A PHASE 3 MASTER PROTOCOL TO EVALUATE ADDITIONAL DOSE(S) OF BNT162B2 IN HEALTHY INDIVIDUALS PREVIOUSLY VACCINATED WITH BNT162B2
Phase: PHASE3
Conditions: SARS-CoV-2 Infection, COVID-19
Sponsor: BioNTech SE

PF-07302048 (BNT162b2 RNA-Based COVID-19 Vaccine)
Protocol C4591031
Final Protocol Amendment 12, 20 Sep 2023
PFIZER CONFIDENTIAL
Page 1
A PHASE 3 MASTER PROTOCOL TO EVALUATE ADDITIONAL DOSE(S) OF 
BNT162b2 IN HEALTHY INDIVIDUALS PREVIOUSLY VACCINATED WITH 
BNT162b2
Study Sponsor:
BioNTech
Study Conducted By:
Pfizer
Study Intervention Number:
PF-07302048
Study Intervention Name:
BNT162b2 RNA-Based COVID-19 Vaccine
US IND Number:
19736
EudraCT Number:
2021-005197-25
Protocol Number:
C4591031
Phase:
3
Sponsor’s Agent’s Legal Address:
Pfizer Inc.
66 Hudson Boulevard East
New York, NY 10001
Brief Title: A Study to Evaluate Additional Dose(s) of BNT162b2 in Healthy Individuals 
Previously Vaccinated With BNT162b2
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information 
in confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.

PF-07302048 (BNT162b2 RNA-Based COVID-19 Vaccine)
Protocol C4591031
Final Protocol Amendment 12, 20 Sep 2023
PFIZER CONFIDENTIAL
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Document History
Document
Version Date
Amendment 12
20 Sep 2023
Amendment 11
20 Sep 2022
Amendment 10
22 Jul 2022
Amendment 9
03 May 2022
Amendment 8
31 Mar 2022
Amendment 7
17 Feb 2022
Amendment 6
08 Feb 2022
Amendment 5
20 Jan 2022
Amendment 4
22 Dec 2021
Amendment 3
28 Oct 2021
Amendment 2
27 Aug 2021
Amendment 1
27 May 2021
Original protocol
13 May 2021
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any protocol administrative 
clarification letter.
Protocol Amendment Summary of Changes Table
Amendment 12 (20 September 2023)
Overall Rationale for the Amendment:
Endpoints and/or analyses that do not pertain to current variant-modified versions of 
BNT162b2 were removed from Substudy C and Substudy D to expedite the remaining 
testing and to focus on analyses of interest.

PF-07302048 (BNT162b2 RNA-Based COVID-19 Vaccine)
Protocol C4591031
Final Protocol Amendment 12, 20 Sep 2023
PFIZER CONFIDENTIAL
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Description of Change
Brief Rationale
Section # and Name
Substantial Modification(s)
Removed the 6 month time
point from the immunogenicity 
analysis and removed the
immune response to VOCs 
objective for Substudy C
To expedite remaining 
testing and to focus on 
analyses of interest
Section 10.9.3 Objectives, 
Estimands, and Endpoints,  
Section 10.9.9.3.2 Primary 
Endpoint(s)/Estimand(s) 
Analysis, Section 10.9.9.3.4
Exploratory Endpoint(s) 
Analysis, and 
Section 10.9.9.4.1 Analysis 
Timing in Substudy C
Changed the superiority and 
noninferiority hypotheses 
G1vG2bA and G2vsG2bA to be 
descriptive, removed ‘super’ 
superiority hypotheses 
G1vG2bB and G2vG2bB, 
removed the original objective 
G5B on noninferiority of 
anti-Omicron immune response 
to anti–reference-strain immune 
response, and renamed G5C to 
G5B in Substudy D
To expedite remaining 
testing and to focus on 
analyses of interest
Section 10.10.3 Objectives, 
Estimands, and Endpoints, 
Section 10.10.9.1.2 Statistical
Hypothesis, and
Section 10.9.9.1.3
Multiplicity Adjustment,
Section 10.10.9.3.3 Secondary 
Endpoint(s)/Estimand(s) 
Analysis, Section 10.10.9.3.4
Exploratory Endpoint(s) 
Analysis and 
Section 10.10.9.4.2 Sample 
Size Determination in 
Substudy D
Clarified that the G1vG2bA and 
G2vsG2bA primary 
immunogenicity analysis will 
be performed on evaluable 
participants with evidence of 
past SARS-CoV-2 infection in 
Substudy D
To expedite remaining 
testing and to focus on 
analyses of interest
Section 10.10.3 Objectives, 
Estimands, and Endpoints and 
Section 10.10.9.3.2 Primary 
Endpoint(s)/Estimand(s)
Clarified that there is no 
multiplicity adjustment needed 
for Cohort 1 in Substudy D
There is no statistical 
hypothesis in Cohort 1
Section 10.10.9.1.3
Multiplicity Adjustment in 
Substudy D
Clarified that the statistical 
hypothesis only applies to 
Cohort 2 and Cohort 3 in 
Substudy D
There is no statistical 
hypothesis in Cohort 1
Section 10.10.9.1.2 Statistical 
Hypothesis in Substudy D

PF-07302048 (BNT162b2 RNA-Based COVID-19 Vaccine)
Protocol C4591031
Final Protocol Amendment 12, 20 Sep 2023
PFIZER CONFIDENTIAL
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Description of Change
Brief Rationale
Section # and Name
Updated text in the sample size 
determination section to state
that a random sample of 
approximately 100 participants 
with evidence of past 
SARS-CoV-2 infection from 
each of Groups 1, 2, and 2b 
selected from the remaining 
approximately 175 participants 
will be used for evaluation of 
the primary immunogenicity 
objectives in each group for 
Cohort 1.
To expedite remaining 
testing and to focus on 
analyses of interest
Section 10.10.9.5 Sample Size 
Determination in Substudy D
Updated the time points of 
analysis for the exploratory 
immunogenicity objective from
“to describe the immune 
response to BNT162b2 OMI or 
BNT162b2 given as the third 
and/or fourth and/or fifth dose 
in BNT162b2-experienced 
participants” to: “For Cohort 1: 
at baseline, 1 month after the 
first study vaccination, and 1 
month after the second study 
vaccination (Group 2 only),
For Cohort 2: at baseline, 1 
month and 3 months after the 
first study vaccination, 1 month, 
3 months, and 6 months after 
the last study vaccination.”
To expedite remaining 
testing and to focus on
analyses of interest
Section 10.10.3 Objectives, 
Estimands, and Endpoints and 
Section 10.10.9.3.4
Exploratory Endpoint(s) 
Analysis in Substudy D
Updated the time points of 
analysis for the exploratory 
immunogenicity objective from
“to describe the immune 
response to BNT162b2 OMI in 
COVID-19 vaccine–naïve 
participants” to: “at baseline, 1 
month and 6 months after Dose 
2, and 1 month and 6 months 
after Dose 3.”
To expedite remaining 
testing and to focus on 
analyses of interest
Section 10.10.3 Objectives, 
Estimands, and Endpoints in 
Substudy D

PF-07302048 (BNT162b2 RNA-Based COVID-19 Vaccine)
Protocol C4591031
Final Protocol Amendment 12, 20 Sep 2023
PFIZER CONFIDENTIAL
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Description of Change
Brief Rationale
Section # and Name
Nonsubstantial Modification(s)
Added the sponsor’s agent’s 
legal address 
Added per updated 
protocol template
Section: Title Page
Added protocol amendment 12 
and the version date to the 
document history table
Added per protocol 
template requirement
Section: Document History 
Table
Added overall rationale for 
protocol amendment 12 
Added per protocol 
template requirement
Section: Protocol Amendment 
Summary of Changes Table
Added a summary of changes 
table for protocol amendment 
12
Added per protocol 
template requirement
Section: Protocol Amendment 
Summary of Changes Table
Moved the overall rationale and 
summary of changes table for 
protocol amendment 11 to 
Appendix 13
Moved per protocol 
template requirement
Section: Protocol Amendment 
Summary of Changes Table 
and Section 10.13 Appendix 
13: Protocol Amendment 
History
Added the rationale for protocol 
amendment 12 to the 
introduction for Substudy C and 
Substudy D
To provide rationale for 
the amendment
Section 10.9.2.1 Study 
Rationale for Substudy C and 
Section 10.10.2.1 Study 
Rationale for Substudy D

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Protocol C4591031
Final Protocol Amendment 12, 20 Sep 2023
PFIZER CONFIDENTIAL
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................19
1. PROTOCOL SUMMARY...................................................................................................20
1.1. Synopsis ..................................................................................................................20
1.2. Schema ....................................................................................................................26
1.3. Schedule of Activities .............................................................................................26
2. INTRODUCTION ...............................................................................................................27
2.1. Study Rationale .......................................................................................................27
2.2. Background .............................................................................................................28
2.2.1. Clinical Overview.......................................................................................30
2.3. Benefit/Risk Assessment.........................................................................................32
2.3.1. Risk Assessment.........................................................................................34
2.3.2. Benefit Assessment.....................................................................................36
2.3.3. Overall Benefit/Risk Conclusion................................................................36
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS ...........................................................36
4. STUDY DESIGN.................................................................................................................37
4.1. Overall Design.........................................................................................................37
4.2. Scientific Rationale for Study Design.....................................................................37
4.2.1. Choice of Contraception/Barrier Requirements .........................................37
4.3. Justification for Dose ..............................................................................................37
4.4. End of Study Definition ..........................................................................................38
5. STUDY POPULATION......................................................................................................38
5.1. Inclusion Criteria.....................................................................................................38
5.2. Exclusion Criteria....................................................................................................38
5.3. Lifestyle Considerations..........................................................................................39
5.3.1. Contraception..............................................................................................39
5.4. Screen Failures ........................................................................................................39
5.5. Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention...........................40
6. SPECIFIC STUDY INTERVENTION(S) AND CONCOMITANT THERAPY...............40
6.1. Study Intervention(s) Administered........................................................................41

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Final Protocol Amendment 12, 20 Sep 2023
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6.1.1. Administration............................................................................................41
6.2. Preparation, Handling, Storage, and Accountability...............................................42
6.2.1. Preparation and Dispensing........................................................................43
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................43
6.3.1. Allocation to Study Intervention ................................................................43
6.3.2. Blinding Arrangements...............................................................................43
6.4. Study Intervention Compliance...............................................................................44
6.5. Dose Modification...................................................................................................44
6.6. Continued Access to Study Intervention After the End of the Study......................44
6.7. Treatment of Overdose............................................................................................44
6.8. Concomitant Therapy..............................................................................................45
6.8.1. Prohibited During the Study.......................................................................45
6.8.2. Permitted During the Study ........................................................................46
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................46
7.1. Discontinuation of Study Intervention ....................................................................46
7.2. Participant Discontinuation/Withdrawal From the Study.......................................47
7.2.1. Withdrawal of Consent...............................................................................47
7.3. Lost to Follow-Up ...................................................................................................48
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................48
8.1. Efficacy Assessments and/or Immunogenicity Assessments..................................49
8.1.1. Biological Samples.....................................................................................49
8.2. Safety Assessments .................................................................................................50
8.2.1. Physical Examinations................................................................................50
8.2.2. Vital Signs ..................................................................................................50
8.2.3. Clinical Safety Laboratory Assessments ....................................................50
8.2.4. Electronic Diary – Applicable Only to Substudies B, C, D, E, and F........50
8.2.4.1. Grading Scales...........................................................................51
8.2.4.2. Local Reactions.........................................................................51
8.2.4.3. Systemic Events ........................................................................52
8.2.4.4. Fever..........................................................................................53
8.2.4.5. Antipyretic/Analgesic Medication ............................................54

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Protocol C4591031
Final Protocol Amendment 12, 20 Sep 2023
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8.2.5. Pregnancy Testing ......................................................................................54
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................54
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......55
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................57
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................57
8.3.2. Method of Detecting AEs and SAEs ..........................................................57
8.3.3. Follow-Up of AEs and SAEs......................................................................58
8.3.4. Regulatory Reporting Requirements for SAEs...........................................58
8.3.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................58
8.3.5.1. Exposure During Pregnancy......................................................59
8.3.5.2. Exposure During Breastfeeding ................................................60
8.3.5.3. Occupational Exposure .............................................................61
8.3.6. Cardiovascular and Death Events...............................................................61
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................61
8.3.7.1. Substudies Including a Potential COVID-19 Illness Visit........61
8.3.7.2. Substudies NOT Including a Potential COVID-19 Illness 
Visit ...................................................................................................62
8.3.8. Adverse Events of Special Interest.............................................................62
8.3.8.1. Substudies NOT Including a Potential COVID-19 Illness 
Visit ...................................................................................................62
8.3.8.2. Lack of Efficacy........................................................................62
8.3.9. Medical Device Deficiencies......................................................................62
8.3.10. Medication Errors.....................................................................................63
8.4. Pharmacokinetics ....................................................................................................64
8.5. Genetics...................................................................................................................64
8.5.1. Specified Genetics ......................................................................................64
8.6. Biomarkers ..............................................................................................................64
8.7. Immunogenicity Assessments.................................................................................64
8.8. Health Economics ...................................................................................................64
9. STATISTICAL CONSIDERATIONS ................................................................................64
9.1. Statistical Hypotheses .............................................................................................64

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Protocol C4591031
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9.1.1. Estimands....................................................................................................64
9.1.2. Statistical Hypotheses.................................................................................64
9.1.3. Multiplicity Adjustments............................................................................65
9.2. Analysis Sets ...........................................................................................................65
9.3. Statistical Analyses .................................................................................................65
9.3.1. General Considerations...............................................................................66
9.3.1.1. Analyses for Binary Data ..........................................................66
9.3.1.2. Analyses for Continuous Data...................................................66
9.4. Interim Analyses .....................................................................................................67
9.5. Sample Size Determination.....................................................................................67
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................68
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............68
10.1.1. Regulatory and Ethical Considerations ....................................................68
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................69
10.1.2. Financial Disclosure .................................................................................69
10.1.3. Informed Consent Process ........................................................................69
10.1.4. Data Protection .........................................................................................70
10.1.5. Committees Structure ...............................................................................71
10.1.5.1. Data Monitoring Committee and Other Independent 
Oversight Committee.........................................................................71
10.1.6. Dissemination of Clinical Study Data ......................................................71
10.1.7. Data Quality Assurance ............................................................................72
10.1.8. Source Documents....................................................................................74
10.1.9. Study and Site Start and Closure ..............................................................74
10.1.10. Publication Policy...................................................................................75
10.1.11. Sponsor’s Qualified Medical Personnel .................................................76
10.2. Appendix 2: Clinical Laboratory Tests .................................................................77
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................78
10.3.1. Definition of AE .......................................................................................78
10.3.2. Definition of an SAE ................................................................................79

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10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................80
10.3.4. Reporting of SAEs....................................................................................84
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................86
10.4.1. Male Participant Reproductive Inclusion Criteria....................................86
10.4.2. Female Participant Reproductive Inclusion Criteria.................................86
10.4.3. Woman of Childbearing Potential ............................................................87
10.4.4. Contraception Methods.............................................................................88
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-Up Assessments .......89
10.6. Appendix 6: Alternative Measures During Public Emergencies ..........................91
10.6.1. Telehealth Visits.......................................................................................91
10.7. Appendix 7: Substudy A .......................................................................................92
10.7.1. Substudy Summary...................................................................................92
10.7.1.1. Synopsis ..................................................................................92
10.7.1.2. Schema ....................................................................................92
10.7.1.3. Schedule of Activities for Substudy A....................................93
10.7.2. Introduction...............................................................................................96
10.7.2.1. Study Rationale .......................................................................96
10.7.2.2. Background .............................................................................96
10.7.2.3. Benefit/Risk Assessment.........................................................96
10.7.3. Objectives, Estimands, and Endpoints......................................................96
10.7.4. Study Design.............................................................................................98
10.7.4.1. Overall Design.........................................................................98
10.7.4.2. Scientific Rationale for Substudy A Design ...........................98
10.7.4.3. Justification for Dose ..............................................................99
10.7.4.4. End of Study Definition ..........................................................99
10.7.5. Study Population.......................................................................................99
10.7.5.1. Inclusion Criteria.....................................................................99
10.7.5.2. Exclusion Criteria..................................................................100
10.7.5.3. Lifestyle Considerations........................................................101
10.7.5.4. Screen Failures ......................................................................102

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Final Protocol Amendment 12, 20 Sep 2023
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10.7.5.5. Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study 
Intervention......................................................................................102
10.7.6. Study Intervention(s) and Concomitant Therapy ...................................102
10.7.6.1. Study Intervention(s) Administered......................................102
10.7.6.2. Measures to Minimize Bias: Randomization and 
Blinding...........................................................................................103
10.7.6.3. Study Intervention Compliance.............................................104
10.7.6.4. Dose Modification.................................................................104
10.7.6.5. Continued Access to Study Intervention After the End of 
the Study..........................................................................................104
10.7.6.6. Treatment of Overdose..........................................................105
10.7.6.7. Concomitant Therapy............................................................105
10.7.7. Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal..........................................................................105
10.7.8. Study Assessments and Procedures........................................................105
10.7.8.1. Efficacy and/or Immunogenicity Assessments for 
Substudy A ......................................................................................105
10.7.8.2. Safety Assessments ...............................................................107
10.7.8.3. Adverse Events, Serious Adverse Events, and Other 
Safety Reporting..............................................................................107
10.7.8.4. Immunogenicity Assessments...............................................107
10.7.8.5. Substudy A Procedures .........................................................107
10.7.9. Statistical Considerations for Substudy A..............................................118
10.7.9.1. Statistical Hypotheses ...........................................................118
10.7.9.2. Analysis Sets .........................................................................118
10.7.9.3. Statistical Analyses ...............................................................119
10.7.9.4. Interim Analyses ...................................................................121
10.7.9.5. Sample Size Determination...................................................123
10.8. Appendix 8: Substudy B .....................................................................................125
10.8.1. Substudy Summary.................................................................................125
10.8.1.1. Synopsis ................................................................................125
10.8.1.2. Schema ..................................................................................125
10.8.1.3. Schedule of Activities for Substudy B ..................................126

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10.8.2. Introduction.............................................................................................128
10.8.2.1. Study Rationale .....................................................................128
10.8.2.2. Background ...........................................................................128
10.8.2.3. Benefit/Risk Assessment.......................................................128
10.8.3. Objectives, Estimands, and Endpoints....................................................129
10.8.4. Study Design...........................................................................................129
10.8.4.1. Overall Design.......................................................................129
10.8.4.2. Scientific Rationale for Substudy B Design..........................129
10.8.4.3. Justification for Dose ............................................................130
10.8.4.4. End of Study Definition ........................................................130
10.8.5. Study Population.....................................................................................130
10.8.5.1. Inclusion Criteria...................................................................130
10.8.5.2. Exclusion Criteria..................................................................131
10.8.5.3. Lifestyle Considerations........................................................132
10.8.5.4. Screen Failures ......................................................................132
10.8.5.5. Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study 
Intervention......................................................................................132
10.8.6. Study Intervention(s) and Concomitant Therapy ...................................132
10.8.6.1. Study Intervention(s) Administered......................................133
10.8.6.2. Measures to Minimize Bias: Randomization and 
Blinding...........................................................................................133
10.8.6.3. Study Intervention Compliance.............................................135
10.8.6.4. Dose Modification.................................................................135
10.8.6.5. Continued Access to Study Intervention After the End of 
the Study..........................................................................................135
10.8.6.6. Treatment of Overdose..........................................................135
10.8.6.7. Concomitant Therapy............................................................135
10.8.7. Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal..........................................................................135
10.8.8. Study Assessments and Procedures........................................................135
10.8.8.1. Safety Assessments ...............................................................135
10.8.8.2. Adverse Events, Serious Adverse Events, and Other 
Safety Reporting..............................................................................135

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10.8.8.3. Substudy B Procedures..........................................................135
10.8.9. Statistical Considerations for Substudy B ..............................................143
10.8.9.1. Statistical Hypotheses ...........................................................143
10.8.9.2. Analysis Sets .........................................................................144
10.8.9.3. Statistical Analyses ...............................................................144
10.8.9.4. Interim Analyses ...................................................................146
10.8.9.5. Sample Size Determination...................................................146
10.9. Appendix 9: Substudy C .....................................................................................147
10.9.1. Substudy Summary.................................................................................147
10.9.1.1. Synopsis ................................................................................147
10.9.1.2. Schema ..................................................................................147
10.9.1.3. Schedule of Activities for Substudy C ..................................148
10.9.2. Introduction.............................................................................................150
10.9.2.1. Study Rationale .....................................................................150
10.9.2.2. Benefit/Risk Assessment.......................................................151
10.9.3. Objectives, Estimands, and Endpoints....................................................151
10.9.4. Study Design...........................................................................................152
10.9.4.1. Overall Design.......................................................................152
10.9.4.2. Justification for Dose ............................................................153
10.9.4.3. End of Study Definition ........................................................153
10.9.5. Study Population.....................................................................................153
10.9.5.1. Inclusion Criteria...................................................................153
10.9.5.2. Exclusion Criteria..................................................................154
10.9.5.3. Lifestyle Considerations........................................................155
10.9.5.4. Screen Failures ......................................................................155
10.9.5.5. Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study
Intervention......................................................................................155
10.9.6. Study Intervention(s) and Concomitant Therapy ...................................156
10.9.6.1. Study Intervention(s) Administered......................................156
10.9.6.2. Measures to Minimize Bias: Randomization and 
Blinding...........................................................................................156
10.9.6.3. Study Intervention Compliance.............................................158

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10.9.6.4. Dose Modification.................................................................158
10.9.6.5. Continued Access to Study Intervention After the End of 
the Study..........................................................................................158
10.9.6.6. Treatment of Overdose..........................................................158
10.9.6.7. Concomitant Therapy............................................................158
10.9.7. Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal..........................................................................158
10.9.8. Study Assessments and Procedures........................................................158
10.9.8.1. Efficacy and/or Immunogenicity Assessments for 
Substudy C.......................................................................................158
10.9.8.2. Safety Assessments ...............................................................158
10.9.8.3. Adverse Events, Serious Adverse Events, and Other 
Safety Reporting..............................................................................158
10.9.8.4. Substudy C Procedures..........................................................159
10.9.8.5. Additional Procedures for Monitoring of Potential 
Myocarditis or Pericarditis ..............................................................163
10.9.9. Statistical Considerations for Substudy C ..............................................164
10.9.9.1. Statistical Hypotheses ...........................................................165
10.9.9.2. Analysis Sets .........................................................................165
10.9.9.3. Statistical Analyses ...............................................................165
10.9.9.4. Interim Analyses ...................................................................167
10.9.9.5. Sample Size Determination...................................................168
10.10. Appendix 10: Substudy D .................................................................................170
10.10.1. Substudy Summary...............................................................................170
10.10.1.1. Synopsis ..............................................................................170
10.10.1.2. Schema ................................................................................171
10.10.1.3. Schedule of Activities for Substudy D................................174
10.10.2. Introduction...........................................................................................187
10.10.2.1. Study Rationale ...................................................................187
10.10.2.2. Benefit/Risk Assessment.....................................................188
10.10.3. Objectives, Estimands, and Endpoints..................................................189
10.10.4. Study Design.........................................................................................192
10.10.4.1. Overall Design.....................................................................192

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10.10.4.2. Scientific Rationale for Substudy D Design .......................193
10.10.4.3. Justification for Dose ..........................................................193
10.10.4.4. End of Study Definition ......................................................194
10.10.5. Study Population...................................................................................194
10.10.5.1. Inclusion Criteria.................................................................194
10.10.5.2. Exclusion Criteria................................................................195
10.10.5.3. Lifestyle Considerations......................................................196
10.10.5.4. Screen Failures ....................................................................196
10.10.5.5. Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study 
Intervention......................................................................................196
10.10.6. Study Intervention(s) and Concomitant Therapy .................................196
10.10.6.1. Study Intervention(s) Administered....................................197
10.10.6.2. Measures to Minimize Bias: Randomization and 
Blinding...........................................................................................197
10.10.6.3. Study Intervention Compliance...........................................199
10.10.6.4. Dose Modification...............................................................199
10.10.6.5. Continued Access to Study Intervention After the End 
of the Study......................................................................................199
10.10.6.6. Treatment of Overdose........................................................199
10.10.6.7. Concomitant Therapy..........................................................199
10.10.7. Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal..........................................................................199
10.10.8. Study Assessments and Procedures......................................................200
10.10.8.1. Surveillance for COVID-19 ................................................200
10.10.8.2. Immunogenicity ..................................................................202
10.10.8.3. Safety Assessments .............................................................202
10.10.8.4. Adverse Events, Serious Adverse Events, and Other 
Safety Reporting..............................................................................202
10.10.8.5. Specified Genetics...............................................................202
10.10.8.6. Substudy D Procedures .......................................................202
10.10.9. Statistical Considerations for Substudy D............................................235
10.10.9.1. Statistical Hypotheses .........................................................235
10.10.9.2. Analysis Sets .......................................................................237

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10.10.9.3. Statistical Analyses .............................................................237
10.10.9.4. Interim Analyses .................................................................240
10.10.9.5. Sample Size Determination.................................................241
10.11. Appendix 11: Substudy E..................................................................................243
10.11.1. Substudy Summary...............................................................................243
10.11.1.1. Substudy Synopsis...............................................................243
10.11.1.2. Schema ................................................................................244
10.11.1.3. Schedule of Activities for Substudy E ................................245
10.11.2. Introduction...........................................................................................249
10.11.2.1. Study Rationale ...................................................................249
10.11.2.2. Benefit/Risk Assessment.....................................................249
10.11.3. Objectives, Estimands, and Endpoints..................................................250
10.11.4. Study Design.........................................................................................253
10.11.4.1. Overall Design.....................................................................253
10.11.4.2. Scientific Rationale for Substudy E Design........................256
10.11.4.3. Justification for Dose ..........................................................257
10.11.4.4. End of Study Definition ......................................................257
10.11.5. Study Population...................................................................................257
10.11.5.1. Inclusion Criteria.................................................................257
10.11.5.2. Exclusion Criteria................................................................258
10.11.5.3. Lifestyle Considerations......................................................259
10.11.5.4. Screen Failures ....................................................................259
10.11.5.5. Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study 
Intervention......................................................................................259
10.11.6. Study Intervention(s) and Concomitant Therapy .................................260
10.11.6.1. Study Intervention(s) Administered....................................260
10.11.6.2. Measures to Minimize Bias: Randomization and 
Blinding...........................................................................................261
10.11.6.3. Study Intervention Compliance...........................................263
10.11.6.4. Dose Modification...............................................................263
10.11.6.5. Continued Access to Study Intervention After the End 
of the Study......................................................................................263

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10.11.6.6. Treatment of Overdose........................................................263
10.11.6.7. Concomitant Therapy..........................................................263
10.11.7. Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal..........................................................................263
10.11.8. Study Assessments and Procedures......................................................263
10.11.8.1. Surveillance for COVID-19 ................................................264
10.11.8.2. Immunogenicity ..................................................................265
10.11.8.3. Safety Assessments .............................................................266
10.11.8.4. Adverse Events, Serious Adverse Events, and Other 
Safety Reporting..............................................................................266
10.11.8.5. Specified Genetics...............................................................266
10.11.8.6. Substudy E Procedures........................................................266
10.11.9. Statistical Considerations for Substudy E.............................................279
10.11.9.1. Statistical Hypotheses .........................................................279
10.11.9.2. Analysis Sets .......................................................................283
10.11.9.3. Statistical Analyses .............................................................283
10.11.9.4. Interim Analyses .................................................................286
10.11.9.5. Sample Size Determination.................................................288
10.12. Appendix 12: Substudy F..................................................................................289
10.12.1. Substudy Summary...............................................................................289
10.12.1.1. Substudy Synopsis...............................................................289
10.12.1.2. Schema ................................................................................289
10.12.1.3. Schedule of Activities for Substudy F.................................290
10.12.2. Introduction...........................................................................................292
10.12.2.1. Study Rationale ...................................................................292
10.12.2.2. Benefit/Risk Assessment.....................................................292
10.12.3. Objectives, Estimands, and Endpoints..................................................293
10.12.4. Study Design.........................................................................................293
10.12.4.1. Overall Design.....................................................................293
10.12.4.2. Scientific Rationale for Substudy F Design ........................294
10.12.4.3. Justification for Dose ..........................................................295
10.12.4.4. End of Study Definition ......................................................295
10.12.5. Study Population...................................................................................295

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10.12.5.1. Inclusion Criteria.................................................................295
10.12.5.2. Exclusion Criteria................................................................296
10.12.5.3. Lifestyle Considerations......................................................297
10.12.5.4. Screen Failures ....................................................................297
10.12.5.5. Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study 
Intervention......................................................................................297
10.12.6. Study Intervention(s) and Concomitant Therapy .................................297
10.12.6.1. Study Intervention(s) Administered....................................298
10.12.6.2. Measures to Minimize Bias: Randomization and 
Blinding...........................................................................................299
10.12.6.3. Study Intervention Compliance...........................................300
10.12.6.4. Dose Modification...............................................................300
10.12.6.5. Continued Access to Study Intervention After the End 
of the Study......................................................................................300
10.12.6.6. Treatment of Overdose........................................................300
10.12.6.7. Concomitant Therapy..........................................................300
10.12.7. Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal..........................................................................301
10.12.8. Study Assessments and Procedures......................................................301
10.12.8.1. Surveillance for COVID-19 ................................................301
10.12.8.2. Immunogenicity ..................................................................303
10.12.8.3. Safety Assessments .............................................................303
10.12.8.4. Adverse Events, Serious Adverse Events, and Other 
Safety Reporting..............................................................................303
10.12.8.5. Substudy F Procedures........................................................303
10.12.9. Statistical Considerations for Substudy F.............................................314
10.12.9.1. Statistical Hypotheses .........................................................314
10.12.9.2. Analysis Sets .......................................................................314
10.12.9.3. Statistical Analyses .............................................................314
10.12.9.4. Interim Analyses .................................................................316
10.12.9.5. Sample Size Determination.................................................317
10.13. Appendix 13: Protocol Amendment History.....................................................319
10.14. Appendix 14: Abbreviations .............................................................................356

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10.15. Appendix 15: Criteria for Allowing Inclusion of Participants With
Chronic Stable HIV, HCV, or HBV Infection ........................................................359
10.16. Appendix 16: Genetics......................................................................................360
11. REFERENCES ................................................................................................................361
LIST OF TABLES
Table 1.
Total Number of Participants by Cohort ..................................................23
Table 2.
Local Reaction Grading Scale ..................................................................52
Table 3.
Systemic Event Grading Scale..................................................................52
Table 4.
Scale for Fever..........................................................................................54
Table 5.
Expected Number of COVID-19 Cases Under Assumed Vaccine 
Efficacy and Incidence Rate ...................................................................123
Table 6.
Probability for Vaccine Efficacy Assessment ........................................124
Table 7.
Probability of Observing at Least 1 AE by Assumed True Event 
Rates .......................................................................................................124
Table 8.
Probability of Observing at Least 1 AE by Assumed True Event 
Rates With Different Samples Sizes.......................................................146
Table 9.
Probability of Observing at 1 Least AE by Assumed True Event 
Rates With Different Sample Sizes ........................................................169
Table 10.
Total Number of Participants by Cohort ................................................193
Table 11.
Probability of Observing at 1 Least AE by Assumed True Event 
Rates With Different Sample Sizes ........................................................242
Table 12.
Substudy E – Participants >55 Years of Age – Sentinel and 
Expanded Enrollment .............................................................................255
Table 13.
Substudy E – Participants 18 to 55 Years of Age – Sentinel and 
Expanded Enrollment .............................................................................256
Table 14.
Substudy E – Probability of Observing at Least 1 AE by Assumed 
True Event Rates With Different Sample Sizes .....................................288
Table 15.
Substudy F – Sentinel and Expanded Enrollment ..................................294
Table 16.
Substudy F - Probability of Observing at Least 1 AE by Assumed 
True Event Rates With Different Sample Sizes .....................................318

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1. PROTOCOL SUMMARY
1.1. Synopsis 
Brief Title:
A Study to Evaluate Additional Dose(s) of BNT162b2 in Healthy Individuals Previously 
Vaccinated With BNT162b2
Rationale
A pneumonia of unknown cause detected in Wuhan, China, was first reported in 
December 2019.  In January 2020, the pathogen causing this outbreak was identified as 
2019-nCoV.  The outbreak was declared a Public Health Emergency of International 
Concern on 30 January 2020.  On 11 February 2020, the virus was officially named as 
SARS-CoV-2, and the WHO officially named the disease caused by SARS-CoV-2 as 
COVID-19.  On 11 March 2020, the WHO upgraded the status of the COVID-19 outbreak 
from epidemic to pandemic, which continues to spread globally at high speed. To-date, more 
than 455 million people have been infected with SARS-CoV-2 and >6 million have died, 
demonstrating an urgent need for efficacious vaccines.
Numerous COVID-19 vaccines are currently in development globally, and several candidate 
COVID-19 vaccines (eg, mRNA vaccines and adenovirus-vectored vaccines expressing the 
S protein) have been shown to be efficacious in the prevention of COVID-19 in clinical 
studies and are now available under temporary or emergency authorizations.  BNT162b2, an 
RNA-based COVID-19 vaccine given as a 2-dose series administered 21 days apart, was 
shown to be safe and effective in a Phase 1/2/3 study and has received authorizations for 
temporary or emergency use or marketing authorizations in multiple countries.
Genetic lineages of SARS-CoV-2 have been emerging and circulating around the world since 
the beginning of the COVID-19 pandemic. There have been at least 12 different variants 
identified since December 2020. Within the first 3 months of the start of this global 
pandemic, the Alpha (B.1.1.7 and Q lineages), Beta (B.1.351 and descendent lineages), 
Gamma (P.1 and descendent lineages), and Epsilon (B.1.427 and B.1.429) variants were 
identified as VOCs. This is defined as a variant for which there is evidence of an increase in 
transmissibility, more severe disease, significant reduction in neutralization by antibodies 
generated during previous infection or vaccination, reduced effectiveness of treatment or 
vaccines, or diagnostic detection failures. On 21 September 2021, these variants were 
downgraded to variants being monitored. However, current VOCs include Delta 
(B.1.617.2 and AY lineages) and Omicron (B.1.1.529 and BA lineages). Delta, which has
increased transmissibility, has dominated the number of infections in the latter half of 2021. 
Since the Omicron variant has been newly identified at the time of this protocol amendment, 
additional information will be learned as time progresses.
A 2-dose series of BNT162b2 conferred 95% protection against COVID-19 in persons 
16 years of age or older after a median follow-up period of 2 months after the second dose.
However, as presented in April 2021, the efficacy of BNT162b2 from 7 days through up to 
6 months after the second dose had decreased to 91.3% effective against COVID-19.

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However, the vaccine was 100% effective against severe disease as defined by the US CDC, 
and 95.3% effective against severe COVID-19 as defined by the FDA. Recent data from 
interim analysis of C4591031 Substudy A have demonstrated that a booster dose 
administered to individuals who previously received a primary 2-dose series of BNT162b2 
restored vaccine protection against COVID-19 to the high levels achieved after the second 
dose, showing a relative VE of 95.6% when compared to those who did not receive the 
booster. However, the efficacy of BNT162b2 in the face of ongoing emergence of new 
SARS-CoV-2 variants, with multiple mutations in the S protein, is unknown.  Therefore, the 
substudies within this master protocol will study the safety, and/or immunogenicity, and/or 
efficacy of various BNT162b2 boosting strategies across different populations of participants
(eg, age groups), with the details and rationale for each strategy provided in substudy 
appendices.
Studying boosting strategies under a single master protocol rather than separate protocols 
will allow an organized approach that can be easily adapted as data emerge that can impact 
our understanding of what boosting strategies may be required. This approach will not only 
be more expeditious to implement, which is critical given the public health emergency the 
COVID-19 global pandemic represents, but also more readily understandable for 
investigational sites.
Objectives and Endpoints
Please refer to the substudy appendices for the objectives and endpoints of each substudy.
Estimands
Please refer to the substudy appendices for the rationale of each substudy.
Overall Design
This is a Phase 3 master study to evaluate BNT162b2 boosting strategies in healthy 
individuals previously vaccinated with BNT162b2.  Each substudy design is detailed
separately and these substudies may be conducted in parallel, as required by the clinical plan, 
within the framework of this master protocol.
Substudy A Design
This is a Phase 3 randomized, placebo-controlled, observer-blind substudy to evaluate the 
safety, tolerability, and efficacy of a booster dose of BNT162b2.  Participants ≥16 years of 
age who have completed a 2-dose primary series of BNT162b2 at least 6 months prior to 
randomization will be enrolled, and participants will be randomized at a ratio of 1:1 to 
receive either BNT162b2 or placebo.  Randomization will be stratified by age, such that 
approximately 60% of participants enrolled will be ≥16 to 55 years of age and approximately 
40% of participants >55 years of age.

