125742 45 S211 M5 c4591001 interim ado mth6 protocol

Document text

PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 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.
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 1
FDA-CBER-2022-5812-0224836
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 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 18 07September 2021 Addition of procedures for monitoring potential 
myocarditis or pericarditis. 
Addition of a third dose of BNT16 2b2 for 
participants who meet specified 
recommendations and have not yet recei ved a 
third dose.
Added corresponding objectives, estimands, 
and endpoints .
Added corresponding SoA and procedures .
Added details in the s tatistical methods
sections .
Added the instruction that participants who 
receive COVID -19 vaccines outside of the study 
from protocol amendment 18 onwards should be 
withdrawn .
Protocol amendment 17 20 July 2021 Changed the analysis method for the within -
group comparison of seroresponse rates for 
Phase 3 booster and VOC immunogenicity 
asses sment from the Miettinen and Nurminen 
method to the adjusted Wald interval to provide 
tighter CI and higher pow er for NI in most cases .
Clarified that any nonstudy coronavirus vaccines 
are to be recorded at any time they are given 
during study participatio n.
Clarified that participants who are randomized in 
the C4591031 study should be w ithdrawn from 
this study.
Protocol amendment 16 28 May 2021 Removed the requirement to conduct a potential 
COVID -19 convalescent visit following each 
potential COVID -19 illness visit.
Clarified that only non -Pfizer interventional 
studies for prevention of COVID -19are 
prohibited throughout study participation .
Clarified that d uring the 7 days following each 
vaccination (either as part of this study, 
co-enrolled C459 studi es, or the B7471026 
[20vPnC] study) , potential COVID -19 symptoms 
that overlap with specific systemic events 
(ie,fever, chills, new or increased muscle pain, 
diarrhea, vomiting) should not trigger a potential 
COVID -19 illness visit unless, in the 
investiga tor’s opinion, the clinical picture is 
more indicative of a possible COVID -19 illness 
than vaccine reactogenicity.
Revised the noninferiority margin from 2 -fold to 
1.5-fold and added a minimum GMR point 
estimate of ≥0.8 as another success criterion for 
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 2
FDA-CBER-2022-5812-0224837
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 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
Phase 3 booster and VOC immunogenicity 
assessment. Noninferiority is met if the lower 
limit of the alpha- adjusted CI for the GMR is 
>0.67 and the point estimate of the GMR is ≥0.8.
Added Phase 1 booster participants to the Dose 3 
booster immunogenicity population definitions.
Included a booster safety population definition.
Clarified that the interim analyses for booster 
immunogenicity will be conducted when 
serology data for the reference strain or for the 
SA strain are available.
Protocol amendment 15 25 Ma rch 2021 In order to further characterize booster responses 
induced by BNT162b2, 2 additional lower -dose 
booster groups have been added to the subset for 
evaluation of boostability and protection against 
emerging VOCs . An additional 5 -µg or 10 -µg 
dose of B NT162b2 w ill be given to 
approximately 144 Phase 3 participants 
approximately 5 to 7 months after their second 
dose of BNT162b2.
To further describe cell -mediated immune 
responses following isolations of PBMCs in a 
subset of both the Phase 3 participants w ho 
receive a single booster vaccination and the 
BNT162b2 -naïve group who receive 
BNT162b2 SA,additional genetic testing may also 
be performed; corresponding details and an 
appendix have been added.
An exploratory objective was added for Phase 3 
participants to describe the immune response to a 
third dose of BNT162b2 or a third or fourth dose 
of BNT162b2 SAat later time points to align with 
analyses and corresponding changes detailed in 
the statistical section. 
Removed the lower age limit for eligib ility for 
administration of BNT162b2 to t hose originally 
assigned to placebo : this will now  be covered in 
the recommendations detailed separately, and 
available in the electronic study reference portal .
Allowed a dministration of BNT162b2 at 
Visits 101 and 102 to pregnant participants in 
certain circumstances.
To align with contraception requirements, 
reduced the EDP reporting period to 28 days 
after the last dose of study intervention.
Protocol amendment 14 02 March 2021 In order to further describe duration of 
protection, and heterologous/homologous 
protection against the emerging VOCs, an 
additional dose of BNT162b2 or BNT162b2 SA 
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 3
FDA-CBER-2022-5812-0224838
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 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
will be given to approximately 600 Phase 3 
participants approximately 5 to 7 months after 
their second dose of BNT162b2; a further dose 
of BNT162b2 SAwill be given to approximately 
30 of 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 SA to describe 
heterologous/homologous protection against the 
emerging VOCs and reference strains:
Added corresponding objectives, 
estimands, and endpoints
Added corresponding SoA and 
procedures
Added details in the s tatistical methods
sections .
Cell-mediated immune responses will also be 
described follow ing isolations of PBMCs in a 
subset of both the Phase 3 participants who 
receive a single booster vaccination a nd the 
BNT162b2 -naïve group who receive 
BNT162b2 SA.
Added the asymptomatic case definitions in 
Section 8.1 and further clarified the secondary 
definition for asymptomatic case based on 
seroconversion of N-binding antibody.
Defined the analysis populations used for 
evaluation of asymptomatic infection based on 
seroconversion of N -binding antibody and based 
on NAAT from participants who consent to 
active surveillance.
Clarified that unblinding for a nonemergency 
reason should be conducted outside of the IRT 
system.
Clarified that if multiple visits occur on the same 
day, all procedures for all visits must be 
conducted (including collection of all blood 
samples).
Clarified the plan for stepwise unblinding of the 
sponsor in the study.
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 4
FDA-CBER-2022-5812-0224839
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 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
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 BNT162b1 
or BNT162b2: 
Added corresponding objectives, 
estimands, and endpoints
Added corresponding SoA and 
procedures
Added details in the s tatistical methods
sections .
Clarified the population used for analysis of 
reactogenicity endpoints.
To align with current recommendations, 
investigators may exercise jud gment on review 
of inclusion and exclusion criteria 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 s tudy, 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 dose in the event a 
participant received only 1 dose of BNT162b2.
Protocol amendment 12 14 January 2021 Because of a formatting error in protocol 
amendment 11, exclusion criterion 4 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 whi ch 
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 
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 participate in 
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 5
FDA-CBER-2022-5812-0224840
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 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
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 those who received it subsequently do not 
have blood drawn).
In line with current recommen dations, removed 
the requirement to discontinue study 
intervention because of a diagnosis of 
COVID -19 during the study.
Protocol amendment 11 04 January 2021 Added approaches to evaluate efficacy against 
asymptomatic SARS -CoV -2 infection:
Added objective s, estimands, and endpoints, 
and statistical methods, for assessment via 
N-binding antibody seroconversion;
Added a potential intensive surveillance 
period for nasal sw abbing, for assessment via 
NAAT:
Corresponding objectives, estimands, and 
endpoints added
Corresponding SoA and procedures 
added
Details added in the s tatistical 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 a ny Phase 1 
placebo re cipient 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 years of age. 
Protocol amendment 10 01 December 2020 Added the possibility of administering 
BNT162b2 to participants who originally 
received placebo, following any local or national 
recommendations.
Added the possibility of administering 
BNT162b2 to participants who originally 
received placebo, following completion of the 
active safety surveillance period.
Added corresponding exploratory objectives and 
statistical analysis details.
Removed immunogenicity analyses of titers 
greater than defined threshold(s).
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 6
FDA-CBER-2022-5812-0224841
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 7Document History
Document Version Date Summary and Rationale for Changes
Removed the need for blinded COVID -19 case 
review after the final efficacy analysis.
Included the possibility , due to local 
circumstances related to the COVID -19 
pandemic, that study procedures that do not 
require in -person participant contact may be 
performed by telehealth .
In light of additional information to better 
estimate the standard deviation of SARS -CoV- 2 
neutralizing titers , increased the sample size for 
the noninferiority immunogenicity analysis in 
adolescents 12 to 15 years of age.
Protocol amendment 9 29 October 2020 To better align with the natural history of 
SARS -CoV- 2 infection , added Phase 2/3 
secondary efficacy objectives, estimands, and 
endpoints to include COVID- 19 cases that occur 
from 14 days after th e second dose; also 
modified the existing secondary efficacy 
objectives, estimands, and endpoints to include 
COVID -19 cases that occur from 14 days, as 
well as 7 days, after the second dose;
Made corresponding changes to the study 
design, study assessments and procedures, 
and statistical analysis sections.
For operational reasons, removed the interim 
analysis planned after accrual of 32 cases.
Clarified that interim analyses will be conducted 
after accrual of at least 62, 92, and 120 cases.
Included any participants 16 through 17 years of 
age enrolled under this amendment in the 
reactogenicity subset.
Added an unblinded clinical scientist to support 
DMC activities.
Clarified that 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.
Clarified that the “Process 1” participants 
included in the descriptive analysis of 
“Process 1”-and “Process 2”- manufactured 
study interventions will be selected randomly.
