reactogenicity e-diary events ongoing on the last day that the reactogenicity 
e-diary was completed and record stop dates in the CRF if required.

Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since Visit 1 (if any).

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample (approximately 20 mL for participants ≥16 years of age, and 
approximately 10 mL for participants in the 12- to 15-year age stratum) for 
immunogenicity testing.

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
Ask the participant or his/her parent(s)/legal guardian, as appropriate, 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 or his/her parent(s)/legal guardian, as appropriate, 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.

If Visit 3 is being conducted under amendment 12 onward: If the participant is eligible 
for receipt of BNT162b2 according to recommendations detailed separately and available 
in the electronic study reference portal, determine if he/she is willing to receive 
BNT162b2 as part of the study. If so, unblind the participant’s study intervention 
assignment, and move placebo recipients to the procedures in Section 8.16.
8.11.2.4. Visit 4 – 6-Month Follow-up Visit: (175 to 189 Days After Visit 2)

Record SAEs as described in Section 8.3.

Record nonstudy vaccinations as described in Section 6.5.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since Visit 3 (if any).

Collect a blood sample (approximately 20 mL for participants ≥16 years of age and
approximately 10 mL for participants in the 12- to 15-year age stratum) for 
immunogenicity testing.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact 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 8.3.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

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
If not already unblinded, unblind the participant’s study intervention assignment, and 
move placebo recipients willing to receive BNT162b2 to the procedures in Section 8.16.

Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.
8.11.2.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 2): Only for 
Those Participants Who Originally Received BNT162b2 or Placebo Recipients Who 
Decline BNT162b2

Collect a blood sample (approximately 20 mL for participants ≥16 years of age and 
approximately 10 mL for participants in the 12- to 15-year age stratum) for 
immunogenicity testing.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since Visit 4 (if any).

Ask the participant or his/her parent(s)/legal guardian, as appropriate, 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.

Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.3.
8.11.2.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days After Visit 2) ): Only for 
Those Participants Who Originally Received BNT162b2 or Placebo Recipients Who 
Decline BNT162b2
This visit should not be performed if protocol amendment 20 is approved and participants are 
informed of early study completion prior to reaching this time point.

Collect a blood sample (approximately 20 mL for participants ≥16 years of age and 
approximately 10 mL for participants in the 12- to 15-year age stratum) for 
immunogenicity testing.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

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
For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since Visit 5 (if any).

Request the participant return the e-diary device or assist the participant to delete the 
application from his or her 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 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 or his/her parent(s)/legal guardian, as appropriate, 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 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:

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
Measure body temperature (°F/°C).

Measure minimum and maximum diameters of redness (if present).

Measure minimum and maximum diameters of swelling (if present).

Assess injection site pain (if present) in accordance with the grades provided in 
Section 8.2.2.2.

Assess systemic events (if present) in accordance with the grades provided in
Section 8.2.2.3.

Assess for other findings associated with the reaction and record on the AE page of the 
CRF, if appropriate.
The investigator or an authorized designee will complete the unscheduled visit assessment 
page of the CRF.
8.13. COVID-19 Surveillance (All Participants)
If a participant experiences any of the following (irrespective of perceived etiology or 
clinical significance), he or she is instructed to contact the site immediately and, if 
confirmed, participate in an in-person or telehealth visit as soon as possible, optimally within 
3 days of symptom onset (and at the latest 4 days after symptom resolution). Note that:

If new symptoms are reported within 4 days after resolution of all previous symptoms, 
they will be considered as part of a single illness and a second illness visit is not required;

Surveillance of potential COVID-19 symptoms should continue even if a participant has 
a positive SARS-CoV-2 test earlier in the study.
During the 7 days following each vaccination (either as part of this study, co-enrolled C459 
studies, or the B7471026 [20vPnC] study), potential COVID-19 symptoms that overlap with 
specific systemic events (ie, fever, chills, new or increased muscle pain, diarrhea, vomiting)
should not trigger a potential COVID-19 illness visit unless, in the investigator’s opinion, the 
clinical picture is more indicative of a possible COVID-19 illness than vaccine 
reactogenicity. If, in the investigator’s opinion, the symptoms are considered more likely to 
be vaccine reactogenicity, but a participant is required to demonstrate that they are 
SARS-CoV-2–negative, a local SARS-CoV-2 test may be performed: if positive, the 
symptoms should be recorded as a potential COVID-19 illness; if not, the symptoms should 
be recorded as AEs (unless already captured in the reactogenicity e-diary).
Participants may utilize a COVID-19 illness e-diary through an application (see Section 8.14)
installed on a provisioned device or on the participant’s own personal device to prompt 
him/her to report any symptoms. Note that this does not substitute for a participant’s routine 
medical care. Therefore, participants should be encouraged to seek care, if appropriate, from 

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their usual provider. Sites must arrange return of the participant’s e-diary or assist the 
participant to remove the study application from his or her own personal device at the time of 
final telephone contact after approval of protocol amendment 20.

A diagnosis of COVID-19;

Fever;

New or increased cough; 

New or increased shortness of breath;

Chills; 

New or increased muscle pain; 

New loss of taste/smell;

Sore throat;

Diarrhea;

Vomiting.
8.13.1. Potential COVID-19 Illness Visit: (Optimally Within 3 Days After Potential 
COVID-19 Illness Onset)
This visit may be conducted as an in-person or telehealth visit; a telehealth visit involves the 
sharing of healthcare information and services via telecommunication technologies 
(eg, audio, video, video-conferencing software) remotely, thus allowing the participant and 
investigator to communicate on aspects of clinical care. This visit should not be performed if 
protocol amendment 20 is approved and participants are informed of early study completion 
prior to potential COVID-19 illness onset. Any illness visits not concluded by the time of 
study completion should be considered ongoing and no further data should be collected.
As a participant’s COVID-19 illness may evolve over time, several contacts may be required 
to obtain the following information:

Record AEs, as appropriate as described in Section 8.3. Note: Potential COVID-19 
illnesses that are consistent with the clinical endpoint definition should not be recorded as 
AEs. These data will be captured as efficacy assessment data only on the relevant pages 
of the CRF, as these are expected endpoints.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

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
If the visit is conducted in person, obtain a nasal (midturbinate) swab (collected by site 
staff).  Alternatively, if conducted by telehealth, instruct the participant to self-collect a 
nasal (midturbinate) swab and ship for assessment at the central laboratory.

Collect COVID-19–related standard-of-care clinical and laboratory information. This 
includes, but is not limited to:

Symptoms and signs, including

Clinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per 
minute, HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or 
PaO2/FiO2 <300 mm Hg)

Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiring 
vasopressors)

Significant acute renal, hepatic, or neurologic dysfunction

Respiratory failure (defined as needing high-flow oxygen, noninvasive 
ventilation, mechanical ventilation, or ECMO)

Clinical diagnosis

Local laboratory SARS-CoV-2 test result(s). Note that if it is routine practice to 
perform a repeat local SARS-CoV-2 test for any reason, then a repeat nasal 
(midturbinate) swab should also be obtained and shipped for assessment at the central 
laboratory.

Full blood count

Blood chemistry, specifically creatinine, urea, liver function tests, and C-reactive 
protein

Imaging results (eg, CT or MRI scan) to document neurologic dysfunction

Number and type of any healthcare contact; duration of hospitalization and ICU stay

Death

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

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8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After Potential 
COVID-19 Illness Visit)
Prior to protocol amendment 16, a COVID-19 convalescent visit was required 28 to 35 days 
after each potential COVID-19 illness visit. Sufficient data have now been accrued from 
these visits, so the requirement has been removed from the protocol; however, data collected 
from convalescent visits that occurred prior to protocol amendment 16 will remain part of the 
study data set.
8.14. Communication and Use of Technology
In a study of this nature that requires illness events to be reported outside of scheduled study 
visits, it is vital that communication between the study site and the participant or his/her 
parent(s)/legal guardian, as appropriate, 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 or his/her parent(s)/legal guardian, as appropriate, and the study site 
staff will be established. The participant or his/her parent(s)/legal guardian, as appropriate,
may be able to utilize his or her own devices to access this technology, or use a device 
provided by the sponsor. Traditional methods of telephone communication will also be 
available. The technology solution may facilitate the following:

Contact with the investigator, including the ability of the participant or his/her 
parent(s)/legal guardian, as appropriate, to report whether or not the participant has
experienced symptoms that could represent a potential COVID-19 illness (COVID-19 
illness e-diary; see Section 8.13).

An alert in the event that the participant is hospitalized.

Visit reminders.

Messages of thanks and encouragement from the study team.

A platform for recording local reactions and systemic events (reactogenicity e-diary) –
see Section 8.2.2.
If a participant or his/her parent(s)/legal guardian, as appropriate, is not actively completing 
either the reactogenicity or COVID-19 illness e-diary, the investigator or designee is required 
to contact the participant or his/her parent(s)/legal guardian, as appropriate, to ascertain why 
and also to obtain details of any missed events.
8.15. SARS-CoV-2 NAAT Results
Nasal (midturbinate) swabs for SARS-CoV-2 NAAT are obtained at:

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
Visits 1 and 2: To determine whether a participant will be included in efficacy analyses 
of those with no serological or virological evidence (up to 7 or 14 days after receipt of the 
second dose, depending on the objective) of past SARS-CoV-2 infection.

Potential COVID-19 illness visits: To determine whether symptoms experienced by the 
participant fulfill the COVID-19 case definition.

Asymptomatic SARS-CoV-2 infection surveillance visits: To determine the incidence of 
asymptomatic SARS-CoV-2 infection.
Research laboratory–generated positive results from the Visit 1 and Visit 2 swabs, 
asymptomatic SARS-CoV-2 infection surveillance visit swabs, and all results from the illness 
visit swabs, will be provided to the site once available, but this will not be in real time and 
cannot be relied upon to direct clinical care.  Therefore, the participant should be directed to 
seek additional testing through his/her primary healthcare providers at a licensed clinical 
laboratory when exhibiting potential COVID-19 symptoms or otherwise receiving a positive 
result and counseled on whether to take any precautionary measures pending confirmatory 
testing.
Participants who have a positive SARS-CoV-2 NAAT result, either asymptomatic or a 
COVID-19 diagnosis (signs/symptoms only or signs/symptoms and a positive SARS-CoV-2 
NAAT result), prior to Visit 2 should receive Vaccination 2 as normal.
8.16. Procedures for Administration of BNT162b2 to Those Originally Assigned to 
Placebo
If a participant becomes eligible for receipt of BNT162b2 according to recommendations
detailed separately and available in the electronic study reference portal, the participant will 
be advised to contact the site to determine whether he or she can receive BNT162b2 as part 
of the study.
Placebo recipients who have not already been offered the opportunity to receive BNT162b2 
will be given this opportunity no later than 6 months after Dose 2, and will follow the 
procedures listed in this section for the remainder of their participation in the study. For 
Phase 2/3 participants, Visit 101 could occur at the same time as the original Visit 4.
8.16.1. Visit 101 – Vaccination 3: (From Recommendation or at Least 175 Days After 
Vaccination 2)
Before vaccination and before any study-related procedures are performed, voluntary, 
written, informed consent (via an ICD addendum) will be obtained from the participant or 
his/her parent(s)/legal guardian, as appropriate. 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/participant’s parent(s)/legal guardian.

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
Confirm the participant originally received only placebo at Vaccination 1/2. Secondary 
confirmation by another site staff member is required.

Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since their last visit (if any).

Review and consider inclusion criteria 2, 3, and 6 and exclusion criteria 1, 3, 8, 10, 11, 
12, 13, 16, 17, and 22 prior to vaccination. 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.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Record AEs as described in Section 8.3.

Collect a blood sample (approximately 20 mL) for immunogenicity testing. If a sample
for this purpose has already been collected in the previous 7 days (eg, per the procedures 
at Visit 4 for Phase 2/3 participants), a second sample need not be collected.

Obtain a nasal (midturbinate) swab (collected by site staff).

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.

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 or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator if a medically attended event (eg, doctor’s visit, emergency room 
visit) or hospitalization occurs.

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
Ask the participant or his/her parent(s)/legal guardian, as appropriate, 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 urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

Review and consider inclusion criteria 2, 3, and 6 and exclusion criteria 1, 3, 8, 10, 11, 
12, 13, 16, 17, and 22 prior to vaccination. 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.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Obtain a nasal (midturbinate) swab (collected by site staff).

Obtain the participant’s vaccine vial allocation using the IRT system.

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.

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
Ask the participant or his/her parent(s)/legal guardian, as appropriate, 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 or his/her parent(s)/legal guardian, as appropriate, 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.

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 Follow-up Telephone Contact (After Vaccination 4): (28 to 
35 Days After Visit 102)

Contact the participant/participant’s parent(s)/legal guardian by telephone.

Record AEs as described in Section 8.3.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since Visit 101 (if any).

Ask the participant or his/her parent(s)/legal guardian, as appropriate, 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 or his/her parent(s)/legal guardian, as appropriate, 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.

The investigator or an authorized designee completes the CRFs.
8.16.4. Visit 104 – 6-Month Follow-up Telephone Contact (After Vaccination 4): (175 to 
189 Days After Visit 102)

Contact the participant/participant’s parent(s)/legal guardian by telephone.

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
Record SAEs as described in Section 8.3.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since their Visit 103 (if any).

Ask the participant or his/her parent(s)/legal guardian, as appropriate, 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 or his/her parent(s)/legal guardian, as appropriate, 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.

The investigator or an authorized designee completes the CRFs.
8.16.5. Visit 105 – 18-Month Follow-up Telephone Contact (After Vaccination 4): 
(532 to 560 Days After Visit 102)
This visit should not be performed if protocol amendment 20 is approved and participants are 
informed of early study completion prior to reaching this time point.

Contact the participant/participant’s parent(s)/legal guardian by telephone.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since Visit 104 (if any).

Request the return of the participant’s e-diary or assist the participant/participant’s 
parent(s)/legal guardian to remove the study application from his or her own personal 
device.

