125742 45 S211 M5 c4591001 interim ado protocol

Document text

PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Protocol Amendment 14, 02March 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 1A PHASE 1/2 /3, PLACEBO -CONTROLLED , RANDOMIZED, OBSERV ER-BLIND, 
DOSE -FINDING STUDY T O EVALUATE THE SAFETY, TOLERABI LITY, 
IMMUNOGENICITY, AND EFFICACY OF SARS -COV -
2RNA VACCINE 
CANDIDATES AGAINST C OVID -19 IN HEALTHY INDIVIDUALS
Study Sponsor: BioNTech
Study Conducted By: Pfizer
Study Intervention Number: PF-07302048
Study Intervention Name: RNA -Based COVID -19 Vaccine s
US IND Number: 19736
EudraCT Number: 2020- 002641- 42
Protocol Number: C4591001
Phase: 1/2/3
Short Title: A Phase 1/2 /3Study  to Evaluate the Safety , Tolerabilit y, Immunogenicity, and 
Efficacy  of RNA Vaccine Candidates Against C OVID-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 document s, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by app licable 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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FDA-CBER-2022-5812-0229210
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Protocol Amendment 14, 02March 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 2Protocol Amendment Summary of Changes Table
Document History
Document Version Date Summary and Rationale for Changes
Protocol amendment 14 02March 2021 In order to further describe duration of 
protection, and heterologous/homologous 
protection against the emerging VOCs, an 
additional dose of BNT162b2 or BNT162b2 SA
will be given to approximatel y 600 Phase 3
participants approximately 5 to 7months after 
their second dose of BNT162b2 ;a further dose 
of BNT162b2 SAwill be given to approximately 
30of those participants who receive 
BNT162b2 SA: 
Added corresponding objectives, 
estimands, and endpoints
Added corresponding SoA and 
procedures
Added details in the s tatistical methods
sections .
Approximately 300 BNT162b2 -naïve 
participants will be enrolled and receive 2 doses 
of BNT162b2 SAto 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 s tatistical methods
sections .
Cell-mediated immune responses will also be 
described follow ing isolatio ns of PBMCs in a 
subset of both the Phase 3 participants who 
receive a single booster vaccination and the
BNT162b2 -naïve group who receive 
BNT162b2 SA.
Added the asymptomatic case definitions in 
Section 8.1and 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 .
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PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Protocol Amendment 14, 02March 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 3Document History
Document Version Date Summary and Rationale for Changes
Clarified that ifmultiple 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.
Protocol amendment 13 12February 2021 In order to describe the boostability of BNT162, 
an additional dose of BNT162b2 at 30 µg w ill be 
given to Phase 1 participants approximately 6 to 
12 months after their second dose of BNT162 b1 
or BNT162b2 : 
Added corresponding objectives, 
estimands, and endpoints
Added c orresponding SoA and 
procedures
Added d etails in the s tatistical methods
sections .
Clarified the population used for analysis of 
reactogenicity endpoints.
To align with current recommendations, 
investigators may exercise judgment on review 
of inclusio n and exclusion c riteria ahead of 
vaccination with BNT162b2 for participants 
who originally received placebo.
Clarified that i f 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 w ithout needing 
to reconsent.
Participants who provide biw eekly swab sfor 
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 dos e in the event a 
participant received only 1 dose of BNT162b2.
Protocol amendment 12 14January 2021 Because of a formatting error in protocol 
amendment 11, exclusion criterion 4 w as 
inadvertently added to exclusion criterion 3 and 
the subsequent criteria renumbered. This 
amendment corrects that error.
Because of a change in the pace w ith which 
participants ≥16 years of age who originally 
received placebo wi llbecom e eligible for receipt 
of BNT162b2 , text w as updated throughout the 
protocol to reflect that this will happen in a 
phased manner ,with recommendations detailed 
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Protocol C4591001
Protocol Amendment 14, 02March 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 4Document History
Document Version Date Summary and Rationale for Changes
separately and available in the electronic study 
reference portal .
Clarified that p articipants who are unblinded 
because they becomepotentially eligible for 
receipt of BNT162b2 w ill not p articipate in 
surveillance for asymptomatic SARS CoV- 2 
infection .
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 t hose 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 04January 2021 Added approaches to evaluate efficacy against
asymptomatic SAR S-CoV -2 infection :
Added objective s, estimand s,and endpoint s, 
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 f ull-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 w ho 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 y ears of age .
Protocol amendment 10 01 Dec ember 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 
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Protocol C4591001
Protocol Amendment 14, 02March 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 5Document History
Document Version Date Summary and Rationale for Changes
received placebo, following completion of the 
active safety surveillance period .
Added corresponding exploratory objec tives and 
statistical analysis details.
Removed immunogenicity analyses of titers 
greater than defined threshold(s).
Removed the need for blinded COVID -19case 
review after the final efficacy analysis.
Included thepossibility , due to local 
circumstances r elated to the COVID -19 
pandemic, that study 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 , increas ed the sample size for 
the noninferiority immunogenicity analysis in 
adolescents 12 to 15 years of age.
Protocol amendment 9 29October 2020 To better align with the natural history of 
SARS -CoV- 2 infection , added Phase 2/3 
secondary efficacy objectives, estimand s,and 
endpoint sto 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, 
andstatistical analysis section s.
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 su pport 
DMC activities.
Clarified that s erology data after a postbaseline 
positive SARS -CoV- 2 test result will not be 
included in the analysis based on theevaluable 
immunogenicity population s.
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.
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Protocol C4591001
Protocol Amendment 14, 02March 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 6Document History
Document Version Date Summary and Rationale for Changes
Clarified that the “Process 1” participants 
included in the descriptiv e analysis of 
“Process 1”-and “Process 2”- manufactured 
study intervention swill 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.
Clarified that f or 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 w ith 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 regard ing 
circumstances in which a SARS -CoV -2 test 
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Protocol Amendment 14, 02March 2021
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CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 7Document History
Document Version Date Summary and Rationale for Changes
might be required even if symptoms within 7 
days following each vaccination are considered 
more likely due to vaccine reactogenicity.
Made allow ance in Section 8.13 for a second 
SARS -CoV- 2 test to be performed w ithin the 
same potential COVID -19 illness if it is in 
accordance w ith routine practice.
Added Section 8.15 to describe the reporting of 
SARS -CoV- 2 test results and their implications 
for participants receiving a second vaccine dose.
Added statistical hypot hesis and pow er 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 variou s editorial changes.
Protocol amendment 6 
(Germ any-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 w indow  for the 6 -month follow -up 
visit to be approximately 6 months after 
Vaccination 2.
Reduced the volume o f blood draw s 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 disea se.
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 low er 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; 
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Protocol C4591001
Protocol Amendment 14, 02March 2021
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CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 8Document History
Document Version Date Summary and Rationale for Changes
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 p otential COVID -19 
illnesses that are consistent with the clinical 
endpoint definition should notbe recorded as 
AEs.
Updated the analysis population descriptions to 
align with the study SAP.
Protocol amendment 5 24 July 2020 Follow ing 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 
30µg.
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 unblinde d 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 
participa nts with a p revious clinical or 
microbiological diagnosis of COVID -19are 
excluded from all phases of the study.
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Protocol Amendment 14, 02March 2021
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CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 9Document History
Document Version Date Summary and Rationale for Changes
Clarified that there will be 2 all -available 
efficacy populations.
Clarified that immunogenicity samples will be 
draw n for all participants; an alyses 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 objecti ve w ill be 
evaluated.
Changed to use the same posterior probability 
(99.5%) for all interim analyses, resulting in 
case split changes in T ables 5, 6, and 7 .
Updated the s topping and alert ruleparameter s 
for enhanced COVID -19.
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 pow ered 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 Sta ge 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 definitio ns; 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 ha ve been made to the headings to align 
with the latest Pfizer protocol template.
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Protocol Amendment 14, 02March 2021
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CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 10Document History
Document Version Date Summary and Rationale for Changes
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 low er dose levels of the 
modRNA candidates.  Therefore, a 20 -µg dose 
level is formally included for BNT162b1 and 
BNT162b2.
To permit individual and group dosing 
alterations for the second dose of study 
intervention.
Follow ing 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 a n 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 
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investigator, participants may utilize a COVID -19 
illness e -diary.
Protoco l amendment 2 27 May 2020 Given the urgent nature of the pandemic situation, 
the following changes allow determin ation 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
Protocol amendment 1 13 May 2020 Follow ing 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 d ata supporting the selection of 
vaccine candidate(s)/dose level(s) and 
schedule(s) for Stages 2 and 3 will be submit ted 
to the FDA for review
Follow ing 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 d ecision 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
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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 th at 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 ma y 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 diamete r (cm ) for 
mild redness and swelling
Updated the °C fever scale in Table 4 to ensure 
that all potential °F values are correctly assigned
Incorporated a protocol administrative change to 
clarify that a rapid test for prior COVID -19 
infection will be performed for s entinel 
participants in Stage 1 , and a serum sample will 
be drawn for potential future assessment
Clarified that, after screening, physical 
examinations in s entinel participants in Stage 1
will be directed
Clarified the descriptions of the populations for 
analysis to align with the statistical analysis plan
Added a com plete safety and immunogenicity 
analysis approximately 6 months after Dose 2 
for all participants inStage 3
Amended text so that the stopping rules apply to 
an RNA pla tform  rather than a specific vaccine 
candidate
Original protocol 15April 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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Page 13TABLE OF CONTENTS
LIST OF TABLES ................................ ................................ ................................ ................... 20
LIST OF FIGURES ................................ ................................ ................................ ................. 21
1. PROTOCOL  SUMMARY ................................ ................................ ................................ ...22
1.1. Sy nopsis ................................ ................................ ................................ .................. 22
1.2. Schema ................................ ................................ ................................ .................... 36
1.3. Schedule of Activities ................................ ................................ ............................. 37
1.3.1. Phase 1 ................................ ................................ ................................ ........ 37
1.3.2. Phase 2/3................................ ................................ ................................ .....44
1.3.3. Administration of BNT162b2 to Those Originall y Assigned to 
Placebo ................................ ................................ ................................ ............. 48
1.3.4. Administration of an Additional Dose of BNT162b2 or BNT162b2 SA......50
1.3.5. Administration of BNT162b2 SAto BNT162b2 -Naïve Participants ........... 53
1.3.6. Surveillance for As ymptomatic SARS -CoV -2 Infection ........................... 56
2. INTRODUCTION ................................ ................................ ................................ ............... 57
2.1. Study  Rationale ................................ ................................ ................................ .......57
2.2. Background .............................................................................................................57
2.2.1. Clinical Overview ................................ ................................ ....................... 59
2.3. Benefit/Risk Assessment................................ ................................ ......................... 59
2.3.1. Risk Assessment ................................ ................................ ......................... 61
2.3.2. Benefit Assessment ................................ ................................ ..................... 63
2.3.3. Overall Benefit/R isk Conclusion ................................ ................................ 63
3. OBJECTI VES, ESTIMANDS, AND ENDPOINTS ...........................................................63
3.1. For Phase 1 ................................ ................................ ................................ .............. 63
3.2. For Phase 2/3 ................................ ................................ ................................ ........... 65