Clarified that surv eillance of potential 
COVID -19 symptoms should continue even if a 
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 7
FDA-CBER-2022-5812-0224842
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 8Document History
Document Version Date Summary and Rationale for Changes
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 amendme nt 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 dos e refers to second dose.
Added an additional exploratory objective to 
describe safety and immunogenicity in 
participants 16 to 55 years of age vaccinated 
with study intervention produced by 
manufacturing “Process 1” or “Process 2.”
Clarified exclusion criterion 5.
Added Section 6.1.1 to describe manufacturing 
“Process 1” and “Process 2.”
Clarified the degree of unblinding on the 
unblinded submissions team in Section 6.3.3 .
Made provision for a second dose of BNT162b2 
in participants who were affected by a 
medication error at Visit 2 in Section 6.6 .
Provided further clarification regarding 
discontinuation of study intervention in 
Section 7.1 .
Modified the circumstances in which a local 
NAAT result may be used in the COVID -19 
case definition.
Added that 2 periods of potential COVID -19 
symptoms within 4 days will be considered as a 
single illness.
Provided guidance in Section 8.13 regarding 
circumstances in which a SARS -CoV- 2 test 
might be required even if symptoms within 7 
days following each vaccination a re considered 
more likely due to vaccine reactogenicity.
Made allow ance in Section 8.13 for a second 
SARS -CoV -2 test to be performed within the 
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 8
FDA-CBER-2022-5812-0224843
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 9Document History
Document Version Date Summary and Rationale for Changes
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 hypothesis 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 various 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 of blood draw s to ~20 mL.
Removed the need to have safety data reported 
for participants to be included in the safety 
object ive assessment.
Added an exploratory objective to describe 
safety, immunogenicity, and efficacy in 
participants with stable HIV disease.
Increased the sample size for Phase 2/3 to 
~43,998.
Clarified that inclusion criterion 4 (ie, 
participants at higher ri sk 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 a nd removed the 
upper age limit for inclusion in Phase 2/3 in 
order to evaluate BNT162b2 30 µg in older 
adolescents and those over 85 years of age; 
updated the title and other references to adults to 
align with this change.
Renamed the immunological assays to align 
with other program -level documents.
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 9
FDA-CBER-2022-5812-0224844
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 10Document History
Document Version Date Summary and Rationale for Changes
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 
discontinu ation 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 th at 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 unblinded in Phase 2/3.
Clarified which stopping rules apply to which 
phase of the study.
In addition:
Clarified the AE reporting requirements for 
potential COVID -19 illnesses.
Updated that Visit 1 may be conducted across 2 
consecutive days in Phase 2/3.
Moved the immunogenicity objectives in 
Phase 2/3 to become exploratory.
Added an additional inclusion criterion to enroll 
participants who, in the judgment of the 
investigator, are at risk for acquiring COVID -19.
Modified exclusion criterion 5, so that 
participants with a p revious clinical or 
microbiological diagnosis of COVID -19are 
excluded from all phases of the study.
Clarified that there will be 2 all -available 
efficacy popul ations.
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 10
FDA-CBER-2022-5812-0224845
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 11Document History
Document Version Date Summary and Rationale for Changes
Clarified that immunogenicity samples will be 
draw n for all participants; analyses will be based 
upon results from subsets of samples, according 
to the purpose.
Updated that the 3 -tier approach to summarizing 
AEs will only be performed in Phase 2/3 .
Updated that at each interim analysis for 
efficacy, only the first primary objective 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 Stage 3 
participants, to allow  collection of an 
immunogenicity blood sample.
The COVID- 19 illness visit has now added 
flexibility to permit a remote or in -person visit.
The COVID- 19 illness symptoms have been updated 
to align with the FDA- accepted definitions; this 
change is also reflected in the criteria for temporary 
delay of enrollment.
AEs that occur between consent and dosing will now 
be reported on the AE (rather tha n Medical History) 
CRF, to align with the latest Pfizer protocol 
template.
Changes have been made to the headings to align 
with the latest Pfizer protocol template.
Clarified that only an unblinded site staff member 
may obtain the participant’s randomiza tion number 
and study intervention allocation. 
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 11
FDA-CBER-2022-5812-0224846
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 12Document History
Document Version Date Summary and Rationale for Changes
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 
investigator, participants may utilize a COVID -19 
illness e -diary.
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 12
FDA-CBER-2022-5812-0224847
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 13Document History
Document Version Date Summary and Rationale for Changes
Protocol 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, BNT162b 1, 
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 
abnorma lities 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 submitted 
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 decision to 
progress group(s) into Stages 2 and 3 can be 
based upon safety and immunogenicity data 
after Dose 1 or 2
Clarified safety data requirements to permit dose 
escalation
Amended text so that the progression to 
participants 65 to 85 years of age can be based 
upon data from the same RNA platform
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 13
FDA-CBER-2022-5812-0224848
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 14Document History
Document Version Date Summary and Rationale for Changes
Incorporated a protocol administrative change to 
correct the variant designation and the encoded 
antigen to BNT162c2
Clarifi ed that the SARS -CoV -2 neutralizing 
assay does not employ wild -type virus
Clarified that the SARS -CoV -2 spike protein –
binding antibody assay is specific for the S1 
subunit
Clarified that efficacy against COVID -19 is 
based upon illness (not infection) rate ratio
Incorporated a protocol administrative change to 
state that the study placebo may be supplied in a 
glass or plastic vial
Corrected a typographical error in Section 6.5.1 
regarding the time frame for prior receipt of 
blood/plasma products or immunoglo bulins
Corrected a typographical error in Table 2 
regarding the lower limit of diameter (cm) for 
mild redness and swelling
Updated the °C fever scale in Table 4 to ensure 
that all potential °F values are correctly assigned
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 , phy sical 
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 platform rather than a specific vaccine 
candidate
Original protocol 15April 2020 N/A
This amendment incorporates all revisions to date, includin g amendments made at the 
request of country  health authorities and IRBs/ECs.
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 14
FDA-CBER-2022-5812-0224849
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 15TABLE OF CONTENTS
LIST OF TABLES ................................ ................................ ................................ ................... 23
LIST OF FIGURES ................................ ................................ ................................ ................. 24
1. PROTOCOL  SUMMARY ................................ ................................ ................................ ...25
1.1. Sy nopsis ................................ ................................ ................................ .................. 25
1.2. Schema ................................ ................................ ................................ .................... 39
1.3. Schedule of Activities ................................ ................................ ............................. 40
1.3.1. Phase 1 ................................ ................................ ................................ ........ 40
1.3.2. Phase 2/3................................ ................................ ................................ .....47
1.3.3. Administration of BNT162b2 to Those Originall y Assigned to 
Placebo ................................ ................................ ................................ ............. 51
1.3.4. Administration of an Additional Dose of BNT162b2 (5, 10, or 
30µg) or BNT162b2 SA(30µg) (Subset for Evaluation of Boostability  
and Protection Against Emerging VOCs)................................ ........................ 53
1.3.5. Administration of BNT162b2 SAto BNT162b2 -Naïve Participants ........... 56
1.3.6. Surveillance for Asy mptomatic SARS -CoV -2 Infection ........................... 59
1.3.7. Administration of a Third Dose of B NT162b2 to Participants Who 
Have Not Previousl y Received a Third Dose ................................ .................. 60
2. INTRODUCTION ................................ ................................ ................................ ............... 62
2.1. Study  Rationale ................................ ................................ ................................ .......62
2.2. Background ................................ ................................ ................................ ............. 62
2.3. Clinical Overview ................................ ................................ ................................ ...64
2.4. Benefit/Risk Assessment................................ ................................ ......................... 64
2.4.1. Risk Assessment ................................ ................................ ......................... 66
2.4.2. Benefit Assessment ................................ ................................ ..................... 68
2.4.3. Overall Benefit/Risk Conclusion ................................ ................................ 68
3. OBJECTI VES, ESTIMANDS, AND ENDPOINTS ...........................................................68
3.1. For Phase 1 ................................ ................................ ................................ .............. 68
3.2. For Phase 2/3 ................................ ................................ ................................ ........... 70
4. STUDY DESIGN ................................ ................................ ................................ ................. 77
4.1. Overall Desig n................................ ................................ ................................ ......... 77
4.1.1. Phase 1 ................................ ................................ ................................ ........ 78
4.1.2. Phase 2/3................................ ................................ ................................ .....79
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 15
FDA-CBER-2022-5812-0224850
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 164.2. Scientific Rationale for Study  Design ................................ ................................ .....82
4.3. Justification for Dose ................................ ................................ .............................. 83
4.4. End of Study  Definition ................................ ................................ .......................... 84
5. STUDY POPUL ATION ................................ ................................ ................................ ......84
5.1. I nclusion Criteria ................................ ................................ ................................ .....84
5.2. Exclu sion Criteria ................................ ................................ ................................ ....85
5.3. L ifesty le Considerations ................................ ................................ .......................... 88
5.3.1. Contraception ................................ ................................ .............................. 88
5.4. Screen Failures ................................ ................................ ................................ ........ 88
5.5. Criteria for Temporarily  Delay ing Enrollment/Randomization/Study  