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Participants who are randomized to receive placebo at the booster vaccination visit will be 
offered the opportunity to receive BNT162b2 if indicated by the outcome of the interim 
analyses, or at the discretion of the study sponsor.  The timing of this booster vaccination 
may be informed by the outcome of the interim analyses or at a time decided by the sponsor.
The study may be terminated early, for reasons including (but not limited to) access to and 
availability of BNT162b2 in the real world, reducing the value of participant involvement 
and observation in this clinical trial. Further to this, participants who are offered the 
possibility to participate in a future study within the Pfizer/BioNTech COVID-19 vaccine 
development program will be discontinued from this study.
Substudy B Design
This is a randomized, placebo-controlled, observer-blind, crossover substudy to evaluate the 
safety and tolerability of a booster (third or fourth) dose of BNT162b2.  Participants 
≥12 years of age to ≤30 years of age who have received 2 or 3 doses of BNT162b2 
(30-µg doses) with their last dose at least 4 months (120 days) prior to randomization will be 
enrolled. Participants will be randomized at a ratio of 1:1 to receive either BNT162b2 or 
placebo at Visit 1 and the alternative at Visit 3, four weeks later.  Randomization will be 
stratified by age (stratified as 12-17, 18-24, and 25-30 years of age). Approximately 
1500 participants will be randomized in the study. A blood sample will be collected to 
obtain a serum sample for troponin testing before each administration of blinded study 
intervention, 2 to 5 days after each administration, and 1 month after the second 
administration.
Substudy C Design
This is a randomized, observer-blinded substudy to evaluate the safety, tolerability, and 
immunogenicity of a booster (third) dose of BNT162b2 at 10 µg and at 30 µg. Participants 
≥12 years of age who have completed a 2-dose primary series of BNT162b2 (30-µg doses) at 
least 5 months (150 days) prior to randomization will be enrolled. Participants will be 
randomized at a ratio of 1:1 to receive BNT162b2 at either a 10-µg or 30-µg dose level at 
Visit 301. Randomization will be stratified by age with escalation to each higher age group
guided by immunogenicity results at 7 days after the third dose. A DMC will review safety 
(e-diary and AE) and immunogenicity data in the first approximately 100 participants with 
available immunogenicity (~50 participants in each dose level) 7 days after the third dose.
Upon confirmation of an acceptable safety and immunogenicity assessment by the DMC, 
progression of the next age group will occur independently.
As part of Protocol Amendment 11, progression beyond the 12 through 17 years age group 
will not occur and no further participants will be enrolled. The rationale for this amendment 
is that a third dose of COVID-19 vaccine has been recommended for all age groups for a 
considerable period of time (hence the potential substrate for enrollment is essentially 
nonexistent) and, for Fall 2022, the recommended booster vaccine will switch to a bivalent 
original/Omicron-modified vaccine. Both factors contribute to age escalation being 
operationally unfeasible. Furthermore, since the 30-µg dose level is well tolerated, and in the 

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face of emergence of SARS-CoV-2 Omicron sublineages for which a maximum immune 
response is desirable, the rationale for a reduced dose level no longer holds.
Substudy D Design
This is a randomized substudy composed of open-labeled and observer-blinded groups to 
evaluate the safety, tolerability, and immunogenicity of a 2-dose primary series of 
BNT162b2 OMI, and as a booster (third or fourth or fifth) dose at investigator sites in the US 
and South Africa only.  Participants ≥18 years of age to ≤55 years of age will be enrolled.
Approximately 1420 participants will be enrolled in the study.
Participants in Cohort 1 will have completed a 2-dose primary series of BNT162b2 
(30-µg doses), with their last dose 90 to 240 days prior to enrollment. Approximately 
615 participants will be randomized at a ratio of 1:1:1 either to receive 1 dose (third) of 
BNT162b2 OMI, 2 doses (third and fourth) of BNT162b2 OMI, 4 weeks apart, or 1 dose 
(third) of BNT162b2. Randomization will be stratified by age (stratified as 18-30 and 
31-55 years of age). Participants in Cohort 1 will remain blinded to whether they will be 
receiving a fourth dose through 1 month after their first dose, but the investigator and sponsor 
will not be blinded.
Participants in Cohort 2 will be enrolled from Study C4591001 and C4591031 Substudy A 
and will have completed a 2-dose primary series and received a single booster (third) dose of 
BNT162b2, with their last dose 90 to 180 days prior to randomization. Approximately
600 participants will be randomized at a ratio of 1:1 to receive a fourth dose of either 
BNT162b2 or BNT162b2 OMI at Visit 401. Participants will be offered a dose of 
BNT162b2 OMI at Visit 404 (3-month follow-up). Randomization will be stratified by age 
(stratified as 18-30 and 31-55 years of age). Cohort 2 will be observer-blinded.
In Cohort 3, 205 participants 18 through 55 years of age who are COVID-19 vaccine–naïve 
and have not experienced COVID-19 will be enrolled to receive 2 doses (primary series) of 
BNT162b2 OMI, 3 weeks apart, with a dose of BNT162b2 approximately 5 months
(150 days) later. If participants do not consent to receive BNT162b2 as a third dose, they 
will not receive a third dose. No participants should receive BNT162b2 OMI as a third dose.
Table 1 details the number of participants by cohort and group, their prior BNT162b2 
experience, the vaccine that will be administered, and the number of doses administered as 
part of Substudy D.
Table 1.
Total Number of Participants by Cohort
Cohort
Group
Prior 
BNT162b2 
Experience
Vaccine
Number of Doses 
Administered as 
Part of 
Substudy D
Total Number of 
Participants
Cohort 1
Group 1
2 Doses
BNT162b2 OMI
1
205
Group 2 
2 Doses
BNT162b2 OMI
2
205
Group 2b
2 Doses
BNT162b2
1
205

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Table 1.
Total Number of Participants by Cohort
Cohort
Group
Prior 
BNT162b2 
Experience
Vaccine
Number of Doses 
Administered as 
Part of 
Substudy D
Total Number of 
Participants
Cohort 2
Group 3 
3 Doses
BNT162b2 OMI
1 or 2
300
Group 4
3 Doses
BNT162b2 (and 
BNT162b2 OMI 
at Visit 404)
1 or 2
300
Cohort 3
Group 5
Naïve
BNT162b2 OMI
2
205
BNT162b2
1
Note: Cohorts 1 and 2 are observer-blinded. Participants in Cohort 1 will remain blinded to whether they 
will be receiving a fourth dose through 1 month after their first dose. Cohort 2 participants will be unblinded
once they have completed Visit 404. Cohort 3 is open-labeled.
As part of protocol amendment 11, active participants in Cohort 1 and Cohort 2 at the time of 
this amendment will only be followed for 6 months after their last study vaccination, which 
aligns with the protocol-specified safety reporting period. As of Fall 2022, the recommended 
booster vaccine will switch to a bivalent original/Omicron-modified vaccine, and therefore it 
is unnecessary to prolong the participation of individuals in the study and take 
immunogenicity samples 12 months after vaccination for the monovalent Omicron vaccine. 
Their final visit will be V405. 
Substudy E Design
This is a randomized, observer-blinded substudy to evaluate the safety, tolerability, and 
immunogenicity of high-dose BNT162b2 (60 µg), high-dose BNT162b2 OMI (60 µg), and a 
high-dose combination of BNT162b2 and BNT162b2 OMI at 60 µg (30 µg each), given as a 
single dose). Approximately 1920 participants 55 years of age and 990 participants 18 to 
55 years of age who have received 3 prior doses of BNT162b2 (30-µg doses) with the most 
recent dose being 5 to 12 months (150 to 360 days) prior to randomization, will be enrolled at 
investigator sites in the US only. Participants >55 years of age will be randomized at a ratio 
of 1:1:1:1:1:1 to receive BNT162b2 at 30 µg, BNT162b2 at 60 µg, BNT162b2 OMI at 30 µg, 
BNT162b2 OMI at 60 µg, a combination of BNT162b2 and BNT162b2 OMI at 30 µg (15 µg
each), or a combination of BNT162b2 and BNT162b2 OMI at 60 µg (30 µg each) at Visit 
601 as a fourth dose. Participants 18 to 55 years of age will be randomized to receive
bivalent BNT162b2 and BNT162b2 OMI at 60 µg (30 µg each), bivalent BNT162b2 and 
BNT162b2 OMI at 30 µg (15 µg each), or BNT162b2 OMI at 60 µg at Visit 601 as a fourth 
dose.
Initially, for participants >55 years of age, sentinel cohorts (sponsor open-label) of 
20 participants per group will be enrolled. E-diary data from Day 1 and Day 2 for the first 
30 participants enrolled in the sentinel cohort (5 per group) will be evaluated prior to 
enrollment of the remaining 90 sentinel-cohort participants. An IRC will review all reported 
AEs and reactogenicity e-diary data from the sentinel cohorts collected through Day 7 to 
allow expanded enrollment of an additional 300 participants per group upon confirmation of 

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an acceptable safety assessment. If the safety assessment is considered not to be acceptable, 
the protocol may be amended to include a further sentinel cohort employing 50-µg dose 
levels of BNT162b2, BNT162b2 OMI, and a combination of BNT162b2 and BNT162b2 
OMI (25 µg each).
For participants 18 to 55 years of age, sentinel cohorts (sponsor open-label) of 30 participants 
per group will be enrolled. E-diary data from Day 1 and Day 2 for the first 15 participants 
enrolled in the sentinel cohort (5 per group) will be evaluated prior to enrollment of the 
remaining 75 sentinel-cohort participants. An IRC will review all reported AEs,
reactogenicity e-diary data, and troponin levels from the sentinel cohorts collected through 
Day 7 to allow expanded enrollment upon confirmation of an acceptable safety assessment. 
An additional 900 participants will be enrolled and randomized in a 3:1:2 ratio to receive 
bivalent BNT162b2 and BNT162b2 OMI at 60 µg (30 µg each), bivalent BNT162b2 and 
BNT162b2 OMI at 30 µg (15 µg each), and BNT162b2 OMI at 60 µg.
Substudy F Design
This is a randomized, observer-blinded substudy to describe the safety, tolerability, and 
immunogenicity of high-dose BNT162b2 (60 µg), high-dose BNT162b2 OMI (60 µg), and a 
high-dose combination of BNT162b2 and BNT162b2 OMI at 60 µg (30 µg each), given as a 
single dose. Approximately 180 participants ≥60 years of age who have received 3 prior 
doses of BNT162b2 (30 µg doses), with the most recent dose being ≥4 months prior to 
randomization, will be enrolled in Israel. Participants will be randomized at a ratio of 
1:1:1:1:1:1 to receive BNT162b2 at 30 µg, BNT162b2 at 60 µg, BNT162b2 OMI at 30 µg, 
BNT162b2 OMI at 60 µg, a combination of BNT162b2 and BNT162b2 OMI at 30 µg
(15 µg each), or a combination of BNT162b2 and BNT162b2 OMI at 60 µg (30 µg each) at 
Visit 701 as a fourth dose.
Initially, sentinel cohorts (sponsor open-label) of 5 participants per group will be enrolled. 
An IRC and site representatives will review all reported AEs and reactogenicity e-diary data 
from the sentinel cohorts collected through Day 7 to allow expanded enrollment of an 
additional 25 participants per group upon confirmation of an acceptable safety assessment. If 
the safety assessment is considered not to be acceptable, the protocol may be amended to 
include a further sentinel cohort employing 50-µg dose levels of BNT162b2, 
BNT162b2 OMI, and a combination of BNT162b2 and BNT162b2 OMI (25 µg each).
Number of Participants
Substudy A will include 10,000 participants.
Substudy B will include up to 1500 participants.
Substudy C will include up to 150 participants.

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Substudy D will include up to 1420 participants.
Substudy E will include up to 2910 participants.
Substudy F will include up to 180 participants. 
Data Monitoring Committee or Other Independent Oversight Committee
An external DMC will be formed and will review cumulative unblinded data throughout the 
study.
Substudy C will utilize a DMC that will be used to review safety and immunogenicity data in 
the first approximately 100 participants with available immunogenicity data (~50 participants 
in each dose level of BNT162b2)7 days after the third dose.
Substudies E and F will utilize an IRC that will be used to review all reported AEs and
reactogenicity data collected through Day 7 from all participants enrolled in the sentinel 
cohorts to evaluate if enrollment can be expanded in each group.
Statistical Methods:
The statistical methods will be specified in the respective substudy appendices.
1.2. Schema
Please refer to the appendices for the schema of each substudy.
1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the 
STUDY ASSESSMENTS AND PROCEDURES section of the protocol for detailed 
information on each procedure and assessment required for compliance with the protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA
table, in order to conduct evaluations or assessments required to protect the well-being of the 
participant.
Refer to the SoA for Substudy A in Section 10.7.1.3, for Substudy B in Section 10.8.1.3, for 
Substudy C in Section 10.9.1.3, Substudy D in Section 10.10.1.3, Substudy E in 
Section 10.11.1.3 and Substudy F in Section 10.12.1.3.

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2. INTRODUCTION
BNT162b2 is an RNA-based COVID-19 vaccine that is currently being investigated for the 
prevention of COVID-19 in individuals ≥6 months of age.  On 02 December 2020, the 
MHRA in the UK granted a temporary authorization.1  On 11 December 2020, the US FDA 
issued an EUA for use in individuals 16 years of age and older.  BNT162b2 has now been 
granted a conditional marketing authorization, EUA, or temporary authorization in a total of 
more than 60 countries2,3,4 and has been fully licensed for use in individuals 16 years of age 
and above in the US as of 23 August 2021.5
2.1. Study Rationale 
Like other COVID-19 vaccines recently developed, the long-term persistence of immunity 
and efficacy of BNT162b2 has yet to be studied.  In addition, genetic lineages of 
SARS-CoV-2 have been emerging and circulating around the world since the beginning of 
the COVID-19 pandemic. There have been at least 12 different variants identified since 
December 2020. Within the first 3 months of the start of this global pandemic, the Alpha 
(B.1.1.7 and Q lineages), Beta (B.1.351 and descendent lineages), Gamma (P.1 and 
descendent lineages), and Epsilon (B.1.427 and B.1.429) variants were identified as VOCs. 
This is defined as a variant for which there is evidence of an increase in transmissibility, 
more severe disease, significant reduction in neutralization by antibodies generated during 
previous infection or vaccination, reduced effectiveness of treatment or vaccines, or 
diagnostic detection failures. On 21 September 2021, these variants were downgraded to 
variants being monitored. However, current VOCs include Delta (B.1.617.2 and AY 
lineages) and Omicron (B.1.1.529 and BA lineages). Delta, which has increased 
transmissibility, has dominated the number of infections in the latter half of 2021. Since the 
Omicron variant has been newly identified at the time of this protocol amendment, additional 
information will be learned as time progresses.6
A 2-dose series of BNT162b2 conferred 95% protection against COVID-19 in persons 
16 years of age or older after a median follow-up period of 2 months after the second dose.7
However, as presented in April 2021, the efficacy of BNT162b2 from 7 days through up to 
6 months after the second dose had decreased to 91.3% effective against COVID-19. 
However, the vaccine was 100% effective against severe disease as defined by the US CDC, 
and 95.3% effective against severe COVID-19 as defined by the FDA.8 Recent data from 
interim analysis of C4591031 Substudy A have demonstrated that a booster dose 
administered to individuals who previously received a primary 2-dose series of BNT162b2
restored vaccine protection against COVID-19 to the high levels achieved after the second 
dose, showing a relative VE of 95.6% when compared to those who did not receive the 
booster.9 However, the efficacy of BNT162b2 in the face of recurring emergence of new 
SARS-CoV-2 variants, with multiple mutations in the S protein, is unknown.  Therefore, the
substudies within this master protocol will evaluate the safety, and/or immunogenicity, 
and/or efficacy of various BNT162b2 boosting strategies across different populations of 
participants (eg, age groups) having previously received 2 doses of BNT162b2 administered 
21 days apart, with the details and rationale for each strategy provided in the substudy
appendices (Section 10.7 through Section 10.12).

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Studying boosting strategies under a single master protocol, rather than separate protocols,
will allow an organized approach that can be easily adapted as data emerge that can impact 
our understanding of what boosting strategies may be required. This approach will not only 
be more expeditious to implement, which is critical given the public health emergency the 
COVID-19 global pandemic represents, but also more readily understandable for 
investigational sites.
2.2. Background
In December 2019, a pneumonia outbreak of unknown cause occurred in Wuhan, China.  
In January 2020, it became clear that 2019-nCoV was the underlying cause.  The outbreak 
was declared a Public Health Emergency of International Concern on 30 January 2020.10  
On 11 February 2020, the virus was officially named as SARS-CoV-2, and the WHO 
officially named the disease caused by SARS-CoV-2 as COVID-19.10,11  SARS-CoV-2 
infections and the resulting disease, COVID-19, have spread globally, and on 
11 March 2020, the WHO characterized the COVID-19 outbreak as a pandemic.12  To-date, 
more than 455 million people have been infected with SARS-CoV-2 and >6 million have 
died, demonstrating an urgent need for efficacious vaccines.13
Numerous COVID-19 vaccines are currently in development globally, and several candidate 
COVID-19 vaccines (eg, mRNA vaccines and adenovirus-vectored vaccines expressing the 
S protein) have been shown to be efficacious in the prevention of COVID-19 in clinical 
studies and are now available under temporary or emergency authorizations.14 BNT162b2,
an RNA-based COVID-19 vaccine given as a 2-dose series administered 21 days apart, was 
shown to be safe and effective in a Phase 1/2/3 study and has received authorizations for 
temporary or emergency use or marketing authorizations in multiple countries and has been 
fully licensed for use in individuals 16 years of age and above in the US as of 
23 August 2021.5,15
Recent evolution of SARS-CoV-2 is resulting in an emergence of new virus variants with 
multiple mutations in the S protein, which might be associated with the lower efficacy of 
some of the current vaccines.  Therefore, there is a need to continue research including new 
approaches, such as evaluation of booster doses, to overcome waning immunity and/or the 
development of modified vaccines.16
Substudy B
Myocarditis and pericarditis are inflammatory conditions of the myocardium and the 
pericardium, respectively. A definitive diagnosis of myocarditis requires histological or 
immunohistological confirmation of an endomyocardial biopsy or other tissue specimen 
(eg, from an autopsy). Because of their invasive nature, biopsies are rarely obtained, and 
therefore a diagnosis of myocarditis is often based upon a compatible clinical scenario 
associated with noninvasive biomarker and imaging features.17 This results in case 
definitions that are very complex, potentially based on multiple parameters (eg, Brighton 
Collaboration definitions).18

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Abnormal ECG, echocardiogram, or troponin findings consistent with myocarditis with no 
cardiac symptoms have been reported in association with SARS-CoV-2 infection19 but are 
not well characterized phenomena, and there is no widely accepted definition of subclinical 
myocarditis.
Substudy C
The results from 306 18- to 55-year-old participants from the C4591001 study who received 
a third (booster) dose of BNT162b2 30 µg a median of 6.8 months after their second dose 
demonstrated a strong immune response. The geometric mean neutralizing antibody titers 
against the reference strain were more than 3 times higher 1 month after the booster dose 
compared to 1 month after Dose 2.20 Immunogenicity of the primary series in participants
12 to 15 of age was shown to be greater than in participants 16 to 25 years of age.21 Further, 
a lower dose may produce a more favorable reactogenicity profile, with the additional benefit 
that it could improve vaccine accessibility by making more doses available. Therefore, the 
assessment of a 10-µg booster dose in individuals ≥12 years of age who have received the 
authorized 30-µg 2-dose primary series warrants further investigation.
Substudy D
On 24 November 2021, South Africa reported the identification of a new SARS-CoV-2 
variant, B.1.1.529, to the WHO; the new variant has been named Omicron and has now been 
detected globally. The Omicron variant has many concerning spike protein mutations, some 
of which are known from other variants to be associated with reduced neutralization by 
convalescent and vaccinee sera. In regard to transmissibility, it is currently clear that 
Omicron spreads more efficiently from person to person.22 However, it is unclear if infection 
with Omicron is associated with more severe disease.23 Lastly, preliminary data announced
on 08 December 2021 from an initial laboratory study demonstrated that serum antibodies 
induced by BNT162b2 neutralize the SARS-CoV-2 Omicron variant after 3 doses. Sera 
obtained from vaccinees 1 month after receiving the booster vaccination (third dose of 
BNT162b2) neutralized the Omicron variant to levels that are comparable to those observed 
for the wild-type SARS-CoV-2 spike protein after 2 doses. A third dose also strongly 
increases CD8+ T-cell levels against multiple spike protein epitopes, which are considered to 
correlate with the protection against severe disease. Compared to the wild-type virus, the vast 
majority of these epitopes remain unchanged in the Omicron spike variant.24 Therefore, 
Substudy D has been designed to assess an Omicron-specific vaccine clinically.
Substudies E and F
The SARS-CoV-2 variant B.1.1.529, also known as Omicron, was identified on 
24 November 2021. As of 08 January 2022, it is now the dominant variant within the US, 
identified in 98.3% of sequenced COVID-19 cases.25 It is currently unknown whether a 
single booster dose of BNT162b2, which has previously been demonstrated to have 95% 
clinical efficacy against SARS-CoV-2 (Delta being the dominant variant), will be as effective 
against the Omicron variant.

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Data published on 31 December 2021 from the UK consisted of 2 studies examining the 
association between both variant and vaccination status and risk of hospitalization. Study 1 
assessed the risk of hospitalization, and Study 2 assessed vaccine effectiveness against 
symptomatic infection and hospitalization. The results for Study 1 noted that the risk of 
hospitalization was lower for Omicron cases after 2 and 3 doses of vaccine, with an 81% 
(77%-85%) reduction in the risk of hospitalization after 3 doses compared to unvaccinated 
Omicron cases. With regard to Study 2, the vaccine effectiveness against hospitalization was 
88% (78%-93%) for Omicron cases after 3 doses of vaccine.26
A recent laboratory study compared the neutralization of Omicron-infected cells in serum 
samples obtained from participants who had received 2 doses of BNT162b2 with 
neutralization in samples obtained from participants who had received 3 doses of BNT162b2. 
The neutralization efficiency of the BNT162b2 vaccine was also tested against wild-type 
SARS-CoV-2 and the Beta, Delta, and Omicron variants. The importance of a third vaccine 
dose was evidenced by a higher neutralization efficiency (by a factor of 100) against the 
Omicron variant after the third dose than after the second dose. However, even with 
3 vaccine doses, neutralization against the Omicron variant was lower (by a factor of 4) than 
that against the Delta variant.27 Therefore, the addition of a higher-dose booster may improve 
protection, particularly in older individuals, with increased longevity of an immune response, 
provided it has a tolerable safety profile. Therefore, Substudies E and F have been designed 
to evaluate high-dose BNT162b2 OMI (60 µg), high-dose BNT162b2 (60 µg), and a high-
dose combination of BNT162b2 OMI and BNT162b2 (30 µg of each), compared to 
BNT162b2 OMI 30 µg, BNT162b2 30 µg, and a combination of BNT162b2 OMI and 
BNT162b2 (15 µg of each), given as a fourth dose.
2.2.1. Clinical Overview
Study C4591001 (NCT04368728) is an ongoing Phase 1/2/3 trial in ~46,000 participants 
designed to generate safety, tolerability, immunogenicity, and efficacy data from a novel 
RNA-based vaccine candidate.7  The trial is being conducted in a heterogeneous study 
population: eligible participants ≥12 years of age, healthy participants, including those 
participants with stable chronic medical conditions, including HIV-, HCV-, and 
HBV-positive participants.  The study consists of 2 parts: Phase 1: to identify the preferred 
vaccine candidate (BNT162b1 or BNT162b2) and dose level (10 µg, 20 µg, 30 µg, or 100 µg 
[for BNT162b1]); Phase 2/3: an expanded-cohort and efficacy part for the selected vaccine 
candidate (BNT162b2).
The available immunogenicity data from Phase 1 participants show that BNT162b2 induced 
a robust IgG-binding response to S1 and a SARS-CoV-2–neutralizing response.  
Immunogenicity substantially increased following the second dose of vaccine.  BNT162b2 
induces a strong antigen-specific Th1-skewed CD4+ response and a strong antigen-specific 
CD8+ response.  BNT162b2 was selected from the Phase 1 part of the study based on the 
overall safety, tolerability, and immunogenicity.  In a mid-November 2020 analysis of 
36,621 participants randomized 1:1 to vaccine or placebo, who were included in the 
per-protocol efficacy analysis population of participants without evidence of SARS-CoV-2 
infection prior to 7 days after completion of the vaccination schedule, the efficacy in 
preventing confirmed COVID-19 occurring at least 7 days after the second dose of vaccine 

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was 95.0%, with 8 COVID-19 cases in the active vaccine group and 162 COVID-19 cases in 
the placebo group.  Subgroup analyses of the primary efficacy endpoint showed similar 
efficacy point estimates across age groups, sexes, racial and ethnic groups, and participants 
with medical comorbidities associated with high risk of severe COVID-19.  Secondary 
efficacy analyses suggested benefit of the vaccine in preventing severe COVID-19, in 
preventing COVID-19 following the first dose, and in preventing COVID-19 in individuals 
with prior SARS-CoV-2 infection, although available data for these outcomes did not allow 
for firm conclusions.28
In a subsequent analysis of 927 confirmed symptomatic cases of COVID-19, an efficacy rate 
of 91.3% was observed for BNT162b2 in preventing such cases occurring between 7 days to 
6 months after the second dose.29 Furthermore, from the same analysis, BNT162b2 was 
shown to have an efficacy of:

100% in preventing severe disease as defined by the CDC.

95.3% in preventing severe disease as defined by the FDA.

100% in preventing COVID-19 cases in South Africa, where the B.1.351 lineage is 
prevalent.
Safety data from approximately 38,000 participants at least 16 years of age randomized 1:1 
to vaccine or placebo with a median of 2 months of follow-up after the second dose 
demonstrated a favorable safety profile.  Available safety data from all participants enrolled 
through the 14 November 2020 data cutoff (N=43,252, which includes late enrollment of 
additional adolescent and adult participants) were consistent with the safety profile for the 
approximately 38,000 participants with a median follow-up of 2 months and also did not 
raise specific safety concerns.28
The most common solicited adverse reactions were injection site reactions (84.1%), fatigue 
(62.9%), headache (55.1%), muscle pain (38.3%), chills (31.9%), joint pain (23.6%), and 
fever (14.2%); severe adverse reactions occurred in 0.0% to 4.6% of participants, were more 
frequent after Dose 2 than after Dose 1, and were generally less frequent in participants 
≥55 years of age (≤2.8%) as compared to younger participants (≤4.6%).  The frequency of 
SAEs was low (<0.5%), without meaningful imbalances between study arms. 
Lymphadenopathy was observed in 0.3% of vaccine recipients as compared to <0.1% of
those who received placebo. Otherwise, there were no notable patterns or numerical 
imbalances between vaccine groups for specific categories of nonserious AEs (including 
other neurologic, neuroinflammatory, and thrombotic events) that would suggest a causal 
relationship to BNT162b2.  With the exception of more frequent, generally mild to moderate 
reactogenicity in participants <55 years of age, the safety profile of BNT162b2 was generally 
similar across age groups, sexes, ethnic and racial groups, participants with or without 
medical comorbidities, and participants with or without evidence of prior SARS-CoV-2 
infection at enrollment.28

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On 22 September 2021, based on safety and immunogenicity data from approximately 
300 immunocompetent adult booster dose recipients from Study C4591001, the FDA issued 
the EUA for a single booster dose of BNT162b2 30 µg for 1) individuals 65 years of age and 
older; 2) individuals 18 through 64 years of age at high risk of severe COVID-19; and
3) individuals 18 through 64 years of age whose frequent institutional or occupational 
exposure to SARS-CoV-2 puts them at high risk of serious complications of COVID-19,
including severe COVID-19.30 On 19 November 2021, the FDA amended the EUA,
authorizing use of a single booster dose for all individuals 18 years of age and older after 
completion of primary vaccination with an FDA-approved COVID-19 vaccine.31 On 
09 December 2021, the FDA again amended the EUA to authorize the use of a single booster 
dose for administration to individuals 16 and 17 years of age at least 6 months after 
completion of primary vaccination with BNT162b2.32 In addition, a booster dose of the 
vaccine is authorized in the EU and other countries, with recommendations for populations 
varying based on local health authority guidance.33,34
The per-protocol interim safety and efficacy analysis was conducted in October 2021 for 
Study C4591031 Substudy A. In this study, approximately 10,000 participants who had 
previously received 2 doses of BNT162b2 as a primary series in Study C4591001 were 
randomized 1:1 in Study C4591031 to receive either a 30-µg booster dose (the same dosage 
strength as in the 2-dose primary series) or placebo. The time between the second dose and 
administration of the booster dose or placebo for most participants was ≥10 to <12 months.
Symptomatic COVID-19 occurrence was measured from ≥7 days after booster or placebo, 
with a median follow-up of 2.5 months. During the blinded placebo-controlled study period
up to a data cutoff date of 05 October 2021, there were a total of 6 cases of COVID-19 in the 
booster group, and 123 cases in the nonboosted placebo group, in the evaluable efficacy 
population without evidence of prior SARS-CoV-2 infection. The observed relative VE was
95.3% (2-sided 95% CI: 89.5%, 98.3%), which reflects the reduction in disease occurrence in 
the boosted group versus the nonboosted group. The AE profile was generally consistent 
with other previously submitted clinical safety data for the vaccine, with no new safety 
concerns identified. No cases of myocarditis or pericarditis were reported.35
2.3. Benefit/Risk Assessment
There is an ongoing global pandemic of COVID-19 with no approved or licensed preventive 
or therapeutic options available.  However, based on the data available from the C4591001
study, multiple temporary or EUAs have been granted.  The available safety and 
immunogenicity data from the ongoing Pfizer-BioNTech clinical trial combined with 
available nonclinical data with BNT162 vaccines and data from nonclinical studies and 
clinical trials with the same or related RNA components, or antigens, support a favorable 
benefit/risk profile and support continued clinical development of BNT162b2.

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In the C4591001 study, BNT162b2 has been shown to elicit increased local and systemic 
adverse reactions as compared to those in the placebo arm, usually lasting a few days.  The 
most common solicited adverse reactions were injection site reactions (84.1%), fatigue 
(62.9%), headache (55.1%), muscle pain (38.3%), chills (31.9%), joint pain (23.6%), and 
fever (14.2%).28  Adverse reactions characterized as reactogenicity were generally mild to 
moderate. The number of participants reporting hypersensitivity-related AEs was 
numerically higher in the vaccine group compared with the placebo group (137 [0.63%] vs 
111 [0.51%]). Severe adverse reactions occurred in 0.0% to 4.6% of participants, were more 
frequent after Dose 2 than after Dose 1, and were generally less frequent in older adults 
(>55 years of age) (≤2.8%) as compared to younger participants (≤4.6%).  Among reported 
unsolicited AEs, lymphadenopathy occurred much more frequently in the active vaccine 
group than the placebo group and is plausibly related to vaccination. SAEs, while 
uncommon (<1.0%), represented medical events that occur in the general population at 
similar frequency as observed in the study.28
No specific safety concerns were identified in subgroup analyses by age, race, ethnicity, 
medical comorbidities, or prior SARS-CoV-2 infection.  The risks are based on the observed 
safety profile to date, which shows mostly mild reactogenicity, low incidence of severe or 
serious events, and no clinically concerning safety observations.  The preponderance of 
severe cases of COVID-19 in the placebo group relative to the BNT162b2 group (9 of 10) 
suggests no evidence of VAED.28
In the latest analysis from C4591001, vaccine safety has been evaluated in more than 
44,000 participants ≥16 years of age, with more than 12,000 vaccinated participants having at 
least 6 months follow-up after their second dose.  No serious safety concerns have been 
observed in this timeframe. Side effects observed in this analysis were generally consistent 
with previously reported results.29
Continued clinical investigation is justified, given:

the threat posed by the increasing number of globally distributed outbreaks of SARS-CoV-2 
infection.

the potential of the BioNTech platform of RNA-based vaccines to deliver high numbers of 
vaccine doses rapidly in a single production campaign.

the threat posed by the SARS-CoV-2 variants emerging worldwide.

the potential need for enhancing immunoresponses to overcome waning immunity.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of BNT162b2 may be found in the IB, which is the SRSD for this study.

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2.3.1. Risk Assessment
Identified/Potential Risk of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Study Intervention(s): BNT162b2 RNA-Based COVID-19 Vaccine
Local reactions and systemic events 
may occur (injection site redness, 
injection site swelling, and 
injection site pain; fever, fatigue, 
headache, chills, muscle pain, and 
joint pain) following vaccination.
These are common adverse 
reactions seen with other vaccines 
as well as the COVID-19 vaccine.  
The most common events reported 
in Study C4591001 were mild to 
moderate pain at the injection site, 
fatigue, and headache.28

Local reactions and systemic 
events will be recorded as AEs
or captured in an e-diary (in 
Substudies B, C, D, E, and F).

All study participants will be 
observed for at least 
30 minutes after vaccination.

Given that higher dose levels 
of BNT162b2, 
BNT162b2 OMI, and a 
combination of BNT162b2 and 
BNT162b2 OMI will be 
administered in Substudies E 
and F, these substudies will 
include review of e-diary data 
reported through Day 7 from 
sentinel cohorts of 20 
participants per group in 
Substudy E and 5 participants 
per group in Substudy F by an 
IRC before expanding 
enrollment. See Sections
10.11.4.1 and 10.12.4.1 for 
details.
Safety profile of a novel vaccine 
not yet fully characterized.
Adverse reactions (risks) identified 
from the postauthorization safety 
data include the following: 
anaphylaxis, other hypersensitivity 
reactions (eg, rash, pruritus, 
urticaria, angioedema), pain in 
extremity (injected arm), vomiting,
and diarrhea.
Data available from the C4591001 
study showed low incidence of 
severe or serious events and no 
clinically concerning safety 
observations across the safety 
population and within demographic 
subgroups based on age, sex, 
race/ethnicity, country, and 
baseline SARS-CoV-2 status.28
Postauthorization safety data 
surveillance has confirmed the 
safety profile observed in 
C4591001 and has resulted in 
identification of some additional 
adverse reactions (risks) as noted in 
this table.

Collection of AEs from 
signing of the ICD through 
1 month after the booster or 
last study vaccination.

Collection of SAEs from 
signing of the ICD through 
6 months after the booster or 
last study vaccination.

DMC review throughout the 
study to review all safety data.

All participants will be 
observed for at least 
30 minutes after vaccination.

Given that higher dose levels 
of BNT162b2, 
BNT162b2 OMI, and a 
combination of BNT162b2
and BNT162b2 OMI will be 
administered in Substudies E 
and F, these substudies will 
include review of AE data 
reported through Day 7 from 
sentinel cohorts of 20 
participants per group in 
Substudy E and 5 participants 

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Identified/Potential Risk of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
per group in Substudy F by an 
IRC before expanding 
enrollment. See Sections
10.11.4.1 and 10.12.4.1 for 
details.
Theoretical risk for COVID-19 
enhancement.
Disease enhancement has been seen 
following vaccination with RSV, 
feline coronavirus, and Dengue 
virus vaccines. It is a modified 
and/or severe presentation of an 
infectious disease affecting 
individuals exposed to the 
wild-type pathogen after having 
received vaccine designed to 
prevent infection. No evidence of 
disease enhancement has been seen 
in large-scale clinical study of 
BNT162b2 in humans or in 
postauthorization surveillance.
Monitoring for cases of COVID-19 
developing during the study, which 
will be reported at COVID-19 
illness visits for substudies that 
include those visits or as AESIs for 
those substudies that do not.  
Assessments of individual cases for 
disease enhancement is challenging 
based on current understanding of 
mechanism of pathogenesis, thus 
evaluations of any adverse or 
unexpected imbalances in severe 
COVID-19 cases may provide 
insight to a potential signal for this 
theoretical risk.
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 
following vaccination with mRNA 
COVID-19 vaccines. Typically, 
the cases have occurred more often 
in younger men and after the 
second dose of the vaccine and 
within 14 days after vaccination. 
These are generally mild cases, and 
individuals tend to recover within a 
short time following standard 
treatment and rest. Healthcare 
professionals should be alert to the 
signs and symptoms of myocarditis 
and pericarditis in vaccine 
recipients.
Specific reference to these risks is 
made within the ICD, with 
instruction to contact a healthcare 
professional if a case is suspected.
For anaphylaxis, there is an on-site 
30-minute observation period after 
vaccination.
Instructions for handling suspected 
cases of myocarditis and 
pericarditis are found in 
Section 10.7.8.5.9 for Substudy A,
Section 10.8.8.3.6 for Substudy B,
Section 10.9.8.5 for Substudy C, 
Section 10.10.8.6.7 for Substudy D,
Section 10.11.8.6.12 for 
Substudy E, and 
Section 10.12.8.5.10 for 
Substudy F.

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Identified/Potential Risk of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Study Procedures
Participants will be required to 
attend healthcare facilities during 
the global SARS-CoV-2 pandemic.
Without appropriate social 
distancing and PPE, there is a 
potential for increased exposure to 
SARS-CoV-2.

Pfizer will work with sites to 
ensure an appropriate 
COVID-19 prevention 
strategy.

Monitoring for cases of 
COVID-19 developing during 
the study, which will be 
reported as AESIs.
Venipuncture will be performed 
during the study.
There is the risk of bleeding, 
bruising, hematoma formation, and 
infection at the venipuncture site.
Only appropriately qualified 
personnel will obtain the blood 
draw.
2.3.2. Benefit Assessment
Benefits to individual participants enrolled in Substudy A are detailed in Section 10.7.2.3.1, 
for Substudy B in Section 10.8.2.3.1, for Substudy C in Section 10.9.2.2.1, Substudy D in
Section 10.10.2.2.1, for Substudy E in Section 10.11.2.2.1, and for Substudy F in 
Section 10.12.2.2.1.
2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risks to participants participating in each 
substudy, the potential risks identified in association with BNT162b2 are justified by the 
anticipated benefits that may be afforded to healthy participants.
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS
For substudy-specific objectives and endpoints, refer to each respective substudy appendix.
For Substudy A, refer to Section 10.7.3.
For Substudy B, refer to Section 10.8.3.
For Substudy C, refer to Section 10.9.3.
For Substudy D, refer to Section 10.10.3.
For Substudy E, refer to Section 10.11.3.
For Substudy F, refer to Section 10.12.3.

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4. STUDY DESIGN
4.1. Overall Design
This is a Phase 3 master study to evaluate BNT162b2 boosting strategies in healthy 
individuals previously vaccinated with BNT162b2.  Each substudy design is detailed in 
Section 10.7 through Section 10.12.  Each substudy may be conducted in parallel, as required 
by the clinical plan, within the framework of this master protocol.
4.2. Scientific Rationale for Study Design
Refer to Section 2.1 for the master protocol study rationale.
See the substudy appendices for the rationales supporting each substudy.
4.2.1. Choice of Contraception/Barrier Requirements
Human reproductive safety data are not available for BNT162b2, but there is no suspicion of 
human teratogenicity based on the intended pharmacology of the compound.  Therefore, the 
use of a highly effective method of contraception is required (see Appendix 4) if indicated by 
the substudy eligibility criteria.
4.3. Justification for Dose
Based on data from the Phase 1 component of clinical trial C4591001 and available 
nonclinical data, the modRNA BNT162b2 vaccine candidate was selected at a dose of 30 µg 
for Phase 2/3 evaluation of safety, immunogenicity, and efficacy after 2 doses administered 
3 weeks apart.  This is the dose that was shown to be effective and has been approved in 
multiple countries worldwide.
The vaccine candidate BNT162b1 was initially studied in clinical trial C4591001, but 
BNT162b2 was selected for Phase 2/3 development due to its better tolerability profile.36
While the 30-µg dose level of BNT162b2 was advanced, higher dose levels of BNT162b1 
(50 µg, 60 µg, and 100 µg) were studied in 18- to 55-year-old participants.37,38 Due to the 
level of reactogenicity observed, these dose levels were not advanced. The Phase 2/3 part of 
clinical trial C4591001 demonstrated that systemic reactogenicity was higher in 16- to 
55-year-olds compared to those older than 55 years of age.7 In light of better tolerability in 
older adults, the waning of efficacy observed, and the immune escape exhibited by the 
Omicron variant, study of a higher dose of the vaccine is warranted.
For Substudies E and F, high-dose BNT162b2 OMI, high-dose BNT162b2, and a high-dose 
combination of BNT162b2 OMI and BNT162b2, given as a fourth dose, will be evaluated. 
BNT162b2 at a dose of 30 µg will be used as a control in Substudies E and F.