4. STUDY DESIGN ................................ ................................ ................................ ................. 72
4.1. Overall Design ................................ ................................ ................................ ......... 72
4.1.1. Phase 1 ................................ ................................ ................................ ........ 73
4.1.2. Phase 2/3................................ ................................ ................................ .....74
4.2. Scientific Rationale for Study  Design ................................ ................................ .....77
4.3. Justification for Dose ................................ ................................ .............................. 77
4.4. End of Study  Definition ................................ ................................ .......................... 78
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Page 145. STUDY POPUL ATION ................................ ................................ ................................ ......79
5.1. I nclusion Criteria ................................ ................................ ................................ .....79
5.2. Exclusion Criteria ................................ ................................ ................................ ....80
5.3. L ifesty le Considerations ................................ ................................ .......................... 82
5.3.1. Contraception ................................ ................................ .............................. 82
5.4. Screen Failures ................................ ................................ ................................ ........ 83
5.5. Criteria for Temporarily  Delay ing Enrollment/Randomization/Study  
Intervention Administration ................................ ................................ ...................... 83
6. STUDY INTERVENTIO N................................ ................................ ................................ ..84
6.1. Study  Intervention(s) Administered ................................ ................................ ........ 84
6.1.1. Manufacturing Process ................................ ................................ ............... 85
6.1.2. Administration ................................ ................................ ............................ 85
6.2. Preparation/Handling/Storage/Accountability ................................ ........................ 86
6.2.1. Preparation and Dispensing ................................ ................................ ........ 87
6.3. Measures to Minimize Bias: Randomization and Blinding ................................ .....88
6.3.1. Allocation to Study Intervention ................................ ................................ 88
6.3.2. Blinding of Site Personnel ................................ ................................ .......... 88
6.3.3. Blinding of the Sponsor................................ ................................ .............. 88
6.3.4. Breaking the Blind ................................ ................................ ...................... 90
6.4. Study  Intervention Compliance ................................ ................................ ............... 90
6.5. Concomitant Therapy ................................ ................................ .............................. 91
6.5.1. Prohibited During the Study ................................ ................................ .......91
6.5.2. Permitted During the Study ................................ ................................ ........ 92
6.6. Dose Modification ................................ ................................ ................................ ...92
6.7. I ntervention After the End of the Study ................................ ................................ ..93
7. DI SCONTINUATION O F STUDY INTERVENTION AND PARTI CIPANT 
DISCONTINUATION/WI THDRAWAL ................................ ................................ ........... 93
7.1. Discontinuation of Study  Intervention ................................ ................................ ....93
7.2. Participant Discontinuation/Withdrawal From the Study ................................ .......94
7.2.1. Withdrawal of Consent ................................ ................................ ............... 94
7.3. L ost to Follow -up ................................ ................................ ................................ ....95
8. STUDY ASSESSMENTS AND PROCEDURES ................................ ............................... 95
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Page 158.1. Efficacy  and/or Immunogenicity Assessments ................................ ....................... 97
8.1.1. Efficacy  Against COVID -19 ................................ ................................ ......97
8.1.2. Efficacy  Against Asy mptomatic SARS -CoV -2 Infection .......................... 99
8.1.2.1. Seroconversion of N -Binding Antibod y ................................ ...99
8.1.2.2. NAAT -Confirmed SARS -CoV -2 Infection .............................. 99
8.1.3. Vaccine -Induced Immunogenicit y................................ ............................ 100
8.1.4. Biological Samples ................................ ................................ ................... 100
8.1.5. Surveillance for Asy mptomatic SARS -CoV -2 Infection ......................... 100
8.2. Safet y Assessments ................................ ................................ ............................... 101
8.2.1. C linical Safety  Laboratory  Assessments (Phase 1 Participants Onl y).....101
8.2.2. Electronic Diary ................................ ................................ ........................ 102
8.2.2.1. Grading Scales ................................ ................................ ......... 103
8.2.2.2. L ocal Reactions ................................ ................................ .......103
8.2.2.3. Systemic Events ................................ ................................ ......104
8.2.2.4. Fever ................................ ................................ ........................ 105
8.2.2.5. Antipy retic Medication ................................ ........................... 105
8.2.3. Phase 1 Stopping Rules ................................ ................................ ............ 105
8.2.4. Surveillance of Events That Could Represent Enhanced COVID -19 
and Phase 2/3 Stopping Rule ................................ ................................ ......... 107
8.2.5. Randomization and Vaccination After a Stopping Rule Is Met ............... 107
8.2.6. Pregnancy  Testing ................................ ................................ .................... 108
8.3. Adverse Events and Serious Adverse Events................................ ........................ 108
8.3.1. Time Period and Frequency  for Collecting AE and SAE Information .....108
8.3.1.1. Reporting SAEs to Pfizer Safety ................................ ............. 109
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF ................. 110
8.3.2. Method of Detecting AEs and SAEs ................................ ........................ 110
8.3.3. Follow -up of AEs and SAEs ................................ ................................ .....110
8.3.4. Regulatory Reporting Requirements for SAEs ................................ ......... 110
8.3.5. Exposure During Pregnancy  or Breastfeeding, and Occupational 
Exposure ................................ ................................ ................................ ........ 111
8.3.5.1. Exposure During Pregnancy ................................ .................... 111
8.3.6. Exposure During Breastfeeding ................................ ................................ 112
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Page 168.3.6.1. Occupational Exposure ................................ ........................... 113
8.3.7. Cardiovascular and Death Events ................................ ............................. 113
8.3.8. Disease -Related Events and/or Disease -Related Outcomes Not 
Qualifying as AEs or SAEs ................................ ................................ ............ 113
8.3.9. Adverse Events of Special Interest ................................ ........................... 114
8.3.9.1. Lack of Efficacy ................................ ................................ ......114
8.3.10. Medical Device Deficiencies ................................ ................................ ..114
8.3.11. Medication Errors ................................ ................................ ................... 114
8.4. Treatment of Overdose................................ ................................ .......................... 115
8.5. Pharmacokinetics ................................ ................................ ................................ ..116
8.6. Pharmacod ynamics ................................ ................................ ................................ 116
8.7. Genetics ................................ ................................ ................................ ................. 116
8.8. Biomarkers ................................ ................................ ................................ ............ 116
8.9. I mmunogenicit y Assessments ................................ ................................ ............... 116
8.10. Health Economics ................................ ................................ ............................... 116
8.11. Stud y Procedures ................................ ................................ ................................ .116
8.11.1. Phase 1 ................................ ................................ ................................ ....116
8.11.1.1. Screening: (0 to 28 Day s Before Visit 1) .............................. 116
8.11.1.2. Visit 1 – Vaccination 1: (Day  1) ................................ ........... 118
8.11.1.3. Visit 2 – Next -Day Follow -up Visit (Vaccination 1): (1 
to 3 Day s After Visit 1) ................................ ................................ ...120
8.11.1.4. Visit 3 – 1- Week Follow -up Visit (Vaccination 1): (6 to 
8 Day s After Visit 1) ................................ ................................ .......121
8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Day s After Visit 1) ......... 122
8.11.1.6. Visit 5 – 1- Week Follow -up Visit (Vaccination 2): (6 to 
8 Day s After Visit 4) ................................ ................................ .......124
8.11.1.7. Visit 6 – 2- Week Follow -up Visit (Vaccin ation 2): (12 to 
16 Day s After Visit 4) ................................ ................................ .....126
8.11.1.8. Visit 7 – 1- Month Follow -up Visit: (28 to 35 Day s After 
Visit 4) ................................ ................................ ............................. 127
8.11.1.9. Visit 8 – 6- Month Follow -up Visit: (175 to 189 Day s 
After Visit 4) ................................ ................................ .................... 127
8.11.1.10. Between Visits 8 and 9 ................................ ........................ 128
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Page 178.11.1.11. Visit 8a –Vaccination 3: (175 to 315 Day s After 
Vaccination 2) ................................ ................................ ................. 128
8.11.1.12. Visit 8b – 1- Week Follow -up Visit (After Vaccination 
3): (6 to 8 Day s After Visit 8a) ................................ ........................ 130
8.11.1.13. Visit 8c – 1 -Month Follow -up Visit (After Vaccination 
3): (28 to 35 Days After Visit 8a) ................................ .................... 130
8.11.1.14. Visit 9 – 12- Month Follow -up Visit: (350 to 378 Day s 
After Visit 4): Onl y for Those Participants Who Originall y 
Receive d BNT162b1 or BNT162b2 or Placebo Recipients Who 
Decline BNT162b2 ................................ ................................ .......... 131
8.11.1.15. Visit 10 – 24- Month Follow -up Visit: (714 to 742 Day s 
After Visit 4):  Onl y for Those Participants Who Originall y 
Received BNT162b1 or BNT162b2 or Placebo Recipients Who 
Decline BNT162b2 ................................ ................................ .......... 132
8.11.2. Phase 2/3................................ ................................ ................................ .132
8.11.2.1. Visit 1 – Vaccination 1: (Day  1) ................................ ........... 132
8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Day s After Visit 1) ......... 135
8.11.2.3. Visit 3 – 1- Month Follow -up Visit (After Vaccination 2): 
(28 to 35 Day s After Visit 2) ................................ ........................... 137
8.11.2.4. Visit 4 – 6- Month Follow -up Visit: (175 to 189 Day s 
After Visit 2) ................................ ................................ .................... 138
8.11.2.5. Visit 5 – 12- Month Follow -up Visit: (350 to 378 Day s 
After Vis it 2): Onl y for Those Participants Who Originall y 
Received BNT162b2 or Placebo Recipients Who Decline 
BNT162b2 ................................ ................................ ....................... 138
8.11.2.6. Visit 6 – 24- Month Follow -up Visit: (714 to 742 Day s 
After Visit 2) ): Onl y for Those Participants Who Originall y 
Received BNT162b2 or Placebo Recipients Who Decline 
BNT162b2 ................................ ................................ ....................... 139
8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction ...................... 140
8.13. COVID -19 Surveillance (All Participants) ................................ ......................... 141
8.13.1. Potential COVI D-19 Illness Visit: (Optimally Within 3 Day s After 
Potential COVI D-19 Illness Onset) ................................ ............................... 142
8.13.2. Potential COVI D-19 Convalescent Visit: (28 to 35 Day s After 
Potential  COVI D-19 Illness Visit) ................................ ................................ 143
8.14. Communication and Use of Technology ................................ ............................. 144
8.15. SARS -CoV -2 NAAT Results ................................ ................................ .............. 144
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Page 188.16. Procedures for Administration of BNT162b2 to Those Originally  Assigned 
to Placebo ................................ ................................ ................................ ................ 145
8.16.1. Visit 101 – Vaccination 3: (From Recommendation or at Least 175 
Days After Vaccination 2) ................................ ................................ ............. 145
8.16.2. Visit 102 – Vaccination 4: (19 to 23 Day s After Visit 101) ................... 147
8.16.3. Visit 103 – 1- Month Follow -up Telephone Contact (After 
Vaccination 4): (28 to 35 Days After Visit 102) ................................ ............ 148
8.16.4. Visit 104 – 6- Month Follow -up Telephone Contact (After 
Vaccination 4): (175 to 189 Days After Visit 102) ................................ ........ 148
8.16.5. Visit 105 – 18- Month Follow -up Telephone Contact (After 
Vaccination 4): (532 to 560 Days After Visit 102) ................................ ........ 149
8.17. Administration of an Additional Dose of BNT162b2 or BNT162b2 SA.............. 149
8.17.1. Visit 301 – Vaccination 3: (150 to 210 Days After Visit 2) ................... 149
8.17.2. Visit 302 – 1- Week Follow -up Visit (After Vaccination 3): (6 to 8 
Days After Visit 301) ................................ ................................ ..................... 152
8.17.3. Visit 303 – 1- Month Follow -up Visit (After Vaccination 3): (28 to 
35 Day s After Visit 301) ................................ ................................ ................ 152
8.17.4. Visit 304 – 1- Week Follow -up Visit (Vaccination 4): (6 to 8 Day s 