Intervention Administration ................................ ................................ ...................... 88
6. STUDY INTERVENTIO N................................ ................................ ................................ ..89
6.1. Study  Intervention(s) Administered ................................ ................................ ........ 90
6.1.1. Manufacturing Process ................................ ................................ ............... 90
6.1.2. Administration ................................ ................................ ............................ 91
6.2. Prepara tion/Handling/Storage/Accountability ................................ ........................ 92
6.2.1. Preparation and Dispensing ................................ ................................ ........ 93
6.3. Measures to Minimize Bias: Randomization and Blinding ................................ .....93
6.3.1. Allocation to Study Intervention ................................ ................................ 93
6.3.2. Blinding of Site Personnel ................................ ................................ .......... 93
6.3.3. Blinding of the Sponsor................................ ................................ .............. 94
6.3.4. Breaking the Blind ................................ ................................ ...................... 95
6.4. Study  Intervention Compliance ................................ ................................ ............... 96
6.5. Concomitant Therapy ................................ ................................ .............................. 96
6.5.1. Prohibited During the Study ................................ ................................ .......97
6.5.2. Permitted During the Study ................................ ................................ ........ 97
6.6. Dose Modification ................................ ................................ ................................ ...98
6.7. I ntervention After the End of the Study ................................ ................................ ..98
7. DI SCONTINUATION O F STUDY INTERVENTION AND PARTI CIPANT 
DISCONTINUATION/WI THDRAWAL ................................ ................................ ........... 99
7.1. Discontinuation of Study  Intervention ................................ ................................ ....99
7.2. Participant Discontinuation/Withdrawal From the Study ................................ .......99
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 16
FDA-CBER-2022-5812-0224851
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 177.2.1. Withdrawal of Consent ................................ ................................ ............. 100
7.3. L ost to Follow -up ................................ ................................ ................................ ..101
8. STUDY A SSESSMENTS AND PROCE DURES ................................ ............................. 101
8.1. Efficacy  and/or Immunogenicity Assessments ................................ ..................... 102
8.1.1. Efficacy  Against COVID -19 ................................ ................................ ....102
8.1.2. Efficacy  Against Asy mptomatic SARS -CoV -2 Infection ........................ 104
8.1.2.1. Seroconversion of N -Binding Antibod y ................................ .105
8.1.2.2. NAAT -Confirmed SARS -CoV -2 Infection ............................ 105
8.1.3. Vaccine -Induced Immunogenicit y................................ ............................ 105
8.1.4. Biological Samples ................................ ................................ ................... 106
8.1.5. Surveillance for Asy mptomatic SARS -CoV -2 Infection ......................... 106
8.2. Safet y Assessments ................................ ................................ ............................... 107
8.2.1. Clinical Safety  Laboratory  Assessments (Phase 1 Participants Onl y).....107
8.2.2. Electronic Diary ................................ ................................ ........................ 108
8.2.2.1. Grading Scales ................................ ................................ ......... 109
8.2.2.2. L ocal Reactions ................................ ................................ .......109
8.2.2.3. Sy stemic Events ................................ ................................ ......110
8.2.2.4. Fever ................................ ................................ ........................ 111
8.2.2.5. Antipy retic Medication ................................ ........................... 111
8.2.3. Phase 1 Stopping Rules ................................ ................................ ............ 111
8.2.4. Surveillance of Events That Could Represent Enhanced COVID -19 
and Phase 2/3 Stopping Rule ................................ ................................ ......... 113
8.2.5. Randomization and Vaccination After a Stopping Rule Is Met ............... 113
8.2.6. Pregnancy  Testing ................................ ................................ .................... 114
8.3. Adverse Events and Serious Adverse Events................................ ........................ 114
8.3.1. Time Period and Frequency  for Collecting AE and SAE Information .....114
8.3.1.1. Reporting SAEs to Pfizer Safety ................................ ............. 116
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF................. 116
8.3.2. Method of Detecting AEs and SAEs ................................ ........................ 116
8.3.3. Follow -up of AEs and SAEs ................................ ................................ .....116
8.3.4. Regulatory Reporting Requirements for SAEs ................................ ......... 117
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 17
FDA-CBER-2022-5812-0224852
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 188.3.5. Exposure During Pregnancy  or Breastfeeding, and Occupational 
Exposure ................................ ................................ ................................ ........ 117
8.3.5.1. Exposure During Pregnancy ................................ .................... 117
8.3.6. Exposure During Breastfeeding ................................ ................................ 119
8.3.6.1. Occupational Exposure ................................ ........................... 119
8.3.7. Cardiovascular and Death Events ................................ ............................. 119
8.3.8. Disease -Related Events and/or Disease -Related Outcomes Not 
Qualifying as AEs or SAEs ................................ ................................ ............ 120
8.3.9. Adverse Events of Speci al Interest ................................ ........................... 120
8.3.9.1. Lack of Efficacy ................................ ................................ ......120
8.3.10. Medical Device Deficiencies ................................ ................................ ..120
8.3.11. Medication Errors ................................ ................................ ................... 120
8.4. Treatment of Overdose................................ ................................ .......................... 121
8.5. Pharmacokinetics ................................ ................................ ................................ ..122
8.6. Pharmacod ynamics ................................ ................................ ................................ 122
8.7. Genetics ................................ ................................ ................................ ................. 122
8.8. Biomarker s ................................ ................................ ................................ ............ 122
8.9. I mmunogenicit y Assessments ................................ ................................ ............... 122
8.10. Health Economics ................................ ................................ ............................... 122
8.11. Study  Procedures ................................ ................................ ................................ .123
8.11.1. Phase 1 ................................ ................................ ................................ ....123
8.11.1.1. Screening: (0 to 28 Day s Before Visit 1) .............................. 123
8.11.1.2. Visit 1 – Vaccination 1: (Day  1) ................................ ........... 124
8.11.1.3. Visit 2 – Next -Day Follow -up Visit (Vaccination 1): (1 
to 3 Day s After Visit 1) ................................ ................................ ...126
8.11.1.4. Visit 3 – 1- Week Follow -up Visit (Vaccination 1): (6 to 
8 Days After Visit 1) ................................ ................................ .......127
8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Day s After Visit 1) ......... 129
8.11.1.6. Visit 5 – 1- Week Follow -up Visit (Vaccination 2): (6 to 
8 Day s After Visit 4) ................................ ................................ .......131
8.11.1.7. Visit 6 – 2- Week Follow -up Visit (Vaccination 2): (12 to 
16 Day s After Visit 4) ................................ ................................ .....132
8.11.1.8. Visit 7 – 1- Month Follow -up Visit: (28 to 35 Day s After 
Visit 4) ................................ ................................ ............................. 133
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 18
FDA-CBER-2022-5812-0224853
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 198.11.1.9. Visit 8 – 6- Month Follow -up Visit: (175 to 189 Day s 
After Visit 4) ................................ ................................ .................... 134
8.11.1.10. Between Visits 8 and 9 ................................ ........................ 134
8.11.1.11. Visit 8a – Vaccination 3: (175 to 315 Day s After 
Vaccination 2) ................................ ................................ ................. 134
8.11.1.12. Visit 8b – 1- Week Follow -up Visit (After Vaccination 
3): (6 to 8 Day s After Visit 8a) ................................ ........................ 136
8.11.1.13. Visit 8c – 1 -Month Follow -up Visit (After Vaccination 
3): (28 to 35 Days After Visit 8a) ................................ .................... 137
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 
Received BNT162b1 or BNT162b2 or Placebo Recipients Who 
Decline BNT162b2 ................................ ................................ .......... 138
8.11.1.15. Visit 10 – 24- Month Follow -up Vis it: (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 ................................ ................................ .......... 138
8.11.2. Phase 2/3................................ ................................ ................................ .138
8.11.2.1. Visit 1 – Vaccination 1: (Day  1) ................................ ........... 138
8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Day s After Visit 1) ......... 141
8.11.2.3. Visit 3 – 1- Month Follow -up Visit (After Vac cination 2): 
(28 to 35 Day s After Visit 2) ................................ ........................... 143
8.11.2.4. Visit 4 – 6- Month Follow -up Visit: (175 to 189 Day s 
After Visit 2) ................................ ................................ .................... 144
8.11.2.5. Visit 5 – 12- Month Follow -up Visit: (350 to 378 Day s 
After Visit 2): Onl y for Those Participants Who Originall y 
Received BNT162b2 or Placebo Recipients Who Decline 
BNT162b2 ................................ ................................ ....................... 145
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 ................................ ................................ ....................... 145
8.12. Unscheduled Vi sit for a Grade 3 or Suspected Grade 4 Reaction ...................... 146
8.13. COVID -19 Surveillance (All Participants) ................................ ......................... 147
8.13.1. Potential COVI D-19 Illness Visit: (Optimally Within 3 Day s After 
Potential COVI D-19 Illness Onset) ................................ ............................... 148
8.13.2. Potential COVI D-19 Convalescent Visit: (28 to 35 Day s After 
Potential  COVI D-19 Illness Visit) ................................ ................................ 149
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 19
FDA-CBER-2022-5812-0224854
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 208.14. Communication and Use of Technology ................................ ............................. 150
8.15. SARS -CoV -2NAAT Results ................................ ................................ .............. 150
8.16. Procedures for Administration of BNT162b2 to Those Originally  Assigned 
to Placebo ................................ ................................ ................................ ................ 151
8.16.1. Visit 101 – Vaccination 3: (From Recommendation or at Least 175 
Days After Vaccination 2) ................................ ................................ ............. 151
8.16.2. Visit 102 – Vaccination 4: (19 to 23 Day s After Visit 101) ................... 153