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4.4. End of Study Definition
The end of the (sub)study is defined as the date of the last visit of the last participant in the 
(sub)study.
A participant is considered to have completed the (sub)study if he/she has completed all 
phases of the (sub)study, including the last visit.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds. Use of a 
prescreener for study recruitment purposes will include collection of information that reflects 
the enrollment of a diverse participant population including, where permitted under local 
regulations, age, sex, race, and ethnicity. The following eligibility criteria are designed to 
select participants for whom participation in the study is considered appropriate. All relevant 
medical and nonmedical conditions should be taken into consideration when deciding 
whether a particular participant is suitable for this protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the substudy-specific 
inclusion criteria are met.
For Substudy A, see Section 10.7.5.1.
For Substudy B, see Section 10.8.5.1.
For Substudy C, see Section 10.9.5.1.
For Substudy D, see Section 10.10.5.1.
For Substudy E, see Section 10.11.5.1.
For Substudy F, see Section 10.12.5.1.
Some inclusion criteria are common to all substudies: participants (and their parent[s]/legal 
guardian[s]) willing and able to comply with all scheduled visits, vaccination plan, laboratory 
tests, lifestyle considerations, and other study procedures; participants should be healthy; and 
participants (or their parent[s]/legal guardian[s]) must be capable of giving personal signed 
informed consent.
5.2. Exclusion Criteria 
Participants are excluded from the study if any of the substudy-specific exclusion criteria
apply.

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Some exclusion criteria are common to all substudies: participants with medical or 
psychiatric conditions that may increase the risk of study participation; history of severe 
adverse reactions associated with a vaccine and/or severe allergic reaction to any component 
of the study vaccination; previous clinical or microbiological diagnosis of COVID-19;
immunocompromised individuals; or participants with bleeding diathesis.
For Substudy A, see Section 10.7.5.2.
For Substudy B, see Section 10.8.5.2.
For Substudy C, see Section 10.9.5.2.
For Substudy D, see Section 10.10.5.2.
For Substudy E, see Section 10.11.5.2.
For Substudy F, see Section 10.12.5.2.
5.3. Lifestyle Considerations
5.3.1. Contraception
The following section is applicable if indicated by the substudy eligibility criteria.
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods 
(see Appendix 4, Section 10.4.4) and will confirm that the participant has been instructed in 
its consistent and correct use. At time points indicated in the SoA, the investigator or 
designee will inform the participant of the need to use highly effective contraception 
consistently and correctly and document the conversation and the participant’s affirmation in 
the participant’s chart (participants need to affirm their consistent and correct use of at least 1 
of the selected methods of contraception) considering that their risk for pregnancy may have 
changed since the last visit. 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 assigned to study intervention.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the CONSORT publishing requirements and to respond to queries from regulatory 
authorities.  Minimal information includes demography, screen failure details, eligibility 
criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened under a different participant number.

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5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Administration of 
Study Intervention 
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.  Participants 
meeting these criteria at Vaccination 1 will be considered screen failures if enrollment has 
closed once the condition(s) has/have resolved.

Current febrile illness (body temperature ≥100.4°F [≥38.0°C]) or other acute illness 
within 48 hours before study intervention administration.  This includes current 
symptoms that could represent a potential COVID-19 illness:

New or increased cough;

New or increased shortness of breath;

Chills;

New or increased muscle pain;

New loss of taste/smell;

Sore throat;

Diarrhea;

Vomiting.

Receipt of any seasonal or pandemic influenza vaccine within 14 days, or any other 
nonstudy vaccine within 28 days, before study intervention administration.

Anticipated receipt of any seasonal or pandemic influenza vaccine within 14 days, or any 
other nonstudy vaccine within 28 days, after study intervention administration.

Receipt of short-term (<14 days) systemic corticosteroids.  Study intervention 
administration should be delayed until systemic corticosteroid use has been discontinued 
for at least 28 days.  Inhaled/nebulized, intra-articular, intrabursal, or topical (skin or 
eyes) corticosteroids are permitted.
6. SPECIFIC STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.

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6.1. Study Intervention(s) Administered
For the purposes of the master protocol, study intervention refers to the 30 µg dose level of 
BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S).  
Additional study intervention(s) are detailed for each substudy, if applicable.  Additional
study interventions administered in Substudy A are detailed in Section 10.7.6, Substudy B in 
Section 10.8.6, Substudy C in Section 10.9.6, Substudy D in Section 10.10.6, Substudy E in 
Section 10.11.6, and Substudy F in Section 10.12.6.
Intervention Name
BNT162b2 
(BNT162 RNA-LNP vaccine utilizing modRNA)
Type
Vaccine
Dose Formulation
modRNA
Unit Dose Strength(s)
250 µg/0.5 mL
Dosage Level(s) 
30-µg
Route of Administration
Intramuscular injection
Use
Experimental
IMP or NIMP
IMP
Sourcing
Provided centrally by the sponsor
Packaging and Labeling
Study intervention will be provided in a glass vial as open-label supply. 
Each vial will be labeled as required per country requirement
6.1.1. Administration
Standard vaccination practices must be observed and vaccine must not be injected into blood 
vessels. Appropriate medication and other supportive measures for management of an acute 
hypersensitivity reaction should be available in accordance with local guidelines for standard 
immunization practices.
Administration of study interventions should be performed by an appropriately qualified, 
GCP-trained, and vaccine-experienced member of the study staff (eg, physician, nurse, 
physician’s assistant, nurse practitioner, pharmacist, or medical assistant) as allowed by 
local, state, and institutional guidance.
Study intervention administration details will be recorded on the CRF.
See Section 10.7.6.1.1 for further study intervention administration details for Substudy A.
See Section 10.8.6.1.1 for further study intervention administration details for Substudy B.
See Section 10.9.6.1.1 for further study intervention administration details for Substudy C.
See Section 10.10.6.1.1 for further study intervention administration details for Substudy D.
See Section 10.11.6.1.1 for further study intervention administration details for Substudy E.
See Section 10.12.6.1.1 for further study intervention administration details for Substudy F.

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6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study interventions received and any discrepancies are 
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study interventions
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated recording) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff. At a minimum, daily minimum and 
maximum temperatures for all site storage locations must be documented and available 
upon request. Data for nonworking days must indicate the minimum and maximum 
temperatures since previously documented for all site storage locations upon return to 
business.
3. Any excursions from the study intervention label storage conditions should be reported to 
Pfizer upon discovery along with any actions taken. The site should actively pursue 
options for returning the study intervention to the storage conditions described in the 
labeling, as soon as possible. Once an excursion is identified, the study intervention must 
be quarantined and not used until Pfizer provides permission to use the study 
intervention. Specific details regarding the definition of an excursion and information the 
site should report for each excursion will be provided to the site in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the label.
5. Study interventions should be stored in their original containers.
6. See the IP manual for storage conditions of the study intervention once diluted.
7. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records), such as the IPAL or 
sponsor-approved equivalent. All study interventions will be accounted for using a study 
intervention accountability form/record.
8. Further guidance and information for the final disposition of unused study interventions 
are provided in the IP manual. All destruction must be adequately documented. If 
destruction is authorized to take place at the investigator site, the investigator must ensure 
that the materials are destroyed in compliance with applicable environmental regulations, 
institutional policy, and any special instructions provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IP manual.

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6.2.1. Preparation and Dispensing
See the IP manual for instructions on how to prepare the study intervention for 
administration.  Study intervention should be prepared and dispensed by an appropriately 
qualified and experienced member of the study staff (eg, physician, nurse, physician’s 
assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as allowed by 
local, state, and institutional guidance.  A second staff member will verify the preparation 
and dispensing.
See Section 10.7.6.1.2 for additional preparation and dispensing details for Substudy A.
See Section 10.8.6.1.2 for additional preparation and dispensing details for Substudy B.
See Section 10.9.6.1.2 for additional preparation and dispensing details for Substudy C.
See Section 10.10.6.1.2 for additional preparation and dispensing details for Substudy D.
See Section 10.11.6.1.2 for additional preparation and dispensing details for Substudy E.
See Section 10.12.6.1.2 for additional preparation and dispensing details for Substudy F.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
Allocation (randomization) of participants to vaccine groups will proceed using an IRT 
system (IWR).  The site personnel (study coordinator or specified designee) will be required 
to enter or select information including but not limited to the user’s ID and password, the 
protocol number, and the participant number.  The site personnel will then be provided with a 
vaccine assignment and randomization number.  The IRT system will provide a confirmation 
report containing the participant number, randomization number, and study intervention 
allocation assigned.  The confirmation report must be stored in the site’s files.
Study intervention will be dispensed at the study visits summarized in the SoA.
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
6.3.2. Blinding Arrangements
Blinding arrangements for site personnel and the sponsor for Substudy A are detailed in 
Section 10.7.6.2.1 and Section 10.7.6.2.2.
Blinding arrangements for site personnel and the sponsor for Substudy B are detailed in
Section 10.8.6.2.1 and Section 10.8.6.2.2.
Blinding arrangements for site personnel and the sponsor for Substudy C are detailed in 
Section 10.9.6.2.1 and Section 10.9.6.2.2.

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Blinding arrangements for site personnel and the sponsor for Substudy D are detailed in 
Section 10.10.6.2.1 and Section 10.10.6.2.2.
Blinding arrangements for site personnel and the sponsor for Substudy E are detailed in 
Section 10.11.6.2.1 and Section 10.11.6.2.2.
Blinding arrangements for site personnel and the sponsor for Substudy F are detailed in 
Section 10.12.6.2.1 and Section 10.12.6.2.2.
6.4. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF.  
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention.
6.5. Dose Modification
Not applicable.
6.6. Continued Access to Study Intervention After the End of the Study
For Substudies A, B, D, E, and F, no intervention will be provided to study participants at the 
end of their study participation.
For Substudy C, if the 10-µg dose is found to have a suboptimal immune response, as 
determined by the sponsor, this group will be offered a single 30-µg dose.
6.7. Treatment of Overdose
For this study, any dose of study intervention greater than 1 dose of study intervention within 
a 24-hour time period will be considered an overdose.
Pfizer does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs.
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF.
4. Overdose is reportable to Pfizer Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.

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6.8. Concomitant Therapy
The following concomitant medications and vaccinations will be recorded in the CRF:

Any vaccinations received from 28 days prior to study enrollment until 28 days following 
administration of the last study intervention.

Prohibited medications listed in Section 6.8.1 will be recorded to include start and stop 
dates, name of the medication, dose, unit, route, and frequency.
6.8.1. Prohibited During the Study
Receipt of the following vaccines and medications during the time periods listed below may 
exclude a participant from the per-protocol analysis from that point onward and may require 
vaccinations to be discontinued in that participant; however, it is anticipated that the 
participant would not be withdrawn from the study (unless documented as per Section 7).  
Medications should not be withheld if required for a participant’s medical care.

Unless considered medically necessary, no vaccines other than study intervention should 
be administered within 28 days before and 28 days after each study vaccination. One 
exception to this is that seasonal and pandemic influenza vaccine can be given at least 
14 days after, or at least 14 days prior to, the administration of study intervention.

Receipt of chronic systemic treatment with known immunosuppressant medications, or 
radiotherapy, within 60 days before enrollment through conclusion of the study.

Receipt of systemic corticosteroids (≥20 mg/day of prednisone or equivalent) for 
≥14 days is prohibited from 28 days prior to enrollment through 28 days after 
administration of the last study intervention.

Receipt of blood/plasma products, immunoglobulins, or monoclonal antibodies, from 
60 days before study intervention administration, or receipt of any passive antibody 
therapy specific to COVID-19 within 90 days before enrollment through conclusion of 
the study.

Receipt of any other (nonstudy) coronavirus vaccine at any time during study 
participation is prohibited.

Prophylactic antipyretics and other pain medication to prevent symptoms associated with 
study intervention administration are not permitted.  However, if a participant is taking a 
medication for another condition, even if it may have antipyretic or pain-relieving 
properties, it should not be withheld prior to study vaccination.

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6.8.2. Permitted During the Study
Medication other than that described as prohibited in Section 6.8.1 required for treatment of 
preexisting conditions or acute illness is permitted.
Inhaled, topical, or localized injections of corticosteroids (eg, intra-articular or intrabursal 
administration) are permitted.
Hormonal contraceptives that meet the requirements of this study can be used in participants 
who are WOCBP (see Appendix 4).
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. Reasons for permanent discontinuation of study intervention include the 
following: AEs; participant request; investigator request; pregnancy; protocol deviation 
(including no longer meeting all the inclusion criteria, or meeting 1 or more exclusion 
criteria*).
*A positive SARS-CoV-2 NAAT result without symptoms or a COVID-19 diagnosis (based 
on signs/symptoms only or signs/symptoms and a positive SARS-CoV-2 NAAT result) 
should not result in discontinuation of study intervention.  If study intervention (other than 
Dose 1) has been delayed per Section 5.5, because of febrile or other acute illness (Item 1 in 
the Section 5.5 list), and the investigator later diagnoses the signs and symptoms as 
COVID-19 (with or without a positive SARS-CoV-2 NAAT result), the participant may 
receive a further dose of study intervention.
Note that discontinuation of study intervention does not represent withdrawal from the study.
If study intervention is permanently discontinued, the participant will remain in the study to 
be evaluated for safety and immunogenicity. See the SoA for data to be collected at the time 
of discontinuation of study intervention and follow-up for any further evaluations that need 
to be completed.  Participants who remain in the study for evaluation of safety will be 
contacted by telephone 6 months after their last study vaccination to record AEs as described 
in Section 8.3.
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information.

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7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study include the following:

Refused further study procedures;

Lost to follow-up;

Death;

Study terminated by sponsor;

AEs;

Participant or parent/legal guardian request; 

Investigator request;

Protocol deviation (Note: from site receipt of a PACL dated 21 September 2021, receipt 
of a nonstudy COVID-19 vaccine during study participation will result in study 
withdrawal).
If a participant does not return for a scheduled visit, every effort should be made to contact 
the participant.  All attempts to contact the participant and information received during 
contact attempts must be documented in the participant’s source document.  In any 
circumstance, every effort should be made to document participant outcome, if possible.
The investigator or his or her designee should capture the reason for withdrawal in the CRF 
for all participants.
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
7.2.1. Withdrawal of Consent
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible. The withdrawal of consent 

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should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of study intervention or also from study procedures 
and/or posttreatment study follow-up, and entered on the appropriate CRF page. In the event 
that vital status (whether the participant is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed 
in accordance with local law.
If a participant has previously withdrawn consent and wishes to receive a COVID-19 vaccine 
outside the study, he or she may request to know which study intervention he or she received 
at Visit 1 without needing to reconsent.
7.3. Lost to Follow-Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to attend a required study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible. Counsel the participant on the importance of maintaining the assigned visit 
schedule, and ascertain whether the participant wishes to and/or should continue in the 
study;

Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record;

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
8. STUDY ASSESSMENTS AND PROCEDURES
See Section 10.7.8 for assessments and procedures specific to Substudy A, Section 10.8.8 for 
Substudy B, Section 10.9.8 for Substudy C, Section 10.10.8 for Substudy D, Section 10.11.8
for Substudy E, and Section 10.12.8 for Substudy F.
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.
The date of birth will be collected to critically evaluate the immune response and safety 
profile by age.
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.

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Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
8.1. Efficacy Assessments and/or Immunogenicity Assessments
Serum samples may be obtained for immunogenicity testing at the visits specified in the 
substudy SoA and assays performed as detailed for each substudy.
8.1.1. Biological Samples
Blood and nasal swab samples will be used only for scientific research. Each sample will be 
labeled with a code so that the laboratory personnel testing the samples will not know the 
participant’s identity. Samples that remain after performing assays outlined in the protocol 
may be stored by Pfizer (and by the site [Sheba] and BioNTech for Substudy F). Unless a 
time limitation is required by local regulations or ethical requirements, the samples will be 
stored for up to 15 years after the end of the study and then destroyed. If allowed by the 
ICD, stored samples may be used for additional testing to better understand the immune 
responses to the vaccine(s) under study in this protocol, to inform the development of other 
vaccines or vaccine-related products, and/or for vaccine related assay work supporting 
vaccine programs. No testing of the participant’s genetic material will be performed, with 
the exception of those participants who have provided specific consent to genetic testing of 
the blood samples for PBMC isolation and HLA typing.
The participant may request that his or her samples, if still identifiable, be destroyed at any 
time; however, any data already collected from those samples will still be used for this 
research. The biological samples may be shared with other researchers as long as 

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confidentiality is maintained and no testing of the participant’s genetic material is performed, 
with the exception of those participants who have provided specific consent to genetic testing 
of the blood samples for PBMC isolation and HLA typing.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
A clinical assessment, including medical history, will be performed on all participants at their 
first visit to establish a baseline.  Significant medical history and observations from any 
physical examination, if performed, will be documented in the CRF.
AEs and SAEs are collected, recorded, and reported as defined in Section 8.3.
Acute reactions within the first 30 minutes after administration of the study intervention will 
be assessed and documented in the AE CRF.
For Substudies B, C, D, E, and F:
The safety parameters also include reactogenicity e-diary reports of local reactions, systemic 
events (including fever), and use of antipyretic medication that occur in the 7 days after 
administration of the study intervention.  These prospectively self-collected occurrences of 
local reactions and systemic events are graded as described in Section 8.2.4.
8.2.1. Physical Examinations
If the clinical assessment indicates that a physical examination is necessary to 
comprehensively evaluate the participant, a physical examination will be performed.
Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.3.1 to Section 8.3.3.
8.2.2. Vital Signs
The participant’s body temperature will be measured prior to each vaccination.
8.2.3. Clinical Safety Laboratory Assessments
Clinical safety laboratory assessments will not be collected in this study.
8.2.4. Electronic Diary – Applicable Only to Substudies B, C, D, E, and F
Participants will be required to complete a reactogenicity e-diary through an application 
installed on a provisioned device or on the participant’s own personal device.  All 
participants will be asked to monitor and record local reactions, systemic events, and 

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antipyretic medication usage for 7 days from the day of administration of the study 
intervention.  The reactogenicity e-diary allows recording of these assessments only within a 
fixed time window, thus providing the accurate representation of the participant’s experience 
at that time.  Data on local reactions and systemic events reported in the reactogenicity 
e-diary will be transferred electronically to a third-party vendor, where they will be available 
for review by investigators and the Pfizer clinicians at all times via an internet-based portal.
At intervals agreed to by the vendor and Pfizer, these data will be transferred electronically 
into Pfizer’s database for analysis and reporting.  Generally, these data do not need to be 
reported by the investigator in the CRF as AEs.
Investigators (or designee) will be required to review the reactogenicity e-diary data online at 
frequent intervals as part of the ongoing safety review.
The investigator or designee must obtain stop dates from the participant for any ongoing 
local reactions, systemic events, or use of antipyretic medication on the last day that the 
reactogenicity e-diary was completed.  The stop dates should be documented in the source 
documents and the information entered in the CRF.
8.2.4.1. Grading Scales
The grading scales used in this study to assess local reactions and systemic events as 
described below are derived from the FDA CBER guidelines on toxicity grading scales for 
healthy adult volunteers enrolled in preventive vaccine clinical trials.39
8.2.4.2. Local Reactions
During the reactogenicity e-diary reporting period, participants will be asked to assess 
redness, swelling, and pain at the injection site and to record the symptoms in the 
reactogenicity e-diary.  If a local reaction persists beyond the end of the reactogenicity 
e-diary period following vaccination, the participant will be requested to report that 
information.  The investigator will enter this additional information in the CRF.
Redness and swelling will be measured and recorded in measuring device units 
(range: 1 to 21) and then categorized during analysis as absent, mild, moderate, or severe 
based on the grading scale in Table 2.  Measuring device units can be converted to 
centimeters according to the following formula: 1 measuring device unit = 0.5 cm.  Pain at 
the injection site will be assessed by the participant as absent, mild, moderate, or severe 
according to the grading scale in Table 2.
If a Grade 3 local reaction is reported in the reactogenicity e-diary, a telephone contact 
should occur to ascertain further details and determine whether a site visit is clinically 
indicated.  Only an investigator or medically qualified person is able to classify a 
participant’s local reaction as Grade 4.  If a participant experiences a confirmed Grade 4 local 
reaction, the investigator must immediately notify the sponsor and, if it is determined to be 
related to the administration of the study intervention, further vaccinations will be 
discontinued in that participant.

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Table 2.
Local Reaction Grading Scale
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life 
Threatening
(Grade 4a)
Pain at the injection 
site
Does not interfere 
with activity
Interferes with 
activity
Prevents daily 
activity
Emergency room 
visit or 
hospitalization for 
severe pain
Redness
>2.0 cm to 5.0 cm 
(5 to 10 measuring 
device units)
>5.0 cm to 10.0 cm 
(11 to 20 measuring 
device units)
>10 cm 
(≥21 measuring 
device units)
Necrosis or 
exfoliative 
dermatitis
Swelling
>2.0 cm to 5.0 cm 
(5 to 10 measuring 
device units)
>5.0 cm to 10.0 cm 
(11 to 20 measuring 
device units)
>10 cm 
(≥21 measuring 
device units)
Necrosis
a.
Only an investigator or medically qualified person is able to classify a reaction as Grade 4; therefore, a 
confirmed Grade 4 reaction should be reported as an AE in the case report form.
8.2.4.3. Systemic Events
During the reactogenicity e-diary reporting period, participants will be asked to assess 
vomiting, diarrhea, headache, fatigue/tiredness, chills, new or worsened muscle pain, and 
new or worsened joint pain and to record the symptoms in the reactogenicity e-diary.  The 
symptoms will be assessed by the participant as absent, mild, moderate, or severe according 
to the grading scale in Table 3.
If a Grade 3 systemic event is reported in the reactogenicity e-diary, a telephone contact 
should occur to ascertain further details and determine whether a site visit is clinically 
indicated.  Only an investigator or medically qualified person is able to classify a 
participant’s systemic event as Grade 4.  If a participant experiences a confirmed Grade 4 
systemic event, the investigator must immediately notify the sponsor and, if it is determined 
to be related to the administration of the study intervention, further vaccinations will be 
discontinued in that participant.
Table 3.
Systemic Event Grading Scale
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Vomiting
1-2 times in 
24 hours
>2 times in 
24 hours
Requires IV 
hydration
Emergency room visit 
or hospitalization for 
hypotensive shock
Diarrhea
2 to 3 loose stools 
in 24 hours
4 to 5 loose stools 
in 24 hours
6 or more loose stools 
in 24 hours
Emergency room visit 
or hospitalization for 
severe diarrhea
Headache
Does not interfere 
with activity
Some interference 
with activity
Prevents daily routine 
activity
Emergency room visit 
or hospitalization for 
severe headache

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Table 3.
Systemic Event Grading Scale
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Fatigue/tiredness
Does not interfere 
with activity
Some interference 
with activity
Prevents daily routine 
activity
Emergency room visit 
or hospitalization for 
severe fatigue
Chills
Does not interfere 
with activity
Some interference 
with activity
Prevents daily routine 
activity
Emergency room visit 
or hospitalization for 
severe chills
New or worsened 
muscle pain
Does not interfere 
with activity
Some interference 
with activity
Prevents daily routine 
activity
Emergency room visit 
or hospitalization for 
severe new or worsened 
muscle pain
New or worsened 
joint pain
Does not interfere 
with activity
Some interference 
with activity
Prevents daily routine 
activity
Emergency room visit 
or hospitalization for 
severe new or worsened 
joint pain
Abbreviation: IV = intravenous.
During the 7 days following each vaccination, potential COVID-19 symptoms that overlap 
with solicited systemic events (ie, fever, chills, new or increased muscle pain, diarrhea, 
vomiting) should be assessed by the investigator.
If, in the investigator’s opinion, the symptoms are considered more likely to be vaccine 
reactogenicity, but a participant is required to demonstrate that he or she is SARS-CoV-2–
negative, a local SARS-CoV-2 test may be performed: if positive, the symptoms should be 
recorded as an AE rather than as systemic events in the reactogenicity e-diary.
Potential COVID-19 symptoms that do not overlap with systemic events should be reported 
as AEs as per Section 8.3.
8.2.4.4. Fever
In order to record information on fever, a thermometer will be given to participants with 
instructions on how to measure oral temperature at home.  Temperature will be collected in 
the reactogenicity e-diary in the evening daily during the reactogenicity e-diary reporting 
period.  It will also be collected at any time during the reactogenicity e-diary data collection 
periods when fever is suspected.  Fever is defined as an oral temperature of ≥38.0°C 
(≥100.4°F).  The highest temperature for each day will be recorded in the reactogenicity 
e-diary.  Temperature will be measured and recorded to 1 decimal place.  Temperatures 
recorded in degrees Fahrenheit will be programmatically converted to degrees Celsius and 
then categorized according to the scale shown in Table 4 during analysis.
If a fever of ≥39.0°C (≥102.1°F) is reported in the reactogenicity e-diary, a telephone contact 
should occur to ascertain further details and determine whether a site visit is clinically 
indicated.  Only an investigator or medically qualified person is able to confirm a 

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participant’s fever as >40.0°C (>104.0°F).  If a participant experiences a confirmed fever 
>40.0°C (>104.0°F), the investigator must immediately notify the sponsor and, if it is 
determined to be related to the administration of the study intervention, further vaccinations 
will be discontinued in that participant.
Table 4.
Scale for Fever
≥38.0-38.4°C (100.4-101.1°F)
>38.4-38.9°C (101.2-102.0°F)
>38.9-40.0°C (102.1-104.0°F)
>40.0°C (>104.0°F)
8.2.4.5. Antipyretic/Analgesic Medication
The use of antipyretic/analgesic medication to treat symptoms associated with study 
intervention administration will be recorded in the reactogenicity e-diary daily during the 
reporting period (Day 1 through Day 7).
8.2.5. Pregnancy Testing
Pregnancy tests may be urine or serum tests but must have a sensitivity of at least 
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA, 
immediately before the administration of each vaccine dose. A negative pregnancy test result 
will be required prior to the participant’s receiving the study intervention. Pregnancy tests 
may also be repeated if requested by IRBs/ECs or if required by local regulations. In the 
case of a positive confirmed pregnancy, the participant will be withdrawn from 
administration of study intervention but may remain in the study.
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally 
authorized representative), or they may arise from clinical findings of the Investigator or 
other healthcare providers (clinical signs, test results, etc.).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1).
During the active collection period as described in Section 8.3.1, each participant/parent/legal 
guardian will be questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.

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8.3.1. Time Period and Frequency for Collecting AE and SAE Information
For all participants, information about AEs will be collected for events occurring within 
approximately 1 month after each vaccination, and information about SAEs will be collected 
for events occurring approximately 6 months after each vaccination.
Substudy A
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant/parent(s)/legal guardian 
provides informed consent, which is obtained before the participant’s participation in the 
study (ie, before undergoing any study-related procedure and/or receiving study 
intervention), through and including Visit 2, and from Visit 101 to Visit 102.
In addition, any AEs occurring up to 48 hours after any subsequent blood draw must be 
recorded on the CRF.
SAEs will be collected from the time the participant/parent(s)/legal guardian provides 
informed consent to Visit 3 (approximately 6 months after the booster vaccination), and from 
Visit 101 to 103 (approximately 6 months after participants who originally received placebo 
are administered BNT162b2).
Substudy B
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant/parent(s)/legal guardian 
provides informed consent, which is obtained before the participant’s participation in the 
study (ie, before undergoing any study-related procedure and/or receiving study 
intervention), through and including Visit 205 (1 month after Vaccination 2).
In addition, any AEs occurring up to 48 hours after any subsequent blood draw must be 
recorded on the CRF.
Substudy C
The time period for actively eliciting and collecting AEs and SAEs (“active collection
period”) for each participant begins from the time the participant/parent(s)/legal guardian 
provides informed consent, which is obtained before the participant’s participation in the 
study (ie, before undergoing any study-related procedure and/or receiving study 
intervention), through and including Visit 303 (1 month after the third dose).
In addition, any AEs occurring up to 48 hours after any subsequent blood draw must be 
recorded on the CRF.
SAEs will be collected from the time the participant/parent(s)/legal guardian provides 
informed consent to Visit 304 (approximately 6 months after the participant’s last study 
vaccination).

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Substudy D
For Cohorts 1 and 2, the time period for actively eliciting and collecting AEs and SAEs 
(“active collection period”) for each participant begins from the time the participant provides 
informed consent, which is obtained before the participant’s participation in the study 
(ie, before undergoing any study-related procedure and/or receiving study intervention), 
through and including Visit 402 (1 month after the participant’s study vaccination) for 
Groups 1, 2b, 3, and 4, through and including Visit 403 for Group 2, and from Visit 404 
through and including Visit 404b for Group 3 and Group 4 participants who receive a dose of 
BNT162b2 OMI at Visit 404.
For Group 5, the time period for actively eliciting and collecting AEs and SAEs 
(“active collection period”) for each participant begins from the time the participant provides 
informed consent, which is obtained before the participant’s participation in the study 
(ie, before undergoing any study-related procedure and/or receiving study intervention), 
through and including Visit 504 (1 month after the participant’s second study vaccination), 
and from Visit 506 through Visit 507 (1 month after the participant’s third study 
vaccination).
In addition, any AEs occurring up to 48 hours after any subsequent blood draw must be 
recorded on the CRF.
SAEs will be collected from the time the participant provides informed consent through
Visit 405 for Groups 1 to 4, and Visit 508 for Group 5 (approximately 6 months after the
participant’s last study vaccination).
Substudy E
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including 
Visit 603 (1 month after the participant’s study vaccination).
In addition, any AEs occurring up to 48 hours after any subsequent blood draw must be 
recorded on the CRF.
SAEs will be collected from the time the participant provides informed consent to Visit 605
(approximately 6 months after the participant’s study vaccination).
Substudy F
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including 
Visit 703 (1 month after the participant’s study vaccination).

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In addition, any AEs occurring up to 48 hours after any subsequent blood draw must be 
recorded on the CRF.
SAEs will be collected from the time the participant provides informed consent to Visit 705
(approximately 6 months after the participant’s study vaccination).
For all participants, follow-up by the investigator continues throughout and after the active 
collection period and until the AE or SAE or its sequelae resolve or stabilize at a level 
acceptable to the investigator.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the Vaccine SAE Reporting Form.
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any 
SAE, including a death, at any time after a participant has completed the study, and he/she 
considers the event to be reasonably related to the study intervention, the investigator must 
promptly report the SAE to Pfizer using the Vaccine SAE Reporting Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the Vaccine SAE Reporting Form immediately 
upon awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.

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Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-Up of AEs and SAEs
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety.
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include exposure during pregnancy, exposure during 
breastfeeding, and occupational exposure.

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Any such exposure to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing study 
intervention.

A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.

A female is found to be pregnant while being exposed or having been exposed to study 
intervention due to environmental exposure. Below are examples of environmental EDP:

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by inhalation or skin contact.

A male family member or healthcare provider who has been exposed to the study 
intervention by inhalation or skin contact then exposes his female partner prior to or 
around the time of conception.

The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information 
submitted should include the anticipated date of delivery (see below for information 
related to termination of pregnancy).

If EDP occurs in a participant or a participant’s partner, the investigator must report this 
information to Pfizer Safety on the Vaccine SAE Reporting Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until 28 days after the 
last dose of study intervention. Beyond 28 days after the last dose of study intervention, 
any pregnancy that occurs will not be considered EDP for this study.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the Vaccine SAE Reporting Form and EDP 
Supplemental Form. Since the exposure information does not pertain to the participant 
enrolled in the study, the information is not recorded on a CRF; however, a copy of the 
completed Vaccine SAE Reporting Form is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 

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integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs 
when the investigator assesses the infant death as related or possibly related to exposure 
to the study intervention.
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if: 

A female participant is found to be breastfeeding while receiving or after discontinuing 
study intervention.

A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental exposure 
during breastfeeding is a female family member or healthcare provider who reports that 
she is breastfeeding after having been exposed to the study intervention by inhalation or 
skin contact.
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the Vaccine SAE Reporting Form. When exposure 
during breastfeeding occurs in the setting of environmental exposure, the exposure 
information does not pertain to the participant enrolled in the study, so the information is not 
recorded on a CRF. However, a copy of the completed Vaccine SAE Reporting Form is 
maintained in the investigator site file.

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An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use. However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
The investigator must report any instance of occupational exposure to Pfizer Safety within 
24 hours of the investigator’s awareness using the Vaccine SAE Reporting Form, regardless 
of whether there is an associated SAE. Since the information about the occupational 
exposure does not pertain to a participant enrolled in the study, the information is not 
recorded on a CRF; however, a copy of the completed Vaccine SAE Reporting Form must be 
maintained in the investigator site file.
8.3.6. Cardiovascular and Death Events
Not applicable.
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs
or SAEs
8.3.7.1. Substudies Including a Potential COVID-19 Illness Visit
The following substudies include a potential COVID-19 illness visit: Substudies A, D, E, and 
F.
Only for substudies including a potential COVID-19 illness visit, potential COVID-19 
illnesses and their sequelae that are consistent with the clinical endpoint definition should not
be recorded as AEs. These data will be captured as efficacy assessment data only on the 
relevant pages of the CRF, as these are expected endpoints.
Potential COVID-19 illnesses and their sequelae will not be reported according to the 
standard process for expedited reporting of SAEs, even though the event may meet the 
definition of an SAE.  These events will be recorded on the COVID-19 illness pages in the 
participant’s CRF within 1 day.
NOTE: However, if either of the following conditions applies, then the event must be 
recorded and reported as an SAE (instead of a disease-related event):
The event is, in the investigator’s opinion, of greater intensity, frequency, or duration than 
expected for the individual participant.
OR
The investigator considers that there is a reasonable possibility that the event was related to 
study intervention.

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Potential COVID-19 illness events and their sequelae will be reviewed by a group of internal 
blinded case reviewers.  Any SAE that is determined by the internal case reviewers NOT to 
meet endpoint criteria is reported back to the investigator site of incidence.  The investigator 
must report the SAE to Pfizer Safety within 24 hours of being made aware that the SAE did 
not meet endpoint criteria.  The investigator’s SAE awareness date is the date on which the 
investigator site of incidence receives the SAE back from the internal case reviewers.
8.3.7.2. Substudies NOT Including a Potential COVID-19 Illness Visit
For substudies not including a potential COVID-19 illness visit, confirmed COVID-19 
diagnoses will be considered AESIs (Section 8.3.8).
8.3.8. Adverse Events of Special Interest
The following events are considered AESIs:

A confirmed diagnosis of myocarditis or pericarditis. See Section 10.7.8.5.9 for 
Substudy A, Section 10.8.8.3.6 for Substudy B, Section 10.9.8.5 for Substudy C, 
Section 10.10.8.6.7 for Substudy D, Section 10.11.8.6.12 for Substudy E, and 
Section 10.12.8.5.10 for Substudy F for additional procedures for monitoring of potential 
myocarditis or pericarditis.
8.3.8.1. Substudies NOT Including a Potential COVID-19 Illness Visit
This section provides information on AESIs that may be detected during the study:

Confirmed COVID-19 diagnosis (clinical signs/symptoms and positive SARS-CoV-2 
NAAT test)
AESIs are examined as part of routine safety data review procedures throughout the clinical 
trial and as part of signal detection processes.
All AESIs must be reported as an AE or SAE following the procedures described in 
Sections 8.3.1 through Section 8.3.4. An AESI is to be recorded as an AE or SAE on the 
CRF. In addition, an AESI that is also an SAE must be reported using the Vaccine SAE
Reporting Form.
8.3.8.2. Lack of Efficacy
The investigator must report signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy. Lack of efficacy or failure of expected pharmacological action is reportable to 
Pfizer Safety only if associated with an SAE.
8.3.9. Medical Device Deficiencies
Not applicable.

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8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the Vaccine SAE
Reporting Form to Pfizer Safety 
Within 24 Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do or 
do not involve the study participant.

The administration of expired study intervention;

The administration of an incorrect study intervention;

The administration of an incorrect dosage;

The administration of study intervention that has undergone temperature excursion from 
the specified storage range, unless it is determined by the sponsor that the study 
intervention under question is acceptable for use.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a Vaccine SAE
Reporting Form only when associated with an SAE.

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8.4. Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.5. Genetics
8.5.1. Specified Genetics
For Substudies A, B, C, and F, genetics (specified analyses) are not evaluated.
For Substudies D and E, please see Section 10.16.
8.6. Biomarkers
Biomarkers are not evaluated in this study.
8.7. Immunogenicity Assessments
Immunogenicity assessments are described in Section 8.1.
8.8. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Methodology for summary and statistical analyses of the data collected in this study is 
outlined here and further detailed in a SAP, which will be maintained by the sponsor. The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Statistical Hypotheses
9.1.1. Estimands
For estimands, refer to the respective appendix for each substudy. For Substudy A, refer to 
Section 10.7.3. For Substudy B, refer to Section 10.8.3. For Substudy C, refer to 
Section 10.9.3. For Substudy D, refer to Section 10.10.3. For Substudy E, refer to 
Section 10.11.3. For Substudy F, refer to Section 10.12.3.
9.1.2. Statistical Hypotheses
For Substudy A, refer to Section 10.7.9.1.2 for hypotheses.
For Substudy B, refer to Section 10.8.9.1.2 for hypotheses.
For Substudy C, refer to Section 10.9.9.1.2 for hypotheses.
For Substudy D, refer to Section 10.10.9.1.2 for hypotheses.
For Substudy E, refer to Section 10.11.9.1.2 for hypotheses.

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For Substudy F, refer to Section 10.12.9.1.2 for hypotheses.
9.1.3. Multiplicity Adjustments
For Substudy A, refer to Section 10.7.9.1.3 for multiplicity adjustments.
For Substudy B, refer to Section 10.8.9.1.3 for multiplicity adjustments.
For Substudy C, refer to Section 10.9.9.1.3 for multiplicity adjustments.
For Substudy D, refer to Section 10.10.9.1.3 for multiplicity adjustments.
For Substudy E, refer to Section 10.11.9.1.3 for multiplicity adjustments.
For Substudy F, refer to Section 10.12.9.1.3 for multiplicity adjustments.
9.2. Analysis Sets
For analysis sets, refer to the respective appendix for each substudy. 
For Substudy A, refer to Section 10.7.9.2.
For Substudy B, refer to Section 10.8.9.2.
For Substudy C, refer to Section 10.9.9.2.
For Substudy D, refer to Section 10.10.9.2.
For Substudy E, refer to Section 10.11.9.2.
For Substudy F, refer to Section 10.12.9.2.
9.3. Statistical Analyses
The SAP will be developed and finalized for each substudy before any analyses are 
performed and will describe the analyses and procedures for accounting for missing, unused, 
and spurious data. This section is a summary of the general considerations of statistical 
analyses.
Refer to each substudy appendix for description of the statistical analyses for primary, 
secondary, and/or exploratory endpoints. For Substudy A, refer to Section 10.7.9.3. For 
Substudy B, refer to Section 10.8.9.3. For Substudy C, refer to Section 10.9.9.3. For 
Substudy D, refer to Section 10.10.9.3. For Substudy E, refer to Section 10.11.9.3. For 
Substudy F, refer to Section 10.12.9.3.