After Visit 303): Onl y for Those Participants Who Received a fourth 
dose of BNT162b2 SA................................ ................................ ..................... 154
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 BNT162 b2SA................................ ................................ ........... 155
8.17.6. Visit 306 – 6- Month Follow -up Visit: (175 to 189 Day s After Visit 
301): ................................ ................................ ................................ ............... 155
8.17.7. Visit 307 – 18- Month Follow -up Visit: (532 to 560 Day s After 
Visit 301): ................................ ................................ ................................ ......156
8.18. Administration of BNT162b2 SAto BNT162b2 -naïve Participants ..................... 156
8.18.1. Visit 401 – Vaccination 1: (Day  1)................................ ......................... 156
8.18.2. Visit 402 – Vaccination 2: (19 to 23 Day s After Visit 401)................... 159
8.18.3. Visit 403 – 1- Week Follow -up Visit (After Vaccination 2): (6 to 8 
Days After Visit 402) ................................ ................................ ..................... 161
8.18.4. Visit 404 – 1- Month Follow -up Visit (After Vaccination 2): (28 to 
35 Day s After Visit 402) ................................ ................................ ................ 161
8.18.5. Visit 405 – 6- Month Follow -up Visit: (175 to 189 Day s After Visit 
402) ................................ ................................ ................................ ................ 162
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Page 198.18.6. Visit 406 – 18- Month Follow -up Visit: (532 to 560 Day s After 
Visit 402) ................................ ................................ ................................ .......163
8.19. Surveillance for Asy mptomatic SARS -CoV -2 Infection ................................ ....163
8.19.1. Visit 201 –Asymptomatic SARS -CoV -2 Infection Surveillance 
Consen t: From Approval of Protocol Amendment 11 ................................ ...163
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 ................................ ................................ ........ 164
9. STATI STICAL CONSI DERATIONS ................................ ................................ .............. 165
9.1. Estimands and Statistical Hy potheses ................................ ................................ ...165
9.1.1. Estimands ................................ ................................ ................................ ..165
9.1.2. Statistic al Hy potheses ................................ ................................ ............... 166
9.1.2.1. Statistical Hy pothesis Evaluation for Efficacy ........................ 166
9.1.2.2. Statistical Hy pothesis Evaluation for Immunogenicity ........... 166
9.2. Sample Size Determination ................................ ................................ ................... 168
9.2.1. Phase 1 ................................ ................................ ................................ ......168
9.2.2. Efficacy  Against COVID -19 ................................ ................................ ....168
9.2.3. Efficacy  Agains t Asy mptomatic Infection ................................ ............... 169
9.2.4. I mmunogenicit y Bridging of 12 to 15 Years to 16 to 25 Years ............... 169
9.2.5. Boostability  and Protection Against Emerging SARS -CoV -2 VOCs ......169
9.2.6. Safet y ................................ ................................ ................................ ........ 170
9.3. Analy sis Sets ................................ ................................ ................................ ......... 172
9.4. Statistic al Analy ses................................ ................................ ............................... 174
9.4.1. I mmunogenicit y Analyses ................................ ................................ ........ 174
9.4.2. Efficacy  Anal yses................................ ................................ ..................... 184
9.4.3. S afety Anal yses................................ ................................ ........................ 189
9.4.4. Other Anal yses................................ ................................ .......................... 191
9.5. I nterim Anal yses................................ ................................ ................................ ...191
9.5.1. Analy sis Timing ................................ ................................ ........................ 194
9.6. Data Monitoring Committee or Other Independent Oversight Committee...........195
10. SUPPORTING DOCUM ENTATION AND OPERATI ONAL 
CONSI DERATIONS ................................ ................................ ................................ ........ 197
10.1. Appendix 1: Regulatory , Ethical, and Study  Oversight Considerations ............. 197
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Page 2010.1.1. Regulatory and Ethical Considerations ................................ .................. 197
10.1.1.1. Reporting of Safety  Issues and Serious Breaches of the 
Protocol or I CH GCP ................................ ................................ .......197
10.1.2. I nformed Consent Proce ss................................ ................................ ......198
10.1.3. Data Protection ................................ ................................ ....................... 199
10.1.4. Dissemination of Clinical Study  Data ................................ .................... 199
10.1.5. Data Qualit y Assurance ................................ ................................ .......... 200
10.1.6. Source Documents ................................ ................................ .................. 202
10.1.7. Study  and Site Start and Closure ................................ ............................ 202
10.1.8. Sponsor’s Qualified Medical Personnel ................................ ................. 203
10.2. Appendix 2: Clinical Laboratory  Tests ................................ ............................... 204
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recor ding, 
Evaluating, Follow -up, and Reporting ................................ ................................ ....206
10.3.1. Definition of AE ................................ ................................ ..................... 206
10.3.2. Definition of SAE ................................ ................................ ................... 207
10.3.3 . Recording/Reporting and Follow- up of AEs and/or SAEs ..................... 209
10.3.4. Reporting of SAEs................................ ................................ .................. 212
10.4. Appendix 4: Contraceptive Guidance ................................ ................................ .213
10.4.1. Male Participant Reproductive Inclusion Criteria ................................ ..213
10.4.2. Female Participant Reproductive Inclusion Criteria ............................... 213
10.4.3. Woman of Childbearing Potential ................................ .......................... 214
10.4.4. Contraception Methods ................................ ................................ ........... 215
10.5. Appendix 5: L iver Safety : Suggested Actions and Follow -up Assessments ......217
10.6. Appendix 6: Abbreviations ................................ ................................ ................. 219
10.7. Appendix 7: Stopping and Alert Rules for Enhanced COVID -19 ...................... 223
10.8. Appendix 8: Criteria for A llowing Inclusion of Participants With Chronic 
Stable HIV, HCV, or HBV Infection ................................ ................................ ......226
11. REFERENCES ................................ ................................ ................................ ................ 227
LIST OF TABLES
Table 1. Local Reaction Grading Scale ................................ ................................ 103
Table 2. Systemic Event Grading Scale ................................ ................................ 104
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Page 21Table 3. Scale for Fever ................................ ................................ ........................ 105
Table 4. Power Anal ysis for Noninferiorit y Assessment ................................ .....169
Table 5. Probability  of Observing at Least 1 AE by  Assumed True Event 
Rates With D ifferent Sample Sizes ................................ ........................ 171
Table 6. Interim Anal ysis Plan and Boundaries for Efficacy  and Futility ............ 192
Table 7. Statistical Design Operating Characteristics: Probability  of Success 
or Failure for Interim Analy ses................................ ............................... 193
Table 8. Statistical Design Operating Characteristics: Probability  of Success 
for Final Anal ysis and Overall ................................ ................................ 193
Table 9. Laboratory  Abnormality  Grading Scale ................................ ................. 204
Table 10. Stopping Rule: Enrollment I s Stopped if the Number of Severe 
Cases in the Vaccine Group I s Greater Than or Equal to the 
Prespecified Stopping Rule Value (S) ................................ .................... 224
Table 11. Alert Rule: Further Action I s Taken if the Number of Severe Cases 
in the Vaccine Group Is Greater Than or Equal to the Prespecified 
Alert Rule Value (A) ................................ ................................ .............. 225
LIST OF FIGURES
Figure 1. Multiplicity  Schema ................................ ................................ ................ 168
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Page 221.PROTOCOL SUMMARY
1.1.Synopsis
Short Title: A Phase 1/2 /3Study  to Evaluate the Safety , Tolerabilit y, 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 officiall y 
named as se vere acute respiratory  syndrome corona virus 2 (SARS -CoV -2), and the WHO 
officiall y named the disease caused by SARS -CoV -2 as coronavirus disease 2019 
(COVID -19). On11 March 2020 , the WHO upgraded the status of the COVID- 19 outbreak 
from epidemic to pande mic, which is now spreading globall y at high speed.
There are currently  no licensed vaccines to prevent infection with SARS -CoV -2or 
COVID -19. Given the rapid transmission of COV ID-19 and incidence of disease in the 
United States and elsewhere, the rapid development of an effective vaccine is of utmost 
importance.
BioNTech has developed RNA -based vaccine candidates using a platform approach that 
enables the rapid development of vaccines against emerging viral diseases, including 
SARS -CoV -2.Each vaccine candidate is based on aplatform ofnucleoside -modified 
messenger RNA (modRNA , BNT162b ). Each vaccine candidate expresses 1 of 3 antigen s:
BNT162b1 (variant RBP020.3) : a modRNA encoding the trimerized SARS -CoV -2 spike 
glycoprotein receptor -binding domain ( RBD ) (version 5) ;
BNT162b 2 (variant RBP020.2) :a modRNA encoding the SARS -CoV -2 full- length, P2 
mutant, prefusion spike gly coprotein ( P2 S) (version 9);
BNT162b2s01 (variant RBP020.11 ): amodRNA encoding the P2 S containing South Africa 
B.1.351 variant –specific mutations, hereafter referred to as BNT162b2 SA, 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 safet y, immunogenicity , and /orefficacy  of these proph ylactic 
BNT162 vaccines against COVI D-19 .
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Page 23Objectives , 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 1or 2 
dosesIn 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 (AE s) from 
Dose 1 to1 month after the last 
dose
 Serious AEs (SAE s) from Dose 1 
to 6 months after the last dose Local reactions (pain at the 
injection site , rednes s, 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 2Hematology and chemistry laboratory 
parame tersdetailed in Section 10.2
Secondary: Secondary: Secondary: 
To describe the immune responses 
elicited by prophylactic BNT162 
vaccines in healthy adults after 1or 2 
dosesIn 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 , 6, 12, and 24 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 vaccinationSARS -CoV -2neutralizing titers
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Page 24Objectives Estimands Endpoints
 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 vaccinationS1-binding IgGlevels 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 IgGlevels at each 
time point SARS -CoV -2neutralizing titers
 S1-binding IgGlevels
 RBD -binding IgGlevels
Exploratory : Exploratory : Exploratory : 
To describe the immune responses 
elicited by a third dose of prophylactic 
BNT162b2 administered tohealthy 
adults 6 to 12 months after the second 
dose of either BNT162b1 or 
BNT162b2 GMC/GMT and GMFR at the 
time of Dose 3 and 7days and 
1month after Dose 3. 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 -2reference -
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 -2SA-variant
neutralizing titers 1 month after 
Dose 3 to SARS -CoV -2reference -
strain neutralizing titers 1 month 
after Dose 2 SARS -CoV -2 reference -strain 
neutralizing titers
 SARS -CoV -2 SA-variant
neutralizing titers
To de scribe the safety profile of a third 
dose of prophylactic BNT162 b2
administered to healthy adults 6 to 
12months after the second dose of 
either BNT162b1 or BNT162b2In 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 3to 
1month 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
090177e19668af9a\Approved\Approved On: 02-Mar-2021 14:41 (GMT) 
Page 24
FDA-CBER-2022-5812-0229233
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Protocol Amendment 14, 02March 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 25For Phase 2/3
ObjectivesaEstimands Endpoints
Prim ary Efficacy
To evaluate the efficac yof 
prophylactic BNT162 b2against 
confirmed COVID -19occurring from 
7 days after the second dose in 
participants without evidence of 
infection before vaccinationIn 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 efficac yof 
prophylactic BNT162 b2against 
confirmed COVID -19 occurring from 
7 days after the second dose in 
participants with and without 
evidence of infection before 
vaccinationIn 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 follo w-up based on 
central laboratory or locally 
confirmed NAAT
Prim ary Safety
To define the safety profile of 
prophylactic BNT162 b2in 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 BNT162 b2in all 
participants randomized in Phase 2/3In 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 fr om 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 BNT162 b2in 
participants 12 to 15 years of age in 
Phase 3In participants receiving at least 
1dose 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
090177e19668af9a\Approved\Approved On: 02-Mar-2021 14:41 (GMT) 
Page 25
FDA-CBER-2022-5812-0229234
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Protocol Amendment 14, 02March 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 26ObjectivesaEstimands Endpoints
To describe the safety and tolerability 
profile of BNT162 b2SAgiven 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 BNT162 b2given as a third
dose to BNT162b2-experienced
participantsIn partic ipants receiving at least 
1dose 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
Prim ary Immunogenicity
BNT162b2 -experienced participants 
Todemonstrate the noninferiority of 
the anti –reference strain immune 
response after a third dose of 
BNT162b2 compared to after 2 doses 
of BNT162b2, in the same individualsGMR of reference strain NT 1 month 
after the third dose of BNT162b2 to 
1month after thesecond dose of 
BNT162b2
The d ifference inpercentage sof 
participants with seroresponse tothe 
reference strain at1 month after the 