Inform the participant/participant’s parent(s)/legal guardian that his or her study 
participation has ended.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

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8.17. Administration of an Additional Dose of BNT162b2 (5, 10, or 30 µg) or 
BNT162b2SA (30 µg) (Subset for Evaluation of Boostability and Protection Against 
Emerging VOCs)
The assessment of boostability will be further expanded in a subset of Phase 3 participants at 
selected sites in the US who will receive a third dose of BNT162b2 or a third and potentially 
a fourth dose of prototype BNT162b2SA.
8.17.1. Visit 301 – Vaccination 3: (150 to 210 Days After Visit 2)
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. If the participant does not consent 
to administration of a third dose of BNT162b2, he or should remain on the Phase 2/3 visit 
schedule.
Note: This visit can occur on the same day as Visit 4, but all procedures for both visits must 
be conducted (including collection of all blood samples).

Confirm that the participant originally received BNT162b2 at Vaccinations 1 and 2. 
Secondary confirmation by another site staff member is required.

Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Record nonstudy vaccinations as described in Section 6.5.

Measure the participant’s body temperature.

Ensure and document that inclusion criteria 1, 2, 3, 5, and 6 are met and exclusion criteria
1, 3, 5, 8, 10, 11, 12, 13, 15, 16, 17, and 22 are not met prior to vaccination.

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 50 mL) for immunogenicity testing.

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
If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation 
and a further blood sample (approximately 5 mL) for HLA typing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Obtain the participant’s randomization number and study intervention allocation number 
using the IRT system.  The IRT system will also assign an additional single 
participant number; this number will not be used as the primary identifier for the 
participant, but must be included in the participant’s source documents and 
transcribed into the CRF. The system will also identify those participants who are to 
receive a fourth dose; this should be kept blinded until from the participant until 
Visit 303.

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.

Remind the participant of the e-diary technologies available for this study (see 
Section 8.14).  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 (see Section 8.12):

Fever ≥39.0°C (≥102.1°F)

Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units)

Severe pain at the injection site

Any severe systemic event

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
Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if 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.

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.
8.17.2. Visit 302 – 1-Week Follow-up Visit (After Vaccination 3): (6 to 8 Days After 
Visit 301)

Record AEs as described in Section 8.3.

Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample of approximately 50 mL for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.

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.

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
The investigator or an authorized designee completes the CRFs.
8.17.3. Visit 303 – 1-Month Follow-up Visit (After Vaccination 3): (28 to 35 Days After 
Visit 301)

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.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample of approximately 50 mL for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.
Only if the participant is to receive a further dose of BNT162b2SA:

Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Measure the participant’s body temperature.

Ensure and document that inclusion criteria 1, 2, 3, 5, and 6 are met and exclusion 
criteria 1, 3, 5, 8, 10, 11, 12, 13, 15, 16, 17, and 22 are not met prior to vaccination.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of BNT162b2SA 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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
Remind the participant of the e-diary technologies available for this study (see 
Section 8.14).  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 (see Section 8.12):

Fever ≥39.0°C (≥102.1°F)

Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units)

Severe pain at the injection site

Any severe systemic event

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
8.17.4. Visit 304 – 1-Week Follow-up Visit (Vaccination 4): (6 to 8 Days After Visit 303): 
Only for Those Participants Who Received a fourth dose of BNT162b2SA

Record AEs as described in Section 8.3.

Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

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
Collect a blood sample of approximately 50 mL for immunogenicity testing.

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
8.17.5. Visit 305 – 1-Month Follow-up Visit (Vaccination 4): (28 to 35 Days After Visit 
303): Only for Those Participants Who Received a fourth dose of BNT162b2SA

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.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample of approximately 50 mL for immunogenicity testing.

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

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8.17.6. Visit 306 – 6-Month Follow-up Visit: (175 to 189 Days After Visit 301)

Record AEs as described in Section 8.3.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.

Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record latest CD4 count and HIV viral load.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3.
8.17.7. Visit 307 – 18-Month Follow-up Visit: (532 to 560 Days After Visit 301)
This visit should not be performed if protocol amendment 20 is approved and participants are 
informed of early study completion prior to reaching this time point.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record latest CD4 count and HIV viral load.

Request the participant return the e-diary device or assist the participant to delete the 
application from his or her 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.
8.18. Administration of BNT162b2SA to BNT162b2-Naïve Participants
To further describe potential homologous and heterologous protection against emerging 
SARS-CoV-2 VOCs, a new cohort of participants will be enrolled who are COVID-19 
vaccine-naïve (ie, BNT162b2-naïve) and have not experienced COVID-19. They will 
receive BNT162b2SA given as a 2-dose series, separated by 21 days.
8.18.1. Visit 401 – 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. The visit 
may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and 
exclusion criteria onwards must be conducted on the same day.

Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).  
The full date of birth will be collected to critically evaluate the immune response 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.

Measure the participant’s body temperature.

Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.

Record nonstudy vaccinations as described in Section 6.5.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

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
Ensure and document that all of the inclusion criteria and none of the exclusion criteria
are met.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Record AEs as described in Section 8.3.

Collect a blood sample approximately 50 mL for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation 
and a further blood sample (approximately 5 mL) for HLA typing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Obtain the participant’s vaccine vial allocation using the IRT system.

Site staff member(s) will dispense/administer 1 dose of BNT162b2SA 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.

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 reactogenicity 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.

Provide instructions on COVID-19 illness e-diary completion and ask the participant 
to complete the COVID-19 illness e-diary if the participant is diagnosed with 
COVID-19 or has possible new or increased symptoms, and when he/she receives a 
reminder, at least weekly.  See Section 8.14 for further details.

Ask the participant to contact the site staff or investigator immediately if the participant 
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 is 
the day of vaccination) to determine if an unscheduled reactogenicity visit is required: 

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
Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units).

Severe pain at the injection site.

Any severe systemic event.

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs and 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.
8.18.2. Visit 402 – Vaccination 2: (19 to 23 Days After Visit 401) 
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 8.2.6.

Discuss contraceptive use as described in Section 10.4.

Record nonstudy vaccinations as described in Section 6.5.

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
Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met.  If not, the participant may not receive further study intervention but will remain 
in the study to be evaluated for safety, immunogenicity, and efficacy (see Section 7.1).

Measure the participant’s body temperature.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Obtain a nasal (midturbinate) swab (collected by site staff).

Obtain the participant’s vaccine vial allocation using the IRT system.

Site staff member(s) will dispense/administer 1 dose of BNT162b2SA 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.

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 the 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 the participant 
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 is 
the day of vaccination) to determine if an unscheduled reactogenicity visit is required:

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units).

Severe pain at the injection site.

Any severe systemic event.

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
Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs and 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.
8.18.3. Visit 403 – 1-Week Follow-up Visit (After Vaccination 2): (6 to 8 Days After 
Visit 402)

Record AEs as described in Section 8.3.

Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample of approximately 50 mL for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.

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.

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
The investigator or an authorized designee completes the CRFs.
8.18.4. Visit 404 – 1-Month Follow-up Visit (After Vaccination 2): (28 to 35 Days After 
Visit 402)

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.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Discuss contraceptive use as described in Section 10.4.

Collect a blood sample of approximately 50 mL for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.

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.
8.18.5. Visit 405 – 6-Month Follow-up Visit: (175 to 189 Days After Visit 402)

Record AEs as described in Section 8.3.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.

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
Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 8.13.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3.
8.18.6. Visit 406 – 18-Month Follow-up Visit: (532 to 560 Days After Visit 402)
This visit should not be performed if protocol amendment 20 is approved and participants are 
informed of early study completion prior to reaching this time point.

Collect a blood sample (approximately 50 mL) for immunogenicity testing.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Request the participant return the e-diary device or assist the participant to delete the 
application from his or her 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.
8.19. Surveillance for Asymptomatic SARS-CoV-2 Infection
An intensive period of surveillance for asymptomatic SARS-CoV-2 infection may be 
conducted at selected sites among Phase 2/3 participants following approval of protocol 
amendment 11 until Visit 4, or a sufficient number of cases of SARS-CoV-2 infection have 

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accrued to evaluate this objective, whichever is sooner. The surveillance will be conducted 
per the procedures listed below.
Participants who are unblinded because they become potentially eligible for receipt of 
BNT162b2 according to recommendations detailed separately, and available in the electronic 
study reference portal, will not participate in surveillance for asymptomatic SARS-CoV-2 
infection. However, participants who provided additional consent to conduct biweekly 
swabbing for surveillance of asymptomatic infection should continue to swab even after 
unblinding if they originally received BNT162b2.
Surveillance for asymptomatic SARS-CoV-2 infection (swabbing) should cease in 
participants enrolled into the subset of participants who will receive an additional dose of 
BNT162b2 or BNT162b2SA.
8.19.1. Visit 201– Asymptomatic SARS-CoV-2 Infection Surveillance Consent: From 
Approval of Protocol Amendment 11
Before surveillance begins and any study-related procedures are performed, voluntary, 
written, informed consent (via an ICD addendum) will be obtained from the participant or 
his/her parent(s)/legal guardian, as appropriate. 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/participant’s parent(s)/legal guardian.
The visit should be conducted only if the participant has no symptoms of potential 
COVID-19 (see Section 8.13). If the participant has such symptoms, a potential COVID-19 
illness visit should be performed (see Section 8.13.1) and this visit should be temporarily 
delayed until the symptoms have resolved.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

Collect a blood sample (approximately 20 mL for participants ≥16 years of age and 
approximately 10 mL for participants in the 12- to 15-year age stratum) for 
immunogenicity testing. If a sample for this purpose has already been collected in the 
previous 7 days (eg, per the procedures at Visit 3 for Phase 2/3 participants), a second 
sample need not be collected.

Obtain a nasal (midturbinate) swab (collected by site staff).

Record AEs as described in Section 8.3 (only if the participant remains in the AE 
reporting period; see Section 8.3.1).

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator immediately if a medically attended event (eg, doctor’s visit, 
emergency room visit) or hospitalization occurs.

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
Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact 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.

Ask the participant to obtain a surveillance self-swab at home in approximately 14 days 
or schedule an appointment for the participant to return to collect the swab at the site.  
The swab should be collected only if the participant has no symptoms of potential 
COVID-19 (see Section 8.13). If the participant has such symptoms, a potential 
COVID-19 illness visit should be performed (see Section 8.13.1).

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
8.19.2. Visit 202 Onward – Asymptomatic SARS-CoV-2 Infection Surveillance Swab: 
Repeating Every 10 to 18 Days After Each Previous Surveillance Swab Collection
This is a repeating swab collection and will be conducted approximately every 14 days until 
the intensive surveillance period ends.

Participant collects a self-swab and ships it to the site for assessment at the central 
laboratory. The swab should be collected as part of this visit only if the participant has 
no symptoms of potential COVID-19 (see Section 8.13). If the participant has such 
symptoms, the swab should be collected as part of a potential COVID-19 illness visit 
(see Section 8.13.1).

If the visit is conducted in person, obtain a nasal (midturbinate) swab (collected by site 
staff). The swab should be collected as part of this visit only if the participant has no 
symptoms of potential COVID-19 (see Section 8.13). If the participant has such 
symptoms, the swab should be collected as part of a potential COVID-19 illness visit 
(see Section 8.13.1).

Complete the source documents with the swab information.

The investigator or an authorized designee completes the CRFs with the swab 
information.
8.20. Administration of a Third Dose of BNT162b2 to Participants Who Have Not 
Previously Received a Third Dose
The opportunity to receive a third dose of BNT162b2 will be offered as part of the study, 
according to recommendations detailed separately, and available in the electronic study 
reference portal.
The additional information collected at Visits 501, 502, 503, and 504 will be collected in a 
supplementary database; further information on the recording of this information will be 
provided in the study CRF Completion Requirements document.

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8.20.1. Visit 501 – Third Dose of BNT162b2
Before vaccination and before any study-related procedures are performed, voluntary, 
written, informed consent (via an ICD addendum) will be obtained from the participant or 
his/her parent(s)/legal guardian, as appropriate. 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/participant’s parent(s)/legal guardian.

Confirm the participant has only received 2 doses of BNT162 as part of the study and 
not outside. Secondary confirmation by another site staff member is required.

Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.

Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received 
by the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results 
from the most recent test performed since their last visit (if any).

Review and consider inclusion criteria 2, 3, and 6 and exclusion criteria 1, 3, 8, 10, 11, 
12, 13, 16, 17, and 22 prior to vaccination.  If, in the investigator’s judgment, 
vaccination is in the best interests of the participant (and meets local 
recommendations/guidelines), vaccination may proceed, even if inclusion criteria are not 
met (excluding inclusion criterion 6, which must be met in all cases) and exclusion 
criteria are met (excluding exclusion criterion 12, applicable to vaccines received 
outside the study only, which must never be met in any case). Such exceptions should 
be recorded in the participant’s source documents.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Record AEs as described in Section 8.3.

Collect a blood sample (approximately 20 mL) for immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

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 or his/her parent(s)/legal guardian, as appropriate, 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 or his/her parent(s)/legal guardian, as appropriate, 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.

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator immediately if the participant experiences acute chest pain, 
shortness of breath, or palpitations (see Section 8.22).

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.
8.20.2. Visit 502 – 1-Month Follow-up Telephone Contact: (28 to 35 Days After Visit 
501)

Contact the participant/participant’s parent(s)/legal guardian by telephone.

Record AEs as described in Section 8.3.

Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since Visit 501 (if any).

Ask the participant or his/her parent(s)/legal guardian, as appropriate, 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 or his/her parent(s)/legal guardian, as appropriate, 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.

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
Schedule an appointment to call the participant by telephone for the next study contact.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
8.20.3. Visit 503 – 6-Month Follow-up Telephone Contact: (175 to 189 Days After Visit
501)

Contact the participant/participant’s parent(s)/legal guardian by telephone.

Record SAEs as described in Section 8.3.

Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since their Visit 502 (if any).

Ask the participant or his/her parent(s)/legal guardian, as appropriate, 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 or his/her parent(s)/legal guardian, as appropriate, 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.
8.20.4. Visit 504 – 12-Month Follow-up Visit: (350 to 378 Days After Visit 501):
This visit should not be performed if protocol amendment 20 is approved and participants are 
informed of early study completion prior to reaching this time point.