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9.3.1. General Considerations
Each substudy will be reported separately.
CIs for all endpoints in the statistical analysis will be presented as 2-sided at the 95% level 
unless specified otherwise.
The safety analyses are based on the safety population.  Participants will be summarized by 
vaccine group according to the study interventions they received.  Missing reactogenicity 
e-diary data will not be imputed; missing AE dates will be handled according to the Pfizer 
safety rules.
For all the immunogenicity endpoints, the analysis will be based on the evaluable 
immunogenicity population. An additional analysis may be performed based on the 
all-available immunogenicity populations if there is a large enough difference in sample size 
between the all-available immunogenicity population and the evaluable immunogenicity 
population.  Participants will be summarized according to the vaccine group to which they 
were randomized.  Missing serology data will not be imputed.
The evaluable efficacy population will be the primary analysis population for all efficacy 
analyses.  Additional analyses based on the all-available efficacy (mITT) population will be 
performed. Participants will be summarized according to the vaccine group to which they 
were randomized. Missing laboratory results will not be imputed.
9.3.1.1. Analyses for Binary Data
Descriptive statistics for categorical variables (eg, proportions) are the percentage (%), the 
numerator (n) and the denominator (N) used in the percentage calculation, and the 95% CIs 
where applicable.
The exact 95% CI for binary endpoints for each group will be computed using the 
F distribution (Clopper-Pearson method).  The 95% CI for the between-group difference for 
binary endpoints will be calculated using the Miettinen and Nurminen method.
The 3-tier approach may be used to summarize AEs for certain substudies (refer to each 
substudy for specification).  For both Tier 1 (if any are identified during the study) and Tier 2 
events, a 95% CI for the between-group difference in proportions will be calculated based on 
the Miettinen and Nurminen method.  In addition, for Tier 1 events (if any), the asymptotic 
p-values will also be presented for the difference in proportions, based on the same test 
statistic and under the assumption that the test statistic is asymptotically normally distributed.  
For Tier 3 events, counts and percentages for each vaccine group will be provided.
9.3.1.2. Analyses for Continuous Data
Unless otherwise stated, descriptive statistics for continuous variables are n, mean, median, 
standard deviation, minimum, and maximum.

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9.3.1.2.1. Geometric Means
The geometric means will be calculated as the mean of the assay results after making the 
logarithm transformation and then exponentiating the mean to express results on the original 
scale.  Two-sided 95% CIs will be obtained by taking log transforms of assay results, 
calculating the 95% CI with reference to Student’s t-distribution, and then exponentiating the 
confidence limits.
9.3.1.2.2. Geometric Mean Fold Rises
GMFRs are defined as ratios of the results after vaccination to the results before vaccination.  
GMFRs are limited to participants with nonmissing values at both time points.
GMFRs will be calculated as the mean of the difference of logarithmically transformed assay 
results (later time point minus earlier time point) and exponentiating the mean.  The 
associated 2-sided 95% CIs will be obtained by constructing CIs using Student’s 
t-distribution for the mean difference on the logarithm scale and exponentiating the 
confidence limits.
9.3.1.2.3. Geometric Mean Ratios
The GMR will be calculated as the mean of the difference of logarithmically transformed 
assay results and exponentiating the mean.  Two-sided CIs will be obtained by calculating 
CIs using Student’s t-distribution for the mean difference of the logarithmically transformed 
assay results and exponentiating the confidence limits.
9.3.1.2.4. Reverse Cumulative Distribution Curves
Empirical RCDCs will plot proportions of participants with values equal to or exceeding a 
specified assay value versus the indicated assay value, for all observed assay values.  Data 
points will be joined by a step function with data points on the left side of the step.
9.4. Interim Analyses
Interim analyses will be determined by substudy, and details are provided in each 
corresponding appendix as necessary.
9.5. Sample Size Determination
Sample size will be determined by substudy, and details are provided in each corresponding 
appendix.

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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC 
by the investigator, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by IRB/EC 
procedures;

Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 536/2014 for clinical 
studies (if applicable), European Medical Device Regulation 2017/745 for clinical device 
research (if applicable), and all other applicable local regulations.

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10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately.
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study, including the 
risks and benefits, to the participant or his/her parent(s)/legal guardian(s) and answer all 
questions regarding the study. The participant or his/her parent(s)/legal guardian(s) should 
be given sufficient time and opportunity to ask questions and to decide whether or not to 
participate in the trial.
Participants must be informed that their participation is voluntary. Participants or their 
parent(s)/legal guardian(s) will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and data 
protection requirements, where applicable, and the IRB/EC or study center.
When consent is obtained from a participant’s parent(s)/legal guardian(s), the participant’s 
assent (affirmative agreement) must be subsequently obtained when the participant has the 
capacity to provide assent, as determined by the IRB/EC.
The investigator must ensure that each study participant or his/her parent(s)/legal guardian(s)
is fully informed about the nature and objectives of the study, the sharing of data related to 
the study, and possible risks associated with participation, including the risks associated with 
the processing of the participant’s personal data.
The participant or his/her parent(s)/legal guardian(s) must be informed that the participant’s
personal study-related data will be used by the sponsor in accordance with local data 
protection law. The level of disclosure must also be explained to the participant or his/her 
parent(s)/legal guardian(s).

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The participant or his/her parent(s)/legal guardian(s) must be informed that the participant’s
medical records may be examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the sponsor, by appropriate IRB/EC members, and by inspectors 
from regulatory authorities.
The investigator further must ensure that each study participant or his/her parent(s)/legal 
guardian(s) is fully informed about his or her right to access and correct his or her personal 
data and to withdraw consent for the processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
Participants or their parent(s)/legal guardian(s) must be reconsented to the most current 
version of the ICD(s) during the participant’s participation in the study.
A copy of the ICD(s) must be provided to the participant or his/her parent(s)/legal 
guardian(s).
Participants who are rescreened are required to sign a new ICD.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password-protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record ID. In case of 
data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws.

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10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee and Other Independent Oversight Committee
This study will use a DMC. The DMC is independent of the study team and includes only 
external members. The DMC charter describes the role of the DMC in more detail.
The DMC will be responsible for ongoing monitoring of the safety of participants in the 
study according to the charter. The recommendations made by the DMC will be forwarded 
to the appropriate authorized Pfizer personnel for review and final decision. Pfizer will 
communicate such decisions, which may include summaries of aggregate analyses of safety 
data, to regulatory authorities, investigators, as appropriate.
Substudies E and F will also use an IRC that will be responsible for reviewing safety data as 
described in Sections 10.11.9.4.2 and 10.12.9.4.2.
Any further involvement of the DMC in each substudy is specified in the corresponding 
substudy appendix.
See Section 10.7.9.4.2 for details of the DMC’s role in Substudy A.
See Section 10.8.9.4.1 for details of the DMC’s role in Substudy B.
See Section 10.9.9.4.2 for details of the DMC’s role in Substudy C.
See Section 10.10.9.4.2 for details of the DMC’s role in Substudy D.
See Section 10.11.9.4.2 for details of the DMC’s role in Substudy E.
See Section 10.12.9.4.2 for details of the DMC’s role in Substudy F.
10.1.6. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.

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EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website. Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data. Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015.
Data sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class. Pfizer will make data from these trials available 
24 months after study completion. Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.7. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.

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The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password-protected or secured in a locked room to 
prevent access by unauthorized third parties.
QTLs are predefined parameters that are monitored during the study. Important deviations 
from the QTLs and any remedial actions taken will be summarized in the clinical study 
report.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. This 
verification may also occur after study completion. It is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, virtual, or on-site monitoring), are provided in the data management plan and 
monitoring plan maintained and utilized by the sponsor or designee.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory retain
notification in relation to the study. Furthermore, the investigator will cooperate with the 
sponsor or its agents to prepare the investigator site for the inspection and will allow the 
sponsor or its agent, whenever feasible, to be present during the inspection. The investigator 
site and investigator will promptly resolve any discrepancies that are identified between the 
study data and the participant’s medical records. The investigator will promptly provide 
copies of the inspection findings to the sponsor or its agent. Before response submission to 
the regulatory authorities, the investigator will provide the sponsor or its agents with an 
opportunity to review and comment on responses to any such findings.

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10.1.8. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes source data and its origin can be found in the study monitoring 
plan, which is maintained by the sponsor.
Description of the use of the computerized system is documented in the study monitoring 
plan, which is maintained by the sponsor.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements.
10.1.9. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/EC 
or local health authorities, the sponsor’s procedures, or the ICH GCP guidelines;

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
Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.10. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first.
The investigator agrees to refer to the primary publication in any subsequent publications,
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission. This allows the sponsor to protect proprietary information and to 
provide comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer 
intervention-related information necessary for the appropriate scientific presentation or 
understanding of the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites. In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements.
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.

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10.1.11. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor’s appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study 
documentation/study portal or other electronic system.
To facilitate access to appropriately qualified medical personnel for study-related medical 
questions or problems, participants are provided with an ECC at the time of informed 
consent. The ECC contains, at a minimum, (a) protocol and study intervention identifiers, 
(b) participant’s study identification number, (c) site emergency phone number active 
24 hours/day, 7 days per week, and (d) Pfizer Call Center number.
The ECC is intended to augment, not replace, the established communication pathways 
between the investigator, site staff, and study team. The ECC is to be used by healthcare 
professionals not involved in the research study only, as a means of reaching the investigator 
or site staff related to the care of a participant. The Pfizer Call Center number should only be 
used when the investigator and site staff cannot be reached. The Pfizer Call Center number is 
not intended for use by the participant directly; if a participant calls that number directly, he 
or she will be directed back to the investigator site.

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10.2. Appendix 2: Clinical Laboratory Tests
If required based on each substudy design and participant population, a pregnancy test will 
be performed at times defined in the SoA section of each substudy.

Pregnancy test (β-hCG): Local urine testing will be standard for the protocol unless 
serum testing is required by local regulation or IRB/EC for participants who are WOCBP.
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.  Investigators must document their review of each 
laboratory safety report.

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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention.

Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator. Any abnormal laboratory test 
results that meet any of the conditions below must be recorded as an AE:

Is associated with accompanying symptoms.

Requires additional diagnostic testing or medical/surgical intervention.

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency and/or intensity of the condition.

New condition detected or diagnosed after study intervention administration, even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae.

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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads 
to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
10.3.2. Definition of an SAE
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed below:
a. Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.

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d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle), that may interfere with or prevent everyday 
life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is a suspected transmission via a Pfizer product of an infectious agent, pathogenic 
or non-pathogenic, is considered serious.

The event may be suspected from clinical symptoms or laboratory findings indicating an 
infection in a participant exposed to a Pfizer product. The terms “suspected 
transmission” and “transmission” are considered synonymous. These cases are 
considered unexpected and handled as serious expedited cases by pharmacovigilance 
personnel. Such cases are also considered for reporting as product defects, if 
appropriate.
g. Other situations:

Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as significant medical 
events that may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. These 
events should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs on the Vaccine SAE Reporting Form to Pfizer Safety throughout the active 
collection period. These requirements are delineated for 3 types of events: (1) SAEs; 

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(2) nonserious AEs; and (3) exposure to the study intervention under study during 
pregnancy or breastfeeding, and occupational exposure.
It should be noted that the Vaccine SAE Reporting Form for reporting of SAE information 
is not the same as the AE page of the CRF. When the same data are collected, the forms 
must be completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the Vaccine SAE
Reporting Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the Vaccine 
SAE Reporting Form to 
Pfizer Safety Within 
24 Hours of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding 
All AEs or SAEs associated 
with exposure during 
pregnancy or breastfeeding
Note:  Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)*
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE)**
Environmental or 
occupational exposure to 
the product under study to a 
non-participant (not 
involving EDP or EDB)
None.  Exposure to a study 
non-participant is not 
collected on the CRF
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported***
*
EDP (with or without an associated AE or SAE): any pregnancy information is reported to Pfizer 
Safety using the Vaccine SAE Reporting Form and EDP Supplemental Form; if the EDP is 
associated with an SAE, then the SAE is reported to Pfizer Safety using the Vaccine SAE Reporting
Form.
** EDB is reported to Pfizer Safety using the Vaccine SAE Reporting Form, which would also include 
details of any SAE that might be associated with the EDB.
*** Environmental or occupational exposure: AEs or SAEs associated with occupational exposure are 
reported to Pfizer Safety using the Vaccine SAE Reporting Form.

When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic reports) 
related to the event.

The investigator will then record all relevant AE or SAE information in the CRF.

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
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Pfizer Safety in lieu of completion of the Vaccine SAE Reporting Form/AE
or SAE CRF page.

There may be instances when copies of medical records for certain cases are requested 
by Pfizer Safety. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories: 
GRADE 
If required on the AE page of the CRF, the investigator will use the 
adjectives MILD, MODERATE, SEVERE, or LIFE-THREATENING to 
describe the maximum intensity of the AE.  For purposes of consistency, 
these intensity grades are defined as follows:
1
MILD
Does not interfere with participant’s usual 
function.
2
MODERATE
Interferes to some extent with participant’s usual 
function.
3
SEVERE
Interferes significantly with participant’s usual 
function.
4
LIFE-THREATENING
Life-threatening consequences; urgent 
intervention indicated.

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Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE or SAE. The investigator will use clinical judgment to 
determine the relationship.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.

The investigator will also consult the IB and/or product information, for marketed 
products, in his/her assessment.

For each AE or SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE or SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very 
important that the investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study intervention caused the event, 
then the event will be handled as “related to study intervention” for reporting purposes, 
as defined by the sponsor. In addition, if the investigator determines that an SAE is 
associated with study procedures, the investigator must record this causal relationship in 
the source documents and CRF, and report such an assessment in the dedicated section 
of the Vaccine SAE Reporting Form and in accordance with the SAE reporting 
requirements.

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Follow-Up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations, as medically indicated or as requested by the sponsor,
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other healthcare providers.

If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Pfizer Safety with a copy of any postmortem 
findings, including histopathology.

New or updated information will be recorded in the originally submitted documents.

The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the electronic 
data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data become 
available.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or to Pfizer Safety by telephone.

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SAE Reporting to Pfizer Safety via Vaccine SAE Reporting Form

Facsimile transmission of the Vaccine SAE Reporting Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the Vaccine SAE Reporting Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the Vaccine SAE Reporting Form pages within the designated 
reporting time frames.

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10.4. Appendix 4: Contraceptive and Barrier Guidance 
The following appendix applies as specified in each substudy eligibility criteria section.
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s):

Refrain from donating sperm.

PLUS either:

Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent.
OR

Must agree to use contraception/barrier as detailed below:

Agree to use a male condom when having sexual intercourse with a woman of 
childbearing potential who is not currently pregnant.

In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly effective 
methods below in Section 10.4.4).
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using an acceptable contraceptive method as described below during 
the intervention period (for a minimum of 28 days after the last dose of study 
intervention). The investigator should evaluate the effectiveness of the contraceptive 
method in relationship to the first dose of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.

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10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenarchal.
2. Premenopausal female with 1 of the following:
3. Documented hysterectomy;
4. Documented bilateral salpingectomy;
5. Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study.

Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. In addition:

A high FSH level in the postmenopausal range must be used to confirm a postmenopausal 
state in women under 60 years of age and not using hormonal contraception or HRT.

A female on HRT and whose menopausal status is in doubt will be required to use one of 
the nonestrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.

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10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion (eg, bilateral tubal ligation).
5. Vasectomized partner:

A vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. The spermatogenesis cycle is approximately 90 days.
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

Oral;

Intravaginal;

Transdermal.
7. Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral;

Injectable.
8. Sexual abstinence:

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant.
9. Progestogen-only oral hormonal contraception where inhibition of ovulation is not the 
primary mode of action.
10. Male or female condom with or without spermicide.
11. Cervical cap, diaphragm, or sponge with spermicide.
12. A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods).

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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-Up Assessments 
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
“susceptible” to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.”
LFTs are not required as a routine safety monitoring procedure in this study. However, 
should an investigator deem it necessary to assess LFTs because a participant presents with 
clinical signs/symptoms, such LFT results should be managed and followed as described 
below.
In the majority of DILI cases, elevations in AST and/or ALT precede Tbili elevations 
(>2 × ULN) by several days or weeks. The increase in Tbili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and Tbili values will be 
elevated within the same laboratory sample). In rare instances, by the time Tbili elevations 
are detected, AST/ALT values might have decreased. This occurrence is still regarded as a 
potential DILI. Therefore, abnormal elevations in either AST OR ALT in addition to Tbili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and Tbili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a Tbili value >2 × ULN 
with no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or not 
available.

For participants with baseline AST OR ALT OR Tbili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT values 
>2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is smaller).

Preexisting values of Tbili above the normal range: Tbili level increased from baseline 
value by an amount of at least 1 × ULN or if the value reaches >3 × ULN (whichever is 
smaller).

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Rises in AST/ALT and Tbili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and Tbili for suspected Hy’s law
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should also be given 
to drawing a separate tube of clotted blood and an anticoagulated tube of blood for further 
testing, as needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. A detailed history, including relevant information, such 
as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection, liver imaging (eg, biliary tract), and collection of serum 
samples for acetaminophen/paracetamol drug and/or protein adduct levels may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
Tbili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.

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10.6. Appendix 6: Alternative Measures During Public Emergencies
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of 
the COVID-19 pandemic globally and will become effective for other public emergencies 
only upon written notification from Pfizer.
Use of these alternative study measures are expected to cease upon the return of business as 
usual (including the lifting of any quarantines and travel bans/advisories).
10.6.1. Telehealth Visits
In the event that in-clinic study visits cannot be conducted, every effort should be made to 
follow up on the safety of study participants at scheduled visits per the SoA or unscheduled 
visits.  Telehealth visits may be used to continue to assess participant safety and collect data 
points.  Telehealth includes the exchange of healthcare information and services via 
telecommunication technologies (eg, audio, video, video-conferencing software) remotely, 
allowing the participant and the investigator to communicate on aspects of clinical care, 
including medical advice, reminders, education, and safety monitoring.  The following 
assessments must be performed during a telehealth visit:

Review and record any AEs and SAEs since the last contact.  Refer to Section 8.3.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8 received by 
the participant if required for his or her clinical care.

Review and record contraceptive method and results of pregnancy testing.  Confirm that 
the participant is adhering to the contraception method(s) required in the protocol.  Refer 
to Appendix 4.
Study participants must be reminded to promptly notify site staff about any change in their 
health status.

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10.7. Appendix 7: Substudy A
10.7.1. Substudy Summary
10.7.1.1. Synopsis
See Section 1.1 for a synopsis of Substudy A.
10.7.1.2. Schema
Visit Number
1
2
3
4
Unplanned
Visit 
Description
Booster 
Vaccination
1-Month
Telephone 
Contact
6-Month
Follow-Up
Visit
12-Month 
Telephone 
Contact
Potential 
COVID-19 
Illness Visit
Participants having 
received 2 prior doses of 
30 µg BNT162b2 at least 
6 months prior to 
randomization
Group 1
(n=5000)
BNT162b2
Group 2
(n=5000)
Placebo
Blood draw
20 mL
20 mL
Visit
Number
101
102
103
Unplanned
Visit 
Description
BNT162b2 
Vaccination
1-Month Telephone 
Contact 2
6-Month Telephone 
Contact
Potential COVID-19 
Illness Visit
Group 2
BNT162b2
Blood Draw
20 mL

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10.7.1.3. Schedule of Activities for Substudy A
Visit Number
1
2
3
4
Unplanned
Visit Description
Booster 
Vaccination
1-Month
Telephone 
Contact
6-Month
Follow-Up 
Visita
12-Month 
Telephone 
Contacta
Potential COVID-19 Illness 
Visitb
Visit Window
Day 1c
28 to 35 Days 
After Visit 1
175 to 189 Days
After Visit 1
350 to 378 Days 
After Visit 1
Optimally Within 3 Days After 
Potential COVID-19 Illness 
Onset
Obtain informed consent
X
Obtain the participant’s prior participant number from Study 
C4591001
X
Assign participant number 
X
Obtain demography and medical history data
X
Perform clinical assessmentd
X
For participants who are HIV-positive, record latest CD4 
count and HIV viral load
X
X
X
X
Measure height and weight
X
Measure temperature (body)
X
Perform urine pregnancy test (if appropriate)
X
Confirm use of contraceptives (if appropriate)
X
X
Collect nonstudy vaccine information 
X
X
Collect prohibited medication use
X
X
X
X
Confirm eligibility
X
Review temporary delay criteria
X
Collect blood sample for immunogenicity assessment
~20 mL
~20 mL
Obtain nasal (midturbinate) swab
X
X
Obtain randomization number and study intervention 
allocation
X
Administer study intervention
X
Assess acute reactions for at least 30 minutes after study 
intervention administration
X
Explain participant communication methods, assist the 
participant with downloading the app, or issue provisioned 
device, if required
X

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Visit Number
1
2
3
4
Unplanned
Visit Description
Booster 
Vaccination
1-Month
Telephone 
Contact
6-Month
Follow-Up 
Visita
12-Month 
Telephone 
Contacta
Potential COVID-19 Illness 
Visitb
Visit Window
Day 1c
28 to 35 Days 
After Visit 1
175 to 189 Days
After Visit 1
350 to 378 Days 
After Visit 1
Optimally Within 3 Days After 
Potential COVID-19 Illness 
Onset
Provide/ensure the participant has a thermometer 
X
Request the participant return the e-diary or assist the 
participant to delete the application
X
Collect AEs and SAEs as appropriate
X
X
Xe
Xf
Collection of COVID-19–related clinical and laboratory 
information (including local diagnosis)
X
Contact the participant by telephone
X
X
a.
This visit will be conducted for all participants if the study remains blinded at the time of the visit or, if the study has been unblinded, for participants who 
originally received BNT162b2 or placebo recipients who declined BNT162b2 booster vaccination.
b.
The COVID-19 illness visit may be conducted as an in-person or telehealth visit.
c.
The visit may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and exclusion criteria onwards must be conducted on the 
same day.
d.
Including, if indicated, a physical examination.
e.
Any AEs occurring up to 48 hours after the blood draw must be recorded (see Section 8.3.1).
f.
AEs need only be recorded if the participant remains in the AE reporting period (see Section 8.3.1).

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10.7.1.3.1. Administration of BNT162b2 to Those Originally Assigned to Placebo
Participants who originally received placebo will have the opportunity to receive BNT162b2 as part of the study either indicated by, 
and at a time informed by, the outcome of the interim analyses detailed in Section 10.7.9.4 or at a time decided at the discretion of the 
sponsor.
Visit Number
101
102
103
Unplanned
Visit Description
BNT162b2 Vaccination
1-Month Telephone 
Contact 2
6-Month Telephone 
Contact
Potential COVID-19 Illness Visit
Visit Window
As Informed by the Outcome of 
the Interim Analyses, or at the 
Discretion of the Sponsor
28 to 35 Days After 
Visit 101
175 to 189 Days 
After Visit 101
Optimally Within 3 Days After 
Potential COVID-19 Illness Onset
Confirm participant originally received placebo
X
For participants who are HIV-positive, record latest 
CD4 count and HIV viral load
X
X
X
Perform urine pregnancy test (if appropriate)
X
Confirm use of contraceptives (if appropriate)
X
Collect prohibited medication use
X
X
X
X
Confirm eligibility
X
Review temporary delay criteria
X
Collect blood sample for immunogenicity assessment
~20 mL
Obtain nasal (midturbinate) swab
X
X
Obtain vaccine vial allocation via IRT
X
Administer BNT162b2
X
Assess acute reactions for at least 30 minutes after 
study intervention administration
X
Request the participant return the e-diary or assist the 
participant to delete the application
X
Collect AEs and SAEs as appropriate
X
X
X
Xa
Collection of COVID-19–related clinical and 
laboratory information (including local diagnosis)
X
Contact the participant by telephone
X
X
Abbreviations: HIV = human immunodeficiency virus; IRT = interactive response technology.
a.
AEs need only be recorded if the participant remains in the AE reporting period (see Section 8.3.1).

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10.7.2. Introduction
10.7.2.1. Study Rationale
Substudy A will evaluate the safety, tolerability, and efficacy of a booster dose of BNT162b2 
when administered to participants having previously received 2 doses of BNT162b2 at least 
6 months prior to randomization.
10.7.2.2. Background
See Section 2.2 for the study background.
10.7.2.3. Benefit/Risk Assessment
No additional risks are identified for Substudy A beyond those detailed for the master study 
(see Section 2.3).
10.7.2.3.1. Benefit Assessment
Benefits to individual participants enrolled in Substudy A may be:

Receipt of a booster dose of an efficacious or potentially efficacious COVID-19 vaccine 
that may convey a longer duration of protection during a global pandemic.

Access to COVID-19 diagnostic testing.

Contributing to research to help others in a time of global pandemic.
10.7.3. Objectives, Estimands, and Endpoints
Objectives
Estimands
Endpoints
Primary Efficacy
Primary Efficacy
Primary Efficacy
To describe the efficacy of a booster 
dose of BNT162b2 against confirmed 
COVID-19 occurring from 7 days after 
the booster dose through the blinded 
follow-up period in participants without 
evidence of past SARS-CoV-2 
infection 
In participants complying with the key protocol 
criteria (evaluable participants) and with no 
serological or virological evidence (prior to 
7 days after receipt of the booster dose) of past 
SARS-CoV-2 infection:
100 × (1 – IRR) [ratio of active vaccine to 
placebo]
Confirmed COVID-19 
incidence from 7 days after 
the booster dose per 
1000 person-years of 
blinded follow-up 
To describe the efficacy of a booster 
dose of BNT162b2 against confirmed 
COVID-19 occurring from 7 days after 
the booster dose through the blinded 
follow-up period in participants with 
and without evidence of past 
SARS-CoV-2 infection 
In participants complying with the key protocol 
criteria (evaluable participants) with or without 
serological or virological evidence (prior to 
7 days after receipt of the booster dose) of past 
SARS-CoV-2 infection:
100 × (1 – IRR) [ratio of active vaccine to 
placebo]
Confirmed COVID-19 
incidence from 7 days after 
the booster dose per 
1000 person-years of 
blinded follow-up 

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Objectives
Estimands
Endpoints
Primary Safety
Primary Safety
Primary Safety
To define the safety profile of a booster 
dose of BNT162b2
In participants receiving 1 dose of study 
intervention, the percentage of participants 
reporting:

AEs from the booster dose to 1 month after 
the booster dose

SAEs from the booster dose to 6 months after 
the booster dose

AEs

SAEs
Secondary Efficacy
Secondary Efficacy
Secondary Efficacy
To describe the efficacy of a booster 
dose of BNT162b2 against confirmed 
severe COVID-19 (based on FDA 
definition) occurring from 7 days after 
the booster dose through the blinded 
follow-up period in participants without 
evidence of past SARS-CoV-2 
infection 
In participants complying with the key protocol 
criteria (evaluable participants) and with no 
serological or virological evidence (prior to 
7 days after receipt of the booster dose) of past 
SARS-CoV-2 infection:
100 × (1 – IRR) [ratio of active vaccine to 
placebo]
Confirmed severe 
COVID-19 (based on FDA
definition) incidence from 
7 days after the booster 
dose per 1000 person-years 
of blinded follow-up 
To describe the efficacy of a booster 
dose of BNT162b2 against confirmed 
severe COVID-19 (based on FDA 
definition) occurring from 7 days after 
the booster dose through the blinded 
follow-up period in participants with 
and without evidence of past 
SARS-CoV-2 infection 
In participants complying with the key protocol 
criteria (evaluable participants) and with or 
without serological or virological evidence (prior 
to 7 days after receipt of the booster dose) of past 
SARS-CoV-2 infection:
100 × (1 – IRR) [ratio of active vaccine to 
placebo]
Confirmed severe 
COVID-19 (based on FDA 
definition) incidence from 
7 days after the booster 
dose per 1000 person-years 
of blinded follow-up
To describe the efficacy of a booster 
dose of BNT162b2 against confirmed 
severe COVID-19 (based on CDC
definition) occurring from 7 days after 
the booster dose through the blinded 
follow-up period in participants without 
evidence of past SARS-CoV-2 
infection 
In participants complying with the key protocol 
criteria (evaluable participants) and with no 
serological or virological evidence (prior to 
7 days after receipt of the booster dose) of past 
SARS-CoV-2 infection:
100 × (1 – IRR) [ratio of active vaccine to 
placebo]
Confirmed severe 
COVID-19 (based on CDC 
definition) incidence from 
7 days after the booster 
dose per 1000 person-years 
of blinded follow-up 
To describe the efficacy of a booster 
dose of BNT162b2 against confirmed 
severe COVID-19 (based on CDC 
definition) occurring from 7 days after 
the booster dose through the blinded 
follow-up period in participants with 
and without evidence of past 
SARS-CoV-2 infection 
In participants complying with the key protocol 
criteria (evaluable participants) and with or 
without serological or virological evidence (prior 
to 7 days after receipt of the booster dose) of past 
SARS-CoV-2 infection:
100 × (1 – IRR) [ratio of active vaccine to 
placebo]
Confirmed severe 
COVID-19 (based on CDC 
definition) incidence from 
7 days after the booster 
dose per 1000 person-years 
of blinded follow-up
Exploratory
To describe the incidence of confirmed 
COVID-19 through the entire study 
follow-up period in participants who 
received the BNT162b2 booster dose
In participants who received BNT162b2 at the 
booster vaccination (at initial randomization or 
subsequently):
Incidence per 1000 person-years of follow-up
Confirmed COVID-19 
incidence per 
1000 person-years of 
follow-up 

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10.7.4. Study Design
10.7.4.1. Overall Design
This is a Phase 3 randomized, placebo-controlled, observer-blind substudy to evaluate the 
safety, tolerability, and efficacy of a booster dose of BNT162b2.  Participants ≥16 years of 
age who have completed a 2-dose primary series of BNT162b2 at least 6 months prior to 
randomization will be enrolled, and participants will be randomized at a ratio of 1:1 to 
receive either BNT162b2 or placebo as shown in Section 10.7.1.2.  Randomization will be 
stratified by age, such that approximately 60% of participants enrolled will be ≥16 to 
55 years of age and approximately 40% of participants >55 years of age. Approximately 
10,000 participants will be randomized in the study. Assuming a 15% nonevaluable rate, 
there will be approximately 4250 evaluable participants in each group.
Participants who are randomized to receive placebo at the booster vaccination visit will be 
offered the opportunity to receive BNT162b2 if indicated by the outcome of the interim 
analyses, as outlined below in Section 10.7.4.2.1 and further detailed in Section 10.7.9.4, or 
at the discretion of the sponsor.  The timing of this booster vaccination may be informed by 
the outcome of the interim analyses detailed in Section 10.7.9.4 or at a time decided by the 
sponsor.
The study may be terminated early, for reasons including (but not limited to) access to and 
availability of BNT162b2 in the real world, reducing the value of participant involvement 
and observation in this clinical trial. Further to this, participants who are offered the 
possibility to participate in a future study within the Pfizer/BioNTech COVID-19 vaccine 
development program will be discontinued from this study.
10.7.4.2. Scientific Rationale for Substudy A Design
See Section 10.7.2.1.
10.7.4.2.1. Statistical Rationale for Substudy A Design
In addition to assessing the safety of administering a booster dose in a large number of 
participants, a key objective of this study is to characterize the potential for waning VE over 
time in participants who do not receive a booster.  It is important to identify when a booster 
is needed to protect the participants in this trial, as well as to inform vaccine policy 
decision-makers.  Consequently, the most appropriate statistical framework to facilitate 
decision-making in this setting is periodic statistical summaries (every 2 months over the 
scheduled 6-month follow-up period) using statistical guidelines, rather than the traditional 
hypothesis testing framework with strong control of overall type 1 error across analysis time 
points.
Using a traditional hypothesis testing framework, a policy of recommending a booster would 
be implemented only if the lower limit of the alpha-adjusted CI for VE of the boosted group 
relative to the unboosted group was greater than some specified value (eg, 20% or 30%).  
This approach controls the overall type 1 error, that is, deciding that a booster is necessary to 
maintain VE when it is actually not necessary.  But strong control of type 1 error inflates type 

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2 error for a fixed sample size.  And in this setting, type 2 error, that is, deciding that a 
booster is not necessary when it actually is, has a greater negative impact on public health.
For this reason, a descriptive statistical approach will be used with point estimates of VE 
(boosted relative to unboosted) and unadjusted (for multiplicity) 95% CIs at each time point 
(2, 4, and 6 months).  In addition, to help put these results into perspective, an inferred VE 
for the unboosted group (relative to an unvaccinated population) will be calculated.  
Specifically, assuming that the newly boosted group has the same VE (relative to an 
unvaccinated population) over time that was observed in the parent C4591001 trial, an 
inferred unvaccinated (placebo) disease rate can be obtained at various time points and used 
to calculate the inferred VE (relative to unvaccinated) for the unboosted group.  If this value 
is lower than a specified value (eg, 60%) at a given analysis time point, then a decision to 
offer a booster to the unboosted participants at that time may be implemented.
10.7.4.2.2. Diversity of Study Population 
Reasonable attempts will be made to enroll participants with the distribution of 
characteristics shown to reflect that achieved in C4591001.40
10.7.4.3. Justification for Dose
See Section 4.3 for a justification of the BNT162b2 dose used in Substudy A.
10.7.4.4. End of Study Definition
See Section 4.4.
10.7.5. Study Population
Details of the master eligibility criteria are shown in Section 5.  Participants must meet all of 
the general inclusion and exclusion criteria as specified for both the master protocol and
Substudy A–specific inclusion and exclusion criteria.
10.7.5.1. Inclusion Criteria
Participants are eligible to be included in Substudy A only if all of the following criteria 
apply:
Age and Sex:
1. Male or female participants ≥16 years of age at Visit 1 (Day 1) who participated in 
Study C4591001.
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, vaccination 
plan, laboratory tests, lifestyle considerations, and other study procedures.

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3. Healthy participants who are determined by medical history, physical examination
(if required), and clinical judgment of the investigator to be eligible for inclusion in the 
study.
Note: Healthy participants with preexisting stable disease, defined as disease not requiring 
significant change in therapy or hospitalization for worsening disease during the 6 weeks 
before enrollment, can be included.  Specific criteria for participants with known stable 
infection with HIV, HCV, or HBV can be found in Section 10.15.
Informed Consent:
4. Capable of giving personal signed informed consent/assent, have parent(s)/legal guardian 
capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the ICD and in this protocol.
The investigator, or a person designated by the investigator, will obtain written/electronically 
signed informed consent (and assent) from each study participant’s legal guardian (as defined 
in Appendix 1), and the participant’s assent, when applicable, before any study-specific 
activity is performed, unless a waiver of informed consent has been granted by an IRB/EC. 
All legal guardians should be fully informed, and participants should be informed to the 
fullest extent possible, about the study in language and terms they are able to understand. 
The investigator will retain the original copy of each participant’s signed consent/assent 
document.
Other Inclusions:
5. Participants who have received 2 prior doses of 30 µg BNT162b2 19 to 42 days apart,
with the second dose being at least 175 days before Visit 1 (Day 1).
Documented confirmation of prior BNT162b2 receipt must be obtained prior to 
randomization.
10.7.5.2. Exclusion Criteria
Participants are excluded from Substudy A if any of the following criteria apply:
Medical Conditions:
1. Other medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for the 
study.
2. History of severe adverse reaction associated with a vaccine and/or severe allergic 
reaction (eg, anaphylaxis) to any component of the study intervention(s).

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3. 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.
4. Immunocompromised individuals with known or suspected immunodeficiency, as 
determined by history and/or laboratory/physical examination.
5. Bleeding diathesis or condition associated with prolonged bleeding that would, in the 
opinion of the investigator, contraindicate intramuscular injection.
6. Women who are pregnant or breastfeeding.
Prior/Concomitant Therapy:
7. Individuals who receive treatment with radiotherapy or immunosuppressive therapy, 
including cytotoxic agents or systemic corticosteroids (if systemic corticosteroids are 
administered for ≥14 days at a dose of ≥20 mg/day of prednisone or equivalent), eg, for 
cancer or an autoimmune disease, or planned receipt throughout the study.  
Inhaled/nebulized, intra-articular, intrabursal, or topical (skin or eyes) corticosteroids are 
permitted.
8. Receipt of blood/plasma products, immunoglobulin, or monoclonal antibodies, from 
60 days before study intervention administration, or receipt of any passive antibody 
therapy specific to COVID-19, from 90 days before study intervention administration, or 
planned receipt throughout the study.
Prior/Concurrent Clinical Study Experience:
9. Prior receipt of any COVID-19 vaccine other than BNT162b2.
Other Exclusions:
10. Investigator site staff or Pfizer-BioNTech employees directly involved in the conduct of 
the study, site staff otherwise supervised by the investigator, and their respective family 
members.
11. Receipt of medications intended to prevent COVID-19.
12. Prior receipt of more than 2 doses of BNT162b2 30 µg.
13. Participation in other studies involving study intervention within 28 days prior to study 
entry, other than C4591001, and/or within 28 days of confirmed receipt of BNT162b2 
within the study.
10.7.5.3. Lifestyle Considerations
Contraception requirements will apply to Substudy A as detailed in Section 5.3 and
Section 10.4.

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10.7.5.4. Screen Failures
See Section 5.4.
10.7.5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Administration 
of Study Intervention
See Section 5.5.
10.7.6. Study Intervention(s) and Concomitant Therapy
For the purposes of this substudy, study intervention refers to:

BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S): 
30 µg

Normal saline (0.9% sodium chloride solution for injection)
10.7.6.1. Study Intervention(s) Administered
See Section 6.1 for details of BNT162b2.
Additional Intervention 
Name
Saline Placebo
Type
Placebo
Dose Formulation
Normal saline (0.9% sodium chloride solution for injection)
Unit Dose Strength(s)
N/A
Dosage Level(s) 
N/A
Route of Administration
Intramuscular injection
Use
Placebo
IMP or NIMP
IMP
Sourcing
Provided centrally by the sponsor
Packaging and Labeling
Study intervention will be provided in a glass or plastic vial as open-label 
supply. Each vial will be labeled as required per country requirement
10.7.6.1.1. Administration
Participants will receive 1 dose of study intervention at Visit 1 in accordance with the 
substudy’s SoA (Section 10.7.1.3).
Study intervention at the booster vaccination visit should be administered intramuscularly 
into the deltoid muscle, preferably of the nondominant arm, by an unblinded administrator.
Study intervention administration at Visit 101 will be conducted in an open-label manner.