third dose of BNT162b2 and 1 month 
after the second dose of BNT162b2SARS -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 ) of past SARS -CoV -2 
infection
Todemonstrate the noninferiority of 
the anti -SA immune response after 
1dose of BNT162b2 SAcompared to 
the anti –reference strain immune 
response after 2 doses of BNT162b2, 
in the same individualsGMR of SA NT 1month after 1 dose 
of BNT162b2 SAto the reference strain 
NT 1 month after the second dose of 
BNT162b2
The difference in percentage sof 
participants with seroresponse to the 
SAstrain at 1 month after 1 dose of 
BNT162b2 SAand seroresponse to the 
reference strain at 1 month after the 
second dose of BNT162b2SARS -CoV -2 SA and reference strain 
NTs in participants with no 
serological or virological evidence 
(upto 1 month after receipt of 1dose
of BNT162b2 SA) of past SARS -CoV -
2 infection
BNT162b2 -naïve participants 
Todemonstrate the noninferiority of 
the anti-SA immune response after 2 
doses of BNT162b2 SAcompared to 
the anti –reference strain immune 
response after 2 doses of BNT162b2 GMR of SA NT 1month after the 
second dose of BNT162b2 SAto the 
reference strain NT 1 month after the 
second dose of BNT162b2
The difference in percentages of 
participants with seroresponse to the
SAstrain at 1 month after the second 
dose of BNT162b2 SAand 
seroresponse to the reference strain at 
1 month after the second dose of 
BNT162b2SARS -CoV -2 SA and reference strain 
NTs in participants with no 
serological or virological evidence 
(upto 1 month after receipt of the 
second dose of BNT162b2 SAor 
BNT162b2 as appropriate ) of past 
SARS -CoV -2 infection
090177e19668af9a\Approved\Approved On: 02-Mar-2021 14:41 (GMT) 
Page 26
FDA-CBER-2022-5812-0229235
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Protocol Amendment 14, 02March 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 27ObjectivesaEstimands Endpoints
Secondary Efficacy
To evaluate the efficac yof 
prophylactic BNT162 b2against 
confirmed COVID -19 occurring from 
14days after the second dose in 
participants without evidence of 
infection before vaccinationIn participants complying with the 
key protocol criteria (evaluable 
participants) at least 14days 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 14days after receipt of the 
second dose) of past SARS -CoV -2 
infection
To evaluate the efficac yof 
prophylactic BNT162 b2against 
confirmed COVID -19 occurring from 
14days after the second dose in 
participants with and without 
evidence of infection before 
vaccinationIn participants complying with the 
key protocol criteria (evaluable 
participants) at least 14days 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 efficac yof 
prophylactic BNT162 b2against 
confirmed severe COVID -19
occurring from 7days and from 
14days after the second dose in 
participants without evidence of 
infection before vaccinationIn 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 s evere 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 secon d dose) of past 
SARS -CoV -2 infection
To evaluate the efficac yof 
prophylactic BNT162 b2against 
confirmed severe COVID -19
occurring from 7 days and from 
14days after the second dose in 
participants with and without 
evidence of infection before 
vaccinationIn 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 efficac yof 
prophylactic BNT162 b2against 
confirmed COVID -19 (according to 
the CDC -defined symptoms) 
occurring from 7 days and from 
14days after the second dose in 
participants without evidence of 
infection before vaccinationIn 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 7days and up to 14 days after 
receipt of the second dose) of past 
SARS -CoV -2 infection
To describe the efficac yof 
prophylactic BNT162 b2against 
confirmed COVID -19 (according to 
the CDC -defined symptoms) 
occurring from 7 days and from 
14days after the second dose in 
participants with and without 
evidence of infection before 
vaccinationIn 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 placeb o]COVID -19 incidence per 1000 
person -years of follow -up based on 
central laboratory or locally 
confirmed NAAT
090177e19668af9a\Approved\Approved On: 02-Mar-2021 14:41 (GMT) 
Page 27
FDA-CBER-2022-5812-0229236
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Protocol Amendment 14, 02March 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 28ObjectivesaEstimands Endpoints
To evaluate the efficacy of 
prophylactic BNT162b2 against 
non-S seroconversion to 
SARS -CoV -2 in participants without 
evidence of infection or confirmed 
COVID -19In 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 BNT162b 2against 
asymptomatic SARS -CoV -2 infection 
in participants without evidence of 
infection up to the start of the
asymptomatic surveillance periodIn participants complying with the 
key protocol criteria (evaluable 
participants):
100 × (1 –IRR) [ratio of active 
vaccine to placebo]Incidence of asymp tomatic 
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
Todemonstrate 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 ageGMR, 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 
vaccinationSARS -CoV -2 neutralizing titers in 
participants with no serological or 
virological evidence (up to 1 month
after receipt of the seconddose) of 
past SARS -
CoV -2 infection
BNT162b2 -experienced participants 
Todemonstrate the noninferiority of 
the anti-SA immune response after a 
third dose of BNT162b2 compared to 
the anti –reference strain immune 
response after 2 doses of BNT162b2, 
in the same individuals GMR of SA NT 1month after the 
third dose of BNT162b2 to the 
reference strain NT 1 month after the 
second dose of BNT162b2
The difference in percentages of 
participants w ith seroresponse to the
SAstrain at 1 month after the third 
dose of BNT162b 2and seroresponse 
to the reference strain at 1 month after 
the second dose of BNT162b2SARS -CoV -2 SA and reference strain 
NTs in participants with no 
serological or virological ev idence 
(upto 1 month after receipt of the 
third dose of BNT162b2 ) of past 
SARS -CoV -2 infection
Todemonstrate the noninferiority of 
the anti –reference strain immune 
response after 1 dose of BNT162b2 SA
compared to after 2 doses of 
BNT162b2, in the same individuals GMR of reference strain NT 1 month 
after 1 dose of BNT162b2 SAto 
1month after the second dose of 
BNT162b2
The difference in percentages of 
participants with seroresponse to the 
reference strainat 1 month after 1 
dose of BNT162b2 SAand 1 month 
after the second dose of BNT162b2SARS -CoV -2 reference strain NTs in 
participants with no serological or 
virological evidence (up to 1 month
after receipt of 1 dose of 
BNT162b2 SA) of past SARS -CoV -2 
infection
To descriptively compare the anti-SA
immune response after 1 dose of 
BNT162b2 SAanda third dose of 
BNT162b2GMR of SANT 1 month after 1 dose 
of BNT162b2 SAto1month after the 
third dose of BNT162b2
The difference in percentages of 
participa nts with seroresponse to the 
SAstrain at 1 month after 1 dose of 
BNT162b2 SAand 1 month after the 
third dose of BNT162b2SARS -CoV -2 SA NT in participants 
with no serological or virological 
evidence (up to 1 month after receipt 
of 1dose of BNT162b2 SAor the third
dose of BNT162b2 ) of past 
SARS -CoV -2 infection
090177e19668af9a\Approved\Approved On: 02-Mar-2021 14:41 (GMT) 
Page 28
FDA-CBER-2022-5812-0229237
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Protocol Amendment 14, 02March 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 29ObjectivesaEstimands Endpoints
Todescriptively compare the anti-SA 
immune response after 2 doses of 
BNT162b2 SAand the anti –reference 
strain immune response after 2 doses 
of BNT162b2, in the same individuals GMR of SA NT 1month after the 
second dose of BNT162b2 SAto 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 BNT162b2 SAand 
seroresponse to the reference strain at 
1 month after the second dose of 
BNT162b2SARS -CoV -2 SA and reference strain 
NTs in participants with no 
serological or virological evidence 
(upto 1 month after receipt of the 
second dose of BNT162b2 SA) of past 
SARS -CoV -2 infection
BNT162b2 -naïve participants 
Todemonstrate a statistically greater 
anti-SA immune response after 2 
doses of BNT162b2 SAcompared to 
after 2 doses of BNT162b2 GMR of SA NT 1month after the 
second dose of BNT162b2 SAto 
1month 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 BNT162b2 SAand 1 month 
after the second dose of BNT162b2SARS -CoV -2 SANTs in participants 
with no serological or virological 
evidence (up to 1 month after receipt 
of the second dose of BNT162b2 SAor 
BNT162b2 as appropriate) of past 
SARS -CoV -2 infection
Todescriptively compare the anti–
reference strain immune response 
after 2 doses of BNT162b2 SAand 
after 2 doses of BNT162b2 GMR of reference strain NT 1 month 
after the second dose of BNT162b2 SA
to 1month after the second dose of 
BNT162b2
The difference in percentages of 
participants with seroresponse to the 
refere ncestrain at 1 month after th e 
second dose of BNT162b2 SAand 1 
month after the second dose of 
BNT162b2SARS -CoV -2 reference strain NTs in 
participants with no serological or 
virological evidence (up to 1 month
after receipt of the second doseof 
BNT162b2 SAor BNT162b2 as 
appropriate ) of past SARS -CoV -2 
infection
Exploratory
To describe the efficac yof 
prophylactic BNT162b 2against 
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 
vaccinationIn 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 
subseq uentlyIn participants who received 
BNT162b2 (at initial randomization 
or subsequently):
Incidence per 1000 person-ye ars of 
follow -upCOVID -19 incidence per 1000 
person -years of follow -up based on 
central laboratory or locally 
confirmed NAAT
090177e19668af9a\Approved\Approved On: 02-Mar-2021 14:41 (GMT) 
Page 29
FDA-CBER-2022-5812-0229238
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Protocol Amendment 14, 02March 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 30ObjectivesaEstimands Endpoints
To evaluate the immune response 
over time to prophylactic BNT162 b2
and persistence of immune response 
in participants with and without 
serological or virological evidence of 
SARS -CoV -2infection before 
vaccinationGMC/ GMT and GMFR at baseline 
and 1, 6, 12, and 24 months after 
completion of vaccination Full-length S -binding or 
S1-binding IgGlevels
 SARS -CoV -2 neutralizing titers
To describe the incidence of non-S 
seroconversion to SARS -CoV -2
through the entire study follow-up 
period in participants who received 
BNT162b2 at initial randomizationIn participants who received 
BNT162b2 at initial randomization:
Incidence per 1000 person-ye ars of 
follow -upIncidence 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 describe the efficac yof 
prophylactic BNT162b 2against 
asymptomatic SARS -CoV -2 infection 
in participants with evidence of 
infection up to the start of the 
asymptomatic surveillance periodIn 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
 Confirmed severe COVID -19
 SARS -CoV -2 infection without 
confirmed COVID -19 Full-length S -binding or 
S1-binding IgGlevels
 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 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”b AEs
 SAEs
 SARS -CoV -2 neutralizing titers
To describe the immune response to 
any VOCs not already specifiedGeometric mean NT for any VOC s
not already specified, after any dose 
of BNT162b2 SAor BNT162b2 SARS -CoV -2NTs for any VOCs
not already specified
090177e19668af9a\Approved\Approved On: 02-Mar-2021 14:41 (GMT) 
Page 30
FDA-CBER-2022-5812-0229239
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Protocol Amendment 14, 02March 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 31ObjectivesaEstimands Endpoints
To describe thecell-mediated immune 
response , and additional humoral 
immune response parameters, to the 
reference strain and SA in a subset of 
participants:
7 Daysand1and 6month safter
BNT162 b2SAgiven as 1 or 2 
doses to BNT162b2 -experienced
participa nts
7 Daysand1and 6month safter 
BNT162 b2SAgiven as 2 doses to 
BNT162b2 -naïve participants
7 Daysand1and 6month safter 
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.
b.See Section 6.1.1 for a description of the manufacturing process.
Overall Design
This is a Phase 1/2 /3, multicenter, multinational, randomized, placebo -controlled, 
observer -blind, dose -finding, vaccine candidate– selection ,and efficacy study  in healthy  
individuals.
The study  consists of 2 parts :Phase 1: to identify  preferred vaccine candidate(s) and dose 
level(s); Phase 2/3: an expanded cohort and efficacy part.  Th ese parts, and the progression 
between them, are detailed in the schema ( Section 1.2).
The study  will evaluate the safet y, tolerability , and immunogenicit yof 3 different 
SARS -CoV-2 R NAvaccine candidate s against C OVID -19and the efficacy  of 1 candidate :
As a 2 -dose (separa ted by  21 day s) schedule ;
At various different dose levels in Phase 1;
As a booster;
In 3 age groups ( Phase 1: 18 to 55 y ears of age, 65 to 85 y ears of age ; Phase 2/3: ≥12 
years of age[stratified as 12-15, 16 -55,or >55years of age] ).
Dependent upon safet y and/or immunogenicit y 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, g roups may  not be started, groups may  be 
terminated early , and /orgroups may  be added with dose levels below the lowest stated dose 
or intermediate between the lowest and highest stated doses.
090177e19668af9a\Approved\Approved On: 02-Mar-2021 14:41 (GMT) 
Page 31
FDA-CBER-2022-5812-0229240
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Protocol Amendment 14, 02March 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 32The vaccine candidate selected for Phase 2/3 evaluation is BNT162b 2at a dose of 30µg.
Participants ≥16 y ears of age who originall y 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, n asal  
swab s 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 originall y received placebo and become eligible for receipt 
of BNT162b2 according to local or national recommendations and then receive BNT162b2 
as part of the stud y will not participate in surveillance for as ymptomatic 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 VOC s, an additional dose of BNT 162b2 at 30 µg will be 
given to Phase 1 participants approximately  6to 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 immunogenicit y.  The assessmen t of boostability  will be further 
expanded in a subset of Phase 3 participants who will receive a third dose of BNT162b2 or a 
third and potentially  a fourth dose of protot ype BNT162b2 VOC(based upon the South African 
variant and hereafter referred to as BNT162b2 SA).
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 BNT162b2 SAgiven as a 2- dose series, separated by  21 day s.
Number of Participants
Each group in Phase 1 will comprise 15 participants (12 receiving active vaccine and 
3receivi ng placebo). In this phase , 13groups will be studied, correspond ingto a total of 
195participants.
The vaccine candidate selected for Phase 2/ 3, BNT162b 2at 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 placeb o, ie, randomized in a 1:1 ratio.
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Page 33For evaluation of boostability  and protection against emerging VOCs, 600 existing Phase 3 
participants 18 to 55 y ears of age will be rerandomized in a 1:1 ratio to receive either a third 
dose of BNT162b2 or a third dose of BNT162b2 SA.
An additional group of 30existing Phase 3 participants 18 to 55 y ears of age will be enrolled 
to receive a third and fourth dose of BNT162b2 SA.For these 30 participants, through 1 
month after their first dose of BNT162b2 SAthe participant swill 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 wi ll be analy zed separately  from the main 
immunogenicit y anal yses.