Collect a blood sample (approximately 20 mL) for immunogenicity testing.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since Visit 503 (if any).

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
Request the participant return the e-diary device or assist the participant to delete the 
application from his or her 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.
8.21. Administration of a Fourth (or Fifth) Dose of BNT162b2 to Eligible Participants 
From Protocol Amendments 13, 14, and 15 
The opportunity to receive an additional dose of BNT162b2 will be offered as part of the 
study. As part of protocol amendment 19, eligible participants who received a third dose of 
BNT162b2 (or BNT162b2SA) or a third and fourth dose of BNT162b2SA under protocol 
amendments 13 to 15 will be offered an additional 30-µg dose of BNT162b2.
The additional information collected at Visits 601, 602, 603, 604, 605, and 606 will be 
collected in a supplementary database; further information on the recording of this 
information will be provided in the study CRF Completion Requirements document.
8.21.1. Visit 601 – Dose 4: (At Least 175 Days After Visit 301 or Visit 8a): Only For 
Those Participants Who Received Dose 3 at Visit 8a or Visit 301
Before vaccination and before any study-related procedures are performed, voluntary, 
written, informed consent (via an ICD addendum) will be obtained from the participant or 
his/her parent(s)/legal guardian, as appropriate.  Each signature on the ICD addendum must 
be personally dated by the signatory.  The investigator or his/her designee will also sign the 
ICD addendum.  A copy of the signed and dated ICD addendum must be given to the 
participant/participant’s parent(s)/legal guardian.

Confirm the participant has received Dose 3 of BNT162 at Visit 301 or Visit 8a as part of 
the study and not outside.  Secondary confirmation by another site staff member is 
required.

Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.

Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

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
For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since their last visit (if any). (Not collected for Phase 1 
participants who received Dose 3 at Visit 8a).

Review and consider inclusion criteria 2, 3, and 6 and exclusion criteria 1, 3, 8, 10, 11, 
12, 13, 16, 17, and 22 prior to vaccination.  If, in the investigator’s judgment, vaccination 
is in the best interests of the participant (and meets local recommendations/guidelines), 
vaccination may proceed, even if inclusion criteria are not met (excluding inclusion 
criterion 6, which must be met in all cases) and exclusion criteria are met (excluding 
exclusion criterion 12, applicable to vaccines received outside the study only, which must 
never be met in any case). Such exceptions should be recorded in the participant’s source 
documents.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Record AEs as described in Section 8.3.

Obtain a nasal (midturbinate) swab (collected by site staff).

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.

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 or his/her parent(s)/legal guardian, as appropriate, 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 or his/her parent(s)/legal guardian, as appropriate, 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.

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator immediately if the participant experiences acute chest pain, shortness 
of breath, or palpitations (see Section 8.22).

Schedule 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 and the 
dispenser/administrator updates the study intervention accountability records.
8.21.2. Visit 602 – 1-Month Follow-up Telephone Contact: (28 to 35 Days After 
Visit 601)

Contact the participant/participant’s parent(s)/legal guardian by telephone.

Record AEs as described in Section 8.3.

Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since Visit 601 (if any). (Not collected for Phase 1 
participants who received Dose 3 at Visit 8a)

Schedule to call the participant by telephone for the next study contact.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
8.21.3. Visit 603 – 6-Month Follow-up Telephone Contact: (175 to 189 Days After Visit 
601)
This visit should not be performed if protocol amendment 20 is approved and participants are 
informed of early study completion prior to reaching this time point.

Contact the participant/participant’s parent(s)/legal guardian by telephone.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since Visit 602 (if any). (Not collected for Phase 1 
participants who received Dose 3 at Visit 8a)

Request that the participant return the 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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8.21.4. Visit 604 – Dose 5: (At Least 175 Days After Visit 303): Only for the Subset of
Participants Who Receive Dose 4 at Visit 303
Before vaccination and before any study-related procedures are performed, voluntary, 
written, informed consent (via an ICD addendum) will be obtained from the participant or 
his/her parent(s)/legal guardian, as appropriate.  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/participant’s parent(s)/legal guardian.

Confirm the participant has received Dose 4 of BNT162 at Visit 303 as part of the study 
and not outside.  Secondary confirmation by another site staff member is required.

Perform urine pregnancy test on WOCBP as described in Section 8.2.6.

Discuss contraceptive use as described in Section 10.4.

Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the recent test performed since their last visit (if any).

Review and consider inclusion criteria 2, 3, and 6 and exclusion criteria 1, 3, 8, 10, 11, 
12, 13, 16, 17, and 22 prior to vaccination.  If, in the investigator’s judgment, vaccination 
is in the best interests of the participant (and meets local recommendations/guidelines), 
vaccination may proceed, even if inclusion criteria are not met (excluding inclusion 
criterion 6, which must be met in all cases) and exclusion criteria are met (excluding 
exclusion criterion 12, applicable to vaccines received outside the study only, which must 
never be met in any case). Such exceptions should be recorded in the participant’s source 
documents.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Record AEs as described in Section 8.3.

Obtain a nasal (midturbinate) swab (collected by site staff).

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 or his/her parent(s)/legal guardian, as appropriate, 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 or his/her parent(s)/legal guardian, as appropriate, 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.

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator immediately if the participant experiences acute chest pain, shortness 
of breath, or palpitations (see Section 8.22).

Schedule to call the participant by telephone 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.
8.21.5. Visit 605 – 1-Month Follow-up Telephone Contact: (28 to 35 Days After 
Visit 604)

Contact the participant/participant’s parent(s)/legal guardian by telephone.

Record AEs as described in Section 8.3.

Record nonstudy vaccinations as described in Section 6.5.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since Visit 604 (if any).

Schedule to call the participant by telephone for the next study contact.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

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8.21.6. Visit 606 – 6-Month Follow-up Telephone Contact: (175 to 189 Days After 
Visit 601)
This visit should not be performed if protocol amendment 20 is approved and participants are 
informed of early study completion prior to reaching this time point.

Contact the participant/participant’s parent(s)/legal guardian by telephone.

Record details of any of the prohibited medications specified in Section 6.5.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since Visit 605 (if any).

Request that the participant return the 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.
8.22. Additional Procedures for Monitoring of Potential Myocarditis or Pericarditis
Any study participant who reports acute chest pain, shortness of breath, palpitations, or any 
other symptom(s) that might be indicative of myocarditis or pericarditis within 4 weeks after 
the third, fourth, or fifth dose of BNT162b2 should be specifically evaluated, preferably by a 
cardiologist, for possible myocarditis or pericarditis.
In addition to a clinical evaluation, the following should be performed:

ECG and

Measurement of the troponin level
If myocarditis or pericarditis is suspected based upon the initial evaluation, the following 
should also be performed:

Cardiac echocardiogram and/or

Cardiac magnetic resonance study
Details of the symptoms reported, and results of the investigations performed, will be 
recorded in the CRF.

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9. STATISTICAL CONSIDERATIONS
Methodology for summary and statistical analyses of the data collected in this study is 
described here and further detailed in a statistical analysis plan (SAP), which will 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 tertiary/exploratory objective is 
described in the table in Section 3.
In the primary safety objective evaluations, missing reactogenicity e-diary data will not be 
imputed. Missing AE dates will be imputed according to Pfizer safety rules. No other 
missing information will be imputed in the safety analysis.
The estimands to evaluate the immunogenicity objectives are based on evaluable populations 
for immunogenicity (Section 9.3).  These estimands estimate the vaccine effect in the 
hypothetical setting where participants follow the study schedules and protocol requirements 
as directed. Missing antibody results will not be imputed. Immunogenicity results that are 
below the LLOQ will be set to 0.5 × LLOQ in the analysis; this may be adjusted once 
additional data on the assay characteristics become available.
The estimands to evaluate the efficacy objectives are based on evaluable populations for 
efficacy (Section 9.3).  These estimands estimate the vaccine effect in the hypothetical 
setting where participants follow the study schedules and protocol requirements as directed. 
In addition, VE will also be analyzed by all-available efficacy population. Missing 
laboratory results will not be imputed for the primary analysis, but missing data imputation 
for the efficacy endpoint may be performed as a sensitivity analysis.
9.1.2. Statistical Hypotheses
9.1.2.1. Statistical Hypothesis Evaluation for Efficacy
Phase 2/3 of the study has 2 primary efficacy endpoints evaluating VE, which is defined as 
VE = 100 × (1 – IRR). IRR is calculated as the ratio of first confirmed COVID-19 illness 
rate in the vaccine group to the corresponding illness rate in the placebo group. In Phase 2/3, 
the assessment of VE will be based on posterior probabilities of VE1 > 30% and VE2 > 30%.
VE1 represents VE for prophylactic BNT162b2 against confirmed COVID-19 in participants 
without evidence of infection before vaccination, and VE2 represents VE for prophylactic 
BNT162b2 against confirmed COVID-19 in all participants after vaccination.
For participants with multiple confirmed cases, only the first case will contribute to the VE 
calculation for each hypothesis. VE1 and VE2 will be evaluated sequentially to control the 
overall type I error to the desired level of 2.5%.  VE is demonstrated if there is sufficient 
evidence (posterior probability) that either VE1 >30% or both VE1 and VE2 are >30%. The 

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assessment for the primary analysis will be based on posterior probability using a Bayesian 
model.
The secondary objectives regarding VE against asymptomatic SARS-CoV-2 infection 
(determined by asymptomatic seroconversion of N-binding antibody and/or asymptomatic 
SARS-CoV-2 infection based on central laboratory–confirmed NAAT) will be evaluated 
based on the lower bound of the 95% CI. VE will be demonstrated if the lower bound of the 
2-sided 95% CI for VE is >20%.
9.1.2.2. Statistical Hypothesis Evaluation for Immunogenicity
9.1.2.2.1. Hypothesis for Immunogenicity Bridging of 12 to 15 Years to 16 to 25 Years
One of the secondary objectives in the Phase 3 part of the study is to evaluate noninferiority 
of the immune response to prophylactic BNT162b2 in participants 12 to 15 years of age 
compared to the response in participants 16 to 25 years of age at 1 month after Dose 2. The 
(Dose 2) evaluable immunogenicity population will be used for the following hypothesis 
testing:
H0: ln(µ2) – ln(µ1) ≤ln(0.67)
where ln (0.67) corresponds to a 1.5-fold margin for noninferiority, ln(µ2) and ln(µ1) are the 
natural log of the geometric mean of SARS-CoV-2 neutralizing titers from BNT162b2 
recipients 12 to 15 years of age and 16 to 25 years of age, respectively, measured 1 month 
after Dose 2.  If the lower limit of the 95% CI for the GMR (12-15 years of age to 
16-25 years of age) is >0.67, the noninferiority objective is met.
9.1.2.2.2. Hypotheses for Boostability and Protection Against Emerging SARS-CoV-2 
VOCs
The primary and secondary objectives for boostability and protection against emerging 
VOCs for BNT162b2-experienced participants and BNT162b2-naïve participants will be 
assessed based on:

GMRs of SARS-CoV-2 SA and/or reference strain neutralizing titers using a 1.5-fold 
noninferiority margin. Noninferiority is met if the lower limit of the alpha adjusted CI 
for the GMR is >0.67 and the point estimate of the GMR is ≥0.8.

The difference in percentages of participants with seroresponse to SA and/or reference 
strain using a 10% noninferiority margin. Noninferiority is met if the lower limit of the 
alpha-adjusted CI for the difference in percentages of participants with seroresponse is 
>-10%.
Seroresponse is defined as achieving ≥4-fold rise from baseline (before Dose 1). If the
baseline measurement is below LLOQ, the postvaccination measure of ≥4 × LLOQ is 
considered seroresponse.

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9.1.2.2.2.1. Multiplicity Control for the Boostability and Protection-Against-VOCs
Objectives
Figure 1 outlines the type I error control strategy for multiple objectives across different
populations (BNT162b2-experienced or BNT162b2-naïve) and estimands (GMR or 
seroresponse).
The objectives for BNT162b2-experienced participants and BNT162b2-naïve participants
will be evaluated independently. The vaccine-experienced and -naïve individuals are 
different populations with different objectives. The 2 populations are included in the same 
study to improve operational efficiency. Therefore, no type I error adjustments will be
applied to the assessments of the 2 populations.
For each population, the objectives will be evaluated separately for each estimand. To 
control the overall type I error, the 1-sided alpha of 0.025 will be split and allocated equally 
to each estimand. Specifically, for each estimand, the hypotheses will be tested in sequential 
order (as listed in the objectives in Section 3) using a 1-sided alpha of 0.0125 (Figure 1,
where E and N represent vaccine-experienced and vaccine-naïve, respectively, and a and b 
represent GMR and seroresponse estimands, respectively).
Figure 1.
Multiplicity Schema
9.2. Sample Size Determination
9.2.1. Phase 1
The study sample size for Phase 1 of the study is not based on any statistical hypothesis 
testing. Phase 1 comprises 15 participants (randomization ratio of 4:1 so that 12 receive 
active vaccine and 3 receive placebo) per group; 13 vaccine groups are studied, 
corresponding to a total of 195 participants.
Overall alpha 
(0.025)
BNT162b2-
experienced 
(0.025)
GMR
(0.0125)
Sequential test E1a, 
E2a, E3a, E4a at 
0.0125
Seroresponse
(0.0125)
Sequential test E1b, 
E2b, E3b, E4b at 
0.0125
BNT162b2-naïve 
(0.025)
GMR
(0.0125)
Sequential test N1a 
and N2a at 0.0125
Seroresponse
(0.0125)
Sequential test N1b 
and N2b at 0.0125