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10.7.6.1.2. Preparation and Dispensing
For booster vaccination during Substudy A, study intervention will be prepared by qualified 
unblinded site personnel according to the IP manual.  The study intervention will be 
administered in such a way as to ensure that the participants remain blinded.
10.7.6.2. Measures to Minimize Bias: Randomization and Blinding
10.7.6.2.1. Blinding of Site Personnel
In this observer-blinded substudy, the study staff receiving, storing, dispensing, preparing, 
and administering the study interventions will be unblinded.  All other study and site 
personnel, including the investigator, investigator staff, and participants, will be blinded to 
study intervention assignments.  In particular, the individuals who evaluate participant safety 
will be blinded.  Because there are differences in physical appearance of the study 
interventions, the study intervention will be administered in a manner that prevents the study 
participants from identifying the study intervention group based on its appearance.
The PI will assign the responsibility of the unblinded dispensers/administrators to persons 
who will not participate in the evaluation of any study participant.  To ensure adequate 
coverage, at least 2 unblinded dispensers/administrators will be assigned per site.  Members 
of the study site staff or clinic pharmacy should fulfill these roles.  Contact between the 
unblinded dispensers and study participants should be kept to a minimum.  The investigator, 
study coordinator, and any site staff other than the unblinded dispensers/administrators must 
not be allowed to know the study intervention assigned to any study participant and must not 
be allowed to see the study intervention container contents.  In the event of a Quality 
Assurance audit, the auditor(s) will be allowed access to unblinded study intervention records 
at the site(s) to verify that randomization/dispensing has been done accurately.
The study will be unblinded to site personnel at a time informed by the outcome of the 
interim analyses, as detailed in Section 10.7.9.4, or at a time decided by the sponsor.
10.7.6.2.2. Blinding of the Sponsor
The majority of sponsor/Pfizer staff will be blinded to study intervention allocation.  All 
laboratory testing personnel performing serology assays will remain blinded to study 
intervention assigned/received throughout the study.  The following sponsor/Pfizer staff, who 
will have no part in the blinded conduct of the study, will be unblinded (further details will 
be provided in a data blinding plan):

Those study team members who are involved in ensuring that protocol requirements for 
study intervention preparation, handling, allocation, and administration are fulfilled at the 
site will be unblinded for the duration of the study (eg, unblinded study manager, 
unblinded clinical research associate).

Unblinded clinician(s), who are not direct members of the study team and will not 
participate in any other study-related activities, will review unblinded protocol 
deviations.

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
An unblinded team supporting interactions with, and analyses for, the DMC 
(see Section 10.7.9.4.2).  This team comprises a statistician, programmer(s), a clinical 
scientist, and a medical monitor who will review cases of severe COVID-19 as they are 
received.

An unblinded submissions team will be responsible for preparing unblinded analyses and 
documents to support regulatory activities that may be required while the study is 
ongoing.  With the exception of the statisticians and programmers, who will become 
unblinded at the participant level at the time of the first planned reporting event to 
perform the analyses, other members of this team will only be unblinded at the group 
level and not have access to individual participant assignments.  A separate group of 
statisticians and programmers will remain blinded and continue supporting the blinded 
conduct of the study after the first planned analysis.

After the study data used for submission become public, the blinded study team will also 
have access to those data and become unblinded at a group level.

The study will be unblinded to all sponsor/Pfizer staff at a time informed by the outcome 
of the interim analyses, as detailed in Section 10.7.9.4, or at a time decided by the 
sponsor.
10.7.6.2.3. Breaking the Blind
The IRT will be programmed with blind-breaking instructions.  In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s study 
intervention assignment is warranted.  Participant safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the sponsor prior to 
unblinding a participant’s vaccine assignment unless this could delay further management of 
the participant.  If a participant’s vaccine assignment is unblinded, the sponsor must be 
notified within 24 hours after breaking the blind.  The date and reason that the blind was 
broken must be recorded in the source documentation and CRF.
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
10.7.6.3. Study Intervention Compliance
See Section 6.4.
10.7.6.4. Dose Modification 
See Section 6.5.
10.7.6.5. Continued Access to Study Intervention After the End of the Study
See Section 6.6.

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10.7.6.6. Treatment of Overdose
See Section 6.7.
10.7.6.7. Concomitant Therapy
See Section 6.8.
10.7.7. Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
See Section 7.
10.7.8. Study Assessments and Procedures
The total blood sampling volume for individual participants in this study is up to 
approximately 60 mL.
For all participants, other additional blood samples may be taken for safety assessments at 
times specified by Pfizer, provided the total volume taken during the study does not exceed 
550 mL during any period of 60 consecutive days.
10.7.8.1. Efficacy and/or Immunogenicity Assessments for Substudy A
10.7.8.1.1. Efficacy Against COVID-19
Efficacy will be assessed throughout a participant’s involvement in the study through 
surveillance for potential cases of COVID-19.  If, at any time, a participant develops acute 
respiratory illness (see Section 10.7.8.5.5.1), for the purposes of the study he or she will be 
considered to potentially have COVID-19 illness.  In this circumstance, the participant 
should contact the site, an in-person or telehealth visit should occur, and assessments should 
be conducted as specified in the SoA.  The assessments will include a nasal (midturbinate) 
swab, which will be tested at a central laboratory using an RT-PCR test (Cepheid; 
FDA-approved under EUA and Pfizer-validated), or other equivalent nucleic acid 
amplification–based test (ie, NAAT) to detect SARS-CoV-2.  In addition, clinical 
information and results from local standard-of-care tests (as detailed in Section 10.7.8.5.5.1) 
will be assessed.  The central laboratory NAAT result will be used for the case definition, 
unless no result is available from the central laboratory, in which case a local NAAT result 
may be used if it was obtained using 1 of the following assays:

Cepheid Xpert Xpress SARS-CoV-2

Roche cobas SARS-CoV-2 real-time RT-PCR test (EUA200009/A001)

Abbott Molecular/RealTime SARS-CoV-2 assay (EUA200023/A001)
Definitions of SARS-CoV-2–related cases, and SARS-CoV-2–related severe cases, will be 
considered as follows (for both, the onset date of the case will be the date that symptoms 
were first experienced by the participant; if new symptoms are reported within 4 days after 
resolution of all previous symptoms, they will be considered as part of a single illness):

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
Confirmed COVID-19: presence of at least 1 of the following symptoms and 
SARS-CoV-2 NAAT-positive during, or within 4 days before or after, the symptomatic 
period, either at the central laboratory or at a local testing facility (using an acceptable 
test):

Fever; 

New or increased cough; 

New or increased shortness of breath; 

Chills; 

New or increased muscle pain; 

New loss of taste or smell;

Sore throat;

Diarrhea;

Vomiting.

Confirmed severe COVID-19 (FDA definition41): confirmed COVID-19 and presence of 
at least 1 of the following:

Clinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per minute, 
HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or PaO2/FiO2
<300 mm Hg);

Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation, 
mechanical ventilation, or ECMO);

Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiring vasopressors);

Significant acute renal, hepatic, or neurologic dysfunction;

Admission to an ICU;

Death.

Confirmed severe COVID-19 (CDC definition42): confirmed COVID-19 and presence of 
at least 1 of the following:

Hospitalization; 

Admission to the ICU;

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
Intubation or mechanical ventilation; 

Death.
The DMC may recommend modification of the definition of severe disease according to 
emerging information.
10.7.8.2. Safety Assessments
See Section 8.2.
10.7.8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting
See Section 8.3.
10.7.8.4. Immunogenicity Assessments
See Section 8.1.
10.7.8.5. Substudy A Procedures
10.7.8.5.1. Visit 1 – Booster Vaccination (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written, 
study-specific informed consent will be obtained from the participant or his/her 
parent(s)/legal guardian, as appropriate.  Each signature on the ICD must be personally dated 
by the signatory.  The investigator or his or her designee will also sign the ICD.  A copy of 
the signed and dated ICD must be given to the participant/participant’s parent(s)/legal 
guardian.  The source data must reflect that the informed consent was obtained before 
participation in the study.
It is anticipated that the procedures below will be conducted in a stepwise manner. The visit 
may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and 
exclusion criteria onwards must be conducted on the same day.

Assign a single participant number using the IRT system.

Obtain the participant’s prior participant number from Study C4591001 and record this in 
the CRF.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).  
The full date of birth will be collected to critically evaluate the immune response and 
safety profile by age.

Obtain any medical history of clinical significance. For participants who are 
HIV-positive, record HIV viral load and CD4 count results from the most recent test 
performed in the previous 6 months.

Perform a clinical assessment. If the clinical assessment indicates that a physical 
examination is necessary to comprehensively evaluate the participant, perform a physical

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examination and record any findings in the source documents and, if clinically 
significant, record any findings on the medical history CRF.

Measure the participant’s height and weight.

Measure the participant’s body temperature.

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 5.3.

Record nonstudy vaccinations as described in Section 6.8.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met.

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Record AEs as described in Section 8.3.

Collect a blood sample (approximately 20 mL) for immunogenicity testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Blinded site staff will obtain the participant’s randomization number using the IRT 
system. The randomization confirmation report with the study intervention allocation 
will only be sent to the unblinded site staff member. 

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into 
the deltoid muscle of the preferably nondominant arm.  Please refer to the IP manual for 
further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study 
intervention administration for any acute reactions.  Record any acute reactions 
(including time of onset) in the participant’s source documents and on the AE page of the 
CRF, and on an SAE form as applicable.

Issue a thermometer to monitor for fever (for COVID-19 surveillance) and provide 
instructions on its use.

Explain the e-diary technologies available for this study (see Section 10.7.8.5.6), and 
assist the participant or his/her parent(s)/legal guardian, as appropriate, in downloading 
the study application onto the participant’s own device or issue a provisioned device if 
required.

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
Provide instructions on COVID-19 illness e-diary completion and ask the participant or 
his/her parent(s)/legal guardian, as appropriate, to complete the COVID-19 illness 
e-diary if the participant is diagnosed with COVID-19 or has possible new or increased 
symptoms, and when he/she receives a reminder, at least weekly.  See Section 10.7.8.5.6
for further details.

Ask the participant to contact the site staff or investigator if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.7.8.5.9).

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator if a medically attended event (eg, doctor’s visit, emergency room 
visit) or hospitalization occurs.

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator (this could be via the COVID-19 illness e-diary) immediately if the 
participant experiences any respiratory symptoms as detailed in Section 10.7.8.5.5.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant or his/her parent(s)/legal guardian, as appropriate, to bring the 
e-diary to the next visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs and an unblinded 
dispenser/administrator updates the study intervention accountability records.
10.7.8.5.2. Visit 2 – 1-Month Telephone Contact (28 to 35 Days After Visit 1)

Record AEs as described in Section 8.3.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since Visit 1 (if any).

Discuss contraceptive use as described in Section 5.3.

Ask the participant to contact the site staff or investigator if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.7.8.5.9).

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator if a medically attended event (eg, doctor’s visit, emergency room 
visit) or hospitalization occurs.

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
Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator (this could be via the COVID-19 illness e-diary) immediately if the 
participant experiences any respiratory symptoms as detailed in Section 10.7.8.5.5.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
10.7.8.5.3. Visit 3 – 6-Month Follow-Up Visit (175 to 189 Days After Visit 1)
This visit will be conducted for all participants if the study remains blinded at the time of the 
visit or, if the study has been unblinded, for participants who originally received BNT162b2 
or placebo recipients who declined the BNT162b2 booster vaccination.

Record SAEs as described in Section 8.3.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since Visit 2 (if any).

Collect a blood sample (approximately 20 mL) for immunogenicity testing.

Record details of any of the prohibited medications specified in Section 6.8 received by 
the participant if required for his or her clinical care.

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator (this could be via the COVID-19 illness e-diary) immediately if the 
participant experiences any respiratory symptoms as detailed in Section 10.7.8.5.5.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3.
10.7.8.5.4. Visit 4 – 12-Month Telephone Contact (350 to 378 Days After Visit 1)

This visit will be conducted for all participants if the study remains blinded at the time of 
the visit or, if the study has been unblinded, for participants who originally received 
BNT162b2 or placebo recipients who declined the BNT162b2 booster vaccination.

Record details of any of the prohibited medications specified in Section 6.8 received by 
the participant if required for his or her clinical care.

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
For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since Visit 3 (if any).

Collect the participant’s e-diary or assist the participant in removing the study application 
from his or her own personal device.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3.
10.7.8.5.5. COVID-19 Surveillance (All Substudy A Participants)
If a participant experiences any of the following (irrespective of perceived etiology or 
clinical significance), he or she is instructed to contact the site immediately and, if 
confirmed, participate in an in-person or telehealth visit as soon as possible, optimally within 
3 days of symptom onset (and at the latest 4 days after symptom resolution).

A diagnosis of COVID-19;

Fever;

New or increased cough; 

New or increased shortness of breath; 

Chills; 

New or increased muscle pain; 

New loss of taste/smell;

Sore throat;

Diarrhea;

Vomiting.
Note that:

If new symptoms are reported within 4 days after resolution of all previous symptoms, 
they will be considered as part of a single illness and a second illness visit is not required;

Surveillance of potential COVID-19 symptoms should continue even if a participant has 
a positive SARS-CoV-2 test earlier in the study.

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During the 7 days following each vaccination, potential COVID-19 symptoms that overlap 
with specific systemic events (ie, fever, chills, new or increased muscle pain, diarrhea, 
vomiting) should not trigger a potential COVID-19 illness visit unless, in the investigator’s 
opinion, the clinical picture is more indicative of a possible COVID-19 illness than vaccine 
reactogenicity. If, in the investigator’s opinion, the symptoms are considered more likely to 
be vaccine reactogenicity, but a participant is required to demonstrate that they are 
SARS-CoV-2–negative, a local SARS-CoV-2 test may be performed: if positive, the 
symptoms should be recorded as a potential COVID-19 illness; if not, the symptoms should 
be recorded as AEs.
Participants may utilize a COVID-19 illness e-diary through an application (see 
Section 10.7.8.5.6) installed on a provisioned device or on the participant’s own personal 
device to prompt him/her to report any symptoms.  Note that this does not substitute for a 
participant’s routine medical care.  Therefore, participants should be encouraged to seek care, 
if appropriate, from their usual provider.
10.7.8.5.5.1. Potential COVID-19 Illness Visit (Optimally Within 3 Days After Potential 
COVID-19 Illness Onset)
This visit may be conducted as an in-person or telehealth visit; a telehealth visit involves the 
sharing of healthcare information and services via telecommunication technologies 
(eg, audio, video, video-conferencing software) remotely, thus allowing the participant and 
investigator to communicate on aspects of clinical care.
As a participant’s COVID-19 illness may evolve over time, several contacts may be required 
to:

Record AEs, as appropriate as described in Section 8.3.  Note: Potential COVID-19 
illnesses that are consistent with the clinical endpoint definition should not be recorded as 
AEs. These data will be captured as efficacy assessment data only on the relevant pages 
of the CRF, as these are expected endpoints.

Record details of any of the prohibited medications specified in Section 6.8 received by 
the participant if required for his or her clinical care.

If the visit is conducted in person, obtain a nasal (midturbinate) swab (collected by site 
staff). Alternatively, if the visit is conducted by telehealth, instruct the participant to 
self-collect a nasal (midturbinate) swab and ship for assessment at the central laboratory.

Collect COVID-19–related standard-of-care clinical and laboratory information. This 
includes, but is not limited to:

Symptoms and signs, including

Clinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per 
minute, HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or
PaO2/FiO2 <300 mm Hg)

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
Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiring 
vasopressors)

Significant acute renal, hepatic, or neurologic dysfunction

Respiratory failure (defined as needing high-flow oxygen, noninvasive 
ventilation, mechanical ventilation, or ECMO)

Clinical diagnosis

Local laboratory SARS-CoV-2 test result(s).  Note that if it is routine practice to 
perform a repeat local SARS-CoV-2 test for any reason, then a repeat nasal 
(midturbinate) swab should also be obtained and shipped for assessment at the central 
laboratory.

Full blood count

Blood chemistry, specifically creatinine, urea, LFTs, and C-reactive protein

Imaging results (eg, CT or MRI scan) to document neurologic dysfunction

Number and type of any healthcare contact; duration of hospitalization and ICU stay

Death

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
10.7.8.5.6. Communication and Use of Technology
In a study of this nature that requires illness events to be reported outside of scheduled study 
visits, it is vital that communication between the study site and the participant or his/her 
parent(s)/legal guardian, as appropriate, is maintained to ensure that endpoint events are not 
missed.  This study will employ various methods, tailored to the individual participant, to 
ensure that communication is maintained and study information can be transmitted securely.  
Using appropriate technology, such as a study application, a communication pathway 
between the participant or his/her parent(s)/legal guardian, as appropriate, and the study site 
staff will be established.  The participant or his/her parent(s)/legal guardian, as appropriate, 
may be able to utilize his or her own devices to access this technology, or use a device 
provided by the sponsor.  Traditional methods of telephone communication will also be 
available.  The technology solution may facilitate the following:

Contact with the investigator, including the ability of the participant or his/her 
parent(s)/legal guardian, as appropriate, to report whether or not the participant has 
experienced symptoms that could represent a potential COVID-19 illness (COVID-19
illness e-diary).

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
An alert in the event that the participant is hospitalized.

Visit reminders.

Messages of thanks and encouragement from the study team.

If a participant or his/her parent(s)/legal guardian, as appropriate, is not actively 
completing the COVID-19 illness e-diary, the investigator or designee is required to 
contact the participant or his/her parent(s)/legal guardian, as appropriate, to ascertain why 
and also to obtain details of any missed events.
10.7.8.5.7. SARS-CoV-2 NAAT Results
Nasal (midturbinate) swabs for SARS-CoV-2 NAAT are obtained at:

Visit 1 and Visit 101: To determine whether a participant will be included in efficacy 
analyses of those with no serological or virological evidence (up to 7 days after receipt of 
the booster dose) of past SARS-CoV-2 infection.

Potential COVID-19 illness visits: To determine whether symptoms experienced by the 
participant fulfill the COVID-19 case definition.
Research laboratory–generated positive results from the Visit 1 and Visit 101 swabs, and all 
results from the illness visit swabs, will be provided to the site once available, but this will 
not be in real time and cannot be relied upon to direct clinical care.  Therefore, the participant 
should be directed to seek additional testing through his/her primary healthcare providers at a 
licensed clinical laboratory when exhibiting potential COVID-19 symptoms or otherwise 
receiving a positive result and counseled on whether to take any precautionary measures 
pending confirmatory testing.
10.7.8.5.8. Procedures for Administration of BNT162b2 to Those Originally Assigned to 
Placebo
Participants who are randomized to receive placebo at the booster vaccination visit will be 
offered the opportunity to receive BNT162b2 if indicated by the outcome of the interim 
analysis, as detailed in Section 10.7.9.4, or at the discretion of the study sponsor. The timing 
of this booster vaccination may be informed by the outcome of the interim analyses or at a 
time decided by the sponsor. 
10.7.8.5.8.1. Visit 101 – BNT162b2 Vaccination

Unblind the participant’s study intervention assignment (if information not already 
available), and confirm the participant originally received only placebo at the booster 
vaccination visit.  Secondary confirmation by another site staff member is required.

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 5.3.1.

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
Record details of any of the prohibited medications specified in Section 6.8 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since their last visit (if any).

Review and consider inclusion criteria and exclusion criteria prior to vaccination.  If, in 
the investigator’s judgment, vaccination is in the best interests of the participant, 
vaccination may proceed, even if inclusion criteria are not met and exclusion criteria are 
met. Such exceptions should be recorded in the participant’s source documents.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Record AEs as described in Section 8.3.

Collect a blood sample (approximately 20 mL) for immunogenicity testing. If a sample 
for this purpose has already been collected in the previous 7 days (eg, per the procedures 
at Visit 3), a second sample need not be collected.

Obtain a nasal (midturbinate) swab (collected by site staff).

Obtain the participant’s vaccine vial allocation using the IRT system.

Site staff member(s) will dispense/administer 1 dose of BNT162b2 into the deltoid 
muscle of the preferably nondominant arm.

Site staff must observe the participant for at least 30 minutes after BNT162b2 
administration for any acute reactions.  Record any acute reactions (including time of 
onset) in the participant’s source documents and on the AE page of the CRF, and on an 
SAE form as applicable.

Ask the participant to contact the site staff or investigator if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.7.8.5.9).

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator if a medically attended event (eg, doctor’s visit, emergency room 
visit) or hospitalization occurs.

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator (this could be via the COVID-19 illness e-diary) immediately if the 
participant experiences any respiratory symptoms as detailed in Section 10.7.8.5.5.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

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
The investigator or an authorized designee completes the CRFs and the 
dispenser/administrator updates the study intervention accountability records.
10.7.8.5.8.2. Visit 102 – 1-Month Telephone Contact 2 (28 to 35 Days After Visit 101)

Contact the participant/participant’s parent(s)/legal guardian by telephone.

Record AEs as described in Section 8.3.

Record details of any of the prohibited medications specified in Section 6.8 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since Visit 101 (if any).

Ask the participant to contact the site staff or investigator if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.7.8.5.9).

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator if a medically attended event (eg, doctor’s visit, emergency room 
visit) or hospitalization occurs.

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator (this could be via the COVID-19 illness e-diary) immediately if the 
participant experiences any respiratory symptoms as detailed in Section 10.7.8.5.5.

Schedule an appointment to call the participant by telephone for the next study contact.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
10.7.8.5.8.3. Visit 103 – 6-Month Telephone Contact (175 to 189 Days After Visit 101)

Contact the participant/participant’s parent(s)/legal guardian by telephone.

Record SAEs as described in Section 8.3.

Record details of any of the prohibited medications specified in Section 6.8 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since their Visit 102 (if any).

Collect the participant’s e-diary or assist the participant in removing the study application 
from his or her own personal device.

Complete the source documents.

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
The investigator or an authorized designee completes the CRFs.
10.7.8.5.9. Additional Procedures for Monitoring of Potential Myocarditis or 
Pericarditis
Any study participant who reports acute chest pain, shortness of breath, palpitations, or any 
other symptom(s) that might be indicative of myocarditis or pericarditis within 4 weeks after 
a study vaccination should be specifically evaluated, preferably by a cardiologist, for possible 
myocarditis or pericarditis. In addition to a clinical evaluation, the following should be 
performed:

ECG and

Measurement of the troponin level
If myocarditis or pericarditis is suspected based upon the initial evaluation, the following 
should also be performed:

Cardiac echocardiogram and/or

Cardiac magnetic resonance study
Details of the symptoms reported, and results of the investigations performed, will be 
recorded in the CRF.

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10.7.9. Statistical Considerations for Substudy A
See Section 9 for master protocol statistical considerations and substudy specifics below.
10.7.9.1. Statistical Hypotheses
10.7.9.1.1. Estimands
The estimands corresponding to the primary, secondary, and exploratory objectives are 
described in the table in Section 10.7.3.
In the primary safety objective evaluations, missing AE start dates will be imputed according 
to Pfizer safety rules.  No other missing information will be imputed in the safety analysis.
The estimands to evaluate the efficacy objectives are based on the evaluable efficacy 
population (Section 10.7.3).  These estimands estimate the vaccine effect in the hypothetical 
setting where participants follow the study schedules and protocol requirements as directed.  
In addition, VE will be analyzed for the all-available efficacy populations. Missing 
laboratory results will not be imputed.
10.7.9.1.2. Statistical Hypotheses
All objectives in this substudy are descriptive. No hypothesis testing is planned.
10.7.9.1.3. Multiplicity Adjustment
No multiplicity adjustment is needed for the study as there is no statistical hypothesis.
10.7.9.2. Analysis Sets
For the purpose of analysis, the following analysis sets are defined for this substudy:
Population
Description
Enrolled
All participants who have a signed ICD.
Randomized
All participants who are assigned a randomization number in the 
IWR system.
Evaluable efficacy
All eligible randomized participants who receive the booster 
vaccination as randomized and have no other important protocol 
deviations as determined by the clinician.
All-available efficacy 
(mITT)
All randomized participants who receive at least 1 dose of the 
study intervention.
Safety
All randomized participants who receive at least 1 dose of the 
study intervention.

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10.7.9.3. Statistical Analyses
The SAP will be developed and finalized for this substudy before any analyses are performed
and will describe the analyses and procedures for missing, unused, and spurious data. This 
section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.
10.7.9.3.1. General Considerations
Refer to Section 9.3.1 for general considerations of statistical analyses.
10.7.9.3.2. Primary Endpoint(s)/Estimand(s) Analysis
Endpoint
Statistical Analysis Methods
Efficacy
Ratio of confirmed COVID-19 illness from 7 days after the booster 
dose per 1000 person-years of blinded follow-up in participants 
without evidence of infection (prior to 7 days after receipt of the 
booster dose) for the active vaccine group to the placebo group
VE will be estimated by 100 × (1 – IRR), where IRR is the calculated 
ratio of confirmed COVID-19 illness per 1000 person-years of 
follow-up in the active vaccine group to the corresponding illness rate in 
the placebo group from 7 days after the booster dose.  The 2-sided 95% 
CI for VE will be provided using the Clopper-Pearson method adjusting 
for surveillance time.
In addition, a summary of VE over different time intervals (ie, prior to 
2 months, from 2 months to 4 months, and from 4 months to 6 months 
after the booster dose, etc.), along with the associated 2-sided 95% CI, 
will be calculated using the same method.
Ratio of confirmed COVID-19 illness from 7 days after the booster 
dose per 1000 person-years of blinded follow-up in participants with 
and without evidence of infection (prior to 7 days after receipt of the 
booster dose) for the active vaccine group to the placebo group
The point estimate of VE and the associated 2-sided 95% CI, including 
VE at different time intervals, will be calculated using the same method 
as for the first primary endpoint described above.
Safety
AEs will be categorized according to MedDRA terms.  Counts, 
percentages, and associated Clopper-Pearson 95% CIs of AEs from the 
booster dose to 1 month after the booster dose will be provided for each 
vaccine group. A 3-tier approach will be used to summarize AEs. 
Under this approach AEs are classified into 1 of 3 tiers: (1) Tier 1 events 
are prespecified events of clinical importance and are identified in a list 
in the product’s safety review plan; (2) Tier 2 events are those that are 
not Tier 1 but are considered “relatively common”; a MedDRA 

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Endpoint
Statistical Analysis Methods
preferred term is defined as a Tier 2 event if there are at least 1% of 
participants in at least 1 vaccine group reporting the event; and (3) Tier 
3 events are those that are neither Tier 1 nor Tier 2 events. Analyses 
methods are described in Section 9.3.1.1.
SAEs will be categorized according to MedDRA terms.  Counts, 
percentages, and the associated Clopper-Pearson 95% CIs of SAEs from 
the booster dose to 6 months after the booster dose will be provided for 
each vaccine group.
10.7.9.3.3. Secondary Endpoint(s)/Estimand(s) Analysis
Endpoint
Statistical Analysis Methods
Efficacy
Ratio of confirmed severe COVID-19 illness (based on FDA 
definition) from 7 days after the booster dose per 1000 person-years 
of blinded follow-up in participants without evidence of infection 
(prior to 7 days after receipt of the booster dose) for the active 
vaccine group to the placebo group
Ratio of confirmed severe COVID-19 illness (based on FDA 
definition) from 7 days after the booster dose per 1000 person-years 
of blinded follow-up in participants with and without evidence of 
infection (prior to 7 days after receipt of the booster dose) for the 
active vaccine group to the placebo group
Ratio of confirmed severe COVID-19 illness (based on CDC 
definition) from 7 days after the booster dose per 1000 person-years 
of blinded follow-up in participants without evidence of infection 
(prior to 7 days after receipt of the booster dose) for the active 
vaccine group to the placebo group
Ratio of confirmed severe COVID-19 illness (based on CDC 
definition) from 7 days after the booster dose per 1000 person-years 
of blinded follow-up in participants with and without evidence of 
infection (prior to 7 days after receipt of the booster dose) for the 
active vaccine group to the placebo group
For each of the above efficacy endpoints, the point estimate of VE and 
the associated 2-sided 95% CI for VE will be calculated using the same 
method as for the first primary endpoint described above.

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10.7.9.3.4. Exploratory Endpoint(s)
Endpoint
Statistical Analysis Methods
Efficacy
Incidence of confirmed COVID-19 through the entire study 
follow-up period in participants who received BNT162b2 at the 
booster vaccination
Incidence rates (per 1000 person-years of follow-up) and 2-sided 95%
CIs based on Poisson distribution for confirmed COVID-19 illness from 
7 days after the booster dose will be provided for participants who 
received BNT162b2 at initial randomization and subsequently, 
respectively.
10.7.9.4. Interim Analyses
In this substudy, interim efficacy analyses were originally planned to be performed every 
2 months by an unblinded statistical team to inform the timing of administration of 
BNT162b2 to those originally assigned to placebo. This substudy has been unblinded after 
the first interim analysis as informed by the outcome of the analysis; follow-up interim 
analyses are no longer applicable. The first interim analysis was performed after all 
participants reach 2 months of blinded follow-up. The final efficacy analyses to assess the 
primary and secondary efficacy objectives are planned to be conducted using complete 
blinded follow-up period data.
At each interim analysis, the following 2 estimates of VE will be obtained: (1) VE of the 
BNT162b2 booster group to the nonbooster group (placebo), which is the primary estimand 
defined for this substudy and directly estimable using the data observed in this substudy, and 
(2) VE of the nonbooster group (who received a primary series of 2 doses of BNT162b2 
approximately 6 months prior to enrollment in this study and did not receive the BNT162b2 
booster) relative to an unvaccinated population (never received a BNT162b2 primary series, 
not observable in this study). These estimates will be obtained using the following 
derivations.
Let 12 be the VE of the BNT162b2 booster group relative to the nonbooster group, 1 be 
the VE of the BNT162b2 booster group relative to an unvaccinated population, 2 be the 
VE of the nonbooster group relative to an unvaccinated population, 1 be the incidence rate 
of COVID-19 illness in the BNT162b2 booster group, 2 be the incidence rate of 
COVID-19 illness in the placebo booster group, and 0 be the nonobservable incidence rate 
in the unvaccinated population;
(1) 12 can be estimated by observed 1 and 2 in the study as 12 = 1 −

1

2;
Since 1 = 1 −

1

0 ,  2 = 1 −

2

0, 

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(2) 2 can then be estimated by observed 1 and 2 in the study and an assumed 1 as
2 = 1 −

2(11)

1
.
Although 1 is also not observable from the study, it is expected that VE after the booster 
dose will be similar to that after the first 2 vaccine doses. Based on the results of the updated 
efficacy analyses from Study C4591001, the VE from 7 days to 2 months, from 2 to 
4 months, and from 4 to 6 months after Dose 2 were approximately 96%, 90%, and 84%, 
respectively. After 6 months, a 6% drop in VE every 2 months will be assumed. These 
assumed values of 1 will be used to estimate 2 at the interim analyses.
If the point estimate of 2 (nonbooster group relative to unvaccinated population) in a 
2-month interval (ie, 7 days to 2 months, 2 to 4 months, etc.) at the interim analysis is <60%, 
the study will be unblinded and the placebo group participants may receive BNT162b2 
earlier than approximately 175 days after the vaccination at Visit 1. If 2 remains ≥60% at 
the interim analyses, all participants may remain blinded in the study and placebo recipients 
may not be offered BNT162b2 booster until the 12-month visit. In addition, the placebo 
group participants may not receive BNT162b2 as part of the study if 2 is ≥60% at the final 
analysis.
10.7.9.4.1. Analysis Timing
Statistical analyses will be carried out when the following data are available:

Interim efficacy analyses after all participants reach 2 months of blinded follow-up;

Efficacy and safety analysis at the end of the study.

Additional analyses may be conducted if required for regulatory purposes.
10.7.9.4.2. Data Monitoring Committee or Other Independent Oversight Committee
This substudy will use a DMC.  The DMC is independent of the study team and includes
only external members.  The DMC charter describes the role of the DMC in more detail.
The DMC will be responsible for ongoing monitoring of the safety of participants in the 
study according to the charter. This may include, but is not limited to:

Contemporaneous review of related AEs up to 1 month after the booster vaccination

Contemporaneous review of all SAEs up to 6 months after the booster vaccination

At the time of the planned interim analyses, and ad hoc if requested by the unblinded 
team, review of COVID-19 cases for an adverse imbalance of COVID-19 cases and/or 
severe COVID-19 cases between the vaccine and placebo groups

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The recommendations made by the DMC to alter the conduct of the study will be forwarded 
to the appropriate Pfizer personnel for final decision.  Pfizer will forward such decisions, 
which may include summaries of aggregate analyses of safety data, to regulatory authorities, 
as appropriate.
10.7.9.5. Sample Size Determination
The sample size of the study is determined to accrue sufficient COVID-19 cases for the VE 
assessment. Assuming a 15% nonevaluable rate, with 10,000 participants randomized in a 
1:1 ratio to receive BNT162b2 booster or placebo, there will be approximately 4250 
evaluable participants in each group. Table 5 presents assumptions of VE at various time 
intervals after the booster dose and the expected number of COVID-19 cases within each 
time interval with 4250 evaluable participants in each group. If the underlying incidence rate
in the unvaccinated population is 0.14 per person-year follow-up, the study will accrue 
approximately 127 cases in 6 months. If, due to vaccination rollout and other public health 
measures, the incidence rate drops by 50%, approximately 63 cases are expected to be 
accrued in 6 months.
Table 5. Expected Number of COVID-19 Cases Under Assumed Vaccine Efficacy and 
Incidence Rate
Follow-Up Time 
Postbooster
Assumed VE
Expected Number of Cases With 4250 Evaluable 
Participants Per Group
VE1
VE2
VE12
IR0 = 0.14/pyr
IR0 = 0.07/pyr
Boosted
Nonboosted
Boosted
Nonboosted
7 Days to 2 months
96%
72%
85.7%
3
24
2
12
2 to 4 Months
90%
66%
70.6%
10
34
5
17
4 to 6 Months
84%
60%
60.0%
16
40
8
20
7 Days to 4 months
92.8%
68.8%
76.9%
13
58
7
29
7 Days to 6 months
89.8%
65.8%
70.2%
29
98
15
49
Abbreviations: IR0 = assumed underlying incidence rate in unvaccinated population. The observed incidence rate 
in placebo group of study C4591001 was 0.14 per person-year follow-up; pyr = person-years; 
VE1 = vaccine efficacy of BNT162b2 booster group relative to unvaccinated population, assumed to be similar to 
the vaccine efficacy after the primary vaccination series observed in Study C4591001; 
VE2 = vaccine efficacy of nonbooster group relative to unvaccinated population, assumed to have 6% drop every 
2 months after the primary vaccination series and the average time after primary vaccination series at study entry is 
approximately 8 months for participants enrolled in this substudy; 
VE12 = vaccine efficacy of BNT162b2 booster group to nonbooster group, calculated by VE12=1-(1-VE1)/(1-VE2).

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Table 6 shows the probability to show the lower limit of the 95% CI for VE >30% for a 
given number of cases observed in the study under various assumed values of VE. For 
example, if the VE of the booster group relative to the nonbooster group is 70% over 
6 months of blinded follow-up, 70 cases will provide 88.9% probability to show that the 
lower limit of the 95% CI for VE is >30%.
Table 6.
Probability for Vaccine Efficacy Assessment
Assumed True 
VE
Probability to Show Lower Limit of 95% CI for VE >30% With Given Total Number 
of Cases
30 cases
50 cases
70 cases
90 cases
110 cases
60%
0.204
0.411
0.560
0.666
0.744
65%
0.306
0.579
0.743
0.842
0.902
70%
0.443
0.750
0.889
0.950
0.978
75%
0.607
0.889
0.970
0.992
0.998
80%
0.777
0.969
0.996
>0.999
>0.999
For safety outcomes, Table 7 shows the probability of observing at least 1 AE for a given 
true event rate of a particular AE. For example, if the true AE rate is 0.1%, with 
5000 participants in a vaccine group, there is 99% probability of observing at least 1 AE.
Table 7.
Probability of Observing at Least 1 AE by Assumed True Event Rates 
Sample Size (N)
Assumed True Event Rate of an AE
0.01%
0.05%
0.1%
0.2%
0.5%
1%
2%
5%
5000
0.39
0.92
0.99
>0.99
>0.99
>0.99
>0.99
>0.99

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10.8. Appendix 8: Substudy B
10.8.1. Substudy Summary
10.8.1.1. Synopsis
See Section 1.1 for a synopsis of Substudy B.
10.8.1.2. Schema
Visit Number
201
202
203
204
205
Visit 
Description
Vaccination 1
4-Day 
Follow-Up 
Visit (After 
Vaccination 
1)
Vaccination 2
4-Day 
Follow-Up 
Visit (After 
Vaccination 
2)
1-Month  
Follow-Up 
Visit (After 
Vaccination 
2)
Participants having 
received 2 or 3 prior 
doses of 30 µg 
BNT162b2, with their 
last dose at least 
4 months (120 days)
prior to randomization
Sequence 1
(n=750)
BNT162b2
Placebo
Sequence 2
(n=750)
Placebo
BNT162b2
Blood draw
10 mL
10 mL
10 mL
10 mL
10 mL

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10.8.1.3. Schedule of Activities for Substudy B
Visit Number
201
202
203
204
205
Visit Description
Vaccination 1
4-Day Follow-
Up Visit (After 
Vaccination 1)
Vaccination 2
4-Day Follow-Up 
Visit (After 
Vaccination 2)
1-Month Follow-Up 
Visit (After 
Vaccination 2)
Visit Window
Day 1a
2-5 Days After 
Visit 201
28-35 Days After 
Visit 201
2-5 Days After Visit 
203
28-35 Days After 
Visit 203
Confirm that the participant has received 2 or 3 prior doses of 
BNT162b2, with their last dose at least 4 months (120 days) 
prior to randomization; secondary confirmation by another site 
staff member is required
X
Obtain informed consent/assentb
X
Obtain the participant’s prior study and participant number 
(if applicable)
X
Assign participant number 
X
Obtain demography and medical history data
X
Perform clinical assessmentc
X
For participants who are HIV-positive, record latest CD4 count 
and HIV viral load
X
X
X
Measure height and weight
X
Measure temperature (body)
X
X
Perform urine pregnancy test (if appropriate)
X
X
Confirm use of contraceptives (if appropriate)
X
X
X
X
Collect nonstudy vaccine information 
X
X
X
X
X
Collect prohibited medication use
X
X
X
X
Confirm eligibility
X
X
Review temporary delay criteria
X
X
Collect blood sample 
~10 mL
~10 mL
~10 mL
~10 mL
~10 mL
Obtain randomization number 
X
Obtain study intervention allocation
X
X
Administer study intervention
X
X
Assess acute reactions for at least 30 minutes after study 
intervention administration
X
X

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Visit Number
201
202
203
204
205
Visit Description
Vaccination 1
4-Day Follow-
Up Visit (After 
Vaccination 1)
Vaccination 2
4-Day Follow-Up 
Visit (After 
Vaccination 2)
1-Month Follow-Up 
Visit (After 
Vaccination 2)
Visit Window
Day 1a
2-5 Days After 
Visit 201
28-35 Days After 
Visit 201
2-5 Days After Visit 
203
28-35 Days After 
Visit 203
Explain/review participant communication methods (including 
for reactogenicity e-diary completion), assist the participant 
with downloading the app, or issue provisioned device, if 
required
X
X
Provide/ensure participant has a thermometer and measuring 
device
X
X
Review reactogenicity e-diary data (daily review is optimal 
during the active diary period of 7 days following each study 
intervention administration)
X 
X 
X 
X 
X
Review ongoing reactogenicity e-diary symptoms with 
participant and obtain and record stop dates
X
X
X
X
Collect the e-diary device or assist the participant to delete the 
application
X
Collect AEs and SAEs as appropriate
X
X
X
X
Xd
Contact the participant by telephone
Abbreviation: HIV = human immunodeficiency virus.
a.
The visit may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and exclusion criteria onwards must be conducted on the 
same day.
b.
For participants <18 years of age (at the time of consent), the parent(s)/legal guardian will provide signed informed consent.  Depending on the age of the 
participant and according to local requirements, participants will also be asked to provide assent as appropriate (verbal or written).
c.
Including, if indicated, a physical examination.
d.
Any AEs occurring up to 48 hours after the blood draw must be recorded (see Section 8.3.1).