Three hundred participants 18 to 55 y ears 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 toreceive BNT162b2 SAgiven as a 2- dose series .
Intervention Groups and Duration
The study  will evaluate a 2-dose (separated b y 21 days) schedule of various different dose 
levels of 3 investigational RNA vaccine candidate s for active immunization against 
COVID -19in 3 age groups ( Phase 1: 18 to 55 years of age ,65 to 85 y ears of age ; Phase 2/3:
≥12years of age [stratified as 12-15, 16 -55,or >55 years of age] ):
BNT162b1 (BNT162 RNA -LNP vaccine utilizing modRNA and encoding the RBD ): 
10µg, 20 µg, 30µg, 100 µg
BNT162b2 (BNT162 RNA -LNP vaccine utilizing modRNA and encoding the P2 S ): 
10µg, 20µg,30µg
BNT162b2 SA(BNT162 RNA -LNP vaccine utilizing modRNA and encoding the P2 S
containing South Africa B.1.351 variant –specific mutations): 30µg
The vaccine candidate selected for Phase 2/3 evaluation is BNT162b 2at a dose of 30µg.
Participants are expected to participate for up to a maximum of approximately  26 months. 
The duration of stud y follow -up may  be shorter among participants enrolled in Phase 1 
dosing arms that are not evaluated in Phase 2/ 3.
Phase 1 participants who originall y 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  6to 12 mon ths after their second dose of BNT162.
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Page 34Data Monitoring Committee or Other Independent Oversight Committee
The study  will utilize an IRC, an internal Pfizer committee thatwill 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
Thesample size for Phase 1of the stud y is not based on an y statistical h ypothesis testing.
For Phase 2/3, the VE evaluation will be the primary  objective . The VE is defined as 
VE= 100 × (1–IRR), where IRR is calculated as the ratio of the first confirmed COVID -19 
illness r ate 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 -19cases 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 y earincidence 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 underly ing 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 asy mptomatic SARS -CoV -2(determined b y 
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 y ears of age. 
Noninferiorit y of immune response to proph ylactic BNT162b2 in participants 12 to 15 years 
of age to response in participants 16 to 25years of age will be assessed based on the GM Rof 
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 GM R(lower limit of 95% CI for GMR>0.67).
Theboostability  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/orreference strain– neutralizing titers using a 2-fold 
noninferiority  margin and the difference in percentages of participants with seroresponse 
using a 10% noninferiority  margin.
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Page 35The primary  safet y objective will be evaluated b y descriptive summary  statistics for local 
reactions, s ystemic events ,AEs/SAEs ,and abnormal hematology  and chemistry  laboratory  
parameters (Phase 1 only), for each vacci ne group. A 3-tier approach will be used to 
summarize AEs in Phase 2/3.
Except for the objective sto assess the noninferiority  of immune response in parti cipants 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 andBNT162b2 SAin 
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 -2neutralizing titers, f ull-length S -binding or S1 -binding IgGlevels ,and/or
RBD- binding IgGlevels (Phase 1 only )at the various time points.
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Page 371.3. S chedule of Activ ities
The SoA table sprovide 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  sche dule visits (unplanned visits) in additi on 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 
Anunplanned potential COVID-19 illness visit and unplanned potential COVID-19 
convalescent visit are requi red at an y time between Visit 1 (Vaccination 1) and Visit 10
(24-month follow -up visit) that COVID- 19 is suspected.
Administration of BNT162b2 to Those Originally Assigned to Placebo: If a participant 
becomes eligible for receipt of BNT162b2 or another COV ID-19 vaccine according to 
recommendations detailed separately , and available in the electronic study reference portal , 
theparticipant 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 wheth er the participant received BNT162b1, BNT162b2, or placebo. If he or she
originall y 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 an y dose level) will continue in the study  as originall y 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 partic ipant received BNT162b1, BNT162b2 ,or placebo. If he or 
sheoriginally  received placebo and want sto receive BNT162b2 ,the participant will move to 
the SoA in Section 1.3.3 for his or her remaining visits.
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Page 441.3.2. Phase 2/ 3
An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 
convalescent visit are required at an y time between Visit 1 (Vaccination 1) and Visit 6
(24-month follow -up visit) that potential COVID -19symptoms are reported, including 
MIS-C.
Administration of BNT162b2 to Those Originally Assigned to Placebo: If a participant 
≥16 years of age becomes eligible for receipt of BNT162b2 or another COVID -19 vaccine 
according to recommendations detailed separatel y, and available in the electronic study 
reference portal, theparticipant will be advised to contact the site to determine whether he or 
shecan receive BNT162b2 in a phased manner aspart of the stud y.When contacted, the s ite 
will conduct aphone visit to confirm eligibility  and, if eligible and wanting to receive 
BNT162b2 if the participant originall y received placebo, will unblind study intervention 
allocation to determine whether theparticipant received BNT162b2 or placebo .If he or she
originall y received placebo and want sto 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 ≥16 y earsof age who have not already  been offe red 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 ,theywill 
be unblinded and those who did originall y receive placebo will move to the SoA in 
Section 1.3.3 for their remaining visits.
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Page 572.INTRODUCTION
The BNT162 RNA -based COVID -19 vaccine sare 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 safet y, tolerabilit y, and immunogenicit y of 
2 BNT162 RNA -based COVID -19 vaccine candidates against COVID-19 , and the efficacy  
of 1 candidate, in healthy individuals. There are currentl y no licensed vaccines to prevent 
infection with SARS -CoV -2or COVID -19. Given the g lobal crisis of COVID -19 and fas t 
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.  
InJanuary  2020, it became c lear that a novel coronavirus (2019 -nCoV) was the underl ying 
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 Betacoronavir ussubfamily .  By  sequence analy sis, the phy logenetic 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 globall y, 
affecting a growing number of countries.
On 11 March 2020 ,the WHO characterized the COVID -19 outbreak as a pandemic.1  
TheWHO Situation Update Report dated 30March 2020 not ed 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 re ported cases globall y. At the time of 
this communication, the number of confirmed case s continues to rise globally . There are 
currentl y no licensed vaccines or effective antiviral drugs to treat SARS -CoV -2 infections or 
the disease it causes, COVID -19.3
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 VOC s have started to emerge, for example in the UK 
(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 proph ylactic, 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 associ ated with infection and may  
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Page 58be 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 eas y and rapid pro duction 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 aplatform 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 capacit y and augmented expression encoding 
the trimerized SARS -CoV -2 spike gly coprotein 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 P2Sconta ining South Africa B.1.351 variant –specific 
mutations, hereafter referred to as BNT162b2 SA, as a representative variant of concern 
(VOC) .
The vaccine candidate selected for Phase 2/3 evaluation is BNT162b 2.
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  6to 12 months after their 
second dose of BNT162 b1 or BNT162b2. This will provide an early  assessment of the safet y 
of a third dose of BNT162, as well as its immunogenici ty.The assessment of boostability  
will be further expanded in a subset of Phase 3 participants who will receive a third dose of 
BNT162b2 or a third and potentially  a fourth dose of prototy pe BNT162b2 VOC(based upon 
the South African variant and hereafter referred to as BNT162b2 SA).
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 C OVID-19. They  will 
receive BNT162b2 SAgiven as a 2- dose series, separated by  21 day s.
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Page 592.2.1. Clinical Overview
Prior to this study , given clinical data from other similarly  formulated uRNA liposomal 
vaccines from BioNTech in oncology  trials7and recent published results from clinical trials 
using modRNA influenza vaccines by Moderna ,8the BNT162 vaccines we re expected to 
have a favorable safet y profile with mild, localized ,and transient effects. BNT162 vaccines 
based on modRNA have now been administered to huma ns for the first time in this study  and 
the BNT162 -01study conducted in German y by BioNTech, at doses between 1 µg and 
100µg. The currently  availa blesafety  and immunogenicity  data are presented in the 
BNT162 IB.
2.3.Benefit/Risk Assessment
There is an ongoing global pandemic of COVID -19 with no preventative or therapeutic 
options available. While there were no data available from clinical trials on the use of 
BNT162 vaccines in humans at the outset of this study , available nonclinical data with these 
vaccines, and data from nonclinical studies and clinical trials with the same or related RNA 
components, or antigens, support eda favorable risk /benefit profile. Anticipated AEs after 
vaccination were expected to be manageable using routine symptom -driven standard of care 
as determined b y the investigators and,as a result, the profile of these vaccine candidate s
support edinitiation of this Phase 1/2 /3clinical study .
Updates as part of protocol amendment 6:
In order for the overall Phase 3 study  populati on 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 diseas e. In addition, with the currently  available 
therapies for the irtreatment, many  individuals with chronic stable HIV, HCV, and HBV 
infections are unlikel y to be at higher safet y 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 reactogenicit y 
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 y ears, 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 y ounger adults 18 t o 25 y ears of 
age. Inclusion of individuals 12 to 15 y ears of age was based upon a satisfactory  blinded 
safet y profile in participants 18 to 25 years of age .
All participants 12 to 15 years of age will be included in the reactogenicit y subset (see 
Section 8.2.2 ).
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Page 60More detailed information about the known and expected benefits and risks and reasonabl y 
expected AEs of BNT162 RNA -based COVID -19 vaccine smay be found in the IB, which is 
the SRSD for t his study . 
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Page 612.3.1. Risk Assessment
Potential Risk of Clinical 
SignificanceSummary 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 c ommo n adverse reactions seen 
with other vaccines, as noted in the FD A 
Center for Biologics Evaluation and 
Research (CBER) guidelines on toxicity 
grading scales for healthy adult volunteers 
enrolled in preventive vaccine clinical 
trials.9The Phase 1 study design includes the use of controlled vaccination and 
dose escalatio n to closely monitor and limit the rate of enrollment to ensure 
participant safety. The study employs the u se of a reactogenicity e-diary to 
monitor local reactions and systemic events in real time. Stopping rules are 
also in place. The first 5 participant s 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.
Unknown AEs and laboratory 
abnormalities with a novel vaccine.This study is one of the first 2 
parallel -running clinical studies with the 
BNT162 vaccine candidates and as such 
there areno clinical data available for t his 
vaccine.The Phase 1 study design includes the use of controlled vaccination and 
dose escalation to c losely monitor and limit the rate of enrollment to ensure 
participant safety. An IRC (in Phase 1) and DMC (throughout the study) 
will also review safety data. Stopping rules are also in place. The first 5 
participants in each group in Phase 1 will be obser ved 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 excludesparticipant s 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 follow ed 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 .
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Page 62Potential Risk of Clinical 
SignificanceSummary of Data/Rationale for Risk Mitigation Strategy
Study Procedures
Participant s will be required to attend 
healthcare facilities during the g lobal 
SARS -CoV-2 pandemic.Without appropriate social distancing and 
PPE, there is a potential for increased 
exposure to SARS -CoV -2.Pfizer w ill work with sites to ensure an appropriate COVID -19 prevention 
strategy. Potential COVID -19 illness visits can be conducted via t elehealth , 
without the need for an in -person visit, if required, w ith the participant 
performing a self -swab.
Venipuncture will be performed 
during the study .There is the risk of bleeding, bruising, 
hematoma formation, and infection at the 
venipuncture site.Only appropriately qualified personnel would obtain the blood draw .
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Page 632.3.2. Benefit Assessment
Benefit s 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
2.3.3. Overall Benefit /Risk Conclusion
Taking into account the measures taken t o minimize risk to participants participating in this 
study , the potential risks identified in association with BNT162 RNA -based COVID -19 
vaccine are justified b y the anticipated benefits that may  be afforded to healthy  participants.