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9.2.2. Efficacy Against COVID-19
For Phase 2/3, with assumptions of a true VE of 60% after the second dose of investigational 
product, a total of approximately 164 first confirmed COVID-19 illness cases will provide 
90% power to conclude true VE >30% with high probability, allowing early stopping for 
efficacy at the IA. This would be achieved with 17,600 evaluable participants per group or 
21,999 vaccine recipients randomized in a 1:1 ratio with placebo, for a total sample size of 
43,998, based on the assumption of a 1.3% illness rate per year in the placebo group, accrual 
of 164 first primary-endpoint cases within 6 months, and 20% of the participants being 
nonevaluable or having serological evidence of prior infection with SARS-CoV-2, 
potentially making them immune to further infection. Dependent upon the evolution of the 
pandemic, it is possible that the COVID-19 attack rate may be much higher, in which case 
accrual would be expected to be more rapid, enabling the study’s primary endpoint to be 
evaluated much sooner. The total number of participants enrolled in Phase 2/3 may vary 
depending on the incidence of COVID-19 at the time of the enrollment, the true underlying 
VE, and a potential early stop for efficacy or futility.
9.2.3. Efficacy Against Asymptomatic Infection
The secondary objectives regarding VE against asymptomatic SARS-CoV-2 infection will be 
assessed in Phase 2/3 participants (determined by asymptomatic seroconversion of N-binding 
antibody and/or asymptomatic SARS-CoV-2 infection based on central laboratory–confirmed 
NAAT). Assuming a true VE of 70%, a total of 53 asymptomatic cases will provide 
approximately 90% power to conclude true VE >20%. A total of 206 cases is needed to have
90% power if the true VE is 50%. The hypothesis for asymptomatic seroconversion of 
N-binding antibody will be tested if at least 206 cases are accrued. The hypothesis for
asymptomatic infection based on central laboratory–confirmed NAAT in participants who 
are consented to participate in the intensive surveillance phase will be tested if at least 
53 cases are accrued.
9.2.4. Immunogenicity Bridging of 12 to 15 Years to 16 to 25 Years
In Phase 3, approximately 2000 participants are anticipated to be 12 to 15 years of age. 
A random sample of 280 participants will be selected for each of the 2 age groups (12 to 
15 years and 16 to 25 years) as an immunogenicity subset for the noninferiority assessment.
With the standard deviation and observed GMT difference assumed in the power analysis 
below, a sample size of 225 evaluable participants (or 280 vaccine recipients) per age group
will provide a power of 90.4% to declare the noninferiority of adolescents to 16- to 
25-year-olds in terms of neutralizing antibody GMR, 1 month after the second dose
(see Table 4).

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Table 4.
Power Analysis for Noninferiority Assessment
Criteria
Standard Deviation 
(Log Value)a
Assumed Observed 
GMT Difference 
(Log Scale)
Number of Evaluable 
Participants per Age 
Group
Powerb
Lower limit of 95% 
CI for GMR
(12-15/16-25) >0.67
0.65
-0.2
225
90.4%
Abbreviations: GMR = geometric mean ratio; GMT = geometric mean titer.
a.
Reference: 1 month after Dose 2, BNT162b2 (30 µg), 18- to 55-year age group (C4591001 Phase 2).
b.
At 0.05 alpha level (2-sided).
9.2.5. Boostability and Protection Against Emerging SARS-CoV-2 VOCs
To assess boostability and protection against emerging SARS-CoV-2 VOCs, approximately 
300 participants will be enrolled in each of the 3 groups (BNT162b2-experienced participants 
to receive either a third dose of BNT162b2 at 30 µg [Group 1] or a third dose of 
BNT162b2SA [Group 2], BNT162b2-naïve participants to receive 2 doses of BNT162b2SA
[Group 3]) to provide an acceptable safety database.
Assuming 20% nonevaluable rate, approximately 240 evaluable participants in each group 
will contribute to immunogenicity evaluation. This will provide sufficient power for 
noninferiority evaluations with appropriate multiplicity adjustment for type I error control.
For comparisons based on GMR, the assay standard deviation in log scale is assumed to be 
0.74 based on results from Phase 2 of the study and adjusted for assay variability. A GMR of 
1 is assumed for each comparison.
For comparisons based on seroresponse, a 90% response rate is assumed for each 
comparative group or at each comparative time point.
Within-Group Comparison for BNT162b2-Experienced Participants
For each randomized group of BNT162b2-experienced participants (Group 1: received a 
third dose of BNT162b2 at 30 µg and Group 2: received a third dose of BNT162b2SA), with 
240 evaluable participants and the stated assumptions for the GMR and standard deviation, 
the study has >99.9% power to demonstrate NI based on GMR for the objectives in 
vaccine-experienced individuals using a 1.5-fold margin.
Assuming true response rate of 90% at each time point and 10% of the participants having a
different response status at 2 comparative time points, the study has 99% power to show NI 
based on seroresponse rate for the objectives in vaccine-experienced individuals using a 10% 
margin. The study will have 89% power to show NI if 20% of the participants have a 
different response status at 2 comparative time points.

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Between-Group Comparison of BNT162b2-Naïve Participants to Selected Existing Phase 3 
Participants Who Received 2 Doses of BNT162b2
Approximately 300 participants will be selected from the existing Phase 3 participants who 
received 2 doses of BNT162b2 to form the control group for the BNT162b2-naïve 
participants. The selection will ensure comparable distribution of age, sex, and other 
demographic factors in the control group and BNT162b2-naïve group. With 240 evaluable 
BNT162b2-naïve participants and 240 evaluable participants in the control group and the 
above stated assumptions for the GMR, standard deviation, and seroresponse rate, the study 
has >99.9%% power to declare NI based on GMR for the objectives in vaccine-naïve 
individuals using a 1.5-fold margin and 89.7% power to declare NI based on seroresponse 
rate using a 10% margin.
9.2.6. Safety
For safety outcomes, Table 5 shows the probability of observing at least 1 AE for a given 
true event rate of a particular AE, for various sample sizes.  For example, if the true AE rate 
is 10%, with 12 participants in a vaccine group, there is 72% probability of observing at least 
1 AE.
Table 5.
Probability of Observing at Least 1 AE by Assumed True Event Rates With 
Different Sample Sizes
Assumed True Event 
Rate of an AE
N=12
N=45
N=180
N=300
N=1000
N=3000
N=6000
N=9000 N=15000
0.01%
0.00
0.00
0.02
0.03
0.10
0.26
0.45
0.59
0.78
0.02%
0.00
0.01
0.04
0.06
0.18
0.45
0.70
0.83
0.95
0.04%
0.00
0.02
0.07
0.11
0.33
0.70
0.91
0.97
>0.99
0.06%
0.01
0.03
0.10
0.16
0.45
0.83
0.97
0.99
>0.99
0.08%
0.01
0.04
0.13
0.21
0.55
0.91
0.99
0.99
>0.99
0.10%
0.01
0.04
0.16
0.26
0.63
0.95
0.99
0.99
>0.99
0.15%
0.02
0.07
0.24
0.36
0.78
0.99
0.99
>0.99
>0.99
0.20%
0.02
0.09
0.30
0.45
0.86
>0.99
>0.99
>0.99
>0.99
0.25%
0.03
0.11
0.36
0.53
0.92
>0.99
>0.99
>0.99
>0.99
0.30%
0.04
0.13
0.42
0.59
0.95
>0.99
>0.99
>0.99
>0.99
0.35%
0.04
0.15
0.47
0.65
0.97
>0.99
>0.99
>0.99
>0.99
0.50%
0.06
0.20
0.59
0.78
0.99
>0.99
>0.99
>0.99
>0.99
1.00%
0.11
0.36
0.84
0.95
>0.99
>0.99
>0.99
>0.99
>0.99
2.00%
0.22
0.60
0.97
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
3.00%
0.31
0.75
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
5.00%
0.46
0.90
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
7.00%
0.58
0.96
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
10.00%
0.72
0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
Note: N = number in sample.

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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.
Dose 1 evaluable 
immunogenicity
For Phase 1 only, all eligible randomized participants who 
receive the vaccine to which they are randomly assigned at the 
first dose, have at least 1 valid and determinate 
immunogenicity result after Dose 1, have blood collection 
within an appropriate window after Dose 1, and have no other 
important protocol deviations as determined by the clinician.
Dose 2 evaluable 
immunogenicity
All eligible randomized participants who receive 2 doses of 
the vaccine to which they are randomly assigned, 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 
important protocol deviations as determined by the clinician.
Dose 3 booster evaluable 
immunogenicity
All eligible randomized participants who receive 2 doses of 
BNT162b2 (or BNT162b1 for Phase 1) as initially
randomized, with Dose 2 received within the predefined 
window, receive a third dose of BNT162b2 or BNT162b2SA as 
rerandomized (or receive a third dose of BNT162b2 for 
Phase 1), have at least 1 valid and determinate 
immunogenicity result after Dose 3 from a blood collection 
within an appropriate window, and have no other important 
protocol deviations as determined by the clinician.
Dose 4 booster evaluable 
immunogenicity
All eligible randomized participants who receive 2 doses of 
BNT162b2 as initially randomized, with Dose 2 received 
within the predefined window, receive 2 booster doses of 
BNT162b2SA as rerandomized, have at least 1 valid and 
determinate immunogenicity result after Dose 4 from a blood 
collection within an appropriate window, and have no other 
important protocol deviations as determined by the clinician.
Dose 1 all-available 
immunogenicity
For Phase 1 only: all randomized participants who receive at 
least 1 dose of the study intervention with at least 1 valid and 
determinate immunogenicity result after Dose 1 but before 
Dose 2.
Dose 2 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.

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Population
Description
Dose 3 booster all-available 
immunogenicity
All randomized participants who receive 2 doses of 
BNT162b2 (or BNT162b1 for Phase 1) at initial 
randomization, receive a third dose of BNT162b2 or 
BNT162b2SA at rerandomization (or receive a third dose of 
BNT162b2 for Phase 1), and have at least 1 valid and 
determinate immunogenicity result after Dose 3.
Dose 4 booster all-available
immunogenicity
All randomized participants who receive 2 doses of 
BNT162b2 at initial randomization, receive 2 booster doses of 
BNT162b2SA at rerandomization, and have at least 1 valid and 
determinate immunogenicity result after Dose 4.
Evaluable efficacy
All eligible randomized participants who receive all 
vaccination(s) as randomized within the predefined window 
and have no other important protocol deviations as determined 
by the clinician.
Evaluable efficacy 
(seroconversion)
All eligible randomized participants who receive all 
vaccinations as randomized, with Dose 2 received within the 
predefined window, have at least 1 N-binding antibody test 
result available at a post–Dose 2 visit, and have no other 
important protocol deviations as determined by the clinician
prior to the first post–Dose 2 N-binding antibody test.
Evaluable efficacy 
(asymptomatic 
surveillance)
All eligible randomized participants who receive all
vaccinations as randomized, with Dose 2 received within the
predefined window, consent to participate in the asymptomatic 
surveillance, and have no other important protocol deviations 
as determined by the clinician on or before the start of the 
asymptomatic surveillance period.
All-available efficacy
Dose 1 all-available: All randomized participants who receive 
at least 1 vaccination.
Dose 2 all-available: All randomized participants who
complete 2 vaccination doses.
Dose 3 all-available: All randomized participants who 
complete 3 vaccination doses.
Safety
All randomized participants who receive at least 1 dose of the 
study intervention.
Analyses of reactogenicity endpoints will be based on a subset 
of the safety population that includes participants with any 
e-diary data reported after vaccination.
Booster safety
All participants who receive at least 1 booster dose of the 
study intervention.

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9.4. Statistical Analyses
The SAP will be developed and finalized before database lock for any of the planned 
analyses in Section 9.5.1.  It will describe the participant populations to be included in 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 
tertiary/exploratory endpoints.
9.4.1. Immunogenicity Analyses
Immunogenicity samples will be drawn for all participants. Immunogenicity analyses will be 
based upon results from appropriately sized subsets of samples, according to the purpose.
The statistical analysis of immunogenicity results will be primarily based on the evaluable 
immunogenicity populations as defined in Section 9.3. Serology data after a postbaseline 
positive SARS-CoV-2 test result will not be included in the analysis based on the evaluable 
immunogenicity populations.
An additional analysis will be performed based on the all-available populations if there is 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.
Empirical RCDCs will be provided for all immunogenicity analyses.
Endpoint
Statistical Analysis Methods
Primary 
immunogenicity 
(Phase 3, 
boostability and 
protection against 
emerging VOCs)
In order to allow direct comparability with the reference strain, the 
anti-SA NTs may be adjusted to account for intrinsic variant or assay 
characteristics.
The small group of existing Phase 3 participants who are to receive a 
third and fourth dose of BNT162b2SA will not be included in the 
primary and secondary analyses except for the last secondary 
descriptive objective.
BNT162b2-Experienced Participants:
E1a: GMR of reference strain NT 1 month after the third dose of 
BNT162b2 at 30 µg to 1 month after the second dose of BNT162b2
in the same individuals
E2a: GMR of SA NT 1 month after 1 dose of BNT162b2SA to the 
reference strain NT 1 month after the second dose of BNT162b2 in 
the same individuals
The comparisons of different NTs (anti-SA or anti–reference strain) or 
the same NTs at different time points within the same group will be 

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limited to participants with nonmissing values at both time points or 
both NT measurements. GMRs will be calculated as the mean of the 
difference of logarithmically transformed titers for each participant (eg, 
later time point minus earlier time point) and exponentiating the mean. 
The associated 2-sided 97.5% CIs will be obtained by constructing CIs 
using Student’s t-distribution for the mean difference on the logarithm 
scale and exponentiating the confidence limits.
Noninferiority of E1a and E2a will be assessed sequentially. 
Noninferiority will be declared if the lower bound of the 2-sided 97.5% 
CI for the GMR is greater than 0.67 and the point estimate of the GMR 
is ≥0.8.
E1b: The difference in percentages of participants with 
seroresponse to the reference strain at 1 month after the third dose 
of BNT162b2 at 30 µg and 1 month after the second dose of 
BNT162b2 in the same individuals
E2b: The difference in percentages of participants with 
seroresponse to the SA strain at 1 month after 1 dose of 
BNT162b2SA and seroresponse to the reference strain at 1 month 
after the second dose of BNT162b2 in the same individuals
Similar to E1a and E2a, the within-group comparisons of seroresponse 
to different NTs (anti-SA or anti–reference strain) or the same NTs at 
different time points within the same group will be limited to 
participants with nonmissing values at both time points or both NT 
measurements. The percentages of participants with seroresponse at 
each time point and the difference in percentages will be provided.
The 2-sided 97.5% CIs for the difference in percentages of participants 
with seroresponse will be calculated using the adjusted Wald interval 
as described by Agresti and Min (2005)13 for comparing matched 
proportions.
Noninferiority of E1b and E2b will be assessed sequentially. 
Noninferiority will be declared if the lower bound of the 2-sided 97.5%
CI for the difference in percentages of participants with seroresponse is 
greater than -10%.
BNT162b2-Naïve Participants:
N1a: GMR of SA NT 1 month after the second dose of 
BNT162b2SA to the reference strain NT 1 month after the second
dose of BNT162b2