8.16.3. Visit 103 – 1- Month Follow -up Telephone Contact (After 
Vaccination 4): (28 to 35 Days After Visit 102) ................................ ............ 154
8.16.4. Visit 104 – 6- Month Follow -up Telephone Contact (After 
Vaccination 4): (175 to 189 Days After Visit 102) ................................ ........ 154
8.16.5. Visit 105 – 18- Month Follow -up Telephone Contact (After 
Vaccination 4): (532 to 560 Days After Visit 102) ................................ ........ 155
8.17. Administ ration of an Additional Dose of BNT162b2 (5, 10, or 30 µg) or 
BNT162b2 SA (30µg) (Subset for Evaluation of Boostability  and Protection 
Against Emerging VOCs) ................................ ................................ ........................ 155
8.17.1. Visit 301 – Vaccination 3: (150 to 210 Days After Visit 2) ................... 156
8.17.2. Visit 302 – 1- Week Follo w-up Visit (After Vaccination 3): (6 to 8 
Days After Visit 301) ................................ ................................ ..................... 158
8.17.3. Visit 303 – 1- Month Follow -up Visit (After Vaccination 3): (28 to 
35 Day s After Visit 301) ................................ ................................ ................ 159
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................................ ................................ ..................... 160
8.17.5. Visit 305 – 1- Month Follow -up Visit (Vaccination 4): (28 to 35 
Days After Visit 303): Only for Those Participants Who Re ceived a 
fourth dose of BNT162b2 SA................................ ................................ ........... 161
8.17.6. Visit 306 – 6- Month Follow -up Visit: (175 to 189 Day s After Visit 
301): ................................ ................................ ................................ ............... 162
8.17.7. Visit 307 – 18- Month Follow -up Visit: (532 to 560 Day s After 
Visit 301): ................................ ................................ ................................ ......162
8.18. Administration of BNT162b2 SAto BNT162b2 -naïve Participants ..................... 163
8.18.1. Visit 401 – Vaccination 1: (Day  1)................................ ......................... 163
8.18.2. Visit 402 – Vaccination 2: (19 to 23 Day s After Visit 401) ................... 165
8.18.3. Visit 403 – 1- Week Follow -up Visit (After Va ccination 2): (6 to 8 
Days After Visit 402) ................................ ................................ ..................... 167
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 20
FDA-CBER-2022-5812-0224855
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 218.18.4. Visit 404 – 1- Month Follow -up Visit (After Vaccination 2): (28 to 
35 Day s After Visit 402) ................................ ................................ ................ 168
8.18.5. Visit 405 – 6- Month Follow -up Visit: (175 to 189 Day s After Visit 
402) ................................ ................................ ................................ ................ 168
8.18.6. Visit 406 – 18- Month Follow -up Visit: (532 to 560 Day s After 
Visit 402) ................................ ................................ ................................ .......169
8.19. Surveillance for Asy mptomatic SARS -CoV -2 Infection ................................ ....169
8.19.1. Visit 201 –Asymptomatic SARS -CoV -2 Infection Surveillance 
Consent: From Approval of Protocol Amendment 11 ................................ ...170
8.19.2. Visit 202 Onward –Asympto matic SARS -CoV -2 Infection 
Surveillance Swab: Repeating Every  10 to 18 Days After Each Previous 
Surveillance Swab Collection ................................ ................................ ........ 171
8.20. Administration of a Third Dose of BNT162b2 to Participants Who Have 
Not Previously  Received a Third Dose ................................ ................................ ...171
8.20.1. Visit 501 – Third Dose of BNT162b2 ................................ .................... 172
8.20.2. Visit 502 – 1- Month Follow -up Telephone Contact: (28 to 35 Day s 
After Visit 501) ................................ ................................ .............................. 173
8.20.3. Visit 503 – 6- Month Follow -up Telephone Contact: (175 to 189 
Days After Visit 501) ................................ ................................ ..................... 174
8.20.4. Visit 504 – 12- Month Follow -up Visit: (350 to 378 Day s After 
Visit 501): ................................ ................................ ................................ ......174
8.21. Additional Procedures for Monitoring of Potential My ocarditis or 
Pericarditis ................................ ................................ ................................ ............... 175
9. STATI STICAL CONSI DERATIONS ................................ ................................ .............. 175
9.1. Estimands and Statistical Hy potheses ................................ ................................ ...175
9.1.1. Estimands ................................ ................................ ................................ ..175
9.1.2. Statistic al Hy potheses ................................ ................................ ............... 176
9.1.2.1. Statistical Hy pothesis Evaluation for Efficacy ........................ 176
9.1.2.2. Statistical Hy pothesis Evaluation for Immunogenicity ........... 176
9.2. Sample Size Determination ................................ ................................ ................... 178
9.2.1. Phase 1 ................................ ................................ ................................ ......178
9.2.2. Efficacy  Against COVID -19 ................................ ................................ ....178
9.2.3. Efficacy  Against Asy mptomatic Infection ................................ ............... 179
9.2.4. I mmunogenicit y Bridging of 12 to 15 Years to 16 to 25 Years ............... 179
9.2.5. Boostability  and Protection Against Emerging SARS -CoV -2 VOCs ......179
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 21
FDA-CBER-2022-5812-0224856
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 229.2.6. Safet y ................................ ................................ ................................ ........ 181
9.3. Analy sis Se ts................................ ................................ ................................ ......... 182
9.4. Statistical Analy ses................................ ................................ ............................... 184
9.4.1. I mmunogenicit y Analyses ................................ ................................ ........ 184
9.4.2. Efficacy  Anal yses................................ ................................ ..................... 194
9.4.3. Safet y Anal yses................................ ................................ ........................ 200
9.4.4. Other Anal yses................................ ................................ .......................... 202
9.5. I nterim Anal yses................................ ................................ ................................ ...202
9.5.1. Ana lysis Timing ................................ ................................ ........................ 205
9.6. Data Monitoring Committee or Other Independent Oversight Committee ........... 206
10. SUPPORTING DOCUM ENTATION AND OPERATI ONAL 
CONSI DERATIONS ................................ ................................ ................................ ........ 208
10.1. Appendix 1: Regulatory , Ethical, and Study  Oversight Considerations ............. 208
10.1.1. Regulatory and E thical Considerations ................................ .................. 208
10.1.1.1. Reporting of Safety  Issues and Serious Breaches of the 
Protocol or I CH GCP ................................ ................................ .......208
10.1.2. I nformed Consent Process ................................ ................................ ......209
10.1.3. Data Protection ................................ ................................ ....................... 210
10.1.4. Dissemination of Clinical Study  Data ................................ .................... 210
10.1.5. Data Qualit y Assurance ................................ ................................ .......... 211
10.1.6. Source Documents ................................ ................................ .................. 213
10.1.7. Study  and Site Start and Closure ................................ ............................ 213
10.1.8. Sponsor’s Qualified Medical Personnel ................................ ................. 214
10.2. Appendix 2: Clinical Laboratory  Tests ................................ ............................... 215
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recor ding, 
Evaluating, Follow -up, and Reporting ................................ ................................ ....217
10.3.1. Definition of AE ................................ ................................ ..................... 217
10.3.2. Definition of SAE ................................ ................................ ................... 218
10.3.3 . Recording/Reporting and Follow- up of AEs and/or SAEs ..................... 220
10.3.4. Reporting of SAEs................................ ................................ .................. 223
10.4. Appendix 4: Contraceptive Guidance ................................ ................................ .224
10.4.1. Male Participant Reproductive Inclusion Criteria ................................ ..224
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 22
FDA-CBER-2022-5812-0224857
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 2310.4.2. Female Participant Reproductive Inclusion Criteria ............................... 224
10.4.3. Woman of Childbearing Potential ................................ .......................... 225
10.4.4. Contraception Methods ................................ ................................ ........... 226
10.5. Appendix 5: L iver Safety : Suggested Actions and Follow -up Assessments ......228
10.6. Appendix 6: Abbreviations ................................ ................................ ................. 230
10.7. Appendix 7: Stopping and Alert Rules for Enhanced COVID -19 ...................... 234
10.8. Appendix 8: Criteria for A llowing Inclusion of Participants With Chronic 
Stable HIV, HCV, or HBV Infection ................................ ................................ ......237
10.9. Appendix 9: Genetics ................................ ................................ .......................... 238
11. REFERENCES ................................ ................................ ................................ ................ 239
LIST OF TABLES
Table 1. Local Reaction Grading Scale ................................ ................................ 109
Table 2. Systemic Event Grading Scale ................................ ................................ 110
Table 3. Scale for Fever ................................ ................................ ........................ 111
Table 4. Power Anal ysis for Noninferiorit y Assessment ................................ .....179
Table 5. Probability  of Observing at Least 1 AE by  Assumed True Event 
Rates With Different Sample Sizes ................................ ........................ 181
Table 6. Interim Anal ysis Plan and Boundaries for Efficacy  and Futility ............ 203
Table 7. Statistical Design Operating Characteristics: Probability  of Success 
or Failure for Interim Analy ses................................ ............................... 204
Table 8. Statistical Design Operating Characteristics: Probability  of Success 
for Final Anal ysis and Overall ................................ ................................ 204
Table 9. Laboratory  Abnormality  Grading Scale ................................ ................. 215
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) ................................ .................... 235
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) ................................ ................................ .............. 236
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 23
FDA-CBER-2022-5812-0224858
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 24LIST OF FIGURES
Figure 1. Multiplicity  Schema ................................ ................................ ................ 178
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 24
FDA-CBER-2022-5812-0224859
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 251.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 s evere 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 pandemic , which continues to spread globall y at high speed. Todate, more 
than 215 million people have been infected with SARS -CoV -2 and >4 million have died, 
demonstrating an urgent need for efficacious vaccines.