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10.8.2. Introduction
10.8.2.1. Study Rationale
Very rare cases of myocarditis and pericarditis have been reported following vaccination 
with mRNA COVID-19 vaccines.  Typically, the cases have occurred more often in younger 
men after the second dose of the vaccine, and within 14 days after vaccination.  These events 
are generally mild, and individuals tend to recover within a short time following standard 
treatment and rest. However, the incidence of subclinical myocarditis and pericarditis prior 
to the presentation of overt clinical signs and symptoms is unknown. Therefore, this 
protocol’s Substudy B will assess the safety and tolerability of a single dose of BNT162b2 as 
compared to placebo control, through the potential analysis of serum troponin levels, in 
participants ≥12 and ≤30 years of age who have received 2 or 3 prior doses of BNT162b2 
(30-µg doses), with their last dose at least 4 months (120 days) prior to randomization.
10.8.2.2. Background
See Section 2.2 for the study background.
10.8.2.3. Benefit/Risk Assessment
No additional risks are identified for Substudy B beyond those detailed for the master study 
(see Section 2.3).
10.8.2.3.1. Benefit Assessment
Benefits to individual participants enrolled in Substudy B may be:

Receipt of a booster (third or fourth) dose of an efficacious or potentially efficacious 
COVID-19 vaccine that may convey a longer duration of protection during a global 
pandemic.

Contributing to research to help others in a time of global pandemic.

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10.8.3. Objectives, Estimands, and Endpoints
Objectives
Estimands
Endpoints
Primary Safety
Primary Safety
Primary Safety
To describe the frequency of 
elevated troponin I levels before
and after a booster dose of 
BNT162b2 or placebo
In participants receiving 1 dose of study 
intervention, the percentage of participants 
with elevated troponin I levels before and at 
subsequent time points after a booster dose 
of BNT162b2 or placebo

Troponin I level
To define the safety profile of a 
booster dose of BNT162b2
In participants receiving 1 dose of study 
intervention, the percentage of participants 
reporting:

Local reactions for up to 7 days 
following each vaccination

Systemic events for up to 7 days 
following each vaccination

AEs within 1 month after each 
vaccination

SAEs within 1 month after each 
vaccination

Local reactions (pain 
at the injection site, 
redness, and 
swelling)

Systemic events 
(fever, 
fatigue/tiredness, 
headache, chills, 
vomiting, diarrhea, 
new or worsened 
muscle pain, and 
new or worsened 
joint pain)

AEs

SAEs
10.8.4. Study Design
10.8.4.1. Overall Design
This is a randomized, placebo-controlled, observer-blind, crossover substudy to evaluate the 
safety and tolerability of a booster (third or fourth) dose of BNT162b2.  Participants 
≥12 years of age to ≤30 years of age who have received 2 or 3 prior doses of BNT162b2 
(30-µg doses), with their last dose at least 4 months (120 days) prior to randomization, will 
be enrolled. Participants will be randomized at a ratio of 1:1 to receive either BNT162b2 or 
placebo at Visit 201 and the alternative at Visit 203, four weeks later. Randomization will be 
stratified by age (stratified as 12-17, 18-24, and 25-30 years of age). Approximately 
1500 participants will be randomized in the study.  A blood sample will be collected to 
obtain a serum sample for troponin testing before each administration of blinded study 
intervention, 2 to 5 days after each administration, and 1 month after the second 
administration.
10.8.4.2. Scientific Rationale for Substudy B Design
See Section 10.8.2.1.
10.8.4.2.1. Diversity of Study Population
Reasonable attempts will be made to enroll participants who align with the US population 
distribution (Census-based), to ensure that the study population is representative of patient 
populations that will benefit from a COVID-19 vaccine in clinical practice.

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10.8.4.3. Justification for Dose
See Section 4.3 for a justification of the BNT162b2 dose used in Substudy B.
10.8.4.4. End of Study Definition
See Section 4.4.
10.8.5. Study Population
Details of the master eligibility criteria are shown in Section 5. Participants must meet all of 
the general inclusion and exclusion criteria as specified for both the master protocol and 
Substudy B–specific inclusion and exclusion criteria.
10.8.5.1. Inclusion Criteria
Participants are eligible to be included in Substudy B only if all of the following criteria 
apply:
Age and Sex:
1. Male or female participants 12 to 30 years of age, inclusive, who have received 2 or 3 
prior doses of 30 µg BNT162b2 (with the first 2 doses 19 to 60 days apart), with the last
dose being at least 4 months (120 days) before Visit 1 (Day 1).
Documented confirmation of prior BNT162b2 receipt must be obtained prior to 
randomization.
Refer to Appendix 4 for reproductive criteria for male Section 10.4.1 and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2.
Participants who are willing and able to comply with all scheduled visits, vaccination 
plan, laboratory tests, lifestyle considerations, and other study procedures.
3.
Healthy participants who are determined by medical history, physical examination
(if required), and clinical judgment of the investigator to be eligible for inclusion in the 
study.
Note: Healthy participants with preexisting stable disease, defined as disease not 
requiring significant change in therapy or hospitalization for worsening disease during 
the 6 weeks before enrollment, can be included.  Specific criteria for participants with 
known stable infection with HIV, HCV, or HBV can be found in Section 10.15.

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Informed Consent:
4.
Capable of giving personal signed informed consent/assent, have parent(s)/legal 
guardian capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in this 
protocol.
The investigator, or a person designated by the investigator, will obtain 
written/electronically signed informed consent (and assent) from each study participant’s 
legal guardian (as defined in Appendix 1), and the participant’s assent, when applicable,
before any study-specific activity is performed, unless a waiver of informed consent has 
been granted by an IRB/EC. All legal guardians should be fully informed, and 
participants should be informed to the fullest extent possible, about the study in language 
and terms they are able to understand. The investigator will retain the original copy of 
each participant’s signed consent/assent document.
10.8.5.2. Exclusion Criteria
Participants are excluded from Substudy B if any of the following criteria apply:
Medical Conditions:
1. Other medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for 
the study.
2. History of severe adverse reaction associated with a vaccine and/or severe allergic 
reaction (eg, anaphylaxis) to any component of the study intervention(s).
3. 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.
4. Immunocompromised individuals with known or suspected immunodeficiency, as 
determined by history and/or laboratory/physical examination.
5. Bleeding diathesis or condition associated with prolonged bleeding that would, in the 
opinion of the investigator, contraindicate intramuscular injection.
6. Women who are pregnant or breastfeeding.
Prior/Concomitant Therapy:
7. Individuals who receive treatment with radiotherapy or immunosuppressive therapy, 
including cytotoxic agents or systemic corticosteroids (if systemic corticosteroids are 
administered for ≥14 days at a dose of ≥20 mg/day of prednisone or equivalent), eg, for 
cancer or an autoimmune disease, or planned receipt throughout the study.

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Inhaled/nebulized, intra-articular, intrabursal, or topical (skin or eyes) corticosteroids are 
permitted.
8. Receipt of blood/plasma products, immunoglobulin, or monoclonal antibodies, from 
60 days before study intervention administration, or receipt of any passive antibody 
therapy specific to COVID-19, from 90 days before study intervention administration, or 
planned receipt throughout the study.
Prior/Concurrent Clinical Study Experience:
9. Prior receipt of any COVID-19 vaccine other than BNT162b2.
Other Exclusions:
10. Investigator site staff or Pfizer-BioNTech employees directly involved in the conduct of 
the study, site staff otherwise supervised by the investigator, and their respective family 
members.
11. Receipt of medications intended to prevent COVID-19.
12. Prior receipt of more than 3 doses of BNT162b2 30 µg.
13. Participation in other studies involving study intervention within 28 days prior to study 
entry through and including 28 days after the last dose of study intervention, with the 
exception of non-Pfizer interventional studies for prevention of COVID-19, which are 
prohibited throughout study participation.
10.8.5.3. Lifestyle Considerations
Contraception requirements will apply to Substudy B as detailed in Section 5.3 and
Section 10.4.
10.8.5.4. Screen Failures
See Section 5.4.
10.8.5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Administration 
of Study Intervention
See Section 5.5.
10.8.6. Study Intervention(s) and Concomitant Therapy
For the purposes of this substudy, study intervention refers to:

BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S): 
30 µg

Normal saline (0.9% sodium chloride solution for injection)

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10.8.6.1. Study Intervention(s) Administered
See Section 6.1 for details of BNT162b2.
Additional Intervention 
Name
Saline Placebo
Type
Placebo
Dose Formulation
Normal saline (0.9% sodium chloride solution for injection)
Unit Dose Strength(s)
N/A
Dosage Level(s) 
N/A
Route of Administration
Intramuscular injection
Use
Placebo
IMP or NIMP
IMP
Sourcing
Provided centrally by the sponsor
Packaging and Labeling
Study intervention will be provided in a glass or plastic vial as open-label 
supply.  Each vial will be labeled as required per country requirement
10.8.6.1.1. Administration
Participants will receive 1 dose of study intervention at Visit 201 (Vaccination 1) and 
Visit 203 (Vaccination 2) in accordance with the substudy’s SoA (Section 10.8.1.3).
Study intervention should be administered intramuscularly into the deltoid muscle, preferably 
of the nondominant arm, by an unblinded administrator.
10.8.6.1.2. Preparation and Dispensing
Study intervention will be prepared by qualified unblinded site personnel according to the IP 
manual.  The study intervention will be administered in such a way as to ensure that the 
participants remain blinded.
10.8.6.2. Measures to Minimize Bias: Randomization and Blinding
10.8.6.2.1. Blinding of Site Personnel
In this observer-blinded substudy, the study staff receiving, storing, dispensing, preparing, 
and administering the study interventions will be unblinded.  All other study and site 
personnel, including the investigator, investigator staff, and participants, will be blinded to 
study intervention assignments.  In particular, the individuals who evaluate participant safety 
will be blinded.  Because there are differences in physical appearance of the study 
interventions, the study intervention will be administered in a manner that prevents the study 
participants from identifying the study intervention sequence based on its appearance.
The PI will assign the responsibility of the unblinded dispensers/administrators to persons 
who will not participate in the evaluation of any study participant.  To ensure adequate 
coverage, at least 2 unblinded dispensers/administrators will be assigned per site.  Members 
of the study site staff or clinic pharmacy should fulfill these roles.  Contact between the 

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unblinded dispensers and study participants should be kept to a minimum.  The investigator, 
study coordinator, and any site staff other than the unblinded dispensers/administrators must 
not be allowed to know the study intervention assigned to any study participant and must not 
be allowed to see the study intervention container contents.  In the event of a Quality 
Assurance audit, the auditor(s) will be allowed access to unblinded study intervention records 
at the site(s) to verify that randomization/dispensing has been done accurately.
10.8.6.2.2. Blinding of the Sponsor
The majority of sponsor/Pfizer staff will be blinded to study intervention allocation.  All 
laboratory testing personnel performing serology assays will remain blinded to study 
intervention assigned/received throughout the study.  The following sponsor/Pfizer staff, who 
will have no part in the blinded conduct of the study, will be unblinded (further details will 
be provided in a data blinding plan):

Those study team members who are involved in ensuring that protocol requirements for 
study intervention preparation, handling, allocation, and administration are fulfilled at the 
site will be unblinded for the duration of the study (eg, unblinded study manager, 
unblinded clinical research associate).

Unblinded clinician(s), who are not direct members of the study team and will not 
participate in any other study-related activities, will review unblinded protocol 
deviations.

An unblinded team supporting interactions with, and analyses for, the DMC (see
Section 10.8.9.4.1).  This team comprises a statistician, programmer(s), a clinical 
scientist, and a medical monitor.
The participant may be unblinded at Visit 205, 1 month after receiving their second study 
vaccination, to confirm the date of BNT162b2 receipt.  The study team will also become 
unblinded to the participant’s original study intervention allocation at this time.
10.8.6.2.3. Breaking the Blind
The IRT will be programmed with blind-breaking instructions.  In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s study 
intervention assignment is warranted.  Participant safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the sponsor prior to 
unblinding a participant’s vaccine assignment unless this could delay further management of 
the participant.  If a participant’s vaccine assignment is unblinded, the sponsor must be 
notified within 24 hours after breaking the blind.  The date and reason that the blind was 
broken must be recorded in the source documentation and CRF.
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.

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10.8.6.3. Study Intervention Compliance
See Section 6.4.
10.8.6.4. Dose Modification
See Section 6.5.
10.8.6.5. Continued Access to Study Intervention After the End of the Study
See Section 6.6.
10.8.6.6. Treatment of Overdose
See Section 6.7.
10.8.6.7. Concomitant Therapy
See Section 6.8.
10.8.7. Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
See Section 7.
10.8.8. Study Assessments and Procedures
The total blood sampling volume for individual participants in this study is up to 
approximately 50 mL.
For all participants, other additional blood samples may be taken for safety assessments at 
times specified by Pfizer, provided the total volume taken during the study does not exceed 
550 mL during any period of 60 consecutive days.
10.8.8.1. Safety Assessments
See Section 8.2.
10.8.8.2. Adverse Events, Serious Adverse Events, and Other Safety Reporting
See Section 8.3.
10.8.8.3. Substudy B Procedures
10.8.8.3.1. Visit 201 – Vaccination (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written, 
study-specific informed consent will be obtained from the participant or his/her 
parent(s)/legal guardian, as appropriate.  Each signature on the ICD must be personally dated 
by the signatory.  The investigator or his or her designee will also sign the ICD.  A copy of 
the signed and dated ICD must be given to the participant/participant’s parent(s)/legal 
guardian.  The source data must reflect that the informed consent was obtained before 
participation in the study.

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It is anticipated that the procedures below will be conducted in a stepwise manner.  The visit 
may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and 
exclusion criteria onwards must be conducted on the same day.

Confirm that the participant has received 2 or 3 prior doses of BNT162b2 (30-µg doses)
with their last dose at least 4 months (120 days) prior to randomization. Secondary
confirmation by another site staff member is required.

Assign a single participant number using the IRT system.

Obtain the participant’s prior study and participant number (if applicable) and record this 
in the CRF.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).  
The full date of birth will be collected to critically evaluate the immune response and 
safety profile by age.

Obtain any medical history of clinical significance.  For participants who are 
HIV-positive, record HIV viral load and CD4 count results from the most recent test 
performed in the previous 6 months.

Perform a clinical assessment.  If the clinical assessment indicates that a physical 
examination is necessary to comprehensively evaluate the participant, perform a physical 
examination and record any findings in the source documents and, if clinically 
significant, record any findings on the medical history CRF.

Measure the participant’s height and weight.

Measure the participant’s body temperature.

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 5.3.

Record nonstudy vaccinations as described in Section 6.8.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Record AEs as described in Section 8.3.

Collect a blood sample (approximately 10 mL) for troponin levels.

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
Blinded site staff will obtain the participant’s randomization number using the IRT 
system. The randomization confirmation report with the study intervention allocation will 
only be sent to the unblinded site staff member. 

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into 
the deltoid muscle of the preferably nondominant arm.  Please refer to the IP manual for 
further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study 
intervention administration for any acute reactions.  Record any acute reactions 
(including time of onset) in the participant’s source documents and on the AE page of the 
CRF, and on an SAE form as applicable.

Explain the e-diary technologies available for this study (see Section 8.2.4), and assist the 
participant or his/her parent(s)/legal guardian(s), as appropriate, in downloading the study 
application onto his or her own device or issue a provisioned device if required.

Provide instructions on reactogenicity e-diary completion and ask the participant or 
his/her parent(s)/legal guardian to complete the reactogenicity e-diary from Day 1 
through Day 7, with Day 1 being the day of vaccination.

Ask the participant or his/her parent(s)/legal guardian to contact the site staff or 
investigator immediately if the participant experiences any of the following from Day 1 
through Day 7 after vaccination (where Day 1 is the day of vaccination) to determine if 
an unscheduled reactogenicity visit is required: 

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units).

Severe pain at the injection site.

Any severe systemic event.

Provide a measuring device to measure local reactions at the injection site and a 
thermometer for recording daily temperatures and provide instructions on their use.

Review reactogenicity e-diary data (daily review is optimal during the active diary period 
of 7 days following each study intervention administration).

Ask the participant or his/her parent(s)/legal guardian to contact the site staff or 
investigator if the participant experiences acute chest pain, shortness of breath, or 
palpitations (see Section 10.8.8.3.6).

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
Ask the participant or his/her parent(s)/legal guardian(s), as appropriate, to contact the 
site staff or investigator if a medically attended event (eg, doctor’s visit, emergency room 
visit) or hospitalization occurs.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant or his/her parent(s)/legal guardian to bring the reactogenicity 
e-diary to the next visit. Complete the source documents.

The investigator or an authorized designee completes the CRFs and an unblinded 
dispenser/administrator updates the study intervention accountability records.
10.8.8.3.2. Visit 202 – 4-Day Follow-Up Visit (After Vaccination 1) (2-5 Days After 
Visit 201)

Record AEs as described in Section 8.3.

Review reactogenicity e-diary data (daily review is optimal during the active diary period 
of 7 days following each study intervention administration).

Review ongoing reactogenicity e-diary symptoms with the participant and obtain and 
record stop dates.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8 received by 
the participant if required for his or her clinical care.

Collect a blood sample (approximately 10 mL) for troponin levels.

Discuss contraceptive use as described in Section 5.3.

Ask the participant or his/her parent(s)/legal guardian to contact the site staff or 
investigator if the participant experiences acute chest pain, shortness of breath, or 
palpitations (see Section 10.8.8.3.6).

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator if a medically attended event (eg, doctor’s visit, emergency room 
visit) or hospitalization occurs.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant or his/her parent(s)/legal guardian to bring the reactogenicity 
e-diary to the next visit. Complete the source documents.

The investigator or an authorized designee completes the CRFs.

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10.8.8.3.3. Visit 203 – Vaccination 2 (28 to 35 Days After Visit 201)

Record AEs as described in Section 8.3.

Review reactogenicity e-diary data (daily review is optimal during the active diary period 
of 7 days following each study intervention administration).

Review ongoing reactogenicity e-diary symptoms with the participant and obtain and 
record stop dates.

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since Visit 201 (if any).

Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met.
Note: a positive SARS-CoV-2 NAAT result without symptoms or a COVID-19 diagnosis 
(based on signs/symptoms only or signs/symptoms and a positive SARS-CoV-2 NAAT 
result) should not result in discontinuation of study intervention.  Please see Section 7.1.

Measure the participant’s body temperature.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Collect a blood sample (approximately 10 mL) for troponin levels.

Unblinded site staff will obtain the participant’s study intervention allocation using the 
IRT system.

Unblinded site staff will administer 1 dose of study intervention into the deltoid muscle 
of the preferably nondominant arm.  Please refer to the IP manual for further instruction 
on this process.

Blinded site staff must observe the participant for at least 30 minutes after study 
intervention administration for any acute reactions.  Record any acute reactions 
(including time of onset) in the participant’s source documents and on the AE page of the 
CRF, and on an SAE form as applicable.

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
Ensure that the participant or his/her parent(s)/legal guardian has a measuring device to 
measure local reactions at the injection site and a thermometer for recording daily 
temperatures.

Ensure that the participant or his/her parent(s)/legal guardian remains comfortable with 
the chosen e-diary platform, confirm instructions on e-diary completion, and ask the 
participant to complete the reactogenicity e-diary from Day 1 through Day 7, with Day 1 
being the day of vaccination.

Discuss contraceptive use as described in Section 5.3.

Ask the participant or his/her parent(s)/legal guardian to contact the site staff or 
investigator if the participant experiences acute chest pain, shortness of breath, or 
palpitations (see Section 10.8.8.3.6).

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator if a medically attended event (eg, doctor’s visit, emergency room 
visit) or hospitalization occurs.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant or his/her parent(s)/legal guardian to bring the reactogenicity 
e-diary to the next visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs and an unblinded 
dispenser/administrator updates the study intervention accountability records.
10.8.8.3.4. Visit 204 – 4-Day Follow-Up Visit (After Vaccination 2) (2 to 5 Days After 
Visit 203)

Record AEs as described in Section 8.3.

Review reactogenicity e-diary data (daily review is optimal during the active diary period 
of 7 days following each study intervention administration).

Review ongoing reactogenicity e-diary symptoms with the participant and obtain and 
record stop dates.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8 received by 
the participant if required for his or her clinical care.

Collect a blood sample (approximately 10 mL) for troponin levels.

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
Discuss contraceptive use as described in Section 5.3.

Ask the participant or his/her parent(s)/legal guardian to contact the site staff or 
investigator if the participant experiences acute chest pain, shortness of breath, or 
palpitations (see Section 10.8.8.3.6).

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator if a medically attended event (eg, doctor’s visit, emergency room 
visit) or hospitalization occurs.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant or his/her parent(s)/legal guardian to bring the reactogenicity 
e-diary to the next visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
10.8.8.3.5. Visit 205 – 1-Month Follow-Up Visit (After Vaccination 2) (28-35 Days After 
Visit 203)

Record AEs as described in Section 8.3.

Review reactogenicity e-diary data (daily review is optimal during the active diary period 
of 7 days following each study intervention administration).

Review ongoing reactogenicity e-diary symptoms with the participant and obtain and 
record stop dates.

Record details of any of the prohibited medications specified in Section 6.8 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since Visit 203 (if any).Collect a blood sample 
(approximately 10 mL) for troponin levels.

Collect the participant’s e-diary or assist the participant or his/her parent(s)/legal 
guardian in removing the study application from his or her own personal device.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3.

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
The participant may be unblinded at Visit 205, 1 month after receiving their second study 
vaccination, to confirm the date of BNT162b2 receipt.  The study team will also become 
unblinded to the participant’s original study intervention allocation at this time.
10.8.8.3.6. Additional Procedures for Monitoring of Potential Myocarditis or 
Pericarditis
Any study participant who reports acute chest pain, shortness of breath, palpitations, or any 
other symptom(s) that might be indicative of myocarditis or pericarditis within 4 weeks after 
a study vaccination should be specifically evaluated, preferably by a cardiologist, for possible 
myocarditis or pericarditis.
In addition to a clinical evaluation, the following should be performed:

ECG and

Measurement of the troponin level (Results from the blood samples collected during the 
study will be provided to the participant’s study physician; however, this will take some 
time, so the participant should be cautioned not to rely on these results for medical 
treatment.)
If myocarditis or pericarditis is suspected based upon the initial evaluation, the following 
should also be performed:

Cardiac echocardiogram and/or

Cardiac magnetic resonance study
Details of the symptoms reported, and results of the investigations performed, will be 
recorded in the CRF.
10.8.8.3.7. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction
If a Grade 3 local reaction (Section 8.2.4.2), systemic event (Section 8.2.4.3), or fever 
(Section 8.2.4.4) is reported in the reactogenicity e-diary, a telephone contact should occur to 
ascertain further details and determine whether a site visit is clinically indicated. If a
suspected Grade 4 local reaction (Section 8.2.4.2), systemic event (Section 8.2.4.3), or fever 
(Section 8.2.4.4) is reported in the reactogenicity e-diary, a telephone contact or site visit 
should occur to confirm whether the event meets the criteria for Grade 4.
A site visit must be scheduled as soon as possible to assess the participant unless any of the 
following is true:

The participant is unable to attend the unscheduled visit.

The local reaction/systemic event is no longer present at the time of the telephone 
contact.

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
The participant or his/her parent(s)/legal guardian, as appropriate, recorded an incorrect 
value in the reactogenicity e-diary (confirmation of a reactogenicity e-diary data entry 
error).

The PI or authorized designee determined it was not needed.
This telephone contact will be recorded in the participant’s source documentation and the 
CRF.
If the participant is unable to attend the unscheduled visit, or the PI or authorized designee 
determined it was not needed, any ongoing local reactions/systemic events must be assessed 
at the next study visit.
During the unscheduled visit, the reactions should be assessed by the investigator or a 
medically qualified member of the study staff such as a study physician or a study nurse, as 
applicable to the investigator’s local practice, who will:

Measure body temperature (°F/°C).

Measure minimum and maximum diameters of redness (if present).

Measure minimum and maximum diameters of swelling (if present).

Assess injection site pain (if present) in accordance with the grades provided in
Section 8.2.4.2.

Assess systemic events (if present) in accordance with the grades provided in
Section 8.2.4.3.

Assess for other findings associated with the reaction and record on the AE page of the 
CRF, if appropriate.
The investigator or an authorized designee will complete the unscheduled visit assessment 
page of the CRF.
10.8.9. Statistical Considerations for Substudy B
See Section 9 for master protocol statistical considerations and substudy specifics below.
10.8.9.1. Statistical Hypotheses
10.8.9.1.1. Estimands
The estimands corresponding to the primary objectives are described in the table in
Section 10.8.3.
In the primary safety objective evaluations, missing AE start dates will be imputed according 
to Pfizer safety rules.  No other missing information will be imputed in the safety analysis.

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10.8.9.1.2. Statistical Hypotheses
All objectives in this substudy are descriptive.  No hypothesis testing is planned.
10.8.9.1.3. Multiplicity Adjustment
No multiplicity adjustment is needed for the study as there is no statistical hypothesis.
10.8.9.2. Analysis Sets
For the purpose of analysis, the following analysis sets are defined for this substudy:
Population
Description
Enrolled
All participants who have a signed ICD.
Randomized
All participants who are assigned a randomization number in the 
IWR system.
Safety
All participants who receive at least 1 dose of the study 
intervention.
10.8.9.3. Statistical Analyses
The SAP will be developed and finalized for this substudy before any analyses are performed
and will describe the analyses and procedures for missing, unused, and spurious data.  This 
section is a summary of the planned statistical analyses of the primary endpoints.
10.8.9.3.1. General Considerations
All safety data will be analyzed separately for each age group (12-17, 18-24, and 25-30 years 
of age) and for all age groups combined.
Refer to Section 9.3.1 for general considerations of statistical analyses.
10.8.9.3.2. Primary Endpoint(s)/Estimand(s) Analysis
Endpoint
Statistical Analysis Methods
Safety
Counts and percentages of participants with elevated troponin I levels
before and 4 days and 1 month after administration of BNT162b2 or
placebo will be provided for Sequence 1 and Sequence 2 combined.
The associated Clopper-Pearson 95% CIs will also be provided
(Section 9.3.1.1).
The difference in percentages of participants with elevated troponin I 
levels between BNT162b2 and placebo will be provided at each time
point after vaccination (4 days after BNT162b2 minus 4 days after 
placebo, or 1 month after BNT162b2 minus 1 month after placebo)
combining Sequence 1 and Sequence 2. This analysis will be limited to
participants with troponin I level measurements at both time points. The 

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Endpoint
Statistical Analysis Methods
2-sided 95% CI for the difference in percentages will be calculated 
using the adjusted Wald interval as described by Agresti and Min 
(2005)43 for comparing matched proportions. The difference in 
percentages of participants with elevated troponin I levels between 
before and after each vaccination (ie, 4 days after BNT162b2 minus 
before BNT162b2, 4 days after placebo minus before placebo) and 
associated 95% CI will be summarized in a similar way. Additional 
assessment based on the crossover design feature may be performed and 
details will be described in the SAP.
In addition, percentages of participants with elevated troponin I levels
before and at subsequent time points after each vaccination will be 
summarized for Sequence 1 and Sequence 2 separately. 
Descriptive statistics will be provided for each reactogenicity endpoint 
after each vaccination for Sequence 1 and Sequence 2 separately. Local 
reactions and systemic events from Day 1 through Day 7 after each 
vaccination (where Day 1 is the day of vaccination) will be presented by 
severity and cumulatively across severity levels. Descriptive summary 
statistics will include counts and percentages of participants with the 
indicated endpoint and the associated Clopper-Pearson 95% CIs
(Section 9.3.1.1). 
Local reactions and systemic events within 7 days after BNT162b2 or 
placebo administration will also be summarized in a similar way for 
Sequence 1 and Sequence 2 combined. 
AEs and SAEs will be categorized according to MedDRA terms.  
Counts, percentages, and associated Clopper-Pearson 95% CIs of AEs
and SAEs within 1 month after each vaccination will be provided for 
Sequence 1 and Sequence 2 separately (Section 9.3.1.1).
AEs/SAEs will also be summarized within 1 month after BNT162b2 or 
placebo administration in a similar way for Sequence 1 and Sequence 2 
combined. 
10.8.9.3.3. Secondary Endpoint(s)/Estimand(s) Analysis
Not applicable.
10.8.9.3.4. Exploratory Endpoint(s)
Not applicable.

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10.8.9.4. Interim Analyses
No formal interim analysis will be conducted for this study. Only 1 analysis will be 
performed at the completion of the study.
10.8.9.4.1. Data Monitoring Committee or Other Independent Oversight Committee
This substudy will use a DMC.  The DMC is independent of the study team and includes
only external members.  The DMC charter describes the role of the DMC in more detail. The 
DMC will be responsible for ongoing monitoring of the safety data throughout the study 
according to the charter.
The recommendations made by the DMC will be forwarded to the appropriate Pfizer 
personnel for final decision.  Pfizer will forward such decisions, which may include 
summaries of aggregate analyses of safety data, to regulatory authorities, investigators as
appropriate.
10.8.9.5. Sample Size Determination
The study size is not based on any formal hypothesis test. All statistical analyses will be 
descriptive.
Table 8 shows the probability of observing at least 1 AE for a given true event rate of a 
particular AE, for various sample sizes based on anticipated enrollment in each age group 
and overall. For example, if the true AE rate is 0.10%, with 750 participants in each 
randomized sequence, there is 53% probability of observing at least 1 AE.
Table 8.
Probability of Observing at Least 1 AE by Assumed True Event Rates 
With Different Samples Sizes
Sample Size 
(N)
Assumed True Event Rate of an AE
0.01%
0.02%
0.05%
0.10%
0.50%
1.00%
2.00%
250
0.02
0.05
0.12
0.22
0.71
0.92
>0.99
500
0.05
0.10
0.22
0.39
0.92
>0.99
>0.99
750
0.07
0.14
0.31
0.53
0.98
>0.99
>0.99
1500
0.14
0.26
0.53
0.78
>0.99
>0.99
>0.99
Note: A total of 250 and 500 participants are to be enrolled in each age group within each randomized 
sequence and overall. A total of 750 and 1500 participants are to be enrolled for all age groups within 
each randomized sequence and overall. 

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10.9. Appendix 9: Substudy C
10.9.1. Substudy Summary
10.9.1.1. Synopsis
See Section 1.1 for a synopsis of Substudy C.
10.9.1.2. Schema
Visit Number
301
302
303
304
Visit Description
Booster (Third) 
Dose of BNT162b2
7 Days After 
Booster
Vaccination
1 Month 
After Booster 
Vaccination
6 Months After 
Booster 
Vaccination
Participants having 
received 2 prior 
doses of 30 µg 
BNT162b2 at least 
5 months (150 days)
prior to 
randomization
BNT162
10-µg OR 30-µg dose
Blood draw for 
immunogenicity
X
X
X
X

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10.9.1.3. Schedule of Activities for Substudy C
Visit Number
301
302
303
304
Visit Description
Booster (Third) Dose of 
BNT162b2
7 Days After Booster 
Vaccination
1 Month After Booster 
Vaccination
6 Months After Booster 
Vaccination
Visit Window
Day 1a
6-8 Days After Visit 301
28 to 35 Days After Visit 
301
175-189 Days After Visit 
301
Confirm the participant has only received 2 
doses of BNT162 at least 5 months (150 days)
prior to randomization.
X
Obtain informed consent/assent
X
Obtain the participant’s prior study and 
participant number (if applicable)
X
Assign participant number 
X
Obtain demography and medical history data
X
Perform clinical assessmentb
X
For participants who are HIV-positive, record 
latest CD4 count and HIV viral load
X
X
X
Measure height and weight
X
Measure temperature (body)
X
Perform urine pregnancy test (if appropriate)
X
Confirm use of contraceptives (if appropriate)
X
X
X
Collect nonstudy vaccine information 
X
X
X
Collect prohibited medication use
X
X
X
Confirm eligibility
X
Review temporary delay criteria
X
Collect blood sample for immunogenicityc
~10 mL
~10 mL
~10 mL
~10 mL
Obtain randomization number 
X
Obtain study intervention allocation
X
Administer study intervention
X
Assess acute reactions for at least 30 minutes 
after study intervention administration
X
Explain/review participant communication 
methods (including for reactogenicity e-diary 
completion), assist the participant with 
downloading the app, or issue provisioned 
device, if required
X
Provide/ensure participant has a thermometer 
and measuring device
X

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Visit Number
301
302
303
304
Visit Description
Booster (Third) Dose of 
BNT162b2
7 Days After Booster 
Vaccination
1 Month After Booster 
Vaccination
6 Months After Booster 
Vaccination
Visit Window
Day 1a
6-8 Days After Visit 301
28 to 35 Days After Visit 
301
175-189 Days After Visit 
301
Review reactogenicity e-diary data (daily 
review is optimal during the active diary period 
of 7 days following study intervention 
administration)
X 
X 
Review ongoing reactogenicity e-diary 
symptoms with participant and obtain stop 
dates
X
X
Request the participant return the e-diary or 
assist the participant to delete the application
X
Collect AEs and SAEs as appropriate
X
X
X
Xd
Abbreviation: HIV = human immunodeficiency virus.
a.
The visit may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and exclusion criteria onwards must be conducted on the 
same day.
b.
Including, if indicated, a physical examination.
c.
10 mL is to be collected from participants 12 to 17 years of age.
d.
Any AEs occurring up to 48 hours after the blood draw must be recorded (see Section 8.3.1).

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10.9.2. Introduction
10.9.2.1. Study Rationale
Substudy C will assess the safety, tolerability, and immunogenicity of a booster (third) dose 
of BNT162b2 at doses of 10 µg or 30 µg in participants who have completed a 2-dose 
primary series of BNT162b2 (30-µg doses) at least 5 months (150 days) prior to 
randomization. The primary immunogenicity objective of the study is to demonstrate that the 
immune response induced by a booster (third) dose of BNT162b2 at a 10-µg dose is 
noninferior to the immune response elicited 1 month after the second dose of BNT162b2 at
30 µg (ie, having completed a 2-dose primary series of BNT162b2 [30-µg doses]).
If this objective is successfully met, a lower dose level would allow for greater vaccine 
accessibility and equity – with more doses being available globally. A more favorable 
reactogenicity profile may also be demonstrated. Additionally, the results from 
306 participants 18 to 55 years of age from the C4591001 study who received a third 
(booster) dose of 30 µg BNT162b2 a median of 6.8 months after their second dose 
demonstrated a strong immune response with robust neutralizing antibody titers against the 
reference strain.20 Immunogenicity of the primary series in participants 12 to 15 of age was 
shown to be greater than in participants 16 to 25 years of age.21 Therefore, the assessment of
a 10-µg booster dose in individuals ≥12 years of age who have received the authorized 
30-µg 2-dose primary series warrants further investigation. Randomization will be stratified 
by age with escalation to each higher age group guided by immunogenicity results. This 
study contains assessments that could be considered standard for a vaccine noninferiority 
study. Blood samples taken for immunogenicity will establish the level of immune response 
elicited by each dose level to provide the necessary data to meet the primary endpoint of the 
study. Immunogenicity will be assessed by SARS-CoV-2 neutralizing titers.
As part of Protocol Amendment 11, progression beyond the 12 through 17 years age group 
will not occur and no further participants will be enrolled. Active participants at the time of 
this amendment will also only be followed for 6 months after their last study vaccination. 
Their final visit will be V304. The rationale for this amendment is that a third dose of 
COVID-19 vaccine has been recommended for all age groups for a considerable period of 
time (hence the potential substrate for enrollment is essentially non-existent) and, for 
Fall 2022, the recommended booster vaccine will switch to a bivalent original/Omicron-
modified vaccine. Both factors contribute to age escalation being operationally unfeasible. 
Furthermore, since the 30-µg dose level is well tolerated, and in the face of emergence of 
Omicron and its sublineages for which maximum immune response is desirable, the rationale 
for a reduced dose level no longer holds.
For participants who have already completed V304 at the time of protocol amendment 11,
they will be informed by the investigator site staff of study completion and that no further 
visits are required.
As part of protocol amendment 12, endpoints and/or analyses that do not pertain to current 
variant-modified versions of BNT162b2 were removed to expedite remaining testing and to 
focus on analyses of interest.

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See Section 2.2 for the study background.
10.9.2.2. Benefit/Risk Assessment
No additional risks are identified for Substudy C beyond those detailed for the master study 
(see Section 2.3).
10.9.2.2.1. Benefit Assessment
Benefits to individual participants enrolled in Substudy C may be:

Receipt of a booster dose of an efficacious or potentially efficacious COVID-19 vaccine 
that may convey a longer duration of protection during a global pandemic.

Receipt of a potentially efficacious booster dose with the potential of reduced 
reactogenicity.