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For the between-group comparison, GMRs will be calculated as the 
mean of the difference of logarithmically transformed assay results 
between 2 groups and exponentiating the mean.  The associated 
2-sided 97.5% CIs will be obtained by calculating CIs using Student’s 
t-distribution for the mean difference of the logarithmically 
transformed titers and exponentiating the confidence limits.
Noninferiority will be declared if the lower bound of the 2-sided 97.5% 
CI for the GMR is greater than 0.67 and the point estimate of the GMR 
is ≥0.8.
N1b: The difference in percentages of participants with 
seroresponse to the SA strain at 1 month after the second dose of 
BNT162b2SA and seroresponse to the reference strain at 1 month 
after the second dose of BNT162b2
The difference in percentages of participants with seroresponse and 
associated 2-sided 97.5% CIs will be calculated using the Miettinen 
and Nurminen method.14
Noninferiority will be declared if the lower bound of the 2-sided 97.5% 
CI for the difference in percentages of participants with seroresponse is 
greater than -10%.
Secondary 
immunogenicity 
(Phase 3, 
boostability and 
protection against 
emerging VOCs)
BNT162b2-Experienced Participants:
E3a: GMR of SA NT 1 month after the third dose of BNT162b2 at 
30 µg to the reference strain NT 1 month after the second dose of 
BNT162b2 in the same individuals
E4a: GMR of reference strain NT 1 month after 1 dose of 
BNT162b2SA to 1 month after the second dose of BNT162b2 in the 
same individuals
E3b: The difference in percentages of participants with 
seroresponse to the SA strain at 1 month after the third dose of 
BNT162b2 at 30 µg and seroresponse to the reference strain at 1 
month after the second dose of BNT162b2 in the same individuals
E4b: The difference in percentages of participants with 
seroresponse to the reference strain at 1 month after 1 dose of 
BNT162b2SA and 1 month after the second dose of BNT162b2 in 
the same individuals

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GMRs and the associated 2-sided 97.5% CIs will be calculated in the 
same way as for the primary endpoints E1a and E2a.
If noninferiority of E1a and E2a are both established, E3a and E4a will 
be assessed sequentially using the same criterion (lower bound of the 
2-sided 97.5% CI for the GMR is greater than 0.67 and the point 
estimate of the GMR is ≥0.8).
The difference in percentages of participants with seroresponse and the 
associated 2-sided 97.5% CIs will be calculated in the same way as for 
the primary endpoints E1b and E2b.
Similarly, if noninferiority of E1b and E2b are both established, E3b 
and E4b will be assessed sequentially using the same criterion (lower 
bound of the 2-sided 97.5% CI for the difference in percentages is 
greater than -10%).
GMR of SA NT 1 month after 1 dose of BNT162b2SA to 1 month 
after the third dose of BNT162b2 at 30 µg
The difference in percentages of participants with seroresponse to 
the SA strain at 1 month after 1 dose of BNT162b2SA and 1 month 
after the third dose of BNT162b2 at 30 µg
GMR and the associated 2-sided 95% CI will be calculated in the same 
way as for the primary endpoint N1a.
The difference in percentages of participants with seroresponse and the 
associated 2-sided 95% CIs will be calculated in the same way as for 
the primary endpoints N1b.
GMR of SA NT 1 month after the second dose of BNT162b2SA to 
the reference strain NT 1 month after the second dose of 
BNT162b2 in the same individuals
The difference in percentages of participants with seroresponse to 
the SA strain at 1 month after the second dose of BNT162b2SA and 
seroresponse to the reference strain at 1 month after the second 
dose of BNT162b2 in the same individuals
GMR and the associated 2-sided 95% CI will be calculated in the same 
way as for the primary endpoint E1a and E2a.

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The difference in percentages of participants with seroresponse and the 
associated 2-sided 95% CIs will be calculated in the same way as for 
the primary endpoints E1b and E2b.
BNT162b2-Naïve Participants:
N2a: GMR of SA NT 1 month after the second dose of 
BNT162b2SA to 1 month after the second dose of BNT162b2
N2b: The difference in percentages of participants with 
seroresponse to the SA strain at 1 month after the second dose of 
BNT162b2SA and 1 month after the second dose of BNT162b2
GMR and the associated 2-sided 97.5% CI will be calculated in the 
same way as for the primary endpoint N1a.
Statistical superiority of N2a will be assessed if noninferiority of N1a
is established. Superiority of N2a will be declared if the lower bound 
of the 2-sided 97.5% CI for the GMR is greater than 1.
The difference in percentages of participants with seroresponse and the 
associated 2-sided 97.5% CIs will be calculated in the same way as for 
the primary endpoints N1b.
Statistical superiority of N2b will be assessed if noninferiority of N1b 
is established. Superiority of N2b will be declared if the lower bound 
of the 2-sided 97.5% CI for the difference in percentages of 
participants with seroresponse is greater than 0%.
GMR of reference strain NT 1 month after the second dose of 
BNT162b2SA to 1 month after the second dose of BNT162b2
The difference in percentages of participants with seroresponse to 
the reference strain at 1 month after the second dose of 
BNT162b2SA and 1 month after the second dose of BNT162b2
GMR and the associated 2-sided 95% CI will be calculated in the same 
way as for the primary endpoint N1a.
The difference in percentages of participants with seroresponse and the 
associated 2-sided 95% CIs will be calculated in the same way as for 
the primary endpoints N1b.

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Statistical Analysis Methods
Secondary
immunogenicity
(Phase 1)
Geometric mean titers/concentrations (GMTs/GMCs) of 
SARS-CoV-2 neutralizing titers, S1-binding IgG level, and 
RBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, and 
RBD-binding IgG levels, GMTs/GMCs and 2-sided 95% CIs will be 
provided for each investigational product within each group before 
vaccination and at each of the following time points:

Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1 and 
6 months 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 concentrations/titers, 
calculating the 95% CI with reference to the t-distribution, and then 
exponentiating the confidence limits.
GMFRs of SARS-CoV-2 neutralizing titers, S1-binding IgG level,
and RBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, and 
RBD-binding IgG levels, the GMFRs and 2-sided 95% CIs will be 
provided for each investigational product within each group at each of 
the following time points:

Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1 and
6 months after Dose 2
GMFRs will be limited to participants with nonmissing values prior to 
the first dose and at the postvaccination time point.  The GMFR will 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.
Percentage of participants with ≥4-fold rise in SARS-CoV-2 
neutralizing titers, S1-binding IgG level, and RBD-binding IgG 
level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, and 
RBD-binding IgG levels, percentages (and 2-sided 95% CIs) of 

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participants with ≥4-fold rise will be provided for each investigational 
product within each group at each of the following time points:

Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1 and
6 months after Dose 2
The Clopper-Pearson method will be used to calculate the CIs.
GMR of SARS-CoV-2 neutralizing titer to S1-binding IgG level
and to RBD-binding IgG level
For SARS-CoV-2 neutralizing titers, S1-binding IgG levels, and 
RBD-binding IgG levels, the GMRs and 2-sided 95% CIs will be 
provided for each investigational product within each group at each of 
the following time points:

Phase 1: 7 and 21 days after Dose 1; 7 and 14 days and 1 and 
6 months after Dose 2
GMRs will be limited to participants with nonmissing values for both 
SARS-CoV-2 neutralizing titers and S1-binding IgG level/
RBD-binding IgG level at each time point.  The GMR will be 
calculated as the mean of the difference of logarithmically transformed 
assay results (eg, SARS-CoV-2 neutralizing titers minus S1-binding 
IgG level for each participant) and exponentiating the mean.  
Two-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.
For all the immunogenicity endpoints, the analysis will be based on the 
Dose 1 and Dose 2 evaluable immunogenicity populations.  An 
additional analysis will be performed based on the all-available 
immunogenicity populations if there is a large enough difference in 
sample size between the all-available immunogenicity populations and 
the evaluable immunogenicity populations.  Participants will be 
summarized according to the vaccine group to which they were 
randomized.  Missing serology data will not be imputed.

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Statistical Analysis Methods
Secondary
immunogenicity
(noninferiority in 
the 12- to 15-year 
age group 
compared to the 
16- to 25-year age 
group)
GMR of SARS-CoV-2 neutralizing titers in participants 12 to 
15 years of age to those 16 to 25 years of age
For participants with no serological or virological evidence (up to 
1 month after receipt of the second dose) of past SARS-CoV-2 
infection, the GMR of SARS-CoV-2 neutralizing titers in participants 
12 to 15 years of age to those in participants 16 to 25 years of age and 
2-sided 95% CIs will be provided at 1 month after Dose 2 for 
noninferiority assessment.
The GMR and its 2-sided 95% CI will be derived by calculating 
differences in means and CIs on the natural log scale of the titers based 
on the Student’s t-distribution and then exponentiating the results.  The 
difference in means on the natural log scale will be 12 to 15 years 
minus 16 to 25 years.  Noninferiority will be declared if the lower 
bound of the 2-sided 95% CI for the GMR is greater than 0.67.
This analysis will be based on Dose 2 evaluable immunogenicity 
populations.  An additional analysis may be performed based on the 
Dose 2 all-available immunogenicity population if needed.  
Participants will be summarized according to the vaccine group to 
which they were randomized.  Missing serology data will not be 
imputed.
Exploratory 
immunogenicity 
(Phase 1)
For Phase 1 participants who received a third dose of BNT162b2 at 
least 6 months after the second dose of either BNT162b1 or 
BNT162b2:
GMTs/GMCs of SARS-CoV-2 reference-strain neutralizing titers, 
SARS-CoV-2 SA-variant neutralizing titers, and full-length 
S-binding or S1-binding IgG level
GMTs/GMCs and 2-sided 95% CIs will be provided by initial vaccine 
and age group for the following time points:

At Dose 3, 7 days and 1 month after Dose 3, and 12 months 
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 concentrations/titers, 
calculating the 95% CI with reference to the t-distribution, and then 
exponentiating the confidence limits.

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GMFRs of SARS-CoV-2 reference-strain neutralizing titers, 
SARS-CoV-2 SA-variant neutralizing titers, and full-length 
S-binding or S1-binding IgG level
GMFRs from before Dose 3 to 7 days and 1 month after Dose 3 and 
2-sided 95% CIs will be provided by initial vaccine and age group.
GMFRs from before Dose 3 to 12 months after Dose 2 may also be 
summarized. 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.
GMRs of SARS-CoV-2 reference-strain neutralizing titers 1 month 
after Dose 3 to 1 month after Dose 2
GMRs will be limited to participants with nonmissing values at both 
time points and provided by initial vaccine and age group.
GMRs will be calculated as the mean of the difference of 
logarithmically transformed reference-strain titers for each participant 
(1 month after Dose 3 – 1 month after Dose 2) and exponentiating the 
mean.  The associated 2-sided 95% CIs will be obtained by 
constructing CIs using Student’s t-distribution for the mean difference 
on the logarithm scale and exponentiating the confidence limits.
GMRs of SARS-CoV-2 SA-variant neutralizing titers 1 month 
after Dose 3 to SARS-CoV-2 reference-strain neutralizing titers 
1 month after Dose 2
GMRs will be limited to participants with nonmissing values at both 
time points and provided by initial vaccine and age group.
GMRs will be calculated as the mean of the difference of 
logarithmically transformed titers for each participant (SA-variant titer 
at 1 month after Dose 3 – reference-strain titer at 1 month after Dose 2) 
and exponentiating the mean.  The associated 2-sided 95% CIs will be 
obtained by constructing CIs using Student’s t-distribution for the
mean difference on the logarithm scale and exponentiating the 
confidence limits.

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Exploratory 
immunogenicity
(Phase 2/3)
GMTs/GMCs of SARS-CoV-2 neutralizing titers and full-length 
S-binding or S1-binding IgG level
For SARS-CoV-2 neutralizing titers and full-length S-binding or 
S1-binding IgG levels, GMTs/GMCs and 2-sided 95% CIs will be 
provided for each investigational product within each group before 
vaccination and at each of the following time points in Phase 2/3:

1 and 6 months after completion of vaccination in participants 
with and without serological or virological evidence of 
SARS-CoV-2 infection before vaccination
Geometric means will be calculated as the mean of the assay results 
after making the logarithm transformation and then exponentiating the 
mean to express results on the original scale. Two-sided 95% CIs will 
be obtained by taking natural log transforms of concentrations/titers, 
calculating the 95% CI with reference to the t-distribution, and then 
exponentiating the confidence limits.
GMFRs of SARS-CoV-2 neutralizing titers and full-length 
S-binding or S1-binding IgG level
For SARS-CoV-2 neutralizing titers and full-length S-binding or 
S1-binding IgG levels, the GMFRs and 2-sided 95% CIs will be 
provided for each investigational product within each group at each of 
the following time points in Phase 2/3:

1 and 6 months after completion of vaccination in participants 
with and without serological or virological evidence of 
SARS-CoV-2 infection before vaccination
GMFRs will be limited to participants with nonmissing values prior to 
the first dose and at the postvaccination time point.  The GMFR will 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.
For all of the immunogenicity endpoints, the analysis will be based on 
the Dose 1 and Dose 2 evaluable immunogenicity populations.  An 
additional analysis will be performed based on the all-available 
immunogenicity populations if there is a large enough difference in 
sample size between the all-available immunogenicity populations and 

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the evaluable immunogenicity populations.  Participants will be 
summarized according to the vaccine group to which they were 
randomized.  Missing serology data will not be imputed.
RCDCs for immunogenicity results
Empirical RCDCs will be provided for SARS-CoV-2 neutralizing titers
and full-length S-binding or S1-binding IgG levels after Dose 1 and 
after Dose 2.
Exploratory
immunogenicity 
(Phase 3, 
boostability and 
protection against 
emerging VOCs)
GMTs of SARS-CoV-2 reference strain neutralizing titers in 
participants receiving a third dose of BNT162b2 (at 30 µg or a 
lower dose of 5 µg or 10 µg) or a third or fourth dose of 
BNT162b2SA
GMTs and associated 2-sided 95% CIs at Dose 3 and each subsequent 
time point will be provided for each vaccine group and age group.
GMFRs of SARS-CoV-2 reference strain neutralizing titers in 
participants receiving a third dose of BNT162b2 (at 30 µg or a 
lower dose of 5 µg or 10 µg) or a third or fourth dose of 
BNT162b2SA
GMFRs from Dose 3 to each subsequent time point and associated 
2-sided 95% CIs will be provided for each vaccine group and age 
group.
Geometric mean NT for any VOC not already specified, after any 
dose of BNT162b2SA or BNT162b2
Geometric means and associated 2-sided 95% CIs of any SARS-CoV-2 
VOC-neutralizing titers will be provided at each time point for each 
group.