Numerous COVID -19 vaccines are currentl y in development globall y,and several candidate 
COVID -19 vaccines ( eg,mRNA vaccines and adenovirus -vectored vaccines expressing the 
S protein) have been shown to be efficacious in the prevention of COVID-19 in clinical 
studies and are now available under temporary  or emergency  authorizations. BNT162b2 ,an 
RNA -based COVID -19 vaccine given as a 2 -dose series administered 21 day s apart, was 
shown to be safe and effective in a Phase 1/2/3 study  and has received authorizations for 
temporary  or emergency  use or marketing authorizations in multiple countries and has been 
fully  licensed for use in individuals 16 y ears of age and above in the US as of 23 Aug 2021.
BioNTech has developed RNA -based vaccine candidates using a platform approach that 
enables the rapid development of vaccines against emergi ng 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 .
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 25
FDA-CBER-2022-5812-0224860
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 26Objectives , 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 , 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 labora tory 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
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
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 26
FDA-CBER-2022-5812-0224861
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 27Objectives 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 s/GMTsat the time of 
Dose 3 and 7days and 1 month 
after Dose 3.
 GMFRs from before Dose 3 to 7 
days 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 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 reacti ons (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
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 27
FDA-CBER-2022-5812-0224862
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 28For 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 
interv ention:
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
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 28
FDA-CBER-2022-5812-0224863
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 29ObjectivesaEstimands 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
participants in the su bset for 
evaluation of boostability and 
protection against emerging VOCsIn 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
To describe the safety and tolerability 
profile of BNT162b2 given as a third 
dose at least 6 months after the second
dose of BNT162b2 (or BNT162b2 SA)
for participants who received a third 
dose as part of protocol 
amendment 18In participants receiving at least 
1dose of study intervention , the 
percentage of participants reporting:
AEs from Dose 3 to 1 month after 
Dose 3
SAEs from Dose 3to 6months 
after Dose 3AEs
SAEs
Prim ary Immunogenicity
BNT162b2 -experienced participants 
Todemonstrate the noninferiority of 
the anti –reference strain immune 
response after a third dose of 
BNT162b2 at 30 µg compared to after 
2 doses of BNT162b2, in the same 
individualsGMR of reference strain NT 1 month 
after the third dose of BNT162b2 at 
30µg 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 at 30 µgand 
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 at 30 µg) 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 referen ce 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
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 29
FDA-CBER-2022-5812-0224864
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 30ObjectivesaEstimands Endpoints
Secondary Efficacy
To evaluate the e fficac 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 l east 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 a fter 
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 second 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 100 0 
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 placebo]COVID -19 incidence per 1000 
person -years of follow -up based on 
central laboratory or locally 
confirmed NAAT
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 30
FDA-CBER-2022-5812-0224865
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 31ObjectivesaEstimands 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 asymptomatic 
SARS -CoV -2 infection per 1000 
person -years of follow -up base d 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 at 30 µg 
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 at 30 µgto 
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 BNT162b 2at 30 µgand 
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 
third dose of BNT162b2 at 30 µg) 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 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 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 
BNT162b2 at 30 µgGMR of SANT 1 month after 1 dose 
of BNT162b2 SAto1month after the 
third dose of BNT162b2 at 30 µg
The difference in percentages of 
participants with seroresponse to the 
SAstrain at 1 month after 1 dose of 
BNT162b2 SAand 1 month after the 
third dose of BNT162b2 at 30 µgSARS -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 at 30 µg) of past 
SARS -CoV -2 infection
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 31
FDA-CBER-2022-5812-0224866
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 32ObjectivesaEstimands 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 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 to 1 month
after receipt of the second doseof 
BNT162b2 SAor BNT162b2 as 
appropriate ) of past SARS -CoV -2 
infectio n
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 prior to 
receiving the third dose of BNT162b2 
in participants who receiv ed 
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 -years of follow -up based on 
central laboratory or locally 
confirmed NAAT
To describe the incidence of 
confirmed COVID -19 after receiving 
the third dose of BNT162b2In participants who received the third 
dose of BNT162b2:
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
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 32
FDA-CBER-2022-5812-0224867
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 33ObjectivesaEstimands 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 infecti on 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 
keyprotocol 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
To describe the immune response to a 
third dose of BNT162 b2 (at 30 µg or 
a lower dose of 5 µg or 10 µg) ora
third or fourth dose of BNT162b2 SA GMTs at Dose 3 and subsequent 
time points
 GMFRs from Dose 3 to 
subsequent time points SARS -CoV -2 reference strain 
NTs 
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 33
FDA-CBER-2022-5812-0224868
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 34ObjectivesaEstimands Endpoints
To describe thecell-mediated immune 
response, and additional humoral 
immune response parameters, tothe 
reference strain and SA in a subset of 
participants:
7 Days and 1 and 6 months after
BNT162 b2SAgiven as 1 or 2 
doses to BNT162b2 -experienced
participants
7 Days and 1 and 6 months after 
BNT162 b2SAgiven as 2 doses to 
BNT162b2 -naïve participants
7 Days and 1 and 6 month 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.  These 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 (separated by  21 days) schedule ;
At various different dose levels in Phase 1;
As a booster;
In 3 age groups ( Phase 1: 18 to 55 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.
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 34
FDA-CBER-2022-5812-0224869
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 35The vaccine candidate selected for Phase 2/3 evaluation is BNT162b 2at a dose of 30µg.
Participants who originally  recei vedplacebo 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 am ong 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 BNT162b2 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 assessment of boostab ility will be further 
expanded in a subset of Phase 3 participants at selected sites in the US who will receive a 
third dose of BNT162b2 at 30 µg or a third and potentially  a fourth dose of prototy pe 
BNT162b2 VOCat 30 µg (based upon the South African varia nt and hereafter referred to as 
BNT162b2 SA).Afurther subset of Phase 3 participants will receive a third, lower, dose of 
BNT162b2 at 5 or 10 µg.
To further describe potential homologous and heterologous protection against emerging 
SARS -CoV -2 VOCs, a new cohort of participants will be enrolled who are COVID-19 
vaccine –naïve ( ie, BNT162b2 -naïve) and have not experienced COVID-19. They  will 
receive B NT162b2 SAgiven as a 2- dose series, separated by  21 day s.
As part of protocol amendment 18, to reflect current and anticipated recommendations for 
COVID -19 vaccine boosters, participants in C4591001 who meet specified recommendations 
(detailed separatel y and available in the electronic study  portal) and have not alread y 
received one, will be offered a third dose of BNT162b2 after their second dose of BNT162. 
This opportunity  is onl y for those participants who received their first 2 doses of BNT162
(including BNT162b1 , BNT162b2, or BNT162b2 SA) as part of the stud y.
Number of Participants
Each group in Phase 1 will comprise 15 participants (12 receiving active vaccine and 
3receiving placebo). In this phase , 13groups will be studied, correspond ingto a total of 
195participants.
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 35
FDA-CBER-2022-5812-0224870
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 36The 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 placebo, ie, randomized in a 1:1 rat io.
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 ratio to receive either a third 
dose of BNT162b2 at 30 µgor a third dose of BNT162b2 SA.
An addit ional 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.
A further group of approximately  144 existing Phase 3 participants 18 years of age and older
will be enrolled to receive a third, lower, dose of BNT162b2 of either 5 or 10 µg.