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 1or 2 
dosesIn 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 (AE s) from 
Dose 1 to1 month after the last 
dose
 Serious AEs (SAE s) 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 2Hematology and chemistry laboratory 
parameters detailed in Section 10.2
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Page 64Objectives Estimands Endpoints
Secondary: Secondary: Secondary: 
To describe the immune responses 
elicited by prophylactic BNT162 
vaccines in healthy adults after 1or 2 
dosesIn 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; 7and 14 days and1, 6, 12 ,and 24
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 vaccinationSARS -CoV -2neutralizing titers
 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 vaccinationS1-binding IgGlevels 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 IgGlevels at each 
time point SARS -CoV -2neutralizing titers
 S1-binding IgGlevels
 RBD -binding IgGlevels
Exploratory : Exploratory : Exploratory : 
To describe the immune responses 
elicited by a third dose of prophylactic 
BNT162 b2administered to healthy 
adults 6 to 12 months after the second 
dose of either BNT162 b1 or 
BNT162 b2 GMC/ GMT and GMFR at the 
time of Dose 3and7days and 1
month after Dose 3. SARS -CoV -2 reference -strain 
neutralizing titers
 SARS -CoV -2 SA-variant
neutralizing titers
 Full-length S -binding or 
S1-binding IgGlevels
 GMR of SARS-CoV -2reference -
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 -2SA-variant
neutralizing titers 1 month after 
Dose 3 to SARS -CoV -2reference -
strain neutralizing titers 1 month 
after Dose 2 SARS -CoV -2 reference -strain 
neutralizing titers
 SARS -CoV -2 SA-variant
neutralizing titers
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CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 65Objectives Estimands Endpoints
To de scribe the safety profile of a third 
dose of prophylactic BNT162 b2
administered to healthy adults 6 to 12 
months after the second dose of either 
BNT162 b1 or BNT162 b2In 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 3to 
1month 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
3.2.For Phase 2/3
ObjectivesaEstimands Endpoints
Prim ary Efficacy
To evaluate the efficac yof 
prophylactic BNT162 b2against 
confirmed COVID -19 occurring from 
7 days after the second dose in 
participants without evidence of 
infection before vaccinationIn 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 7days after recei pt of the 
second dose) of past SARS -CoV -2 
infection
To evaluate the efficac yof 
prophylactic BNT162 b2  against 
confirmed COVID -19occurring from 
7 days after the second dose in 
participants with and without 
evidence of infection before 
vaccinationIn 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 follo w-up based on 
central laboratory or locally 
confirmed NAAT
Prim ary Safety
To define the safety profile of 
prophylactic BNT162b 2in 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 BNT162b 2in all 
participants randomized in Phase 2/ 3In 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 fr om 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)
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Protocol Amendment 14, 02March 2021
CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 66ObjectivesaEstimands Endpoints
To define the safety profile of 
prophylactic BNT162 b2in 
participants 12 to 15 years of age in 
Phase 3In participants receiving at least 
1dose 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
To describe the safety and tolerability 
profile of BNT162 b2SAgiven 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 BNT162 b2given as a third
dose to BNT162b2-experienced
participantsIn participants receiving at least 
1dose 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
Prim ary Immunogenicity
BNT162b2 -experienced participants
Todemonstrate the noninferiority of 
the anti –reference strain immune 
response after a third dose of 
BNT162b2 compared to after 2 doses 
of BNT162b2, in the same individualsGMR of reference strain NT 1 month 
after the third dose of BNT162b2 to 
1month 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 and 1 month 
after the second dose of BNT162b2SARS -CoV -2 reference strain NTs in 
participants with no serological or 
virological evidence (up to 1 month
after receipt of thethird dose of 
BNT162b2 ) of past SARS -CoV -2 
infection
Todemonstrate the noninferiority of 
the anti -SA immune response after 
1dose of BNT162b2 SAcompared to 
the anti –reference strain immune 
response after 2 doses of BNT162b2, 
in the same individualsGMR of SA NT 1month after 1 dose 
of BNT162b2 SAto the reference strain 
NT 1 month after the second dose of 
BNT162b2
The difference in percentages of 
participants with seroresponse to the 
SAstrain at 1 month after 1 dose of 
BNT162b2 SAand seroresponse to the 
reference strain at 1 month after the 
second dose of BNT162b2SARS -CoV -2 SA and reference strain 
NTs in participants with no 
serological or virological evidence (up 
to 1 month after receipt of 1dose of 
BNT162b2 SA) of past SARS -CoV -2 
infection
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Page 67ObjectivesaEstimands Endpoints
BNT162b2 -naïve participants
Todemonstrate the noninferiority of 
the anti-SA immune response after 2 
doses of BNT162b2 SAcompared to 
the anti –reference strain immune 
response after 2 doses of BNT162b2 GMR of SA NT 1month after the 
second dose of BNT162b2 SAto the 
reference strain NT 1 month after the 
second dose of BNT162b2
The difference in percentages of 
participants with seroresponse to the 
SAstrain at 1 month after the second 
dose of BNT162b2 SAand 
seroresponse to thereference strain at 
1 month after the second dose of 
BNT162b2SARS -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 BNT162b2 SAor BNT162b2 as 
appropriate ) of past SARS -CoV -2 
infection
Secondary Efficacy
To evaluate the efficac yof 
prophylactic BNT162 b2against 
confirmed COVID -19 occurring from 
14 days after the second dose in 
participants without evidence of 
infection before vaccinationIn participants complying with the 
key protocol criteria (evaluable 
participants) at least 14days 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 14days after receipt of the 
second dose) of past SARS -CoV -2 
infection
To evaluate the efficac yof 
prophylactic BNT162 b2against 
confirmed COVID -19 occurring from 
14 days after the second dose in 
participants with and without 
evidence of infection before
vaccinationIn participants complying with the 
key protocol criteria (evaluable 
participants) at least 14days 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 efficac yof 
prophylactic BNT162b 2against 
confirmed severe COVID -19
occurring from 7 days and from 14 
days after the second dose in 
participants without evidence of 
infection before vaccinationIn 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 effi cacyof 
prophylactic BNT162b 2against 
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 
vaccinationIn 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 s evere COVID -19 
incidence per 1000 person -years of 
follow -up
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Protocol Amendment 14, 02March 2021
CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 68ObjectivesaEstimands Endpoints
To describe the efficac yof 
prophylactic BNT162b 2against 
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 vaccinationIn participants complyin g 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 efficac yof 
prophylactic BNT162b 2against 
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 
vaccinationIn participants complying wi th 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 serologica l or 
virological evidence of past 
SARS -CoV -2 infection or confirmed 
COVID -19 
To evaluate the efficacy of 
prophylactic BNT162b 2against 
asymptomatic SARS -CoV -2 infection 
in participants without evidence of 
infection up to the start of the 
asymptomatic sur veillance periodIn 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
Todemonstrate 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 ageGMR, 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 
vaccinationSARS - 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
Todemonstrate the noninferiority of 
the anti-SA immune response after a 
third dose of BNT162b2 compared to 
the anti –reference strain immune 
response after 2 doses of BNT162b2, 
in the same individuals GMR of SA NT 1month after the 
third dose of BNT162b2 to the 
reference strain NT 1 month after the 
second dose of BNT162b2
The difference in percentages of 
participants with seroresponse to the
SAstrain at 1 month after the third 
dose of BNT162b2 and seroresponse 
to the reference strain at 1 month after 
the second dose of BNT162b2SARS -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 ) of past 
SARS -CoV -2 infection
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Protocol Amendment 14, 02March 2021
CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 69ObjectivesaEstimands Endpoints
Todemonstrate the noninferiority of 
the an ti–reference strain immune 
response after 1 dose of BNT162b2 SA
compared to after 2 doses of 
BNT162b2, in the same individuals GMR of reference strain NT 1 month 
after 1 dose of BNT162b2 SAto 
1month 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 BNT162b2 SAand 1 month 
after the second dose of BNT162b2SARS -CoV -2 reference strain NTs in 
participants with no serological or 
virological e vidence (up to 1 month
after receipt of 1 dose of 
BNT162b2 SA) of past SARS -CoV -2 
infection
To descriptively compare the anti-SA
immune response after 1 dose of 
BNT162b2 SAanda third dose of 
BNT162b2GMR of SANT 1 month after 1 dose 
of BNT162b2 SAto1month after the 
third dose of BNT162b2
The difference in percentages of 
participants with seroresponse to the
SA strain at 1 month after 1 dose of 
BNT162b2 SAand 1 month after the 
third dose of BNT162b2SARS -CoV -2 SA NT in participants 
with no serological or virological 
evidence (up to 1 month after receipt 
of 1dose of BNT162b2 SAor the third
dose of BNT162b2 ) of past 
SARS -CoV -2 infection
Todescriptively compare the anti-SA 
immune response after 2 doses of 
BNT162b2 SAand the anti –reference 
strain immune response after 2 doses 
of BNT162b2, in the same individuals GMR of SA NT 1month after the 
second dose of BNT162b2 SAto 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 BNT162b2 SAand 
seroresponse to the reference strain at 
1 month after the second dose of 
BNT162b2SARS -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 BNT162b2 SA) of past 
SARS -CoV -2 infection
BNT162b2 -naïve participants 
Todemonstrate a statistically greater 
anti-SA immune response after 2 
doses of BNT162b2 SAcompared to 
after 2 doses of BNT162b2 GMR of SA NT 1month after the 
second dose of BNT162b2 SAto 
1month 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 BNT162b2 SAand 1 month 
after the second dose of BNT162b2SARS -CoV -2 SANTs in participants 
with no serological or virological 
evidence (up to 1 month after receipt 
of the second dose of BNT162b2 SAor 
BNT162b2 as appropriate) of past 
SARS -CoV -2 infection
Todescript ively compare the anti –
reference strain immune response 
after 2 doses of BNT162b2 SAand 
after 2 doses of BNT162b2 GMR of reference strain NT 1 month 
after the second dose of BNT162b2 SA
to 1month after the second dose of 
BNT162b2
The difference in percentages of 
participants with seroresponse to 
refere nce strain at 1 month after the 
second dose of BNT162b2 SAand 1 
month after the second dose of 
BNT162b2SARS -CoV -2 reference strain NTs in 
participants with no serological or 
virological evidence (up t o 1 month
after receipt of the second doseof 
BNT162b2 SAor BNT162b2 as 
appropriate ) of past SARS -CoV -2 
infection
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Protocol Amendment 14, 02March 2021
CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 70ObjectivesaEstimands Endpoints
Exploratory
To describe the efficac yof 
prophylactic BNT162b 2against 
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 
vaccinationIn participants complying with the 
key protocol criteria (evaluable 
participants) after receipt of the 
second dose of study interve ntion:
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 
subsequentlyIn participants who received 
BNT162b2 (at initial randomization 
or subsequently):
Incidence per 1000 person-ye ars of 
follow -upCOVID -19 incidence per 1000 
person -year s 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 -2infection before 
vaccinationGMC/ GMT andGMFR at baseline 
and 1, 6, 12, and 24 months after 
completion of vaccination Full-length S -binding or 
S1-binding IgGlevels
 SARS -CoV -2 neutralizing titers
To describe the incidence of non-S 
seroconversion to SARS -CoV -2
through the entire study follow-up 
period in participants who received 
BNT162b2 at initial randomization In participants who received 
BNT162b2 at initial randomization:
Incidence per 1000 person-ye ars of 
follow -upIncidence 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 describe the efficac yof 
prophylactic BNT162b 2against 
asymptomatic SARS -CoV -2 infection 
in participants with evidence of 
infection up to the start of the 
asymptomatic surveillance periodIn participants complying with the 
key protocol criteria (evaluable 
participants):
100 × (1 –IRR) [ratio of acti ve 
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 p eriod) 
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
 Confirmed severe COVID -19
 SARS -CoV -2 infection without 
confirmed COVID -19 Full-length S -binding or 
S1-binding IgGlevels
 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
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Protocol Amendment 14, 02March 2021
CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 71ObjectivesaEstimands Endpoints
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”b AEs
 SAEs
 SARS -CoV -2 neutralizing titers
To describe the immune response to 
any VOCs not already specifiedGeometric mean NT for any VOC snot 
already specified, after any dose of 
BNT162b2 SAor BNT162b2 SARS -CoV -2NTs for any VOCs
not already specified
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 Daysand1and 6month safter
BNT162 b2SAgiven as 1 or 2 
doses to BNT162b2 -experienced
participants
 7 Daysand 1 and 6month safter 
BNT162 b2SAgiven as 2 doses to 
BNT162b2 -naïve participants
 7 Daysand1and 6month safter 
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.
b.SeeSection 6.1.1 for description of the manufacturing process .
Up until the final efficacy anal ysis, 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 regula r basis throughout the trial
(seeSection 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 an y such AE that meets the criteria for seriousness to Pfizer Safet y.
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Page 724.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  
indiv idual s.
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 safet y, tolerability ,andimmunogenicit y of 3 different 
SARS -CoV-2 R NAvaccine candidate s against C OVID -19and the efficacy  of 1 candidate :
As a 2 -dose (separated by  21 day s) schedule ;
At various different dose levels in Phase 1;
As a booster;
In 3 age groups ( Phase 1: 18 to 55 y ears of age, 65 to 85 y ears of age ; Phase 2/3: ≥12 
yearsof age [stratified as 12-15, 16 -55,or >55 years of age] ).
Dependent upon safet y and/or immunogenicit y 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 sta rted at the next highest dose, g roups may  not be started, groups may  be 
terminated early , and /orgroups 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, a s the ph ysical appearance of the investigational vaccine 
candidates and the placebo may  differ. The participant, investigator, study  coordinator, and 
other site staff will be blinded. At the study  site, only  the dispenser(s)/administrator(s) are 
unblinded.