Contributing to research to help others in a time of global pandemic.
10.9.3. Objectives, Estimands, and Endpoints
Objectives
Estimands
Endpoints
Primary Safety
Primary Safety
Primary Safety

To evaluate the safety of a booster 
dose of BNT162b2 when 
administered at both 10-µg and 
30-µg doses
In participants receiving at least 1 dose of study 
intervention from each vaccine group, the 
percentage of participants reporting:

Local reactions for up to 7 days following 
the booster dose

Systemic events for up to 7 days following 
the booster dose

AEs from the booster dose to 1 month after 
the booster dose

SAEs from the booster dose to 6 months 
after the booster dose

Local reactions (pain at 
the injection site, 
redness, and swelling)

Systemic events (fever, 
fatigue/tiredness, 
headache, chills, 
vomiting, diarrhea, new 
or worsened muscle pain, 
and new or worsened 
joint pain)

AEs

SAEs
Primary Immunogenicity
Primary Immunogenicity
Primary Immunogenicity
To describe the immune response to 
BNT162b2 10 µg and 30 µg given as 
the third dose in participants 12 through 
17 years of age and a third dose of 
BNT162b2 30 µg in a randomly 
selected subset of participants 
18 through 55 years of age from study 
C4591001
In participants complying with the key protocol 
criteria (evaluable participants) from each 
vaccine and age group:
At baseline (before the third dose) and 1 month
after the third dose:

GMTs at each time point

GMFRs from baseline (before the third 
dose) to each subsequent time point after the 
third dose

Percentage of participants with seroresponse 
at each time point after the third dose

SARS-CoV-2 reference-
strain–neutralizing titers

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Objectives
Estimands
Endpoints
Secondary Immunogenicity
Secondary Immunogenicity
Secondary Immunogenicity
To describe the immune response to 
BNT162b2 10 µg and 30 µg given as 
the third dose in participants 12 through 
17 years of agea
At baseline (before the third dose) and 7 days 
after the third dose:

GMTs at each time point

GMFRs from baseline (before the third 
dose) to 7 days after the third dose

Percentage of participants with seroresponse 
at 7 days after the third dose

SARS-CoV-2 reference-
strain–neutralizing titers

SARS-CoV-2 Omicron 
BA.1–neutralizing titers
Note: Seroresponse is defined as achieving a ≥4-fold rise from baseline (before the study vaccination) for 
participants in this substudy.  If the baseline measurement is below the LLOQ, the postvaccination measure of 
≥4 × LLOQ is considered seroresponse. For the comparator group of participants from study C4591001, 
seroresponse is defined as achieving a ≥4-fold rise from before Dose 3. If the pre-Dose 3 measurement is 
below the LLOQ, the postvaccination measure of ≥4 × LLOQ is considered seroresponse.
a.
This objective is applicable to the immunogenicity analysis of the first approximately 100 participants
performed for DMC review.
10.9.4. Study Design
10.9.4.1. Overall Design
This is a randomized, observer-blinded substudy to evaluate the safety, tolerability, and 
immunogenicity of a booster (third) dose of BNT162b2 at 10 µg or 30 µg.  Participants 
≥12 years of age who have completed a 2-dose primary series of BNT162b2 (30-µg doses) at 
least 5 months (150 days) prior to randomization will be enrolled. Participants will be 
randomized at a ratio of 1:1 to receive BNT162b2 at either a 10-µg or 30-µg dose level at 
Visit 301. Randomization will be stratified by age with escalation to each higher age group
guided by immunogenicity results at 7 days after the third dose. A DMC will review safety 
(e-diary and AE) and immunogenicity data in the first approximately 100 participants with 
available immunogenicity (~50 participants in each dose level) 7 days after the third dose. 
Upon confirmation of an acceptable safety and immunogenicity assessment by the DMC, 
progression of the next age group will occur independently.
As part of protocol amendment 11, progression beyond the 12 through 17 years age group 
will not occur and no further participants will be enrolled.
Serum blood samples will be collected for immunogenicity at baseline, 7 days after the 
booster (third) dose, 1 month after the third dose, and 6 months after the third dose. Up to
approximately 150 participants will be randomized in the study.
10.9.4.1.1. Scientific Rationale for Substudy C Design
See Section 1.1.
10.9.4.1.2. Diversity of Study Population 
Reasonable attempts will be made to enroll participants who align with the US population 
distribution (Census-based), to ensure that the study population is representative of patient 
populations that will benefit from a COVID-19 vaccine in clinical practice.

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10.9.4.2. Justification for Dose
See Section 4.3 for a justification of the 30-µg BNT162b2 dose used in Substudy C.
If a booster (third) dose of BNT162b2 at 10 µg induces an immune response that is 
noninferior to the immune responses elicited 1 month after the second dose of BNT162b2 at 
30 µg (ie, following completion of a 2-dose primary series of BNT162b2 [30-µg doses]), this 
finding could have significant implications on vaccine accessibility and equity globally, as it 
would allow for the availability of more doses.
10.9.4.3. End of Study Definition
See Section 4.4.
10.9.5. Study Population
Details of the master and Substudy C eligibility criteria are shown in Section 5. Participants 
must meet all of the general inclusion and exclusion criteria as specified for both the master 
protocol and Substudy C–specific inclusion and exclusion criteria.
10.9.5.1. Inclusion Criteria
Participants are eligible to be included in Substudy C only if all of the following criteria 
apply:
Age and Sex:
1. Male or female participants ≥12 years of age, inclusive, who have received 2 prior doses 
of 30 µg BNT162b2 19 to 60 days apart, with the second dose being at least 150 days 
before Visit 301 (Day 1)
Documented confirmation of prior BNT162b2 receipt must be obtained prior to 
randomization.
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, vaccination 
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Healthy participants who are determined by medical history, physical examination
(if required), and clinical judgment of the investigator to be eligible for inclusion in the 
study.

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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 participants with 
known stable infection with HIV, HCV, or HBV can be found in Section 10.15.
Informed Consent:
4. Capable of giving personal signed informed consent/assent, have parent(s)/legal guardian 
capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the ICD and in this protocol.
The investigator, or a person designated by the investigator, will obtain 
written/electronically signed informed consent (and assent) from each study participant’s 
legal guardian (as defined in Appendix 1, and the participant’s assent, when applicable, 
before any study-specific activity is performed, unless a waiver of informed consent has 
been granted by an IRB/EC. All legal guardians should be fully informed, and 
participants should be informed to the fullest extent possible, about the study in language 
and terms they are able to understand. The investigator will retain the original copy of 
each participant’s signed consent/assent document.
10.9.5.2. Exclusion Criteria
Participants are excluded from Substudy C if any of the following criteria apply:
Medical Conditions:
1. Other medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for the 
study.
2. History of severe adverse reaction associated with a vaccine and/or severe allergic 
reaction (eg, anaphylaxis) to any component of the study intervention(s).
3. 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.
4. Immunocompromised individuals with known or suspected immunodeficiency, as 
determined by history and/or laboratory/physical examination.
5. Bleeding diathesis or condition associated with prolonged bleeding that would, in the 
opinion of the investigator, contraindicate intramuscular injection.
6. Women who are pregnant or breastfeeding.

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Prior/Concomitant Therapy:
7. Individuals who receive treatment with radiotherapy or immunosuppressive therapy, 
including cytotoxic agents or systemic corticosteroids (if systemic corticosteroids are 
administered for ≥14 days at a dose of ≥20 mg/day of prednisone or equivalent), eg, for 
cancer or an autoimmune disease, or planned receipt throughout the study.  
Inhaled/nebulized, intra-articular, intrabursal, or topical (skin or eyes) corticosteroids are 
permitted.
8. Receipt of blood/plasma products, immunoglobulin, or monoclonal antibodies, from 
60 days before study intervention administration, or receipt of any passive antibody 
therapy specific to COVID-19, from 90 days before study intervention administration, or 
planned receipt throughout the study.
Prior/Concurrent Clinical Study Experience:
9. Prior receipt of any COVID-19 vaccine other than BNT162b2.
Other Exclusions:
10. Investigator site staff or Pfizer-BioNTech employees directly involved in the conduct of 
the study, site staff otherwise supervised by the investigator, and their respective family 
members.
11. Receipt of medications intended to prevent COVID-19.
12. Prior receipt of more than 2 doses of BNT162b2 30 µg.
13. Participation in other studies involving study intervention within 28 days prior to study
entry through and including 28 days after the last dose of study intervention, with the 
exception of non-Pfizer interventional studies for prevention of COVID-19, which are 
prohibited throughout study participation.
10.9.5.3. Lifestyle Considerations
Contraception requirements will apply to Substudy C as detailed in Section 5.3 and
Section 10.4.
10.9.5.4. Screen Failures
See Section 5.4.
10.9.5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Administration 
of Study Intervention
See Section 5.5.

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10.9.6. Study Intervention(s) and Concomitant Therapy
For the purposes of this substudy, study intervention refers to:

BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S): 
10 µg

BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S): 
30 µg
10.9.6.1. Study Intervention(s) Administered
See Section 6.1 for details of BNT162b2.
10.9.6.1.1. Administration
Participants will receive 1 dose of study intervention at Visit 301 (booster [third] dose of 
BNT162b2) in accordance with the substudy’s SoA (Section 10.9.1.3).
Study intervention should be administered intramuscularly into the deltoid muscle, preferably 
of the nondominant arm, by an unblinded administrator.
10.9.6.1.2. Preparation and Dispensing
Study intervention will be prepared by qualified unblinded site personnel according to the IP 
manual.  The study intervention will be administered in such a way as to ensure that the 
participants remain blinded.
10.9.6.2. Measures to Minimize Bias: Randomization and Blinding
10.9.6.2.1. Blinding of Site Personnel
In this observer-blinded substudy, the study staff receiving, storing, dispensing, preparing, 
and administering the study interventions will be unblinded.  All other study and site 
personnel, including the investigator, investigator staff, and participants, will be blinded to 
study intervention assignments.  In particular, the individuals who evaluate participant safety 
will be blinded.  
The PI will assign the responsibility of the unblinded dispensers/administrators to persons 
who will not participate in the evaluation of any study participant.  To ensure adequate 
coverage, at least 2 unblinded dispensers/administrators will be assigned per site.  Members 
of the study site staff or clinic pharmacy should fulfill these roles.  Contact between the 
unblinded dispensers and study participants should be kept to a minimum.  The investigator, 
study coordinator, and any site staff other than the unblinded dispensers/administrators must 
not be allowed to know the study intervention assigned to any study participant and must not 
be allowed to see the study intervention container contents.  In the event of a Quality 
Assurance audit, the auditor(s) will be allowed access to unblinded study intervention records 
at the site(s) to verify that randomization/dispensing has been done accurately.

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10.9.6.2.2. Blinding of the Sponsor
The majority of sponsor/Pfizer staff will be blinded to study intervention allocation.  All 
laboratory testing personnel performing serology assays will remain blinded to study 
intervention assigned/received throughout the study.  The following sponsor/Pfizer staff, who 
will have no part in the blinded conduct of the study, will be unblinded (further details will 
be provided in a data blinding plan):

Those study team members who are involved in ensuring that protocol requirements for 
study intervention preparation, handling, allocation, and administration are fulfilled at the 
site will be unblinded for the duration of the study (eg, unblinded study manager, 
unblinded clinical research associate).

Unblinded clinician(s), who are not direct members of the study team and will not 
participate in any other study-related activities, will review unblinded protocol 
deviations.

An unblinded team supporting interactions with, and analyses for, the DMC (see
Section 10.9.9.4.2).  This team comprises a statistician, programmer(s), a clinical 
scientist, and a medical monitor. 

An unblinded submissions team will be responsible for preparing unblinded analyses and 
documents to support regulatory activities that may be required while the study is 
ongoing.  With the exception of the statisticians and programmers, who will become 
unblinded at the participant level at the time of the first planned reporting event to 
perform the analyses, other members of this team will only be unblinded at the group 
level and not have access to individual participant assignments.  A separate group of 
statisticians and programmers will remain blinded and continue supporting the blinded
conduct of the study after the first planned analysis.
The participant may be unblinded to confirm the dose of BNT162b2 received 3 months after 
receiving their study vaccination. The study team will also become unblinded to the 
participant’s original study intervention allocation at this time.
10.9.6.2.3. Breaking the Blind
The IRT will be programmed with blind-breaking instructions.  In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s study 
intervention assignment is warranted.  Participant safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the sponsor prior to 
unblinding a participant’s vaccine assignment unless this could delay further management of 
the participant.  If a participant’s vaccine assignment is unblinded, the sponsor must be 
notified within 24 hours after breaking the blind.  The date and reason that the blind was 
broken must be recorded in the source documentation and CRF.

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The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
10.9.6.3. Study Intervention Compliance
See Section 6.4.
10.9.6.4. Dose Modification
See Section 6.5.
10.9.6.5. Continued Access to Study Intervention After the End of the Study
See Section 6.6.
10.9.6.6. Treatment of Overdose
See Section 6.7.
10.9.6.7. Concomitant Therapy
See Section 6.8.
10.9.7. Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
See Section 7.
10.9.8. Study Assessments and Procedures
The total blood sampling volume for individual participants in this study is up to 
approximately 40 mL.
For all participants, other additional blood samples may be taken for safety assessments at 
times specified by Pfizer, provided the total volume taken during the study does not exceed 
550 mL during any period of 60 consecutive days.
10.9.8.1. Efficacy and/or Immunogenicity Assessments for Substudy C
10.9.8.1.1. Immunogenicity
Serum samples will be obtained for immunogenicity testing at the visits specified in the SoA. 
The test to be performed will be the SARS-CoV-2 neutralizing assay. Note that all 
immunogenicity analyses will be based upon samples analyzed at the central laboratory.
10.9.8.2. Safety Assessments
See Section 8.2.
10.9.8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting
See Section 8.3.

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10.9.8.4. Substudy C Procedures
10.9.8.4.1. Visit 301 – Booster (Third) Dose of BNT162b2 (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written, 
study-specific informed consent will be obtained from the participant or his/her 
parent(s)/legal guardian, as appropriate.  Each signature on the ICD must be personally dated 
by the signatory.  The investigator or his or her designee will also sign the ICD.  A copy of 
the signed and dated ICD must be given to the participant/participant’s parent(s)/legal 
guardian(s).  The source data must reflect that the informed consent was obtained before 
participation in the study.
It is anticipated that the procedures below will be conducted in a stepwise manner.  The visit
may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and 
exclusion criteria onwards must be conducted on the same day.

Confirm the participant has only received 2 doses of BNT162b2 at least 5 months (150 
days) prior to randomization. Secondary confirmation by another site staff member is 
required.

Assign a single participant number using the IRT system.

Obtain the participant’s prior study and participant number (if applicable) and record this 
in the CRF.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).  
The full date of birth will be collected to critically evaluate the immune response and 
safety profile by age.

Obtain any medical history of clinical significance.  For participants who are 
HIV-positive, record HIV viral load and CD4 count results from the most recent test 
performed in the previous 6 months.

Perform a clinical assessment.  If the clinical assessment indicates that a physical 
examination is necessary to comprehensively evaluate the participant, perform a physical 
examination and record any findings in the source documents and, if clinically 
significant, record any findings on the medical history CRF.

Measure the participant’s height and weight.

Measure the participant’s body temperature.

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 5.3.

Record nonstudy vaccinations as described in Section 6.8.

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
Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met.

Ensure that the participant meets none of the temporary delay criteria as described in
Section 5.5.

Record AEs as described in Section 8.3.

Collect a blood sample for immunogenicity.

Blinded site staff will obtain the participant’s randomization number using the IRT 
system. The randomization confirmation report with the study intervention allocation will 
only be sent to the unblinded site staff member. 

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into 
the deltoid muscle of the preferably nondominant arm.  Please refer to the IP manual for 
further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study 
intervention administration for any acute reactions.  Record any acute reactions 
(including time of onset) in the participant’s source documents and on the AE page of the 
CRF, and on an SAE form as applicable.

Explain the e-diary technologies available for this study (see Section 8.2.4), and assist the 
participant or his/her parent(s)/legal guardian, as appropriate, in downloading the study 
application onto his or her own device or issue a provisioned device if required.

Provide instructions on reactogenicity e-diary completion and ask the participant or 
his/her parent(s)/legal guardian to complete the reactogenicity e-diary from Day 1 
through Day 7, with Day 1 being the day of vaccination.

Ask the participant or his/her parent(s)/legal guardian to contact the site staff or 
investigator immediately if the participant experiences any of the following from Day 1
through Day 7 after vaccination (where Day 1 is the day of vaccination) to determine if 
an unscheduled reactogenicity visit is required: 

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units).

Severe pain at the injection site.

Any severe systemic event.

Issue a measuring device to measure local reactions at the injection site and a
thermometer for recording daily temperatures and provide instructions on their use.

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
Review reactogenicity e-diary data (daily review is optimal during the active diary period 
of 7 days following each study intervention administration).

Ask the participant or his/her parent(s)/legal guardian to contact the site staff or 
investigator if the participant experiences acute chest pain, shortness of breath, or 
palpitations (see Section 10.9.8.5).

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator if a medically attended event (eg, doctor’s visit, emergency room 
visit) or hospitalization occurs.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs and an unblinded 
dispenser/administrator updates the study intervention accountability records.
10.9.8.4.2. Visit 302 – 7 Days After Booster Vaccination (6-8 Days After Visit 301)

Record AEs as described in Section 8.3.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8 received by 
the participant if required for his or her clinical care.

Collect a blood sample for immunogenicity.

Review reactogenicity e-diary data (daily review is optimal during the active diary period 
of 7 days following each study intervention administration).

Review ongoing reactogenicity e-diary symptoms with the participant and obtain and 
record stop dates.

Discuss contraceptive use as described in Section 5.3.

Ask the participant or his/her parent(s)/legal guardian to contact the site staff or 
investigator if the participant experiences acute chest pain, shortness of breath, or 
palpitations (see Section 10.9.8.5).

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator if a medically attended event (eg, doctor’s visit, emergency room 
visit) or hospitalization occurs.

Schedule an appointment for the participant to return for the next study visit.

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
Complete the source documents.

The investigator or an authorized designee completes the CRFs.
10.9.8.4.3. Visit 303 – 1 Month After Booster Vaccination (28 to 35 Days After 
Visit 301)

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since Visit 301 (if any).

Record AEs as described in Section 8.3.

Collect a blood sample for immunogenicity.

Review ongoing reactogenicity e-diary symptoms with the participant and obtain and 
record stop dates.

Collect the participant’s reactogenicity e-diary or assist the participant or his/her 
parent(s)/legal guardian to remove the study application from his or her own personal 
device.

Discuss contraceptive use as described in Section 5.3.

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator if a medically attended event (eg, doctor’s visit, emergency room 
visit) or hospitalization occurs.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs and an unblinded 
dispenser/administrator updates the study intervention accountability records.
10.9.8.4.4. Visit 304 – 6 Months After Booster Vaccination (175 to 189 Days After 
Visit 301)
For participants who have already completed V304 at the time of protocol amendment 11, 
they will be informed by the investigator site staff of study completion and that no further 
visits are required.

Record AEs as described in Section 8.3.

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
Record details of any of the prohibited medications specified in Section 6.8 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record HIV viral load and CD4 count results from 
the most recent test performed since Visit 303 (if any).

Collect a blood sample for immunogenicity.

Ask the participant or his/her parent(s)/legal guardian, as appropriate, to contact the site 
staff or investigator if a medically attended event (eg, doctor’s visit, emergency room 
visit) or hospitalization occurs.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
10.9.8.5. Additional Procedures for Monitoring of Potential Myocarditis or Pericarditis
Any study participant who reports acute chest pain, shortness of breath, palpitations, or any 
other symptom(s) that might be indicative of myocarditis or pericarditis within 4 weeks after 
a study vaccination should be specifically evaluated, preferably by a cardiologist, for possible 
myocarditis or pericarditis.
In addition to a clinical evaluation, the following should be performed:

ECG and

Measurement of the troponin level
If myocarditis or pericarditis is suspected based upon the initial evaluation, the following 
should also be performed:

Cardiac echocardiogram and/or

Cardiac magnetic resonance study
Details of the symptoms reported, and results of the investigations performed, will be 
recorded in the CRF.
10.9.8.5.1. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction
If a Grade 3 local reaction (Section 8.2.4.2), systemic event (Section 8.2.4.3), or fever 
(Section 8.2.4.4) is reported in the reactogenicity e-diary, a telephone contact should occur to 
ascertain further details and determine whether a site visit is clinically indicated. If suspected 
Grade 4 local reaction (Section 8.2.4.2), systemic event (Section 8.2.4.3), or fever 
(Section 8.2.4.4) is reported in the reactogenicity e-diary, a telephone contact or site visit 
should occur to confirm whether the event meets the criteria for Grade 4.

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A site visit must be scheduled as soon as possible to assess the participant unless any of the 
following is true:

The participant is unable to attend the unscheduled visit.

The local reaction/systemic event is no longer present at the time of the telephone 
contact.

The participant or his/her parent(s)/legal guardian, as appropriate, recorded an incorrect 
value in the reactogenicity e-diary (confirmation of a reactogenicity e-diary data entry 
error).

The PI or authorized designee determined it was not needed.
This telephone contact will be recorded in the participant’s source documentation and the 
CRF.
If the participant is unable to attend the unscheduled visit, or the PI or authorized designee 
determined that it was not needed, any ongoing local reactions/systemic events must be 
assessed at the next study visit.
During the unscheduled visit, the reactions should be assessed by the investigator or a 
medically qualified member of the study staff such as a study physician or a study nurse, as 
applicable to the investigator’s local practice, who will:

Measure body temperature (°F/°C).

Measure minimum and maximum diameters of redness (if present).

Measure minimum and maximum diameters of swelling (if present).

Assess injection site pain (if present) in accordance with the grades provided in
Section 8.2.4.2.

Assess systemic events (if present) in accordance with the grades provided in
Section 8.2.4.3.

Assess for other findings associated with the reaction and record on the AE page of the 
CRF, if appropriate.
The investigator or an authorized designee will complete the unscheduled visit assessment 
page of the CRF.
10.9.9. Statistical Considerations for Substudy C
See Section 9 for master protocol statistical considerations and substudy specifics below.

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10.9.9.1. Statistical Hypotheses
10.9.9.1.1. Estimands
The estimands corresponding to the primary and secondary objectives are described in the 
table in Section 10.9.3.
In the primary safety objective evaluations, missing AE start dates will be imputed according 
to Pfizer safety rules.  No other missing information will be imputed in the safety analysis.
10.9.9.1.2. Statistical Hypotheses
There is no formal hypothesis testing. All statistical analyses will be descriptive.
10.9.9.1.3. Multiplicity Adjustment
No multiplicity adjustment is needed for the study as there is no statistical hypothesis.
10.9.9.2. Analysis Sets
For the purpose of analysis, the following analysis sets are defined for this substudy:
Population
Description
Enrolled
All participants who have a signed ICD.
Randomized
All participants who are assigned a randomization number in the 
IWR system.
Evaluable 
immunogenicity
All eligible randomized participants who receive the study 
vaccine to which they are randomized, have a valid and
determinate immunogenicity result from the blood sample
collected within an appropriate window, and have no other
important protocol deviations as determined by the clinician.
All-available 
immunogenicity
All randomized participants who receive at least 1 dose of the 
study intervention with a valid and determinate immunogenicity 
result after vaccination.
Safety
All participants who receive at least 1 dose of the study 
intervention.
10.9.9.3. Statistical Analyses
The SAP will be developed and finalized for this substudy before any analyses are performed
and will describe the analyses and procedures for missing, unused, and spurious data.  This 
section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.

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10.9.9.3.1. General Considerations
Refer to Section 9.3.1 for general considerations of statistical analyses.
In this substudy, all safety and immunogenicity data will be analyzed separately for each age 
group.
10.9.9.3.2. Primary Endpoint(s)/Estimand(s) Analysis
Endpoint
Statistical Analysis Methods
Safety

Descriptive statistics will be provided for each reactogenicity
endpoint for each vaccine group in each age group. Local reactions 
and systemic events from Day 1 through Day 7 after the third dose
(where Day 1 is the day of vaccination) will be presented by severity 
and cumulatively across severity levels. Descriptive summary 
statistics will include counts and percentages of participants with the 
indicated endpoint and the associated Clopper-Pearson 95% CIs.

AEs and SAEs will be categorized according to MedDRA terms.  
Counts, percentages, and associated Clopper-Pearson 95% CIs of 
AEs within 1 month and SAEs within 6 months after the third dose
will be provided for each vaccine group within each age group.  
Immunogenicity
GMTs and GMFRs of SARS-CoV-2 reference-strain–neutralizing 
titers
Percentage of participants with seroresponse to the reference strain

GMTs at baseline (before the third dose) and 1 month after 
vaccination and GMFRs of SARS-CoV-2 reference-strain–
neutralizing titers from baseline (before the third dose) to 1 month
after vaccination, along with the associated 2-sided 95% CIs, will be 
provided for each age and vaccine group using the statistical method 
described in Section 9.3.1.2.1 and Section 9.3.1.2.2.

The percentages of participants with seroresponse to the reference 
strain at 1 month after the third dose, and the associated Clopper-
Pearson 95% CIs, will be provided for each age and vaccine group.

The analyses will be performed in participants without evidence of 
SARS-CoV-2 infection, and in participants with and without 
evidence of SARS-CoV-2 infection.

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10.9.9.3.3. Secondary Endpoint(s)/Estimand(s) Analysis
Endpoint
Statistical Analysis Methods
Immunogenicity
GMTs and GMFRs of SARS-CoV-2 reference-strain– and Omicron 
BA.1–neutralizing titers
Percentage of participants with seroresponse to the reference strain 
and Omicron BA.1

GMTs and GMFRs of SARS-CoV-2 reference strain and Omicron 
BA.1–neutralizing titers from baseline (before the third dose) to 
7 days after vaccination, and percentage of participants with 
seroresponse to reference strain and Omicron BA.1 at 7 days after 
vaccination, along with the associated 2-sided 95% CIs, will be 
provided using the same statistical methods as described above for 
the primary endpoint.
10.9.9.3.4. Exploratory Endpoint(s) Analysis
Not applicable.
10.9.9.4. Interim Analyses
An administrative interim analysis is planned for each of the following age groups: 
12 through 17 years, 18 through 30 years, and 31 through 55 years, when 7-day post–booster 
dose immunogenicity data are available from approximately the first 100 participants
(~50 participants in each booster dose–level group). The purpose of the administrative 
interim analysis is to inform initiation of enrollment for the next age group. The analysis will 
be performed by an unblinded DMC reporting team. Only group-level unblinded results will 
be shared with limited sponsor personnel.
The administrative interim analysis of the first 100 participants in the 12 through 17 years
age group was completed. The DMC did not raise any concerns for age escalation; however,
as part of protocol amendment 11, progression beyond the 12 through 17 years age group 
will not occur and no further participants will be enrolled. The rationale for this amendment 
is that a third dose of COVID-19 vaccine has been recommended for all age groups for a 
considerable period of time (hence the potential substrate for enrollment is essentially 
nonexistent) and, for Fall 2022, the recommended booster vaccine will switch to a bivalent 
original/Omicron-modified vaccine. Both factors contribute to age escalation being 
operationally unfeasible. Furthermore, since the 30-µg dose level is well tolerated, and in the 
face of emergence of Omicron and its sublineages for which maximum immune response is 
desirable, the rationale for a reduced dose level no longer holds.
Statistical analyses will be carried out when the final data for specified objectives are 
available while the study is ongoing. The timing of these planned analysis and reporting 
events is described in the section below.

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10.9.9.4.1. Analysis Timing
Statistical analyses will be carried out when the following data are available:

Safety data through 1 month after the third dose in each dose level group.

Immunogenicity data through 1 month after the third dose for participants enrolled in this 
study and for the comparator group from the C4591001 study.

Complete safety analysis approximately 6 months after the third dose in each dose group.
Certain analyses may be combined as 1 regulatory submission report if the data become 
available around the same time.  Additional analyses may be conducted if required for 
regulatory purposes. All analyses conducted while the study is ongoing will be performed by 
an unblinded team.
10.9.9.4.2. Data Monitoring Committee or Other Independent Oversight Committee
The study will utilize a DMC that will be used to review safety data (e-diary and AE) and 
immunogenicity in the first approximately 100 participants with available immunogenicity 
data (~50 participants in each dose level of BNT162b2) 7 days after the third dose. Upon 
confirmation of an acceptable safety and immunogenicity assessment by the DMC, 
progression of each age group will occur independently.
The DMC is independent of the study team and includes only external members.  The DMC 
charter describes the role of the DMC in more detail. The DMC will be responsible for 
ongoing monitoring of the safety data throughout the study according to the charter.  
The recommendations made by the DMC will be forwarded to the appropriate Pfizer 
personnel for final decision.  Pfizer will forward such decisions, which may include 
summaries of aggregate analyses of safety data, to regulatory authorities, investigators as
appropriate.
10.9.9.5. Sample Size Determination
The sample size is not based on any formal hypothesis test. All statistical analyses will be 
descriptive.
For safety outcomes, Table 9 shows the probability of observing at least 1 AE for a given 
true event rate of a particular AE, for various sample sizes. For example, if the true AE rate 
is 1%, with 75 participants in a vaccine group, there is 53% probability of observing at least 
1 AE.

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Table 9.
Probability of Observing at 1 Least AE by Assumed True Event Rates 
With Different Sample Sizes
Assumed True 
Event Rate of an 
AE
N=50
N=75
N=150
0.01%
0
0.01
0.01
0.02%
0.01
0.01
0.03
0.04%
0.02
0.03
0.06
0.06%
0.03
0.04
0.09
0.08%
0.04
0.06
0.11
0.10%
0.05
0.07
0.14
0.15%
0.07
0.11
0.2
0.20%
0.1
0.14
0.26
0.25%
0.12
0.17
0.31
0.30%
0.14
0.2
0.36
0.50%
0.22
0.31
0.53
1%
0.39
0.53
0.78
2%
0.64
0.78
0.95
3%
0.78
0.9
0.99
5%
0.92
0.98
>0.99
10%
0.99
>0.99
>0.99

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10.10. Appendix 10: Substudy D
10.10.1. Substudy Summary
10.10.1.1. Synopsis
See Section 1.1 for a synopsis of Substudy D.

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10.10.1.2. Schema
10.10.1.2.1. Participants in Cohort 1 
Cohort
Visit Number
401
402
403
404
405
Visit Description
SSD Vaccination 1
1-Month 
Follow-Up Visit
and SSD 2nd
Vaccination
1-Month 
Follow-Up Visit
after SSD 2nd
Vaccinationa
3-Month 
Follow-Up Visit
After Last SSD 
Vaccination
6-Month 
Follow-Up Visit
After Last SSD 
Vaccination
Cohort 1: 
Participants 
18-55 years of age 
having received 
2 doses of 
BNT162b2 before 
enrollment 
(3-8 months after 
last dose)
Group 1:
(N=205)
BNT162b2 OMI
30-µg dose
Group 2:
(N=205)
BNT162b2 OMI
30-µg dose
BNT162b2 OMI
30-µg dose
Group 2b:
(N=205)
BNT162b2 
30-µg dose
Blood draw for immunogenicity
~50 mL
~50 mL
~50 mL
~50 mL
~50 mL
Collect blood sample for PBMC isolationb
~120 mL
~120 mL
~120 mL
~120 mL
Abbreviations: HLA = human leukocyte antigen; PBMC = peripheral blood mononuclear cell; SSD = Substudy D.
a.
Only for those participants randomized to receive a second dose of BNT162b2 OMI as part of Substudy D.
b.
Additional 120 mL for PBMC isolation (and 5 mL for HLA typing at Visit 401) for select participants at select sites only. See Section 10.10.8.2

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10.10.1.2.2. Participants in Cohort 2
Cohort
Visit Number
401
402
404
404a
404b
404c
405
Visit 
Description
SSD 
Vaccination 1
1-
Month 
Follow-
Up Visit
3-Month 
Follow-Up Visit
and 2nd SSD 
Vaccination
7-Day 
Follow-Up Visit 
After 2nd SSD 
Vaccinationa
1-Month 
Follow-Up Visit 
After 2nd SSD 
Vaccinationa
3-Month 
Follow-Up Visit 
After 2nd SSD 
Vaccinationa
6-Month 
Follow-Up Visit
After Last SSD 
Vaccination
Cohort 2: 
Participants 
18-55 years of 
age having 
received 
3 doses of 
BNT162b2 
before 
enrollment
(3-6 months 
after last dose)
Group 3:
(N=300)
BNT162b2 OMI
30-µg dose
BNT162b2 OMI
30-µg dose
Group 4: 
(N=300)
BNT162b2
30-µg dose
BNT162b2 OMI
30-µg dose
Blood draw for 
immunogenicity
~50 mL
~50 mL
~50 mL
~50 mL
~50 mL
~50 mL
~50 mL
Collect blood 
sample for 
PBMC isolationb
~120 mL
~120 
mL
~120 mL
~120 mL
~120 mL
~120 mL
Abbreviations: HLA = human leukocyte antigen; PBMC = peripheral blood mononuclear cell; SSD = Substudy D.
a.
Only for those participants who consent to receive a dose of BNT162b2 OMI at Visit 404 as part of Substudy D.
b.
Additional 120 mL for PBMC isolation (and 5 mL for HLA typing at Visit 401) for select participants at select sites only. See Section 10.10.8.2.

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10.10.1.2.3. Participants in Cohort 3
Visit Number
501
502
503
504
505
506
507
508
Visit 
Description
Vaccination 1
Vaccination 2
3 Weeks After 
Vaccination 1 
1-Week
Follow-Up 
Visit After 
Vaccination 
2a
1-Month
Follow-Up 
Visit After 
Vaccination 
2
3-Month 
Follow-Up 
Visit After 
Vaccination 
2
6-Month
Follow-Up Visit 
After 
Vaccination 2
and 
Administration 
of Vaccination 
3b
1-Month 
Follow-Up 
Visit After 
Vaccination 
3
6-Month 
Follow-Up 
Visit After 
Vaccination 
3
Cohort 3: 
COVID-19 
vaccine–
naive
participants 
18-55 years 
of age
Group 5: 
(N=205)
BNT162b2 OMI 
30-µg dose
BNT162b2 OMI 
30-µg dose
BNT162b2 
30-µg dose
Blood draw for 
immunogenicity
~50 mL
~50 mL
~50 mL
~50 mL
~50 mL
~50 mL
~50 mL
Collect blood 
sample for 
PBMC 
isolationc
~120 mL
~120 mL
~120 mL
~120 mL
~120 mL
~120 mL
~120 mL
Abbreviations: HLA = human leukocyte antigen; PBMC = peripheral blood mononuclear cell.
a.
Only for those participants who are part of the group for description of cell-mediated immune response.
b.
Vaccination 3 may be administered as early as 5 months (150 days) after Vaccination 2.
c.
Additional 120 mL for PBMC isolation (and 5 mL for HLA typing at Visit 501) for select participants at select sites only. See Section 10.10.8.2.