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9.4.2. Efficacy Analyses
The evaluable efficacy population will be the primary analysis population for all efficacy
analyses. Additional analyses based on the all-available efficacy population will be 
performed.
Endpoint
Statistical Analysis Methods
Primary efficacy
Ratio of confirmed COVID-19 illness from 7 days after the second 
dose per 1000 person-years of follow-up in participants without 
evidence of infection (prior to 7 days after receipt of the second 
dose) for the active vaccine group to the placebo group 
VE will be estimated by 100 × (1 – IRR), where IRR is the calculated 
ratio of confirmed COVID-19 illness per 1000 person-years of 
follow-up in the active vaccine group to the corresponding illness rate 
in the placebo group from 7 days after the second dose. VE will be 
analyzed using a beta-binomial model.
After the above objective is met, the second primary endpoint will be 
evaluated as below.
Ratio of confirmed COVID-19 illness from 7 days after the second 
dose per 1000 person-years of follow-up in participants with and 
without evidence of infection (prior to 7 days after receipt of the 
second dose) for the active vaccine group to the placebo group
VE will be estimated by 100 × (1 – IRR), where IRR is the calculated 
ratio of confirmed COVID-19 illness per 1000 person-years of 
follow-up in the active vaccine group to the corresponding illness rate 
in the placebo group from 7 days after the second dose. VE will be 
analyzed using a beta-binomial model.
The efficacy analysis for the first primary objective evaluation will be 
based on the participants without evidence of infection before 
vaccination and included in the evaluable efficacy population and in 
the all-available efficacy population.
The efficacy analysis for the second primary objective evaluation will 
be based on all participants included in the evaluable efficacy 
population and in the all-available efficacy population.
For the primary endpoint analysis, missing efficacy data will not be 
imputed.  A sensitivity analysis will be performed by imputing
missing values with the assumption of MAR.  A missing efficacy 
endpoint may be imputed based on predicted probability using the 
fully conditional specification method. Other imputation methods 

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without the MAR assumption may be explored. The details will be 
provided in the SAP.
Secondary 
First: Ratio of confirmed COVID-19 illness from 14 days after the 
second dose per 1000 person-years of follow-up in participants 
without evidence of infection (prior to 14 days after receipt of the 
second dose) for the active vaccine group to the placebo group 
Second: Ratio of confirmed COVID-19 illness from 14 days after 
the second dose per 1000 person-years of follow-up in participants 
with and without evidence of infection (prior to 14 days after 
receipt of the second dose) for the active vaccine group to the 
placebo group 
Third and fourth: Ratios of confirmed severe COVID-19 illness 
from 7 days and from 14 days after the second dose per 1000 
person-years of follow-up in participants without evidence of 
infection (prior to 7 days or 14 days after receipt of the second 
dose) for the active vaccine group to the placebo group 
Fifth and sixth: Ratios of confirmed severe COVID-19 illness from 
7 days and from 14 days after the second dose per 1000 
person-years of follow-up in participants with and without 
evidence of infection (prior to 7 days or 14 days after receipt of the 
second dose) for the active vaccine group to the placebo group
These secondary efficacy objectives will be evaluated sequentially in 
the order specified above after the primary objectives are met. The 
analysis will be based on the evaluable efficacy population and the 
all-available efficacy population. The analysis methodology used for 
the primary efficacy endpoints will be applied for the analysis of the
above secondary efficacy endpoints.
The following secondary efficacy endpoints for COVID-19 illness 
according to CDC-defined symptoms will be evaluated descriptively
with 95% CIs.
Ratios of confirmed COVID-19 illness (according to the 
CDC-defined symptoms) from 7 days and from 14 days after the 
second dose per 1000 person-years of follow-up in participants 
without evidence of infection (prior to 7 days or 14 days after 
receipt of the second dose) for the active vaccine group to the 
placebo group 

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Ratios of confirmed COVID-19 illness (according to the 
CDC-defined symptoms) from 7 days and from 14 days after the 
second dose per 1000 person-years of follow-up in participants 
with and without evidence of infection (prior to 7 days or 14 days 
after receipt of the second dose) for the active vaccine group to the 
placebo group
VE = 100 × (1 – IRR) will be estimated with confirmed COVID-19 
illness according to the CDC-defined symptoms from 7 days or from 
14 days after the second dose. The 2-sided 95% CI for VE will be 
derived using the Clopper-Pearson method as described by Agresti.12
Missing efficacy data will not be imputed.
The following secondary efficacy endpoints regarding asymptomatic 
SARS-CoV-2 infection will be evaluated based on a success criterion 
of the lower bound of the 2-sided 95% CI for VE being >20%.
Ratio of asymptomatic SARS-CoV-2 infection per 1000 
person-years of follow-up based on N-binding antibody 
seroconversion in participants with no serological or virological 
evidence of past SARS-CoV-2 infection or confirmed COVID-19
for the active vaccine group to the placebo group
VE will be estimated by 100 × (1 - IRR), where IRR is the calculated 
ratio of asymptomatic infection rate per 1000 person-years of 
follow-up in the active vaccine group to the corresponding infection 
rate in the placebo group.  The 2-sided 95% CI for VE will be derived 
using the Clopper-Pearson method. The hypothesis will be tested if at 
least 206 cases are accrued.
In addition, a descriptive summary of VE against asymptomatic 
infection over different time intervals (ie, prior to 1 month after
Dose 2, from 1 month after Dose 2 onward), along with the associated 
2-sided 95% CI, will be calculated using the same method.
The analysis of the primary definition of asymptomatic cases will be 
based on the evaluable efficacy (seroconversion) population and the 
Dose 2 all-available efficacy population. The analysis of the 
secondary definition of asymptomatic cases will be based on the 
Dose 1 all-available efficacy population.
Ratio of asymptomatic SARS-CoV-2 infection per 1000 
person-years of follow-up based on central laboratory–confirmed 
NAAT in participants without evidence of infection (up to the 

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start of asymptomatic surveillance period) for the active vaccine 
group to the placebo group
VE will be estimated by 100 × (1 - IRR), where IRR is the calculated 
ratio of asymptomatic infection rate in the active vaccine group to the 
corresponding infection rate in the placebo group. The 2-sided 95%
CI for VE will be derived using the Clopper-Pearson method. The 
hypothesis will be tested if at least 53 cases are accrued.
The analysis will be based on the evaluable efficacy (asymptomatic 
surveillance) population and the all-available efficacy population and 
will include only participants who are consented to participate in the 
asymptomatic surveillance and who do not have serological or 
virological evidence of past SARS-CoV-2 infection up to the start of 
the asymptomatic surveillance period.
Exploratory
Ratios of confirmed COVID-19 illness from 7 days after the 
second dose through the blinded follow-up period per 1000 
person-years of follow-up in participants without, and with and 
without, evidence of infection (prior to 7 days after receipt of the 
second dose) for the active vaccine group to the placebo group
After the primary objectives are met at the final analysis of at least 
164 first primary cases, the study will continue with blinded follow-up 
until the participant is unblinded at the time of being eligible for 
receipt of BNT162b2 according to recommendations detailed 
separately, and available in the electronic study reference portal, or no 
later than at approximately Visit 4.
A descriptive update of VE will be provided with additional follow-up 
data. VE = 100 × (1 – IRR) will be estimated with confirmed 
COVID-19 illness from 7 days after the second dose through the 
blinded follow-up period. The 2-sided 95% CI for VE will be derived 
using the Clopper-Pearson method as described by Agresti.12
Supportive analysis of time to confirmed COVID-19 illness will be 
performed using Kaplan-Meier cumulative incidence curves.
Participants who were randomized to placebo will be censored at the
time of receipt of BNT162b2.
Incidence of confirmed COVID-19 through the entire study 
follow-up period in participants who received BNT162b2
Incidence rate (per 1000 person-years of follow-up) and 2-sided 95% 
CI for confirmed COVID-19 illness after receipt of each dose of 

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BNT162b2 will be provided for participants who received BNT162b2 
at initial randomization and subsequently.
Kaplan-Meier cumulative incidence of COVID-19 cases over time 
will be plotted.
Ratio of asymptomatic SARS-CoV-2 infection per 1000 
person-years of follow-up based on central laboratory–confirmed 
NAAT in participants with evidence of infection (up to the start of 
the asymptomatic surveillance period) for the active vaccine 
group to the placebo group
VE will be estimated by 100 × (1 - IRR), where IRR is the calculated 
ratio of asymptomatic infection rate in the active vaccine group to the 
corresponding infection rate in the placebo group.  The 2-sided 95% 
CI for VE will be derived using the Clopper-Pearson method.
Participants who are consented to participate in the asymptomatic 
surveillance and who have serological or virologic evidence of past 
SARS-CoV-2 infection up to the start of the asymptomatic 
surveillance period will be included in the analysis.
9.4.3. Safety Analyses
Endpoint
Statistical Analysis Methods
Primary
Descriptive statistics will be provided for each reactogenicity endpoint 
for each dose and vaccine group.  Local reactions and systemic events 
from Day 1 through Day 7 after each vaccination will be presented by 
severity and cumulatively across severity levels.  Descriptive summary 
statistics will include counts and percentages of participants with the 
indicated endpoint and the associated Clopper-Pearson 95% CIs.
For Phase 1, descriptive statistics will be provided for abnormal 
hematology and chemistry laboratory values at 1 and 7 days after 
Dose 1 and 7 days after Dose 2, including grading shifts 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.

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AEs will be categorized according to the Medical Dictionary for 
Regulatory Activities (MedDRA) terms.  A 3-tier approach will be used 
to summarize AEs in Phase 2/3.  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 1% 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 Miettinen and Nurminen method14 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 6 months after the last dose will be provided for each 
vaccine group.
AEs and SAEs reported during the open-label follow-up period will be 
summarized separately for participants who were unblinded at the time 
of being eligible for receipt of BNT162b2 according to 
recommendations detailed separately, and available in the electronic 
study reference portal, or no later than at approximately Visit 4.
For Phase 3 participants enrolled for assessment of boostability and 
protection against emerging VOCs, descriptive summary statistics 
(counts, percentages, and associated Clopper-Pearson 95% CIs) will be 
provided for local reactions and systemic events from Day 1 through 
Day 7 after each dose, AEs from Dose 1 to 1 month after the last dose, 
and SAEs from Dose 1 to 5 or 6 months after the last dose. Local 
reactions and systemic events from Day 1 through Day 7 after each 
dose will be presented by severity and cumulatively across severity 
levels.

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For participants who received the third dose of BNT162b2 as part of 
protocol amendment 18, descriptive summary statistics (counts, 
percentages, and associated Clopper-Pearson 95% CIs) will be 
provided for AEs and SAEs from Dose 3 to 1 month after Dose 3.
For participants who received the fourth (or fifth) dose of BNT162b2 as 
part of protocol amendment 19, descriptive summary statistics (counts, 
percentages, and associated Clopper-Pearson 95% CIs) will be 
provided for AEs and SAEs from Dose 4 to 1 month after Dose 4 (or 
Dose 5 to 1 month after Dose 5).
The safety analyses after the first dose and after booster dose(s) are 
based on the safety population and booster safety population, 
respectively. Analyses of reactogenicity endpoints are based on a 
subset of the safety population that includes participants with any 
e-diary data reported after vaccination. Participants will be 
summarized by vaccine group according to the investigational products 
they actually received.  Missing reactogenicity e-diary data will not be 
imputed; missing AE dates will be handled according to the Pfizer 
safety rules.
Secondary
Not applicable (N/A)
Exploratory
(Phase 1)
For Phase 1 participants who received a third dose of BNT162b2 6 to 
12 months after the second dose of either BNT162b1 or BNT162b2:
Descriptive statistics will be provided by initial vaccine and age group 
for local reactions and systemic events from Day 1 through Day 7 after 
Dose 3, and AEs/SAEs from Dose 3 to 1 month after Dose 3. Local 
reactions and systemic events from Day 1 through Day 7 after Dose 3 
will be presented by severity and cumulatively across severity levels.  
Descriptive summary statistics will include counts and percentages of 
participants with the indicated endpoint and the associated Clopper-
Pearson 95% CIs.
For Phase 1 participants who received the fourth dose of BNT162b2 as 
part of protocol amendment 19, descriptive summary statistics (counts, 
percentages, and associated Clopper-Pearson 95% CIs) will be 
provided for AEs and SAEs from Dose 4 to 1 month after Dose 4.