Approximately  24 participants 18 to 55 y ears of age and 48 participants >55 years of age will 
be enrolled in each dose group.
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 vac cine 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 ): 
5µg, 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.
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 36
FDA-CBER-2022-5812-0224871
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 37Participants 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 do se of BNT162b2 at 30 µg 
approximately  6to 12 months after their second dose of BNT162.
Data Monitoring Committee or Other Independent Oversight Committee
The study  will utilize an IRC, an internal Pfizer committee thatwill review data to allow 
dose escal ation 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 1 of the stud y is not based on an ystatistical hy pothesis testing.
For Phase 2/3, the VE evaluation will be the primary  objective . The VE is defined as 
VE= 100 × (1–IRR), where IRR is calculated as the ratio of the first confirmed COVID -19 
illness rate in the vaccine group to the corresponding illness rate in the placebo group. W ith 
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 GMRof 
SARS -CoV -2 neutralizing titers using a 1.5 -fold margin. A sample size of 225 evaluable 
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 37
FDA-CBER-2022-5812-0224872
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 38participants (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 1.5- fold 
noninferiority  margin and the difference in percentages of participants with seroresponse 
using a 10% noninferiority  margin.
The 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 participants 12
to 15 years of age compared to participants 16 to 25 years of age and evaluation of 
boostability  and protection against emerging VOCs by BNT162b2 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.
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 38
FDA-CBER-2022-5812-0224873
FDA-CBER-2022-5812-0224874
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 401.3. 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 visi ts) in addition to those listed i n 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 is required at an y time between Visit 1 
(Vaccinat ion 1) and Visit 10 (24-m onth follow -up v isit) that COVI D-19 is suspected. Prior 
to protocol amendment 16, a COVID -19 convalescent visit was required 28 to 35 day s after 
each potential COVID -19 illness visit. Sufficient data have now been accrued from these 
visits, so the requirement has been removed from the protocol.
Administration of BNT162b2 to Those Originally Assigned to Placebo: If a participant 
becomes eligible for receipt of BNT162b2 or another COVID -19 vaccine according to 
recommendations detailed separately , and available in the electronic study reference portal , 
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 whether 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 p art of the study no later than at the approximate time participants in 
Phase 2/3 reach Visit 4. When contacted, the site will unblind study  intervention allocation 
to determine whether the participant received BNT162b1, BNT162b2 ,or placebo. If he or 
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.
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 40
FDA-CBER-2022-5812-0224875
FDA-CBER-2022-5812-0224876
FDA-CBER-2022-5812-0224877
FDA-CBER-2022-5812-0224878
FDA-CBER-2022-5812-0224879
FDA-CBER-2022-5812-0224880
FDA-CBER-2022-5812-0224881
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 471.3.2. Phase 2/ 3
An unplanned potential COVID- 19 illness visit is 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. Prior to protocol amendment 16, a COVID -19 convale scent 
visit was required 28 to 35 day s after each potential COVI D-19 illness visit. Sufficient data 
have now been accrued from these visits, so the requirement has been removed from the 
protocol.
Administration of BNT162b2 to Those Originally Assigned to Placebo: If a participant 
becomes eligible for receipt of BNT162b2 or another COVID -19 vaccine according to 
recommendations detailed separately , and available in the electronic study  reference portal, 
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 whether the participant received BNT162b2 or placebo .If he or she originally  
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 originall y planned.
All other participants who have not already  been offered the opportunit y 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.
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 47
FDA-CBER-2022-5812-0224882
FDA-CBER-2022-5812-0224883
FDA-CBER-2022-5812-0224884
FDA-CBER-2022-5812-0224885
FDA-CBER-2022-5812-0224886
FDA-CBER-2022-5812-0224887
FDA-CBER-2022-5812-0224888
FDA-CBER-2022-5812-0224889
FDA-CBER-2022-5812-0224890
FDA-CBER-2022-5812-0224891
FDA-CBER-2022-5812-0224892
FDA-CBER-2022-5812-0224893
FDA-CBER-2022-5812-0224894
FDA-CBER-2022-5812-0224895
FDA-CBER-2022-5812-0224896
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 622.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 fast 
expansion of the dise ase 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 clear 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 Betacoronavirus subfamily .  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 noted 693,224 confirmed cases 
with 33,106 deaths globally , including 142,081 confirmed cases with 2457 deaths in the 
Americas .2  The United States currently  has the most re ported cases globall y. At the time of 
this communication, the number of confirmed cases continues to rise globally .To-date, more 
than 215 million people have been infected with SARS -CoV -2 and >4 million have died, 
demonstrating an urgent need for efficacious vaccines.3
Numerous COVID -19 vaccines are currentl y in development globall y,and several candidate 
COVID -19 vaccines ( eg,mRNA vaccines and adenovirus -vectored vaccines expressing the 
S protein) have been shown to be efficacious in the prevention of COVID-19 in clinical 
studies and are now available under temporary  or emergency  authorizations. BNT162b2 ,an 
RNA -based COVID -19 vaccine given as a 2 -dose series administered 21 day s apart, was 
shown to be safe and effective in a Phase 1/2/3 study  and has received authorizations for 
temporary  or emergency  use or marketing authorizations in multiple countries and has b een 
fully  licensed for use in individuals 16 y ears of age and above in the US as of 23 Aug 2021.
As more data about COVID -19 continue to accrue, the potential duration of protection 
afforded after a wild -type SARS -CoV -2 infection, and by  vaccination, remains unknown. In 
addition, mutated SARS -CoV -2 VOC s have started to emerge, for example in the UK 
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 62
FDA-CBER-2022-5812-0224897
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 63(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 vaccin e 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 elici ting protective immune responses, 
provides significant advantages over more traditional vaccine approaches.  Unlike live 
attenuated vaccines, RNA vaccines do not carry the risks associated with infection and may  
be given to people who cannot be administere d 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 production and the prospect of 
producing high numbers of vaccination doses within a shorter time period than achieved with 
traditional vaccine approaches.  This capability  is pivotal to enable the most effective 
response in outbreak scenarios.
Three SARS -CoV -2–RNA lipid nanoparticle (RNA -LNP) vaccines based on 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 c apacit 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 P2Scontaining South Africa B.1.351 variant –specific 
mutations, hereafter referred to as BNT162 b2SA, 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 BNT162b1 or BNT162b2. This will provide an early  assessment of the safet y 
of a third dose of BNT162, as well as its immunogenicity .The assessment of boostability  
will be further expanded in a subset of Phase 3 participants at selected sites in the U S who 
will receive a third dose of BNT162b2 at 30 µgor a third and potentially  a fourth dose of 
prototy pe BNT162b2 VOC(based upon the South African variant and hereafter referred to as 
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 63
FDA-CBER-2022-5812-0224898
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 64BNT162b2 SA).A further subset of Phase 3 participants will receive a third, lower, dose of 
BNT162b2 at 5 or 10 µg.
To further describe potential homologous and heterologous protection against emerging 
SARS -CoV -2 VOCs, a new cohort of participants will be enrolled who are COVID-19 
vaccine –naïve ( ie, BNT162b2 -naïve) and have not experienced COVID -19. They  will 
receive BNT162b2 SAgiven as a 2- dose series, separated by  21 day s.
As part of protocol amendment 18, to reflect current and anticipated recommendations for 
COVID -19 vaccine boosters, participants in C4591001 who meet specified recommendations 
and have not alread y received one, will be offered a third dose of BNT162b2 after their 
second dose of BNT162b1 , BNT162b2 or BNT162b2 SA.The opportunity  to receive a third
dose of BNT162b2 will be offered as part of the study , according to recommendations 
detailed separatel y, and available in the electronic study  reference portal.
2.3. Clinical Overview
Prior to this study , given clinical data from other similarly  formulated uRN Aliposomal 
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 e ffects. BNT162 vaccines 
based on modRNA have now been administered to humans 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.
2.4.Benefit/Risk Assessment
There is an ongoing global pandemic of COVID -19 with no preventative or therapeutic 
options available. While there were no data available from clinical trials on the use of 
BNT162 vaccines in humans at the outset of this study , available nonclinical data with these 
vaccines, and data from nonclinical studies and clinical trials with the same or related RNA 
components, or antigens, support eda favorable risk /benefit prof ile. 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  population to be as representative and diverse as 
possible , the inclusion of participants with known chronic stable HIV, HCV, or HBV
infection is permitted. Individuals with chronic viral diseases are at increased risk for 
COVID -19 complications and severe disease. In addition, with the currently  available 
therapies for the irtreatment, many  individuals with chronic stable HIV, HCV, and HBV 
infections are unl ikely to be at higher safet y risk as a participant in this vaccine study 
than individuals with other chronic stable medical conditions.
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 64
FDA-CBER-2022-5812-0224899
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 65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 years 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 ).
More 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 SR SD for this study . 