To facilitate rapid review of data in real time, sponsor staff will be unblinded to vaccine 
allocation for the participants in Phase 1.
In order to describe the boostability  of BNT162, an additional dose of BNT162b2 at 30 µg 
will be given to Pha se 1 participants approximately  6to 12 months after their second dose of 
BNT162 b1 or BNT162b2. This will provide an early  assessment of the safety  of a third dose 
of BNT162, as well as its immunogenicit y.The assessment of boostability  will be further 
expanded in a subset of Phase 3 participants who will receive a third dose of BNT162b2 or a 
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Page 73third and potentially  a fourth dose of protot ype BNT162b2 VOC(based upon the South African 
variant and hereafter referred to as BNT162b2 SA).
To further describe pote ntial 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 BNT162b 2SAgiven as a 2-dose series, separated by  21 day s.
4.1.1. Phase 1
Each group (vaccine candidate/dose level/ age group ) will comprise 15 participant s; 
12participants will be randomized to receive active vaccine and 3 to receive placebo.
For each vaccine candidate/ dose level /age group , the following apply :
Additional safet y 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
Thefirst 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 24hours 
after the fifth participant received his or her vaccination
Application of stopping rules
IRC review of safet y 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 safet y data in this study  and/or the BioNTech stud y conducted in 
German y (BNT162 -01)
Note that, since both candidates arebased upon the same RNA platform, dose 
escalation for the second candidate studied may be based upon the safet y profile of 
the first candidate studied being deeme d acceptable at the same , or a higher, dose 
level by  the IRC
Groups of participants 65 to 85 y ears of age will not be started until safet y 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 I RC.
In this phase , 13groups will be studied, corresponding to a total of 195participants.
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Page 74The I RC 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
progress ion into Phase 2/ 3.
Participants who originally  received placebo and become eligible for receipt of BNT162b2 or 
another CO VID-19 vaccine according to recommendations detailed separately , and available 
in the electronic stud y reference portal ,will have the opportunity  to receive BNT162b2 in a 
phased manner as part of the study . The investigator will ensure the participant me ets at least 
1of the recommendation criteria. 
Any Phase 1placebo 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 VOC s, an additional dose of BNT162b2 at 30 µg will be 
given to Phase 1 p articipants approximately  6to 12 months after their second dose of 
BNT162 b1 or BNT162b2.
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 a t 30 µg
approximately  6to 12 months after their second dose of BNT162. 
Participants are expected to participate for up to a maximum of approximately  26 months.  
4.1.2. Phase 2/ 3
On the basis of safet y and/or immunogenicit y 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 y ears, 16to 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 strat um w ill be based upon satisfactory  post–Dose 2 safety  and 
immunogenicit y data from the 18 -to 55 -year and 65 -to 85 -yearagegroups in Phase 1, 
respectivel y.  The vaccine candidate selected for Phase 2/3 evaluation is BNT162b 2at a dose 
of 30µg.
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 164primary -endpoint cases of confirmed 
COVID -19 due to SARS -CoV -2 occurring at least 7days 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 
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Page 75may vary depending on the incidence of COVID -19 at the time of the enrollment, the true 
underly ing VE, and a potential earl y stop for efficacy  or futility .
Assuming a COVID -19 attack rate of 1. 3%per y earin 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 t he number of participants 
initially  targeted for Phase 2/ 3 and may be adjusted based on advice from DMC analy ses 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 >55to 85 y ears) will comprise the “Phase 2 ”portion. 
Safety  data through 7 day s after D ose 2 and immunogenicity  data through 1 month after 
Dose 2 from these 360 participants will be anal yzed by  the unblinded statistical team, 
reviewed b y the DMC, and submitted to appropriate regulatory  authorities for review. 
Enrol lment may continue during this period and these participants would be included in the 
efficacy  evaluation in the “Phase 3” portion of the study .
In Phase 3, up to approximately  2000 participants , enrolled at selected sites, are anticipated 
to be 12 to 15 y ears of age. Noninferiority  of immune response to proph ylactic BNT162b2 
in participants 12to 15 years of age to response inparticipants 16 to 25years of ag e will be 
assessed based on the GM Rof SARS -CoV -2 neutralizing titers using a 1.5 -fold margin. A 
sample size of 225 evaluable participants (or 280vaccine recipients) per age group will 
provide a power of 90.4 % to declare the noninferiority in terms of GM R(lower limit of 95%
CIforGMR>0.67) . A random sample of 280 participant s from each of the 2age group s
(12to 15 y ears and 16 to 25 y ears) will be selected as an immunogenicity  subset for the 
noninferiority  assessment.
The initial BNT162b2 was manufac tured using “Process 1”; however, “Process 2” was 
developed to support an increased scale of manufacture. In the stud y, each lot of
“Process 2”-manufactured BNT162b2 will be administered to approximately  250participants
16 to 55 y ears of age . The safet y and immunogenicity  of prophy lactic BNT162b2 in 
individuals 16 to 55 y ears of age vaccinated with “Process 1” and each lot of “Process 2” 
study  intervention will be described. A random sample of 250 participants from those 
vaccinated with study  intervention produced by  manufacturing “Process 1” will be selected 
for this descriptive analysis .
For evaluation of boostability  and protection against emerging VOCs, 600 existing Phase 3 
participants 18 to 55 y ears of age will be rerandomized in a 1:1 ra tio to receive either a third 
dose of BNT162b2 or a third dose of BNT162b2 SA.
An additional group of 30existing Phase 3 participants 18 to 55 y ears of age will be enrolled 
to receive a third and fourth dose of BNT162b2 SA. For these 30 participants, throug h 1 month 
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Page 76after their first dose of BNT162b2 SAthe 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 anal yzed separately  from the main immunogenicity  anal yses.
Three hundred participants 18 to 55 y ears 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 toreceive BNT162b2 SAgiven as a 2 -dose series .
Participants are expected to participate for up to a maximum of approximately 26 months. 
The duration of stud y follow -up may  be shorter among participants enrolled in Phase 1 
dosing arms that are not evaluated in Phase 2/ 3.
Participants ≥16 y ears of age who originall y received placebo and become eligible for receipt 
of BNT162b2 according to recommendations detailed separa tely, and available in the 
electronic stud y 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 1of 
the recommendation criteria.
Any Phase 2/3 placebo recipient ≥16 y ears of age who has not alread y 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 originall y 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 ).
Thechanges to the protocol as part of protocol a mendment 14 to assess boostability  and 
homologous/heterologous protection against emerging VOCs allow the evaluation of safet y 
and immunogenicit y of BNT162b2 SA:
When given as a third dose to C4591001 Phase 3 pa rticipants who received a second dose 
of BNT162b2 approximately  6 months previousl y (ie, BNT162b2- experienced) and have 
not experienced COVID -19. 
In a small separate group of individuals who previously  received 2 doses of BNT162b2 
followed b y 1 dose of BN T162b2 SA, a second BNT162b2 SAdose will also be given 1 
month after Dose 1 of BNT162b2 SA.
When given as a 2 -dose series, separated b y 21 days, in newl y 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 previousl y will receive a third dose of BNT162b2.
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Page 77This approach will allow an evaluation of immunogenicity  against the reference a ncestral 
SARS -CoV -2strain (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 bo ost (with 
BNT162b2 SA), as well as new vaccinees receiving 2 doses of BNT162b2 SA.
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 
participa nts 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, n asal 
(midturbinate) swab s 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 becom epotentially eligible for receipt of BNT162b2 according to 
recommendations detailed separately , and available in the electronic study  reference portal, 
will not participate in surveillance for as ymptomatic SARS -CoV -2 infection. However, 
participants who provided additional consent to conduct biweekl y swabbing for surveillance 
of as ymptomatic infection should continue to swab even after unblinding if they  originall y 
received BNT162b2 .
Surveillance for asymptomatic SARS -CoV -2 infection (swabbing) should cease in 
participants enrolled into the subset of participa nts who will receive an additional d ose of 
BNT162b2 or BNT162b2 SA.
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 s ymptoms, as detailed in 
Section 8.13,a COVID -19 illness and subsequent convalescent visit will occur. As part of 
these visits ,samples ( nasal [midturbinate ]swab and blood) will be taken for antigen and 
antibody  assessment as well as recording of COVID -19–related clinical and laboratory  
information (including local diagnosis). 
Human reproductive safety  data are not available for BNT162 RNA -based COVID -19 
vaccine s,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 newl y emerged COVID -19 pandemic, 
sufficient data were not available to experimentally  validate the dose selection and in itial 
starting dose. Therefore, the original planned starting dose of10 µg (for both BNT162b1 and 
BNT162b2) in this study wasbased on nonclinical experience with the same RNAs encoding 
other viral antigens (such as influenza and HIV antigens). The gene ral safety  and 
effectiveness of uRNA and modRNA platforms have been demonstrated in oncological 
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Page 78clinical trials with different administration routes (NCT02410733, NCT03871348). Doses of 
up to 400 µg total uRNA have been administered IV as RNA lipoplex (RN A-LPX) and doses 
of up to 1000 µg total naked modRNA have been administered intratumorally , both without 
signs of unpredictable overstimulation of the immune sy stem.
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 wasexpected 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 likel y be required to elicit a 
stronger antibod y 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 µgand 100 µgwarran ts 
consideration. Therefore ,a 50-µgdose 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 BNT1 62a1 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-µgdose level is formally  included for both candidates.
Update as part of protocol amendment 4: the 50- µgdose level for BNT162b1 and BNT162b2 
is removed andthe 100- µgdose level for BNT162b2 is removed ; similar dose levels of 
BNT162b3 may  be studied as for BNT162b1 and BNT162b2.
Update as part of protocol ame ndment 5: the vaccine candidate selected for Phase 2/3 
evaluation is BNT162b 2at 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 
6months after the last vaccination).
The end of the stud y is defined as the date of last visit of the last participant in the study .
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Page 795. STUDY POPULATION
This study  can fulfill its objectives only  if appropriate participant s are enrolled.  The 
following eligibility  criteria are designed to select participant s 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 an d 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 onl y if all of the following criteria appl y:
Age and Sex :
1.Male or female participants between the ages of 18 and 55years, inclusive, and 65 and 
85years, inclusive (Phase 1) , or ≥12 years(Phase 2/3) ,at randomization. For the 
boostability  and protection -against -VOCs subset (both existing and newl y enrolled) ,male 
or female participants between the ages of 18 and 55years, inclusive, at 
rerandomization/enrollment. Note that participants <18 y ears 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 o f Participant and Disease Characteristics:
2.Participants who are willing and able to compl y with all scheduled visits, vaccination 
plan, laboratory  tests, lifesty le considerations, and other study  procedures.
3.Health y participants who are determined b y medic al history , phy sical examination
(ifrequired) , 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 therap y or hospitalization for worsening disease during 
the 6 weeks before enrollment, can be included. Specific criteria for Phase 3 participants 
with k nown 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: Participant swho, in the judgment of the investigator, areat higher risk 
for acqu iring COVID -19 (including, but not limited to , use of mass transportation, 
relevant demographics, and frontline essential workers) .
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Page 805.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 I CDand in this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study  if any  of the following criteria apply :
Medical Conditions:
1.Other medical or psy chiatric 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 investig ator’s judgment, make the participant inappropriate for the 
study .
2.Phase s 1 and2 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, anaphy laxis) 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 microbiolo gical (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 y ear
Chronic liver disease
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Page 81Stage 3 or worse chronic kidney  disease (glomerular filtration rate 
<60mL/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 currentl y 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 b y history  and/or laboratory /physical examination.
9.Phase 1 only: Individuals with a history  of autoimmune disease or an active autoimmune 
disease requiring therapeutic intervention, including but not limited to: sy stemic or 
cutaneous lupus ery thematosus, autoimmune arthritis/rheumatoid arthritis, Guillain -Barré 
syndrome, multiple sclerosis, Sjögren’s s yndrome, idiopathic thrombocytopenia purpura, 
glomerulonephritis, autoim mune thy roiditis, 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 cy totoxic 
agents or s ystemic corticoster oids, eg, for cancer or an autoimmune disease, or planned 
receipt throughout the study .  If s ystemic corticosteroids have been administered short 
term (<14 day s) for treatment of an acute illness, participants should not be enrolled into 
the study  until corticosteroid therap y has been discontinued for at least 28 days before 
study  intervention administration.  I nhaled/nebulized (except for participants in 
Phase 1 – see exclusion criterion 14), intra -articular, intrabursal, or topical (skin or ey es) 
corticosteroids are permitted.
14.Phase 1 only: Regular receipt of inhaled/nebulized corticosteroids.