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9.4.4. Other Analyses
The ratios of (GMFR A to GMFR B) and (GMFR A to GMFR C) may be explored, where 
GMFR A is the geometric mean of the ratio of the SARS-CoV-2 neutralizing titer at the 
postvaccination time point to the corresponding titer at the prevaccination time point, 
GMFR B is the geometric mean of the ratio of the S1-binding IgG level at the 
postvaccination time point to the corresponding IgG level at the prevaccination time point, 
and GMFR C is the geometric mean of the ratio of the RBD-binding IgG level at the 
postvaccination time point to the corresponding antibody level at the prevaccination time
point.
The safety data and immunogenicity results for individuals with confirmed stable HIV 
disease will be summarized descriptively. Furthermore, VE may be assessed if there is a
sufficient number of COVID-19 cases in this group of participants.
Exploratory analyses to investigate possible immunological correlates with efficacy, and 
characterization of infecting SARS-CoV-2 variants, may be conducted.
The cell-mediated immune response and additional humoral immune response parameters to 
the reference strain and SA will be summarized for the subset of participants with PBMC
samples collected.
9.5. Interim Analyses
As this is a sponsor open-label study during Phase 1, the sponsor may conduct unblinded 
reviews of the data during the course of the study for the purpose of safety assessment, 
facilitating dose escalation decisions, and/or supporting clinical development.
During Phase 2/3, 4 IAs were planned to be performed by an unblinded statistical team after 
accrual of at least 32, 62, 92, and 120 cases. However, for operational reasons, the first 
planned IA was not performed. Consequently, 3 IAs are now planned to be performed after 
accrual of at least 62, 92, and 120 cases. At these IAs, futility and VE with respect to the 
first primary endpoint will be assessed as follows:

VE for the first primary objective will be evaluated. Overwhelming efficacy will be 
declared if the first primary study objective is met. The criteria for success at an interim 
analysis are based on the posterior probability (ie, P[VE >30%|data]) at the current 
number of cases. Overwhelming efficacy will be declared if the posterior probability is 
higher than the success threshold. The success threshold for each interim analysis will be 
calibrated to protect overall type I error at 2.5%. Additional details about the success 
threshold or boundary calculation at each interim analysis will be provided in the SAP.

The study will stop for lack of benefit (futility) if the predicted probability of success at 
the final analysis or study success is <5%. The posterior predictive POS will be 
calculated using a beta-binomial model. The futility assessment will be performed for the 
first primary endpoint and the futility boundary may be subject to change to reflect 
subsequent program-related decisions by the sponsor.

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
Efficacy and futility boundaries will be applied in a nonbinding way.
Bayesian approaches require specification of a prior distribution for the possible values of the 
unknown vaccine effect, thereby accounting for uncertainty in its value. A minimally 
informative beta prior, beta (0.700102, 1), is proposed for θ = (1-VE)/(2-VE). The prior is 
centered at θ = 0.4118 (VE=30%) which can be considered pessimistic. The prior allows 
considerable uncertainty; the 95% interval for θ is (0.005, 0.964) and the corresponding 95% 
interval for VE is (-26.2, 0.995).
Table 6 illustrates the boundary for efficacy and futility if, for example, IAs are performed 
after accrual of 32, 62, 92, and 120 cases in participants without evidence of infection before 
vaccination. Note that although the first IA was not performed, the statistical criterion for 
demonstrating success (posterior probability threshold) at the interim (>0.995) and final 
(>0.986) analyses remains unchanged. Similarly, the futility boundaries are not changed.
Table 6.
Interim Analysis Plan and Boundaries for Efficacy and Futility
Analysis
Number of 
Cases
Success Criteriaa
Futility Boundary
VE Point Estimate 
(Case Split)
VE Point Estimate
(Case Split)
IA1
32
76.9% (6:26)
11.8% (15:17)
IA2
62
68.1% (15:47)
27.8% (26:36)
IA3
92
62.7% (25:67)
38.6% (35:57)
IA4
120
58.8% (35:85)
N/A
Final
164
52.3% (53:111)
Abbreviations: IA = interim analysis; N/A = not applicable; VE = vaccine efficacy.
Note: Case split = vaccine : placebo.
a.
Interim efficacy claim: P(VE >30%|data) > 0.995; success at the final analysis: P(VE >30%|data) > 0.986.
Additional design operating characteristics (the boundary based on the number of cases 
observed in the vaccine group; the probabilities for efficacy and futility given assumed 
various VEs with a 1:1 randomization ratio) are listed in Table 7 and Table 8, for IAs 
conducted at 32, 62, 92, and 120 cases and the final analysis at 164 cases. Although the IA at 
32 cases was not performed, the overall type I error (overall probability of success when true 
VE=30%) will still be strictly controlled at 0.025 with the originally proposed success/futility
boundaries.

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Table 7.
Statistical Design Operating Characteristics: Probability of Success or 
Failure for Interim Analyses
Vaccine 
Efficacy 
(%)
Interim Analysis 1
(Total Cases = 32)
Interim Analysis 2
(Total Cases = 62)
Interim Analysis 3
(Total Cases = 92)
Interim 
Analysis 4
(Total Cases
= 120)
Probability 
of Success
(Cases in 
Vaccine 
Group ≤6)
Probability 
of Failure
(Cases in 
Vaccine 
Group ≥15)
Probability 
of Success
(Cases in 
Vaccine 
Group ≤15)
Probability 
of Failure
(Cases in 
Vaccine 
Group ≥26)
Probability 
of Success
(Cases in 
Vaccine 
Group ≤25)
Probability 
of Failure
(Cases in 
Vaccine 
Group ≥35)
Probability of 
Success 
(Cases Vaccine 
Group ≤35)
30
0.006
0.315
0.003
0.231
0.002
0.239
0.002
50
0.054
0.078
0.051
0.056
0.063
0.103
0.075
60
0.150
0.021
0.160
0.010
0.175
0.019
0.160
70
0.368
0.003
0.310
<0.001
0.195
0.001
0.085
80
0.722
<0.001
0.238
<0.001
0.037
<0.001
0.003
Table 8.
Statistical Design Operating Characteristics: Probability of Success for 
Final Analysis and Overall
Vaccine Efficacy (%)
Final Analysis
(Total Cases = 164)
Overall Probability of Success
Probability of Success (Cases in Vaccine 
Group ≤53)
30
0.007
0.021
50
0.196
0.439
60
0.220
0.866
70
0.036
>0.999 
80
<0.001
>0.999
If neither success nor futility has been declared after all IAs, the final analysis will be 
performed and the first primary objective will have been met if there are 53 or fewer cases 
observed in the vaccine group out of a total of 164 first confirmed cases from 7 days after 
receipt of the second dose of investigational product onwards.
Only the first primary endpoint will be analyzed at IA. If the first primary objective is met, 
the second primary objective will be evaluated at the final analysis. After the primary 
objectives are met, the first 6 secondary VE endpoints (confirmed COVID-19 occurring from 
14 days after the second dose in participants without evidence of infection and in all 
participants, confirmed severe COVID-19 occurring from 7 days and from 14 days after the 
second dose in participants without evidence of infection and in all participants) will be 
evaluated sequentially in the stated order, by the same method used for the evaluation of 
primary VE endpoints. Success thresholds for secondary VE endpoints will be appropriately 
chosen to control overall type I error at 2.5%. Further details will be provided in the SAP.
The remaining secondary VE endpoints will be evaluated descriptively to calculate the 
observed VE with 95% CIs.

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9.5.1. Analysis Timing
Statistical analyses will be carried out when the following data are available:

Complete safety and immunogenicity analysis approximately 1 month after Dose 2 for 
Phase 1.

Complete safety and immunogenicity analysis approximately 1 month after Dose 3 for 
Phase 1.

Safety data through 7 days after Dose 2 and immunogenicity data through 1 month after 
Dose 2 from the first 360 participants enrolled (180 to active vaccine and 180 to placebo, 
stratified equally between 18 to 55 years and >55 to 85 years) in Phase 2/3.

Safety data through 1 month after Dose 2 from at least 6000 participants enrolled (3000 
to active vaccine and 3000 to placebo) in Phase 2/3. Additional analyses of safety data 
(with longer follow-up and/or additional participants) may be conducted if required for 
regulatory purposes.

IAs for efficacy after accrual of at least 62, 92, and 120 cases and futility after accrual of 
at least 62 and 92 cases.

Safety data through 1 month after Dose 2 and noninferiority comparison of 
SARS-CoV-2 neutralizing titers in participants 12 to 15 years of age compared to those in 
participants 16 to 25 years of age, 1 month after Dose 2.

Safety analyses approximately 1 month after Dose 3 for Phase 3 participants included in 
the booster evaluation (30 µg or low-dose booster) and approximately 1 month after 
Dose 2 for newly enrolled Phase 3 participants included in the BNT162b2SA evaluation.

Immunogenicity analyses approximately 1 month after Dose 3 for Phase 3 participants 
included in the booster evaluation (30 µg or low-dose booster) and approximately 
1 month after Dose 2 for newly enrolled Phase 3 participants included in the 
BNT162b2SA evaluation, when serology data for the reference strain or for the SA strain 
are available.

Analysis of efficacy against asymptomatic SARS-CoV-2 (determined by asymptomatic 
seroconversion of N-binding antibody and/or asymptomatic SARS-CoV-2 infection 
based on central laboratory–confirmed NAAT) when a sufficient number of cases have 
accrued to evaluate the objective(s).

Complete safety and efficacy analysis approximately 6 months after Dose 2 for all 
participants in Phase 2/3.

Safety and efficacy analyses approximately 1 month after the third dose of BNT162b2 for 
participants who received a third dose of BNT162b2 as part of protocol amendment 18.

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
Complete safety, efficacy, and persistence-of-immunogenicity analysis after complete
data are available or at the end of the study.
All analyses conducted on Phase 2/3 data while the study is ongoing will be performed by an 
unblinded statistical team. Certain analyses may be combined as 1 regulatory submission 
report if the data become available around the same time.  Additional analyses may be 
conducted if required for regulatory purposes.
9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will use an IRC, a DMC, and a group of internal case reviewers.  The IRC is 
independent of the study team and includes only internal members. The DMC is independent 
of the study team and includes only external members.  The IRC and DMC charters describe 
the role of the IRC and DMC in more detail.
The responsibilities of the IRC are only in Phase 1 and will include:

Review of safety data to permit dose escalations in the 18- to 55-year age cohort

Review of safety data in the case of a stopping rule being met

Review of safety and/or immunogenicity data to:

Allow groups of participants of 65 to 85 years of age to proceed

Select vaccine candidate/dose level(s) to proceed into Phase 2/3. Data supporting the 
selection, including results for both binding antibody levels and neutralizing titers, 
and the ratio between them, will also be submitted to the FDA for review

Review of any available safety and/or immunogenicity data generated during the course 
of this study, or the BioNTech study conducted in Germany, to determine:

Whether any groups may not be started

Whether any groups may be terminated early

Whether any groups may be added with dose levels below the lowest stated dose or 
intermediate between the lowest and highest stated doses

Contemporaneous review of all NAAT-confirmed COVID-19 illnesses in Phase 1
The DMC will be responsible for ongoing monitoring of the safety of participants in the 
study according to the charter. This may include, but is not limited to:

Contemporaneous review of related AEs up to 1 month after completion of the 
vaccination schedule

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
Contemporaneous review of all SAEs up to 6 months after completion of the vaccination 
schedule

Contemporaneous review of all NAAT-confirmed COVID-19 illnesses in Phase 1

At the time of the planned IAs, and ad hoc if requested by the unblinded team, review of 
cases of COVID-19 for an adverse imbalance of cases of COVID-19 and/or severe 
COVID-19 between the vaccine and placebo groups
The recommendations made by the DMC to alter the conduct of the study will be forwarded 
to the appropriate Pfizer personnel for final decision.  Pfizer will forward such decisions, 
which may include summaries of aggregate analyses of safety data, to regulatory authorities, 
as appropriate.
Up until the final efficacy analysis, 3 blinded case reviewers (medically qualified Pfizer staff 
members) will review all potential COVID-19 illness events. If a NAAT-confirmed case in 
Phase 2/3 may be considered severe, or not, solely on the basis of “significant acute renal, 
hepatic, or neurologic dysfunction,” the blinded data will be reviewed by the case reviewers
to assess whether the criterion is met; the majority opinion will prevail.

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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
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. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant or his or her parent(s)/legal guardian and answer all questions regarding the study.  
The participant or his or her parent(s)/legal guardian should be given sufficient time and 
opportunity to ask questions and to decide whether or not to participate in the trial. When 
consent is obtained from a participant’s parent(s)/legal guardian, the participant’s 
assent (affirmative agreement) must be subsequently obtained when the participant has the 
capacity to provide assent, as determined by the IRB/EC.
Participants must be informed that their participation is voluntary. Participants or their 
parent(s)/legal guardian 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 or his or her parent(s)/legal guardian
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 or his or her parent(s)/legal 
guardian is fully informed about his or her right to access and correct his or her personal data 
and to withdraw consent for the processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant or his or her parent(s)/legal 
guardian. Participants who are rescreened are required to sign a new ICD.
Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate 
section that addresses the use of samples for optional additional research. The optional 
additional research does not require the collection of any further samples.  The investigator 
or authorized designee will explain to each participant the objectives of the additional

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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.
10.1.3. 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.
10.1.4. 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, 
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.

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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.
10.1.5. 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.

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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.
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.

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10.1.6. 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.
10.1.7. 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;

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.

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Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.8. Sponsor’s Qualified Medical Personnel
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 and creatinine
AST, ALT
Total bilirubin
Alkaline phosphatase

Urine pregnancy test (β-hCG)
At screening only:

Hepatitis B core antibody

Hepatitis B surface antigen

Hepatitis C antibody

Human immunodeficiency virus
Investigators must document their review of each laboratory safety report.
Clinically significant abnormal laboratory findings should be recorded in the AE CRF in 
accordance with the following grading scale (Table 9).
Table 9.
Laboratory Abnormality Grading Scale
Hematology
Mild (Grade 1) 
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 9.
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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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 
nonpathogenic, 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
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 Report Form to Pfizer Safety.  
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious adverse 
events (AEs); and (3) exposure to the study intervention under study during pregnancy or 
breastfeeding, and occupational exposure.
It should be noted that the Vaccine SAE Report Form for reporting of SAE information is 
not the same as the AE page of the CRF.  When the same data are collected, the forms must 
be completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the Vaccine SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the Vaccine
SAE Report Form to 
Pfizer Safety Within 
24 Hours of Awareness
SAE
All
All
Nonserious AE
All
None
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 Report 
Form/AE/SAE CRF page.