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 65
FDA-CBER-2022-5812-0224900
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 662.4.1. Risk Assessment
Potential Risk of Clinical 
SignificanceSummary of Data/Rationale 
for RiskMitigation 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 F DA 
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 escalati on 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 m onitor 
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 vacc ine.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 this vaccine.The Phase 1 study design includes the use of 
controlled vaccination and dose escal ation to 
closely monitor and limit the rate of enrollment 
to ensure participant safety. An IRC (in Phase 1) 
and DMC (throughout the study) will also 
review safety data. Stopping rules are also in 
place. The first 5 participants in each group in 
Phase 1 will be observed for 4 hours after 
vaccination to assess any immediate AEs. All 
other participants will 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 .
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 66
FDA-CBER-2022-5812-0224901
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 67Potential Risk of Clinical 
SignificanceSummary of Data/Rationale 
for RiskMitigation Strategy
Study Procedures
Participant s will be 
required to attend 
healthcare facilities during 
the global SARS -CoV-2
pandemic.Without appropriate social 
distancing and PPE, there is a 
potential for increased 
exposure to SARS -CoV -2.Pfizer w ill work with sites to ensure an 
appropri ateCOVID -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 .
Very  rare cases of 
anaphylaxis, myocarditis, 
and pericarditis have been 
reported after authorization 
in recipients of 
BNT162b2.Anaphylaxis: The estimated 
rate is 5.0 per million doses 
administered.
Myocarditis and pericarditis: 
Very  rare cases of myocarditis 
and pericarditis have been 
reported follow ing vaccination 
with mRNA COVID- 19 
vaccin es. Ty pically, the cases 
have occurred more often in 
younger men and after the 
second dose of the vaccine and 
within 14 days after 
vaccination. These are 
generally mild cases, and 
individuals tend to recover 
within a short time following 
standard treatment and rest. 
Healthcare professionals 
should be alert to the signs and 
symptoms of myocarditis and 
pericarditis in vaccine 
recipients.Specific reference to these risks is made within 
the ICD, with instruction to contact a healthcare 
professional if a case i s suspected.
For anaphylaxis, there is an on -site 30 -minute 
observation period after vaccination.
Instructions for handling suspected cases of 
myocarditis and pericarditis are found in
Section 8.2.1 .
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 67
FDA-CBER-2022-5812-0224902
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 682.4.2. 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
2.4.3. Overall Benefit /Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in this 
study , the potential risks identified in association with BNT162 RNA -based COVID -19 
vaccine are justified b y the anticipated benefits that may  be afforded to heal thy 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
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 68
FDA-CBER-2022-5812-0224903
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 69Objectives 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 s/GMTsat the time of 
Dose 3and7days and 1 month 
after Dose 3.
 GMFRs from before Dose 3 to 7 
days 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
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 69
FDA-CBER-2022-5812-0224904
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 70Objectives 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 efficacy of 
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 follo w-up based on 
central laboratory or locally 
confirmed NAAT in participants with 
no serological or virological evidence 
(up to 7days after receipt 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 follow -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 e ach 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, fatig ue, 
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 
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 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 join t pain)
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 70
FDA-CBER-2022-5812-0224905
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 71ObjectivesaEstimands Endpoints
To define the safety profile of 
prophylactic BNT162 b2in 
participants 12 to 15 years of age in 
Phase 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 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
participants in the subset for 
evaluation of boostability and 
protection against emerging VOCsIn 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
To describe the safety and tolerability 
profile of BNT162b2 given as a third 
dose at least 6 months after the second
dose of BNT162b2 (or BNT162b2 SA)
for participants who received a third 
dose as part of protocol 
amendment 18In participants receiving at least 
1dose of study intervention , the 
percentage of participants reporting:
AEs from Dose 3 to 1 month after 
Dose 3
SAEs from Dose 3 to 6 months 
after Dose 3AEs
SAEs
Prim ary Immunogenicity
BNT162b2 -experienced participants
Todemonstrate the noninferiority of 
the anti –reference strain immune 
response after a third dose of 
BNT162b2 at 30 µg compared to after 
2 doses of BNT162b2, in the same 
individualsGMR of reference strain NT 1 month 
after the third dose of BNT162b2 at 
30 µg 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 at 30 µg 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 at 30 µg ) 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 p ercentages 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
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 71
FDA-CBER-2022-5812-0224906
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 72ObjectivesaEstimands 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 w ith 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 -19occurring 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 
recei pt of the second dose) of past 
SARS -CoV -2 infection
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 with and without 
evidence of infection bef ore 
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
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 72
FDA-CBER-2022-5812-0224907
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 73ObjectivesaEstimands 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 complying with the 
key protocol criteria (evaluable 
participants) 
at least 7 days 
and
at least 14 days
after receipt of the second dose of 
study intervention:
100 × (1 –IRR) [ratio of active 
vaccine to placebo]COVID -19 incidence per 1000 
person -years of follow -up based on 
central laboratory or locally 
confirmed NAAT in participants with
no serological or virological evidence 
(up to 7 days and up to 14 days after 
receipt of the second dose) of past 
SARS -CoV -2 infection
To describe the 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 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 pla cebo]COVID -19 incidence per 1000 
person -years of follow -up based on 
central laboratory or locally 
confirmed NAAT
To evaluate the efficacy of 
prophylactic BNT162b2 against 
non-S seroconversion to 
SARS -CoV -2 in participants without 
evidence of infection or confirmed 
COVID -19 In participants complying with the 
key protocol criteria (evaluable 
participants):
100 × (1 –IRR) [ratio of active 
vaccine to placebo]Incidence of asymptomatic 
SARS -CoV -2 infection per 1000 
person -years of follow -up based on 
N-binding antibody seroconversion in 
participants with no serological or 
virological evidence of past 
SARS -CoV -2 infection or confirmed 
COVID -19 
To evaluate the efficacy of 
prophylactic BNT162b 2against 
asympto matic 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 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 at 30 µg 
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 at 30 µg to 
the reference strain NT 1 month after 
the second dose of BNT162b2
The difference in percentages of 
participants with seroresponse to the
SAstrain at 1 month after the third 
dose of BNT162b2 at 30 µg and 
seroresponse to the reference strain at 
1 month after the second dose of 
BNT162b2SARS -CoV -2 SA and reference strain 
NTs in participants with no 
serolo gical or virological evidence (up 
to 1 month after receipt of the third
dose of BNT162b2 at 30 µg ) of past 
SARS -CoV -2 infection
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 73
FDA-CBER-2022-5812-0224908
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 74ObjectivesaEstimands Endpoints
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 st rainat 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 
BNT162b2 at 30 µgGMR of SANT 1 month after 1 dose 
of BNT162b2 SAto1month after the 
third dose of BNT162b2 at 30 µg
The difference in percentages of 
participants with seroresponse to the
SA strain at 1 month after 1 dose of 
BNT162b2 SAand 1 month after the 
third dose of BNT162b2 at 30 µgSARS -CoV -2 SA NT in participants 
with no serological or virological 
evidence (up to 1 month after rec eipt 
of 1dose of BNT162b2 SAor the third
dose of BNT162b2 at 30 µg ) 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
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 
BNT16 2b2
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 to 1 month
after receipt of the second doseof 
BNT162b2 SAor BNT162b2 as 
appropriate ) of past SARS -CoV -2 
infection
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 74
FDA-CBER-2022-5812-0224909
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 75ObjectivesaEstimands 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 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 prior to 
receiving the third dose of BNT162b2 
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 -years of follow -up based on 
central laboratory or locally 
confirmed NAAT
To describe the incidence of 
confirmed COVID -19 after receiving 
the third dose of BNT162b2In participants who received the third 
dose of BNT162b2:
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
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 an tibody 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
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 75
FDA-CBER-2022-5812-0224910
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 76ObjectivesaEstimands 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 immune response to a 
third dose of BNT162 b2 (at 30 µg or 
a lower dose of 5 µg or 10 µg) or a 
third or fourth dose of BNT162b2 SA GMTs at Dose 3 and subsequent 
time points
 GMFRs from Dose 3 to 
subsequent time points SARS -CoV -2 reference strain 
NTs 
To describe the cell-mediated immune 
response , and additional humoral 
immune response parameters, to the 
reference strain and SA in a subset of 
participants:
 7 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 regular 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.
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 76
FDA-CBER-2022-5812-0224911
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 774.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:
≥12yearsof age [stratified as 12-15, 16 -55,or >55 y ears 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.
The study  is observer -blind ed, as 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 Phase 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 
expa nded in a subset of Phase 3 participants at selected sites in the US who will receive a 
third dose of BNT162b2 at 30 µg or a third and potentially  a fourth dose of prototy pe 
BNT162b2 VOCat 30 µg (based upon the South African variant and hereafter referred to as 
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 77
FDA-CBER-2022-5812-0224912
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 78BNT162b2 SA).A further subset of Phase 3 participants will receive a third, lower, dose of 
BNT162b2 at 5 or 10 µg.
To further describe potential homologous and heterologous protection against emerging 
SARS -CoV -2 VOCs, a new cohort of participants wi ll 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 o n 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 study  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 fir st candidate studied being deemed 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.