15.Receipt of blood/plasma products or immunoglobulin, from 60 day s before study  
intervention administration or planned receipt throughout the stud y.
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Page 82Prior/Concurrent Clinical Study Experience:
16.Participation in other studies involving study  intervention within 28 day s prior to study  
entry  through and including 6 month s after the last dose of study  intervention , with the 
exception of interventional studies for prevent ionofCOVID -19,which are prohibited 
throughout stud y participation.
17.Previous participation in other studies involving study  intervention containing lipid 
nanoparticles.
Diagnostic Assessments:
18.Phase 1only: Positive serological test for SARS- CoV -2 IgM and/o r IgG antibodies at 
the screening visit.
19.Phase 1only: Any screening hematology and/or blood chemistry laboratory value that 
meets the definition of a ≥Grade 1 abnormality .
Note: With the exception of bilirubin, participants with any  stable Grade 1 abnormalities 
(according to the toxicity  grading scale) may  be considered eligible at the discretion of 
the investigator.  (Note: A “stable” Grade 1 laboratory  abnormalit y is defined as a report 
of Grade 1 on an initial blood sample that remain s ≤Grade 1 upon repeat testing on a 
second sample from the same participant.)
20.Phase 1only: Positive test for HIV, hepatitis B surface antigen (HBsAg), hepatitis B 
core antibodies (HBc Abs), or he patitis 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. Investigat orsite staff or Pfizer /BioNTech employees directly  involved in the conduct of 
the study , site staff otherwise supervised by  the investigator, and their respective famil y 
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 
(seeAppendix 4 ,Secti on 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 highl y effective contraception 
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Page 83consistently  and correctly  and document the conversation and the participant’s affirmation in 
the participant ’s chart ( participant s 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, eli gibility  
criteria, and an y SAE.
Individuals who do not meet the criteria for participation in this study  (screen failure ) may be 
rescreened under a different participant number .
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention 
Administration
The following conditions are temporary  or self -limiting and a participant may  be 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 c urrent s ymptoms that 
could represent a potential COVID -19 illness :
New or increased cough; 
New or increased shortness of breath;
Chills;
New or increased m uscle pain;
New l oss of taste/smell;
Sore throat;
Diarrhea;
Vomiting.
2.Receipt of an y seasonal or pandemic influenza vaccine within 14 day s, or any  other 
nonstudy  vaccine within 28 days,before study  intervention administration.
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Page 843.Anticipated receipt of any s easonal or pandemic influenza vaccine within 14 day s, or any  
other nonstudy  vaccine within 28 day s,after study  intervention administration.
4.Receipt of short -term (<14 day s) systemic corticosteroids.  Study  intervention
administration should be delay ed unt il systemic corticosteroid use has been discontinued 
for at least 28 day s.  Inhaled/nebulized, intra -articular, intrabursal, or topical (skin or 
eyes) corticosteroids are permitted.
6.STUDY INTERVENTION
Study  intervention is defined as any  investigational in tervention(s), marketed product(s), 
placebo, medical device(s) , or study  procedure(s) intended to be administered to a study  
participant according to the study  protocol.
The study  will evaluate a 2-dose (separated b y 21 days) schedule of various different dose 
levels of 3 investigational RNA vaccine candidate s for active immunization against 
COVID -19in 3 age groups ( 18 to 55 years of age ,65 to 85 y ears of age ,and≥12years of 
age[stratified as 12-15, 16 -55,or >55 years of age] ).
These 3investigational RNA vaccine candidate s, 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 m odRNA and encoding the RBD ): 
10µg, 20µg, 30µg, 100 µg
BNT162b2 (BNT162 RNA -LNP vaccine utilizing m odRNA and encoding the P2 S ): 
10µg, 20µg, 30µg
BNT162b2 SA(BNT162 RNA -LNP vaccine utilizing modRNA and encoding the P2 S
containing South Africa B.1.351 variant –specific mutations): 30µg
Normal s aline (0.9% s odium chloride solution for i njection )
The vaccine candidate selected for Phase 2/3 evaluation is BNT162b 2at a dose of 30µg.
6.1.Study Intervention(s) Administered
Intervention Name BNT162b1 
(BNT162 RNA -
LNP vaccine 
utilizing modRNA)BNT162b2 
(BNT162 RNA -
LNP vaccine 
utilizing modRNA)BNT162b2 SA
(BNT162 RNA -
LNP vaccine 
utilizing modRNA)Saline Placebo
Type Vaccine Vaccine Vaccine Placebo
Dose Form ulation 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)a10-, 20-, 30-, 100 -µg10-, 20-, 30-µg 30-µg N/A
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Page 85Intervention Name BNT162b1 
(BNT162 RNA -
LNP vaccine 
utilizing modRNA)BNT162b2 
(BNT162 RNA -
LNP vaccine 
utilizing modRNA)BNT162b2 SA
(BNT162 RNA -
LNP vaccine 
utilizing modRNA)Saline Placebo
Route of 
AdministrationIntramuscular 
injectionIntramuscular 
injectionIntramuscular 
injectionIntramuscular 
injection
Use Experimental Experimental Experimental Placebo
IMP or NIMP IMP IMP IMP IMP
Sourcing Provided centrally 
by the sponsorProvided centrally 
by the sponsorProvided centrally 
by the sponsorProvided centrally by 
the sponsor
Packaging and 
LabelingStudy intervention 
will be provided in a 
glass vial as open -
label supply. Each 
vial will be labeled 
as required per 
country requirementStudy intervention 
will be provided in a 
glass vial as open -
label supply. Each 
vial will be labeled 
as required per 
country requirementStudy intervention 
will be provided in a 
glass vial as open -
label supply. Each 
vial will be labeled 
as required per 
country requirementStudy 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 betw een the lowest and highest stated doses.
The vaccine candidate selected for Phase 2/3 evaluation is BNT162b 2at a dose of 30µg.
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 y ears of age, 
per lot, in the study .The safet y and immunogenicity  of proph ylactic BNT162b2 in 
individuals 16 to 55 y ears of age vaccinated with material generated using the existing 
manufacturing process “Process 1 ,” and with material from lots generated using the 
manufacturing process supporting increased supply, “Process 2,” will be described.
In brief, the process changes relate to the method of production for the DNA template that 
RNA drug substance is transcribed from, and the RNA drug substance purif ication method.  
The BNT162b2 drug product is then produced using a scaled -up LNP manufacturing process.
6.1.2. Administration
Participants will receive 1 dose of study  intervention as randomized at each vaccination visit 
(Visits 1 and 4 for Phase 1 participants, Visits 1 and 2 for Phase 2/3 participants) in 
accordance with the study’s SoA.Participants ≥16 years of age who originally  received 
placebo and accept the offer to receive BNT162b2 at defined points as part of the stu dywill 
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 I P manual.
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Page 86Phase 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  6to 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 ei ther a third dose of BNT162b2 or BNT162b2 SAapproximately  5 to 
7 months after their second dose of BNT162 at Visit 301. Of those who receive BNT16b2 SA
at Visit 301, a subset will receive a f urther dose of BNT162b2 SAat Visit 303 .
BNT162b2 -naïve participants who are enrolled under p rotocol a mendment 14 to receive 
BNT162b2 SAwill receive 1 dose of study  intervention at each vaccination visit, Visits 401 
and 402.
Study  intervention should be administered intramuscularl y into the delto id muscle , preferabl y
of the nondominant arm ,by an unblinded administrator .
Standard vaccination practices must be observed and vaccine must not be injected into blood 
vessels.  Appropriate medication and other supportive measures for management of an acu te 
hypersensitivity  reaction should be available in accordance with local guidelines for standard 
immunization practices.
Administration of study  interventions should be performed b y an appropriately  qualified, 
GCP -trained, and vaccine- experienced member o f the study  staff (eg, ph ysician, 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  intervention sreceived and an y discrepancies are 
reported and resolved before use of the stud y intervention.
2.Only  participants enrolled in the study  may  receive study  intervention and only  
authorized site staff may  supply  or administer study  intervention. All study intervention s
must be stored in a secure, environmentall y 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 day s must indicate the minimum and maximum 
temperature ssince previously  documented for all site storage locations upon ret urn to 
business.
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Page 873.Any excursions from the study  intervention label storage conditions should be reported to 
Pfizer upon discovery  along with an y actions taken.  The site should actively  pursue 
options for returning the study  intervention to the storage cond itions 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 a n 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 s tored 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 stud y intervention accountability , reconcili ation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records) , such as the IPAL or 
sponsor -approved equivalent . All study  intervention swill 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 I P manua l.All destruction must be adequatel y documented.  If 
destruction is authorized to take place at the investigator site, the investigator must ensu re 
that the materials are destroy ed 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 w ithin 1 business day  of 
discovery  as described in the I P 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 b y an appropriatel y
qualified and experienc ed member of the stud y staff (eg, ph ysician, nurse, phy sician’s 
assistant, nurse practitioner, pharmacy  assistant/technician, or pharmacist) as allowed b y 
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 participant sremain blinded .
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Page 886.3.Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
Allocation (randomiz ation) of participants to vaccine groups will proceed through the use of 
an IRT s ystem (I WR).  The site personnel (study  coordinator or specified designee) will be 
required to enter or select information including but not limited to the user’s I D 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 sy stem will 
provide a confirmation re port 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 I RT reference manual and I P manual will provide the contact information 
and further details on the use of the IRT s ystem.
6.3.2. Blinding of Site Personnel
In this observer blinded study , the study  staff receiving, storing, dispensing, preparing, and 
administering the stud y interventions will be unblinded.  All other study  and site personnel, 
including the investigator, investigator staff, and participants ,will be blinded to study  
intervention assignments.  I n particular, the individuals who evaluate participant safet y will 
be blinded.  Because the BNT162 RNA -based COVID -19 vaccine candidates and placebo
are different in phy sical appearance, the study  intervention syringes will be administered in a 
manner that prevents the study  participants from identify ing 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 an y study  participants.  
Contact between the unblinded dispenser and study participants and unblinded administrator 
andstudy  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 par ticipant s’original study  intervention allocation as the
participants become eligible for vaccination under local/national recommendations or from 
6months after the second dose .
For the group of 30 existing Phase 3 participants 18 to 55 y ears of age who will be enrolled 
to receive a third and fourth dose of BNT162b2 SA, through 1 month after their first dose of 
BNT162b2 SAthe participant swill be blinded to their vaccine allocation ,but the investigator 
will not be.
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 majorit y of sponsor staff will be 
blinded to study  intervention allocation in Phase 2/ 3. All laboratory testing personnel 
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Page 89performing serology  assay s will remain blinded to study  intervention assigned/received 
throughout the stud y.The following s ponsor staff , who will have no part in the blinded 
conduct of the stud y,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 stud y (eg, unblinded study manager, 
unblinded clinical research associate).
Unblinded clinician (s),who arenot direct member sof the study  team and will not 
participate in an y other study -related activities, will review unblinded protocol 
deviations.
An unblinded team supporting interactions with, and anal yses for, the DMC 
(seeSection 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 AE s at least weekl y for additional potential cases of severe COVID -19
(see Section 8.2.3 ).
An unblinded submissions team will be responsible for preparing unblinded anal yses 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 anal ysis or the final 
analysis,as determined by the DMC.
After the formal data release of the final efficacy  analy sis of at least 164 cases , whi ch is 
considered the primary  completion of the study efficacy objective s, additional
statisticians and programmers will become unblinded at the participant level to prepare 
unblinded anal yses and other regulatory  activities. A group of statisticians and 
programmers will remain blinded and continue support ingthe blinded conduct of the 
study .
After the study  data used for submission become public, the blinded study  team will also 
have access to th osedata, 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 y ears of age who will be enrolled 
to receive a third and fourth dose of BNT162b2 SA, through 1 month after their first dose of 
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Page 90BNT162b2 SAthe participant s 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 study visit ,as follows:
Phase 1 (after Visit 8 ).
Phase 2/3, ≥16 y ears (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).
6.3.4. Breaking the Blind
The I RT 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 safet y 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 vaccin eassignment 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 r ecorded in the source documentation and CRF.
The study -specific I RT reference manual and I P manual will provide the contact information 
and further details on the use of the IRT s ystem.
Instructions on how to unblind participants ahead of administration of BNT162b2 to placebo
recipients, or for other, nonemergency  reasons, will be provided separatel y: this unblinding 
will NOT be performed in the I RT. The date (that the participant becomes aware of study  
intervention allocation) and reason that the blind wa s 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 stud y intervention and study participant identification will be confirmed at the 
time of dosing b y a member of the stud y site staff other than the person administering the 
study  intervention.
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