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
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.
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.

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
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.

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 Report Form and in accordance with the SAE 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 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.

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
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.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via Vaccine SAE Report Form

Facsimile transmission of the Vaccine SAE Report 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 Report 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 Report 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. Premenarchal.
2. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than 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.
3. Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. In addition, a

high FSH level in the postmenopausal range must be used to confirm 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.
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;

Intravaginal;

Transdermal.
7. Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral;

Injectable.
8. Sexual abstinence:

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk 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.

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10. Male or female condom with or without spermicide.
11. Cervical cap, diaphragm, or sponge with spermicide.
12. A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods).

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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations 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 for all participants 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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10.6. Appendix 6: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
2019-nCoV
novel coronavirus 2019
20vPnC
20-valent pneumococcal conjugate vaccine
Abs
absolute (in Appendix 2)
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BCR
B-cell receptor
-hCG
beta-human chorionic gonadotropin
BMI
body mass index
BUN
blood urea nitrogen
CBER
Center for Biologics Evaluation and Research
CDC
Centers for Disease Control and Prevention (United States)
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CLIA
Clinical Laboratory Improvement Amendments
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CT
computed tomography
DBP
diastolic blood pressure
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DU
dosing unit
E1, E2, etc
vaccine-experienced (statistical tests)
EC
ethics committee
ECMO
extracorporeal membrane oxygenation
ECG
electrocardiogram
eCRF
electronic case report form
e-diary
electronic diary
EDP
exposure during pregnancy
EMA
European Medicines Agency
EU
European Union
EUA
emergency use authorization
EudraCT
European Clinical Trials Database

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Abbreviation
Term
FDA
Food and Drug Administration
FiO2
fraction of inspired oxygen
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GMC
geometric mean concentration
GMFR
geometric mean fold rise
GMR
geometric mean ratio
GMT
geometric mean titer
HBc Ab
hepatitis B core antibody
HBe
hepatitis B e
HBeAg
hepatitis B e antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCV Ab
hepatitis C virus antibody
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HR
heart rate
HRT
hormone replacement therapy
IA
interim analysis
IB
investigator’s brochure
ICD
informed consent document
ICH
International Council for Harmonisation
ICU
intensive care unit
ID
identification
Ig
immunoglobulin
IgG
immunoglobulin G
IgM
immunoglobulin M
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
IRC
internal review committee
IRR
illness rate ratio
IRT
interactive response technology
ISO
International Organization for Standardization
IV
intravenous(ly)
IWR
interactive Web-based response

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Abbreviation
Term
LFT
liver function test
LL
lower limit
LLOQ
lower limit of quantitation
LNP
lipid nanoparticle
LPX
lipoplex
MAR
missing at random
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MERS
Middle East respiratory syndrome
MIS-C
multisystem inflammatory syndrome in children
modRNA
nucleoside-modified messenger ribonucleic acid
MRI
magnetic resonance imaging
N
SARS-CoV-2 nucleoprotein
N1, N2, etc
vaccine-naïve (statistical tests)
N/A
not applicable
NAAT
nucleic acid amplification test 
NI
noninferiority
non-S
nonspike protein
NT
neutralizing titer
P2 S
SARS-CoV-2 full-length, P2 mutant, prefusion spike glycoprotein
PaO2
partial pressure of oxygen, arterial
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PI
principal investigator
POS
probability of success
PPE
personal protective equipment
PT
prothrombin time
RBC
red blood cell
RBD
receptor-binding domain
RCDC
reverse cumulative distribution curve
RNA
ribonucleic acid
RR
respiratory rate
RSV
respiratory syncytial virus
RT-PCR
reverse transcription–polymerase chain reaction
S1
spike protein S1 subunit
SA
South Africa
SAE
serious adverse event
SAP
statistical analysis plan
saRNA
self-amplifying messenger ribonucleic acid
SARS
severe acute respiratory syndrome

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Abbreviation
Term
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SBP
systolic blood pressure
SoA
schedule of activities
SOP
standard operating procedure
SpO2
oxygen saturation as measured by pulse oximetry
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
TBD
to be determined
TBili
total bilirubin
TCR
T-cell receptor
UK
United Kingdom
ULN
upper limit of normal
uRNA
unmodified messenger ribonucleic acid
US
United States
vax
vaccination
VE
vaccine efficacy
VOC
variant of concern
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman/women of childbearing potential

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10.7. Appendix 7: Stopping and Alert Rules for Enhanced COVID-19
In Phase 2/3, the unblinded team supporting the DMC (reporting team), including an 
unblinded medical monitor, will review cases of severe COVID-19 as they are received, and 
will review AEs at least weekly for additional potential cases of severe COVID-19 and will 
contact the DMC in the event that the stopping rule or an alert is met. Specifically, the 
unblinded reporting team will contact the DMC chair, who will then convene the full DMC 
as soon as possible. The DMC will review all available safety and/or efficacy data at the 
time of the review. The DMC will make one of the following recommendations to Pfizer: 
withhold final recommendation until further information/data are provided, continue the 
study as designed, modify the study and continue, or stop the study. The final decision to 
accept or reject the committee’s recommendation resides with Pfizer management and will be 
communicated to the committee chairperson in writing.
At any point the unblinded team may discuss with the DMC chair whether the DMC should 
review cases for an adverse imbalance of cases of COVID-19 and/or severe COVID-19 
between the vaccine and placebo groups (see Section 9.6). In addition, at the time of the IAs 
after accrual of at least 62, 92, and 120 cases, the number of severe COVID-19 cases in the 
vaccine and placebo groups will be assessed.
Stopping and alert rules will be applied as follows. The stopping rule will be triggered when 
the 1-sided probability of observing the same or a more extreme case split is 5% or less when 
the true incidence of severe disease is the same for vaccine and placebo participants, and alert 
criteria are triggered when this probability is less than 11%. In addition, when the total 
number of severe cases is low (15 or less), the unblinded team supporting the DMC will 
implement the alert rule when a reverse case split of 2:1 or worse is observed. For example, 
at 3 cases 2:1, at 4 cases 3:1, etc. Below 15 cases, this rule is more rigorous than requiring 
the probability of an observed adverse split or worse be <11%.
The stopping rule and alert rules are illustrated in Table 10 and Table 11, respectively, when 
the total number of severe cases is 20 or less. For example, when there are 7 severe cases, 
the adverse split has to be 7:0 to stop the study, but a split of 5:2 would trigger the alert rule. 
Similarly, when there is a total of 9 severe cases, an adverse split of 9:0 triggers the stopping 
rule, while a split of 6:3 or worse triggers the alert rule. The alert rule may be triggered with 
as few as 2 cases, with a split of  2:0.

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Table 10.
Stopping Rule: Enrollment Is Stopped if the Number of Severe Cases in the 
Vaccine Group Is Greater Than or Equal to the Prespecified Stopping Rule 
Value (S)
Total Severe Cases
Prespecified Stopping Rule Value (S): 
Number of Severe Cases in the 
Vaccine Group to Stop
If the True Ratio of Severe Cases
Between Vaccine and Placebo Groups
Is 1:1, Probability of S or More Being 
Observed in the Vaccine Group
4
4
N/A
5
5
3.13%
6
6
1.56%
7
7
0.78%
8
7
3.52%
9
8
1.95%
10
9
1.07%
11
9
3.27%
12
10
1.93%
13
10
4.61%
14
11
2.87%
15
12
1.76%
16
12
3.84%
17
13
2.45%
18
13
4.81%
19
14
3.18%
20
15
2.07%
Abbreviation: N/A = not applicable.

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Table 11.
Alert Rule: Further Action Is Taken if the Number of Severe Cases in the 
Vaccine Group Is Greater Than or Equal to the Prespecified Alert Rule 
Value (A)
Total 
Severe 
Cases
Prespecified 
Alert Rule 
Value (A): 
Number of 
Severe Cases 
in the
Vaccine 
Group to 
Trigger 
Further 
Action
If the True 
Ratio of 
Severe Cases 
Between the 
Vaccine and 
Placebo 
Groups Is 1:1, 
Probability 
of A Being 
Observed in
the Vaccine 
Group
If the True 
Ratio of 
Severe Cases 
Between the 
Vaccine and 
Placebo 
Groups Is 1:1,
Probability of 
A or More 
Being 
Observed in 
the Vaccine 
Group
If the True 
Ratio of 
Severe Cases 
Between the 
Vaccine and 
Placebo 
Groups Is 2:1, 
Probability of 
A or More 
Being 
Observed in 
the Vaccine 
Group
If the True 
Ratio of 
Severe Cases 
Between the 
Vaccine and 
Placebo 
Groups Is 3:1, 
Probability of 
A or More 
Being 
Observed in 
the Vaccine 
Group
If the True 
Ratio of 
Severe Cases 
Between the 
Vaccine and 
Placebo 
Groups Is 4:1, 
Probability of 
A or More 
Being 
Observed in 
the Vaccine 
Group
2
2
25.00%
25.00%
44.49%
56.25%
64.00%
3
2
37.50%
50.00%
74.12%
84.38%
89.60%
4
3
25.00%
31.25%
59.32%
73.83%
81.92%
5
4
15.63%
18.75%
46.16%
63.28%
73.73%
6
4
23.44%
34.38%
68.10%
83.06%
90.11%
7
5
16.41%
22.66%
57.14%
75.64%
85.20%
8
6
10.94%
14.45%
46.90%
67.85%
79.69%
9
6
16.41%
25.39%
65.11%
83.43%
91.44%
10
7
11.72%
17.19%
56.02%
77.59%
87.91%
11
8
8.06%
11.33%
47.35%
71.33%
83.89%
12
8
12.08%
19.38%
63.25%
84.24%
92.74%
13
9
8.73%
13.34%
55.31%
79.40%
90.09%
14
10
6.11%
8.98%
47.66%
74.15%
87.02%
15
10
9.16%
15.09%
61.94%
85.16%
93.89%
16
11
6.67%
10.51%
54.81%
81.03%
91.83%
17
12
4.72%
7.17%
47.88%
76.53%
89.43%
18
13
3.27%
4.81%
41.34%
71.75%
86.71%
19
13
5.18%
8.35%
54.43%
82.51%
93.24%
20
14
3.70%
5.77%
48.06%
78.58%
91.33%

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
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Page 248
10.8. Appendix 8: Criteria for Allowing Inclusion of Participants With Chronic Stable 
HIV, HCV, or HBV Infection
Potential participants with chronic stable HIV, HCV, or HBV infection may be considered 
for inclusion if they fulfill the following respective criteria.
Known HIV infection

Confirmed stable HIV disease defined as documented viral load <50 copies/mL and 
CD4 count >200 cells/mm3 within 6 months before enrollment, and on stable 
antiretroviral therapy for at least 6 months.
Known HCV infection

History of chronic HCV with evidence of sustained virological response (defined as 
undetectable HCV RNA) for ≥12 weeks following HCV treatment or without 
evidence of HCV RNA viremia (undetectable HCV viral load).
Known HBV infection
Confirmed inactive chronic HBV infection, defined as HBsAg present for ≥6 months and the 
following:

HBeAg negative, anti-HBe positive

Serum HBV DNA <2000 IU/mL

Persistently normal ALT and/or AST levels

In those who have had a liver biopsy performed, findings that confirm the absence of 
significant necroinflammation.

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10.9. Appendix 9: Genetics
Use/Analysis of DNA and/or RNA

Genetic variation may impact a participant’s response to study intervention, as well as 
susceptibility to and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA and/or RNA
analysis.

The results of genetic analyses may be reported in a CSR or in a separate study summary, 
or may be used for internal decision making without being included in a study report.

The sponsor will store the DNA and/or RNA samples in a secure storage space with
adequate measures to protect confidentiality.

The samples will be retained as indicated:

Samples for specified genetic analysis (see Section 8.7) will be stored for up to 
15 years or other period as per local requirements.

Samples for genetic research will be labeled with a code. The key between the code and 
the participant’s personally identifying information (eg, name, address) will be held 
securely at the study site.

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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
World Health Organization. COVID-19 weekly epidemiological update – 01 Mar 2022 
(who.int). Available from: https://www.who.int/publications/m/item/weekly-
epidemiological-update-on-covid-19---1-march-2022. Accessed: 18 Mar 2022.
4
Centers for Disease Control and Prevention. Emerging SARS-CoV-2 variants. Available 
from: https://www.cdc.gov/coronavirus/2019-ncov/more/science-and-
research/scientific-brief-emerging-variants.html. Updated: 28 Jan 2021. Accessed: 
10 Feb 2021.
5
Rauch S, Jasny E, Schmidt KE, et al. New vaccine technologies to combat outbreak 
situations. Front Immunol 2018;9:1963.
6
Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics—developing a new class of 
drugs. Nat Rev Drug Discov 2014;13(10):759-80.
7
Pfizer. Working to reach everyone, everywhere. Available from:
https://www.pfizer.com/science/coronavirus/vaccine/working-to-reach-everyone-
everywhere. Accessed: 04 Aug 2022.
8
Ritchie H, Mathieu E, Rodés-Guirao L, et al. Coronavirus pandemic (COVID-19).
OurWorldInData.org website. Available from: https://ourworldindata.org/coronavirus. 
Accessed: 06 Sep 2022.
9
BioNTech RNA Pharmaceuticals GmbH. CorVAC/BNT162 Investigator’s Brochure. 
Mainz, Germany: BioNTech RNA Pharmaceuticals GmbH; 25 Mar 2020.
10
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.
11
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.

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001
Final Protocol Amendment 20, 15 September 2022
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12
Agresti A. Introduction: distributions and inference for categorical data. In: Agresti A, 
ed. Categorical data analysis. 2nd ed. Hoboken, NJ: John Wiley & Sons; 2002:1-35.
13
Agresti A, Min Y. Simple improved confidence intervals for comparing matched 
proportions. Stat Med 2005;24(5):729-40.
14
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med
1985;4(2):213-26.

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