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 78
FDA-CBER-2022-5812-0224913
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 79The 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 COVID -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 meets 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 i n 
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 
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 79
FDA-CBER-2022-5812-0224914
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 80may 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 -19attack 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 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 280vaccine recipients) per age group will 
provide a power of 90.4 % to declare the noninferiority interms 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 manufactured 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 stu dy 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 years of age will be rerandomized in a 1:1 ratio to receive either a third 
dose of BNT162b2 at 30 µg or a third dose of BNT162b2 SA.
A further group of approximately  144 existing Phase 3 participants 18 y ears of age and older 
will be enrolled to receive a third, lower, dose of BNT162b2 of either 5 or 10 µg.  
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 80
FDA-CBER-2022-5812-0224915
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 81Approximately  24 participants 18 to 55 y ears of age and 48 participants >55 y ears of age will 
be enrolled in each dose group. An additional group of 30 existing Phase 3 participants 18 to 
55 years of age will be enrolled to receive a third and fourth dose of BNT162b2 SA.For these 
30 participants, through 1 month after 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  analy ses.
Three hundred participants 18 to 55 y ears of age who are COVID -19 vac cine–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. 
Theduration 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 who originally  received placebo and become eligible for receipt of BNT162b2 
according to recommendations detail ed separatel y, and available in the electronic study 
reference portal ,will have the opportunity  to receive BNT162b2 in a phased manner as part 
of the study . The investigator will ensure the participant meets at least 1of the 
recommendation criteria .
Any Phase 2/3 placebo recipient who has not already  been offered the opportunity  to receive 
BNT162b2 will be given this opportunity  no later than 6 months after Vaccination 2 (at the 
time of the originally  planned Visit 4).
Any participant who originally  received placebo but then goes on to receive BNT162b2 will 
move to a new visit schedule ( Section 1.3.3 ).
The changes to the protocol as part of protocol 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 participants 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 BNT162b2 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.
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 81
FDA-CBER-2022-5812-0224916
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 82In 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.
This approach will allow an evaluation of immunogenicity  against the reference ancestral 
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 boo st (with 
BNT162b2 SA), as well as new vaccinees receiving 2 doses of BNT162b2 SA.
As part of protocol amendment 18, to reflect current and anticipated recommendations for 
COVID -19 vaccine boosters, participants in C4591001 who meet specified recommendations 
(detailed separatel y and available in the electronic study  portal) and have not alread y 
received one, will be offered a third dose of BNT162b2 after their second dose of BNT162.
The opportunity  to receive a third dose of BNT162b2 will be offered as part of the study , 
according to recommendations detailed separatel y, and available in the electronic study 
reference portal. This opportunity  is only  for those participants who received their first 
2doses of BNT162 ( includin g BNT162b1 , BNT162b2, or BNT162b2 SA) 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 
(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 infe ction 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 stud y 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 participants 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 visit will occur and,prior to protocol amendment 16, a 
subsequent convalescent visit would occur. As part of these visits ,samples ( nasal
[midturbinate ]swab and blood) will be taken for antigen and antibody  assessment as well as 
recording of COVID -19–related clinical and laboratory  information (including local 
diagnosis) .
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 82
FDA-CBER-2022-5812-0224917
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 83Human 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 initial 
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 general safety  and 
effectiveness of uRNA and modRNA platforms have been de monstrated in oncological 
clinical trials with different administration routes (NCT02410733, NCT03871348). Doses of 
up to 400 µg total uRNA have been administered IV as RNA lipoplex (RNA- LPX) and doses 
of up to 1000 µg total naked modRNA have been administered intratumorally , both without 
signs of unpredictable overstimulation of the immune 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 cli nical 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 µgwarrants 
consideration. Therefore ,a 50-µgdose level is formally  included for BNT162b1 and 
BNT162b2.
Update as part of protocol amendment 3: as data have become availa ble from this study  and 
the BNT162 -01 study  in Germany , it was decided:
To not study  the BNT162a1 and BNT162c2 vaccine candidates at this time, so these 
candidates have been removed from the protocol; and
That lower dose levels of BNT162b1 and BNT162b2 warrant consideration.  Therefore, a 
20-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 amendment 5: the vaccine candidate selected for Phase 2/3 
evaluation is BNT162b 2at a dose of 30 µg.BNT162b3 will not be studied.
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 83
FDA-CBER-2022-5812-0224918
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 844.4.End of Study Definition
A partici pant 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 .
5. 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 and enrollment criteria ,also 
known as protocol waivers or exemptions, is not permitted .
5.1. Inclusion Criteria
Participants are eligible to be included in the study 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 :
Existing participants enrolled to receive a third dose of BNT162b2 at 30 µg or 
BNT162b2 SA;male or female participants between the ages of 18 and 55 years, 
inclusive, at rerandomization.
Newl y enrolled participants enrolled to receive 2 doses of BNT162b2 SA;male or 
female participants between the ages of 18 and 55years, inclusive, at enrollment.
Existing participants enrolled to receive a third dose of BNT162b2 at 5 or 10 µg ;
male or female participants ≥18 years at rerandomization.
Note that participants <18 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 ) part icipants.
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 84
FDA-CBER-2022-5812-0224919
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 85Type of 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 by  medical 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 therapy  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 acquiring COVID -19 (including, but not limited to , use of mass transportation, 
relevant demographics, and frontline essential workers) .
5.Boostability and protection -against -VOCs existing participant subset only:
Participants who provided a s erum 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 partici pant 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.
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 85
FDA-CBER-2022-5812-0224920
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 865.Previous clinical (based on COVID -19 symptoms/signs alone, if a SARS -CoV -2 NAAT 
result was not available) or microbiological (based on COVID -19 symptoms/signs and a 
positive SARS -CoV -2 NAAT result) diagnosis of COVID -19.
6.Phase 1 only :Individuals at high risk for severe COVID -19, including th ose with an y 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
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 autoimmun e 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 yndrom e, idiopathic thrombocy topenia purpura, 
glomerulonephritis, autoimmune thy roiditis, giant cell arteritis (temporal arteritis), 
psoriasis, and insulin -dependent diabetes mellitus (type 1).
10.Bleeding diathesis or condition associated with prolonged bleeding t hat 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.
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 86
FDA-CBER-2022-5812-0224921
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 8713.Individuals who receive treatment with immunosuppr essive therap y, including cytotoxic 
agents or s ystemic corticosteroids, 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 il lness, participants should not be enrolled into 
the study  until corticosteroid therapy  has been discontinued for at least 28 day s 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 admi nistration or planned receipt throughout the stud y.
Prior/Concurrent Clinical Study Experience:
16.Participation in other studies involving study  intervention within 28 day s prior to study  
entry  through and including 28 day safter the last dose of study  intervention , with the 
exception of non -Pfizer interventional studies for prevent ion of COVID -19,which are
prohibited throughout study  participation.
17.Previous participation in other studies involving study  intervention containing lipid 
nanoparticles.
Diagnostic Assessments:
18.Phase 1only: Positive serological test for SARS- CoV -2 IgM and/or 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 abnorma lity.
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 isdefined 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 hepatitis C virus antibodies (HCV Abs) at the screening 
visit.
21.Phase 1 only: SARS -CoV -2 NAAT -positive nasal swab within 24 hours before receipt of 
study  intervention.
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 87
FDA-CBER-2022-5812-0224922
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 88Other 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. Contracep tion
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 ,Section 10.4.4 )and will confirm that the participant has been instructed in 
its consistent and correct use.  At time points indicated in the SoA, the investigator or 
designee will inform the participant of the need to use highl y effective contraception 
consistently  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 fai lure details, eligibility  
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/St udy 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;
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 88
FDA-CBER-2022-5812-0224923
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 89Chills;
New or increased muscle 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(not applicable for 
the third dose of BNT162b2 at Visit 501) , or an y other nonstudy  vaccine within 28 days,
before study  intervention administration.
3. Anticipated receipt of any seasonal or pandemic influenza vaccine within 14 days (not 
applicable for the third dose of BNT162b2 at Visit 501) , or an y other nonstudy vaccine 
within 28 day s,after study  interventio nadministration.
4.Receipt of short -term (<14 day s) systemic corticosteroids.  Study  intervention
administration should be delay ed until sy stemic 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 intervention(s), marketed product(s), 
placebo, medical device(s) , or study  procedure(s) intended to be administered to a stud y 
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 administe red to a stud y 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 ): 
5µg,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
090177e198027d65\Approved\Approved On: 07-Sep-2021 17:53 (GMT)
Page 89
FDA-CBER-2022-5812-0224924
PF-07302048 (BNT162 RNA- Based COVID- 19 Vaccines)
Protocol C4591001
Final Protocol Amendment 18, 07September 2021
 CONFIDENTIAL
CT02- GSOP Clinical Protocol Template Phase 1 2 3 4 (05 December 2019)
Page 90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 -µg5-, 10-, 20-, 30-µg 30-µg N/A
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 m
…[truncated]