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Page 174
10.10.1.3. Schedule of Activities for Substudy D
10.10.1.3.1. Cohort 1 
Visit Number
401
402
403
404
405
Unplanned
Visit Description
SSD 
Vaccination 1a
1-Month Follow-Up 
Visit After SSD Vax 1 
and SSD Vax 2b
1-Month Follow-Up 
Visit After SSD 
Vax 2b
3-Month Follow-Up 
Visit After Last SSD 
Vaccination
6-Month Follow-Up Visit 
After Last SSD 
Vaccination
Potential COVID-19 
Illness Visitc
Visit Window (Days)
Day 1
28 to 35 Days After 
Visit 401
28 to 35 Days After 
Visit 402
85 to 95 Days After 
Visit 401 (or After 
Visit 402 for 
Participants Who 
Received SSD Vax 2)
175 to 189 Days After Visit 
401 (or After Visit 402 for 
Participants Who 
Received SSD Vax 2)
Optimally Within 3 Days 
After Potential COVID-19 
Illness Onset
ONLY FOR THE 
PARTICIPANTS 
WHO RECEIVE 
SSD 
VACCINATION 2
Obtain informed consent
X
Obtain the participant’s 
prior study and
participant number 
(if applicable)
X
Confirm participant’s 
past BNT162b2 
experience (3-8 months 
since the last dose)
X
Obtain demography and 
medical history data
X
Perform clinical 
assessmentd
X
Measure height and 
weight
X
Measure temperature 
(body)
X
Xb
Perform urine pregnancy 
test (if appropriate)
X
Xb

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Visit Number
401
402
403
404
405
Unplanned
Visit Description
SSD 
Vaccination 1a
1-Month Follow-Up 
Visit After SSD Vax 1 
and SSD Vax 2b
1-Month Follow-Up 
Visit After SSD 
Vax 2b
3-Month Follow-Up 
Visit After Last SSD 
Vaccination
6-Month Follow-Up Visit 
After Last SSD 
Vaccination
Potential COVID-19 
Illness Visitc
Visit Window (Days)
Day 1
28 to 35 Days After 
Visit 401
28 to 35 Days After 
Visit 402
85 to 95 Days After 
Visit 401 (or After 
Visit 402 for 
Participants Who 
Received SSD Vax 2)
175 to 189 Days After Visit 
401 (or After Visit 402 for 
Participants Who 
Received SSD Vax 2)
Optimally Within 3 Days 
After Potential COVID-19 
Illness Onset
ONLY FOR THE 
PARTICIPANTS 
WHO RECEIVE 
SSD 
VACCINATION 2
Confirm use of 
contraceptives 
(if appropriate)
X
X
X
Collect prohibited 
medication use
X
X
X
X
X
Collect nonstudy vaccine 
information 
X
X
X
X
X
For participants who are 
HIV-positive, record the 
latest CD4 count and 
HIV viral load
X
X
X
X
Confirm eligibility
X
Xb
Review temporary delay 
criteria
X
Xb
Collect blood sample for 
immunogenicity 
assessment 
~50 mL
~50 mL
~50 mL
~50 mL
~50 mL
Collect blood sample for 
PBMC isolatione
~120 mL
~120 mL
~120 mL
~120 mL
Collect blood sample for 
HLA typinge
~5 mL

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Visit Number
401
402
403
404
405
Unplanned
Visit Description
SSD 
Vaccination 1a
1-Month Follow-Up 
Visit After SSD Vax 1 
and SSD Vax 2b
1-Month Follow-Up 
Visit After SSD 
Vax 2b
3-Month Follow-Up 
Visit After Last SSD 
Vaccination
6-Month Follow-Up Visit 
After Last SSD 
Vaccination
Potential COVID-19 
Illness Visitc
Visit Window (Days)
Day 1
28 to 35 Days After 
Visit 401
28 to 35 Days After 
Visit 402
85 to 95 Days After 
Visit 401 (or After 
Visit 402 for 
Participants Who 
Received SSD Vax 2)
175 to 189 Days After Visit 
401 (or After Visit 402 for 
Participants Who 
Received SSD Vax 2)
Optimally Within 3 Days 
After Potential COVID-19 
Illness Onset
ONLY FOR THE 
PARTICIPANTS 
WHO RECEIVE 
SSD 
VACCINATION 2
Obtain nasal
(midturbinate) swab(s)
X
Xb
X
Obtain randomization 
number and study 
intervention allocation
using the IRT system
X
Administer study 
intervention
X
Xb
Assess acute reactions for 
at least 30 minutes after 
study intervention 
administration
X
Xb
Explain/review
participant
communication methods 
(including for e-diary 
completion), assist the 
participant with 
downloading the app, or 
issue provisioned device, 
if required
X
X

PF-07302048 (BNT162b2 RNA-Based COVID-19 Vaccine)
Protocol C4591031
Final Protocol Amendment 12, 20 Sep 2023
PFIZER CONFIDENTIAL
Page 177
Visit Number
401
402
403
404
405
Unplanned
Visit Description
SSD 
Vaccination 1a
1-Month Follow-Up 
Visit After SSD Vax 1 
and SSD Vax 2b
1-Month Follow-Up 
Visit After SSD 
Vax 2b
3-Month Follow-Up 
Visit After Last SSD 
Vaccination
6-Month Follow-Up Visit 
After Last SSD 
Vaccination
Potential COVID-19 
Illness Visitc
Visit Window (Days)
Day 1
28 to 35 Days After 
Visit 401
28 to 35 Days After 
Visit 402
85 to 95 Days After 
Visit 401 (or After 
Visit 402 for 
Participants Who 
Received SSD Vax 2)
175 to 189 Days After Visit 
401 (or After Visit 402 for 
Participants Who 
Received SSD Vax 2)
Optimally Within 3 Days 
After Potential COVID-19 
Illness Onset
ONLY FOR THE 
PARTICIPANTS 
WHO RECEIVE 
SSD 
VACCINATION 2
Provide/ensure the 
participant has a
thermometer and 
measuring device
X
Xb
Review reactogenicity 
e-diary data (daily review 
is optimal during the 
active diary period)
Review ongoing 
reactogenicity e-diary 
symptoms and obtain 
stop dates 
X
X
Collect AEs and SAEs as 
appropriate
X
X
X
Xf
Xf
Xf
Collect e-diary or assist 
the participant to delete 
application
X
Collection of 
COVID-19–related 
clinical and laboratory 
information (including 
local diagnosis)
X

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Final Protocol Amendment 12, 20 Sep 2023
PFIZER CONFIDENTIAL
Page 178
Visit Number
401
402
403
404
405
Unplanned
Visit Description
SSD 
Vaccination 1a
1-Month Follow-Up 
Visit After SSD Vax 1 
and SSD Vax 2b
1-Month Follow-Up 
Visit After SSD 
Vax 2b
3-Month Follow-Up 
Visit After Last SSD 
Vaccination
6-Month Follow-Up Visit 
After Last SSD 
Vaccination
Potential COVID-19 
Illness Visitc
Visit Window (Days)
Day 1
28 to 35 Days After 
Visit 401
28 to 35 Days After 
Visit 402
85 to 95 Days After 
Visit 401 (or After 
Visit 402 for 
Participants Who 
Received SSD Vax 2)
175 to 189 Days After Visit 
401 (or After Visit 402 for 
Participants Who 
Received SSD Vax 2)
Optimally Within 3 Days 
After Potential COVID-19 
Illness Onset
ONLY FOR THE 
PARTICIPANTS 
WHO RECEIVE 
SSD 
VACCINATION 2
Provide/ensure the 
participant has a nasal 
self-swab kit and 
instructions on 
self-collection of nasal 
swabs
X
X
X
X
Abbreviations: HIV = human immunodeficiency virus; HLA = human leukocyte antigen; IRT = interactive response technology; PBMC = peripheral blood mononuclear cell; 
SSD = Substudy D.
a.
The visit may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and exclusion criteria onwards must be conducted on the 
same day.
b.
Only for those participants randomized to receive a second dose of BNT162b2 OMI as part of Substudy D.
c.
The COVID-19 illness visit may be conducted as an in-person or telehealth visit.
d.
Including, if indicated, a physical examination.
e.
Additional 120 mL for PBMC isolation and 5 mL for HLA typing for select participants at select sites only.
f.
Any AEs occurring up to 48 hours after the blood draw must be recorded (see Section 8.3.1).

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PFIZER CONFIDENTIAL
Page 179
10.10.1.3.2. Cohort 2
Visit Number
401
402
404
404a
404b
404c
405
Unplanned
Visit Description
SSD 
Vaccination 
1a
1-Month 
Follow-Up 
Visit After 
SSD Vax 1 
3-Month Follow-Up 
Visit and 2nd SSD 
Vaccinationb
7-Day Follow-
Up Visit After 
SSD Vax 2b
1-Month 
Follow-Up Visit 
After SSD Vax 
2b
3-Month 
Follow-Up Visit 
After SSD Vax 
2b
6-Month Follow-Up 
Visit After Last SSD 
Vaccination
Potential COVID-19 
Illness Visitc
Visit Window (Days)
Day 1
28 to 35 
Days After 
Visit 401
85 to 95 Days After 
Visit 401 or 85 to 123 
Days for Participants 
Receiving SSD Vax 
2d
5 to 9 Days 
After Visit 404
28 to 35 Days 
After Visit 404
85 to 95 Days 
After Visit 404
175 to 189 Days After 
Visit 401 (or After 
Visit 404 for 
Participants Who 
Received SSD Vax 2)
Optimally Within 
3 Days After 
Potential COVID-19 
Illness Onset
ONLY FOR THE PARTICIPANTS WHO 
RECEIVE SSD VACCINATION 2
Obtain informed 
consent
X
Xb
Obtain the participant’s 
prior study and
participant number 
(if applicable)
X
Confirm participant’s 
past BNT162b2 
experience (3-8 months 
since the last dose)
X
Obtain demography and 
medical history data
X
Perform clinical 
assessmente
X
Measure height and 
weight
X
Measure temperature 
(body)
X
Xb
Perform urine 
pregnancy test 
(if appropriate)
X
Xb

PF-07302048 (BNT162b2 RNA-Based COVID-19 Vaccine)
Protocol C4591031
Final Protocol Amendment 12, 20 Sep 2023
PFIZER CONFIDENTIAL
Page 180
Visit Number
401
402
404
404a
404b
404c
405
Unplanned
Visit Description
SSD 
Vaccination 
1a
1-Month 
Follow-Up 
Visit After 
SSD Vax 1 
3-Month Follow-Up 
Visit and 2nd SSD 
Vaccinationb
7-Day Follow-
Up Visit After 
SSD Vax 2b
1-Month 
Follow-Up Visit 
After SSD Vax 
2b
3-Month 
Follow-Up Visit 
After SSD Vax 
2b
6-Month Follow-Up 
Visit After Last SSD 
Vaccination
Potential COVID-19 
Illness Visitc
Visit Window (Days)
Day 1
28 to 35 
Days After 
Visit 401
85 to 95 Days After 
Visit 401 or 85 to 123 
Days for Participants 
Receiving SSD Vax 
2d
5 to 9 Days 
After Visit 404
28 to 35 Days 
After Visit 404
85 to 95 Days 
After Visit 404
175 to 189 Days After 
Visit 401 (or After 
Visit 404 for 
Participants Who 
Received SSD Vax 2)
Optimally Within 
3 Days After 
Potential COVID-19 
Illness Onset
ONLY FOR THE PARTICIPANTS WHO 
RECEIVE SSD VACCINATION 2
Confirm use of 
contraceptives 
(if appropriate)
X
X
Xb
X
X
Collect prohibited 
medication use
X
X
X
X
X
X
X
Collect nonstudy 
vaccine information 
X
X
X
X
X
X
X
For participants who are 
HIV-positive, record the 
latest CD4 count and 
HIV viral load
X
X
X
X
X
X
Confirm eligibility
X
Xb
Review temporary 
delay criteria
X
Xb
Collect blood sample 
for immunogenicity 
assessment 
~50 mL
~50 mL
~50 mL
~50 mL
~50 mL
~50 mL
~50 mL
Collect blood sample 
for PBMC isolationf
~120 mL
~120 mL
~120 mL
~120 mL
~120 mL
~120 mL
Collect blood sample 
for HLA typingf
~5 mL
Obtain nasal 
(midturbinate) swab(s)
X
Xb
X

PF-07302048 (BNT162b2 RNA-Based COVID-19 Vaccine)
Protocol C4591031
Final Protocol Amendment 12, 20 Sep 2023
PFIZER CONFIDENTIAL
Page 181
Visit Number
401
402
404
404a
404b
404c
405
Unplanned
Visit Description
SSD 
Vaccination 
1a
1-Month 
Follow-Up 
Visit After 
SSD Vax 1 
3-Month Follow-Up 
Visit and 2nd SSD 
Vaccinationb
7-Day Follow-
Up Visit After 
SSD Vax 2b
1-Month 
Follow-Up Visit 
After SSD Vax 
2b
3-Month 
Follow-Up Visit 
After SSD Vax 
2b
6-Month Follow-Up 
Visit After Last SSD 
Vaccination
Potential COVID-19 
Illness Visitc
Visit Window (Days)
Day 1
28 to 35 
Days After 
Visit 401
85 to 95 Days After 
Visit 401 or 85 to 123 
Days for Participants 
Receiving SSD Vax 
2d
5 to 9 Days 
After Visit 404
28 to 35 Days 
After Visit 404
85 to 95 Days 
After Visit 404
175 to 189 Days After 
Visit 401 (or After 
Visit 404 for 
Participants Who 
Received SSD Vax 2)
Optimally Within 
3 Days After 
Potential COVID-19 
Illness Onset
ONLY FOR THE PARTICIPANTS WHO 
RECEIVE SSD VACCINATION 2
Obtain randomization 
number and study 
intervention allocation
using the IRT system
X
Administer study 
intervention
X
Xb
Assess acute reactions 
for at least 30 minutes 
after study intervention 
administration
X
Xb
Explain/review
participant
communication 
methods (including for 
e-diary completion), 
assist the participant
with downloading the 
app, or issue 
provisioned device, 
if required
X
Xb
Provide/ensure the 
participant has a
thermometer and 
measuring device
X
Xb

PF-07302048 (BNT162b2 RNA-Based COVID-19 Vaccine)
Protocol C4591031
Final Protocol Amendment 12, 20 Sep 2023
PFIZER CONFIDENTIAL
Page 182
Visit Number
401
402
404
404a
404b
404c
405
Unplanned
Visit Description
SSD 
Vaccination 
1a
1-Month 
Follow-Up 
Visit After 
SSD Vax 1 
3-Month Follow-Up 
Visit and 2nd SSD 
Vaccinationb
7-Day Follow-
Up Visit After 
SSD Vax 2b
1-Month 
Follow-Up Visit 
After SSD Vax 
2b
3-Month 
Follow-Up Visit 
After SSD Vax 
2b
6-Month Follow-Up 
Visit After Last SSD 
Vaccination
Potential COVID-19 
Illness Visitc
Visit Window (Days)
Day 1
28 to 35 
Days After 
Visit 401
85 to 95 Days After 
Visit 401 or 85 to 123 
Days for Participants 
Receiving SSD Vax 
2d
5 to 9 Days 
After Visit 404
28 to 35 Days 
After Visit 404
85 to 95 Days 
After Visit 404
175 to 189 Days After 
Visit 401 (or After 
Visit 404 for 
Participants Who 
Received SSD Vax 2)
Optimally Within 
3 Days After 
Potential COVID-19 
Illness Onset
ONLY FOR THE PARTICIPANTS WHO 
RECEIVE SSD VACCINATION 2
Review reactogenicity 
e-diary data (daily 
review is optimal during 
the active diary period)
Review ongoing 
reactogenicity e-diary 
symptoms and obtain 
stop dates 
X
X
X
Collect AEs and SAEs 
as appropriate
X
X
Xg
X
X
Xg
Xg
X
Collect e-diary or assist 
the participant to delete 
application
X
Collection of 
COVID-19–related 
clinical and laboratory 
information (including 
local diagnosis)
X

PF-07302048 (BNT162b2 RNA-Based COVID-19 Vaccine)
Protocol C4591031
Final Protocol Amendment 12, 20 Sep 2023
PFIZER CONFIDENTIAL
Page 183
Visit Number
401
402
404
404a
404b
404c
405
Unplanned
Visit Description
SSD 
Vaccination 
1a
1-Month 
Follow-Up 
Visit After 
SSD Vax 1 
3-Month Follow-Up 
Visit and 2nd SSD 
Vaccinationb
7-Day Follow-
Up Visit After 
SSD Vax 2b
1-Month 
Follow-Up Visit 
After SSD Vax 
2b
3-Month 
Follow-Up Visit 
After SSD Vax 
2b
6-Month Follow-Up 
Visit After Last SSD 
Vaccination
Potential COVID-19 
Illness Visitc
Visit Window (Days)
Day 1
28 to 35 
Days After 
Visit 401
85 to 95 Days After 
Visit 401 or 85 to 123 
Days for Participants 
Receiving SSD Vax 
2d
5 to 9 Days 
After Visit 404
28 to 35 Days 
After Visit 404
85 to 95 Days 
After Visit 404
175 to 189 Days After 
Visit 401 (or After 
Visit 404 for 
Participants Who 
Received SSD Vax 2)
Optimally Within 
3 Days After 
Potential COVID-19 
Illness Onset
ONLY FOR THE PARTICIPANTS WHO 
RECEIVE SSD VACCINATION 2
Provide/ensure the 
participant has a nasal 
self-swab kit and 
instructions on 
self-collection of nasal 
swabs
X
X
X
X
X
X
Abbreviations: HIV = human immunodeficiency virus; HLA = human leukocyte antigen; IRT = interactive response technology; PBMC = peripheral blood 
mononuclear cell; SSD = Substudy D.
a.
The visit may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and exclusion criteria onwards must be conducted on the 
same day.
b.
Only for those participants who consent to receive a dose of BNT162b2 OMI at Visit 404 as part of Substudy D.
c.
The COVID-19 illness visit may be conducted as an in-person or telehealth visit.
d.
For those participants who consent to receive a second dose of BNT162b2 OMI as part of Substudy D, the Visit 3 window is 85 to 123 days.
e.
Including, if indicated, a physical examination.
f.
Additional 120 mL for PBMC isolation and 5 mL for HLA typing for select participants at select sites only.
g.
Any AEs occurring up to 48 hours after the blood draw must be recorded (see Section 8.3.1).

PF-07302048 (BNT162b2 RNA-Based COVID-19 Vaccine)
Protocol C4591031
Final Protocol Amendment 12, 20 Sep 2023
PFIZER CONFIDENTIAL
Page 184
10.10.1.3.3. Cohort 3
Visit Number
501
502
503
504
505
506
507
508
Unplanned
Visit Description
Vaccination 
1
Vaccination 
2
1-Week
Follow-Up 
Visit After 
Vaccination 
2a
1-Month
Follow-Up 
Visit After 
Vaccination 
2
3-Month
Follow-Up 
Visit After 
Vaccination 
2
6-Month
Follow-Up Visit 
After Vaccination 2 
and Administration 
of Vaccination 3b
1-Month
Follow-Up 
Visit After 
Vaccination 3
6-Month 
Follow-Up 
Visit After 
Vaccination 3
Potential 
COVID-19 
Illness Visitc
Visit Window (Days)
Day 1d
19 to 23 
Days After 
Visit 501
6 to 8 Days 
After Visit 
502
28 to 35 
Days After 
Visit 502
85 to 95
Days After 
Visit 502
150 to 199 Days 
After Visit 502
28 to 35 Days 
After Visit 506
175 to 189
Days After 
Visit 506
Optimally 
Within 3 Days 
After Potential 
COVID-19 
Illness Onset
Obtain informed consent
X
Assign participant number 
X
Obtain demography and medical 
history data
X
Perform clinical assessmente
X
Measure height and weight
X
Measure temperature (body)
X
X
X
Perform urine pregnancy test 
(if appropriate)
X
X
X
Confirm use of contraceptives 
(if appropriate)
X
X
X
X
X
X
Collect nonstudy vaccine information 
X
X
X
X
X
X
X
Collect prohibited medication use
X
X
X
X
X
X
X
X
For participants who are HIV-positive, 
record latest CD4 count and HIV viral 
load
X
X
X
X
X
X
Confirm eligibility
X
X
X
Review temporary delay criteria
X
X
X
Collect blood sample for 
immunogenicity assessment
~50 mL
~50 mL
~50 mL
~50 mL
~50 mL
~50 mL
~50 mL
Collect blood sample for PBMC 
isolationf
~120 mL
~120 mL
~120 mL
~120 mL
~120 mL
~120 mL
~120 mL
Collect blood sample for HLA typingf
~5 mL

PF-07302048 (BNT162b2 RNA-Based COVID-19 Vaccine)
Protocol C4591031
Final Protocol Amendment 12, 20 Sep 2023
PFIZER CONFIDENTIAL
Page 185
Visit Number
501
502
503
504
505
506
507
508
Unplanned
Visit Description
Vaccination 
1
Vaccination 
2
1-Week
Follow-Up 
Visit After 
Vaccination 
2a
1-Month
Follow-Up 
Visit After 
Vaccination 
2
3-Month
Follow-Up 
Visit After 
Vaccination 
2
6-Month
Follow-Up Visit 
After Vaccination 2 
and Administration 
of Vaccination 3b
1-Month
Follow-Up 
Visit After 
Vaccination 3
6-Month 
Follow-Up 
Visit After 
Vaccination 3
Potential 
COVID-19 
Illness Visitc
Visit Window (Days)
Day 1d
19 to 23 
Days After 
Visit 501
6 to 8 Days 
After Visit 
502
28 to 35 
Days After 
Visit 502
85 to 95
Days After 
Visit 502
150 to 199 Days 
After Visit 502
28 to 35 Days 
After Visit 506
175 to 189
Days After 
Visit 506
Optimally 
Within 3 Days 
After Potential 
COVID-19 
Illness Onset
Obtain nasal (midturbinate) swab
X
X
X
X
Obtain the participant’s vaccine vial 
allocation using the IRT system
X
X
X
Administer study intervention
X
X
Xb
Assess acute reactions for at least 30 
minutes after study intervention
administration
X
X
X
Explain/review participant
communication methods (including for 
e-diary completion), assist the 
participant with downloading the app, 
or issue provisioned device, if required
X
X
X
Provide/ensure the participant has a
thermometer and measuring device
X
X
X
Review reactogenicity e-diary data 
(daily review is optimal during the 
active diary period)
Review ongoing reactogenicity e-diary 
symptoms and obtain stop dates
X
X
X
Collect AEs and SAEs as appropriate
X
X
X
X
Xg
X
X
Xg
X
Collect e-diary or assist the participant 
to delete application
X

PF-07302048 (BNT162b2 RNA-Based COVID-19 Vaccine)
Protocol C4591031
Final Protocol Amendment 12, 20 Sep 2023
PFIZER CONFIDENTIAL
Page 186
Visit Number
501
502
503
504
505
506
507
508
Unplanned
Visit Description
Vaccination 
1
Vaccination 
2
1-Week
Follow-Up 
Visit After 
Vaccination 
2a
1-Month
Follow-Up 
Visit After 
Vaccination 
2
3-Month
Follow-Up 
Visit After 
Vaccination 
2
6-Month
Follow-Up Visit 
After Vaccination 2 
and Administration 
of Vaccination 3b
1-Month
Follow-Up 
Visit After 
Vaccination 3
6-Month 
Follow-Up 
Visit After 
Vaccination 3
Potential 
COVID-19 
Illness Visitc
Visit Window (Days)
Day 1d
19 to 23 
Days After 
Visit 501
6 to 8 Days 
After Visit 
502
28 to 35 
Days After 
Visit 502
85 to 95
Days After 
Visit 502
150 to 199 Days 
After Visit 502
28 to 35 Days 
After Visit 506
175 to 189
Days After 
Visit 506
Optimally 
Within 3 Days 
After Potential 
COVID-19 
Illness Onset
Collection of COVID-19–related 
clinical and laboratory information 
(including local diagnosis)
X
Provide/ensure the participant has a 
nasal self-swab kit and instructions on 
self-collection of nasal swabs
X
X
X
X
X
X
X
Abbreviations: HIV = human immunodeficiency virus; HLA = human leukocyte antigen; IRT = interactive response technology; PBMC = peripheral blood mononuclear cell.
a.
Only for those participants who are part of the group for description of cell-mediated immune response.
b.
Vaccination 3 may be administered as early as 5 months (150 days) after Vaccination 2.
c.
The COVID-19 illness visit may be conducted as an in-person or telehealth visit.
d.
The visit may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and exclusion criteria onwards must be conducted on the 
same day.
e.
Including, if indicated, a physical examination.
f.
Additional 120 mL for PBMC isolation and 5 mL for HLA typing is for select participants at select sites only.  
g.
Any AEs occurring up to 48 hours after the blood draw must be recorded (see Section 8.3.1).

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10.10.2. Introduction
10.10.2.1. Study Rationale
On 24 November 2021, South Africa reported the identification of a new SARS-CoV-2 
variant, B.1.1.529, to the WHO. On 26 November 2021 and 30 November 2021, the WHO 
and the US, respectively, classified this new variant as a VOC and named it Omicron. The 
Omicron variant has also been detected in several European countries, as well as in 
North/South America, Asia, and Australia.44
The Omicron variant has many concerning spike protein mutations, some of which are 
known from other variants to be associated with reduced neutralization by convalescent and 
vaccine sera. Specific characteristics unique to Omicron are that the spike protein is 
characterized by at least 30 amino acid substitutions, 3 small deletions, and 1 small insertion. 
Notably, 15 of the 30 amino acid substitutions are in the receptor-binding domain. There are 
also a number of changes and deletions in other genomic regions.23
In regard to transmissibility, it is currently unknown how efficiently Omicron can spread 
from person to person. The replacement of Delta by Omicron as the predominant variant in 
South Africa raises concerns that it may be more transmissible than Delta, but because of the 
low number of cases in South Africa when it emerged, it is unclear if this variant is more 
transmissible than the Delta variant. Analysis of the changes in the spike protein indicate 
that Omicron is likely to have increased transmission compared to the original SARS-CoV-2 
virus, but it is difficult to infer if it is more transmissible than Delta. In addition, it is unclear
if infection with Omicron is associated with more severe disease. Lastly, to date there are no 
published data available to assess the ability of sera from vaccinated persons or those with 
previous SARS-CoV-2 infection to neutralize the Omicron variant.23 Laboratory and 
epidemiological studies are needed to assess the impact of the Omicron variant on vaccine 
effectiveness and breakthrough infections, including in individuals who have received 
booster doses.23
Pfizer has developed a new vaccine, BNT162b2 OMICRON (B.1.1.529), which is a 
BNT162b2 RNA-LNP vaccine utilizing modified RNA and encoding the P2 S containing 
Omicron B.1.1.529 variant-specific mutations. This new vaccine will be utilized in 
Substudy D. Substudy D has been designed to assess the safety, tolerability, and 
immunogenicity of BNT162b2 OMI within 3 different cohorts: 1) participants who have 
previously received 2 doses of BNT162b2 and will receive either 1 dose of BNT162b2 or 
1 or 2 doses of BNT162b2 OMI; 2) participants who have previously received 3 doses of 
BNT162b2 and will receive a fourth dose of either BNT162b2 or BNT162b2 OMI
(participants will be offered a dose of BNT162b2 OMI at Visit 404 (3-month follow-up); and 
3) participants who are BNT162b2-naïve and will receive 2 doses of BNT162b2 OMI, 
followed by a dose of BNT162b2.

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As part of protocol amendment 11, active participants in Cohort 1 and Cohort 2 at the time of 
this amendment will only be followed for 6 months after their last study vaccination, which 
aligns with the protocol-specified safety reporting period. As of Fall 2022, the recommended 
booster vaccine will switch to a bivalent original/Omicron-modified vaccine, and therefore it 
is unnecessary to prolong the participation of individuals in the study and take 
immunogenicity samples 12 months after vaccination for the monovalent Omicron vaccine. 
Their final visit will be V405.
For participants who have already completed V405 at the time of protocol amendment 11, 
they will be informed by the investigator site staff of study completion and that no further 
visits are required.
As part of protocol amendment 12, endpoints and/or analyses that do not pertain to current 
variant-modified versions of BNT162b2 were removed to expedite remaining testing and to 
focus on analyses of interest.
See Section 2.2 for the study background.
10.10.2.2. Benefit/Risk Assessment
No additional risks are identified for Substudy D beyond those detailed for the master study 
(see Section 2.3).
10.10.2.2.1. Benefit Assessment
Benefits to individual participants enrolled in Substudy D may be:

Receipt of a third, fourth, or fifth dose of an efficacious or potentially efficacious 
COVID-19 vaccine that may convey a longer duration of protection during a global 
pandemic.

Contributing to research to help others in a time of global pandemic.

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10.10.3. Objectives, Estimands, and Endpoints
Objectives
Estimands
Endpoints
Primary Safety

To describe the safety and 
tolerability profile of 
BNT162b2 OMI given as the 
third, fourth, or fifth dose to 
BNT162b2-experienced 
participants, or as a 2-dose series 
to COVID-19 vaccine–naïve 
participants

To describe the safety and 
tolerability profile of BNT162b2 
given as a third or fourth dose to 
BNT162b2-experienced 
participants (Group 2b, Group 4, 
and Group 5)
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 the first study vaccination
(received in this study) through 1 month 
after the last study vaccination

SAEs from the first study vaccination
(received in this study) through 6 months 
after the last study vaccination

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
Primary Immunogenicity
BNT162b2-experienced participants
G1vG2bA: To descriptively compare
the anti-Omicron immune response 
after 1 dose of BNT162b2 OMI to 
after 1 dose of BNT162b2 given as the 
third dose in BNT162b2-experienced 
participants 
In participants complying with the key protocol 
criteria (evaluable participants) and with
evidence of past SARS-CoV-2 infection:

GMR of the Omicron-neutralizing titers at 
1 month after 1 dose of BNT162b2 OMI to 
those at 1 month after 1 dose of BNT162b2 
given as the third dose in BNT162b2-
experienced participants

The difference in percentages of 
participants with seroresponsea to the 
Omicron strain at 1 month after 1 dose of 
BNT162b2 OMI and at 1 month after 1 
dose of BNT162b2 given as the third dose 
in BNT162b2-experienced participants 
SARS-CoV-2 
Omicron-neutralizing titers
G2vG2bA: To descriptively compare
the anti-Omicron immune response 
after 2 doses of BNT162b2 OMI given 
as the third and fourth dosesto after 
1 dose of BNT162b2 given as the third 
dose in BNT162b2-experienced 
participants 
In participants complying with the key protocol 
criteria (evaluable participants) and with 
evidence of past SARS-CoV-2 infection:

GMR of the Omicron-neutralizing titers at 
1 month after 2 doses of BNT162b2 OMI to 
those at 1 month after 1 dose of BNT162b2 
given as the third (and fourth) dose in 
BNT162b2-experienced participants

The difference in percentages of 
participants with seroresponsea to the 
Omicron strain at 1 month after 2 doses of 
BNT162b2 OMI and at 1 month after 1 
dose of BNT162b2 given as the third (and 
fourth) dose in BNT162b2-experienced 
participants 
SARS-CoV-2 
Omicron-neutralizing titers

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Objectives
Estimands
Endpoints
G3vG4A: To demonstrate the 
superiority with respect to level of 
neutralizing titer and noninferiority 
with respect to seroresponse rate of the 
anti-Omicron immune response after 
1 dose of BNT162b2 OMI compared 
to after 1 dose of BNT162b2 given as 
the fourth dose in BNT162b2-
experienced participants 
In participants complying with the key protocol 
criteria (evaluable participants) and no 
serological or virological evidence (up to 
1 month after receipt of 1 dose of study 
intervention) of past SARS-CoV-2 infection:

GMR of the Omicron-neutralizing titers at 
1 month after 1 dose of BNT162b2 OMI to 
those at 1 month after 1 dose of BNT162b2 
given as the fourth dose in 
BNT162b2-experienced participants

The difference in percentages of 
participants with seroresponsea to the 
Omicron strain at 1 month after 1 dose of 
BNT162b2 OMI and at 1 month after 1 
dose of BNT162b2 given as the fourth dose 
in BNT162b2-experienced participants 
SARS-CoV-2 
Omicron-neutralizing titers
COVID-19 vaccine–naïve participants
G5A: To demonstrate the superiority
with respect to level of neutralizing 
titer and noninferiority with respect to 
seroresponse rate of the anti-Omicron 
immune response after 2 doses of 
BNT162b2 OMI compared to after 
2 doses of BNT162b2 in participantsb
selected from the C4591001 study
In participants complying with the key protocol 
criteria (evaluable participants) and with or 
without serological or virological evidence (up to 
1 month after receipt of the second dose of 
BNT162b2 OMI or BNT162b2 as appropriate) 
of past SARS-CoV-2 infection:

GMR of the Omicron-neutralizing titers 
1 month after the second dose of 
BNT162b2 OMI to 1 month after the 
second dose of BNT162b2 in participants 
selected from the C4591001 study

The difference in percentages of 
participants with seroresponsea to the 
Omicron strain at 1 month after the second 
dose of BNT162b2 OMI and at 1 month 
after the second dose of BNT162b2 in 
participants selected from the C4591001 
study
SARS-CoV-2 
Omicron-neutralizing titers 
Secondary Immunogenicity
BNT162b2-experienced participants
G3vG4B: To demonstrate the “super”
superiority of the anti-Omicron 
immune response after 1 dose of 
BNT162b2 OMI compared to after 
1 dose of BNT162b2 given as the 
fourth dose in BNT162b2-experienced 
participants 
Same as GMR estimand of G3vG4A
Same as G3vG4A

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Objectives
Estimands
Endpoints
COVID-19 vaccine–naïve participants
G5B: To demonstrate the “super”
superiority of the anti-Omicron 
immune response after 2 doses of 
BNT162b2 OMI compared to after 
2 doses of BNT162b2 in participantsb
selected from the C4591001 study
Same as GMR estimand of G5A
Same as G5A
Exploratory
To describe the immune response to 
BNT162b2 OMI or BNT162b2 given 
as the third and/or fourth and/or fifth 
dose in BNT162b2-experienced 
participants
For Cohort 1: at baseline, 1 month after the first 
study vaccination, and 1 month after the second 
study vaccination (Group 2 only),
For Cohort 2: at baseline, 1 month and 3 months 
after the first study vaccination, and 1 month, 
3 months, and 6 months after the last study 
vaccination:

GMT at each time point

GMFRs from before the first dose of study 
intervention to subsequent time points

Percentages of participants with 
seroresponsea at each time point

SARS-CoV-2 
Omicron-neutralizing 
titers

SARS-CoV-2 reference-
strain–neutralizing titers
To describe the immune response to 
BNT162b2 OMI in COVID-19 
vaccine–naïve participants
At baseline, 1 month and 6 months after Dose 2, 
and 1 month and 6 months after Dose 3:

GMT at each time point

GMFRs from before the first dose of 
BNT162b2 OMI to subsequent time points

Percentages of participants with 
seroresponsea at each time point

SARS-CoV-2 
Omicron-neutralizing 
titers

SARS-CoV-2 reference-
strain–neutralizing titers
To describe the immune response to 
the reference strain and VOCs in a 
subset of 30 participantsc per group 

SARS-CoV-2 
neutralizing titers for 
the reference strain and 
VOCs
To describe the immune response to 
any VOCs not already specified 
(eg, Delta)

SARS-CoV-2 
neutralizing titers for 
any VOCs not already 
specified (eg, Delta)
To describe confirmed COVID-19 and 
severe COVID-19 cases

Confirmed COVID-19 
cases

Confirmed severe 
COVID-19 cases

Strain sequencing of 
COVID-19 cases

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Objectives
Estimands
Endpoints
To describe the cell-mediated immune
response, and additional humoral 
immune response parameters, to the 
reference strain and Omicron in a 
subset of participants with PBMC 
samples collected in each group
a.
Seroresponse is defined as achieving a ≥4-fold rise from baseline (before the first dose of study 
vaccination).  If the baseline measurement is below the LLOQ, the postvaccination measure of 
≥4 × LLOQ is considered seroresponse.
b.
A subset of approximately 175 participants (18 through 55 years of age) from Study C4591001 who 
have received 2 doses of BNT162b2 30 µg will be selected for this objective. The subset selected from 
Study C4591001 will include a similar percentage of participants with a positive SARS-CoV-2 infection 
status at baseline as Group 5 of this substudy, whenever feasible.
c.
This subset of participants will not contribute to the assessment of primary and secondary 
immunogenicity objectives.
10.10.4. Study Design
10.10.4.1. Overall Design
This is a randomized substudy composed of open-labeled and observer-blinded groups to 
evaluate the safety, tolerability, and immunogenicity of a 2-dose primary series of 
BNT162b2 OMI, and as a booster (third, fourth, or fifth) dose at investigator sites in the US 
and South Africa only.  Participants ≥18 years of age to ≤55 years of age will be enrolled.
Approximately 1420 participants will be enrolled in the study.
Participants in Cohort 1 will have completed a 2-dose primary series of BNT162b2 
(30-µg doses), with their last dose 90 to 240 days prior to enrollment. Approximately 
615 participants will be randomized at a ratio of 1:1:1 either to receive 1 dose (third) of 
BNT162b2 OMI, 2 doses (third and fourth) of BNT162b2 OMI, 4 weeks apart, or 1 dose 
(third) of BNT162b2. Randomization will be stratified by age (stratified as 18-30 and 
31-55 years of age). Participants in Cohort 1 will remain blinded to whether they will be 
receiving a fourth dose through 1 month after their first dose, but the investigator and sponsor 
will not be blinded.
Participants in Cohort 2 will be enrolled from Study C4591001 and C4591031 Substudy A
and will have completed a 2-dose primary series and received a single booster (third) dose of 
BNT162b2, with their last dose 90 to 180 days prior to randomization. Approximately
600 participants will be randomized at a ratio of 1:1 to receive a fourth dose of either 
BNT162b2 or BNT162b2 OMI at Visit 401. Participants will be offered a dose of 
BNT162b2 OMI at Visit 404 (3-month follow-up). Randomization will be stratified by age 
(stratified as 18-30 and 31-55 years of age). Cohort 2 will be observer-blinded.
In Cohort 3, 205 participants 18 through 55 years of age who are COVID-19 vaccine–naïve 
and have not experienced COVID-19 will be enrolled to receive 2 doses (primary series) of 
BNT162b2 OMI, 3 weeks apart, with a dose of BNT162b2 approximately 5 months later.
If participants do not consent to receive BNT162b2 as a third dose, they will not receive a 
third dose. No participants should receive BNT162b2 OMI as a third dose.

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A subset of 30 participants may be selected from each group to serve as a sentinel group for 
immunogenicity assessment. Participants in the subset will not contribute to the assessment 
of primary and secondary immunogenicity objectives. Immunogenicity data from these 
participants will be summarized separately for the exploratory objective specific for the 
subset. See Section 10.10.9.5 for details.
Table 10 details the number of participants by cohort and group, their prior BNT162b2 
experience, the vaccine that will be administered, and the number of doses administered as 
part of Substudy D.
Table 10.
Total Number of Participants by Cohort
Cohort
Group
Prior 
BNT162b2
Experience
Vaccine
Number of 
Doses 
Administered 
as Part of 
Substudy D
Total Number of 
Participants
Cohort 1
Group 1
2 Doses
BNT162b2 OMI
1
205
Group 2 
2 Doses
BNT162b2 OMI
2
205
Group 2b
2 Doses
BNT162b2
1
205
Cohort 2
Group 3
3 Doses
BNT162b2 OMI
1 or 2
300
Group 4
3 Doses
BNT162b2 (and 
BNT162b2 OMI 
at Visit 404)
1 or 2
300
Cohort 3
Group 5
Naïve
BNT162b2 OMI
2
205
BNT162b2
1
Note: Cohorts 1 and 2 are observer-blinded. Participants in Cohort 1 will remain blinded to whether they 
will be receiving a fourth dose through 1 month after their first dose. Cohort 2 participants will be unblinded 
once they have completed Visit 404. Cohort 3 is open-labeled.
As part of protocol amendment 11, active participants in Cohort 1 and Cohort 2 at the time of 
this amendment will only be followed for 6 months after their last study vaccination, the 
protocol-specified safety reporting period. Their final visit will be V405. 
10.10.4.2. Scientific Rationale for Substudy D Design
See Section 10.10.2.1.
10.10.4.2.1. Diversity of Study Population 
Reasonable attempts will be made to enroll participants who align with the US population 
distribution (Census-based), to ensure that the study population is representative of patient 
populations that will benefit from a COVID-19 vaccine in clinical practice.
10.10.4.3. Justification for Dose
See Section 4.3 for a justification of the BNT162b2 and BNT162b2 OMI dose used in 
Substudy D.

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10.10.4.4. End of Study Definition
See Section 4.4.
10.10.5. Study Population
Details of the master and Substudy D eligibility criteria are shown in Section 5.  Participants 
must meet all of the general inclusion and exclusion criteria as specified for the master 
protocol as well as Substudy D–specific inclusion and exclusion criteria.
10.10.5.1. Inclusion Criteria
Participants are eligible to be included in Substudy D only if all of the following criteria 
apply:
Age and Sex:
1. Male or female participants 18 to 55 years of age inclusive:
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, vaccination 
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Healthy participants who are determined by medical history, physical examination
(if required), and clinical judgment of the investigator to be eligible for inclusion in the 
study.
Note: Healthy participants with preexisting stable disease, defined as disease not 
requiring significant change in therapy or hospitalization for worsening disease during 
the 6 weeks before enrollment, can be included.  Specific criteria for participants with 
known stable infection with HIV, HCV, or HBV can be found in Section 10.15.
4. Cohort 2: Participants who provided a serum sample at Visit 3 in Study C4591001, with 
Visit 3 occurring within the protocol-specified window.
Informed Consent:
5. Capable of giving personal signed informed consent as described in Appendix 1, which
includes compliance with the requirements and restrictions listed in the ICD and in this 
protocol.

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Other Inclusions:
6. Cohort 1: Participants who have received 2 prior doses of 30 µg BNT162b2, with the 
second dose being 90 to 240 days before Visit 401 (Day 1)
or
Cohort 2: Participants who have received 3 prior doses of 30 µg BNT162b2, with the 
third dose being 90 to 180 days before Visit 401 (Day 1).
Documented confirmation of prior BNT162b2 receipt must be obtained prior to 
randomization.
10.10.5.2. Exclusion Criteria
Participants are excluded from Substudy D if any of the following criteria apply:
Medical Conditions:
1. Other medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for the 
study.
2. History of severe adverse reaction associated with a vaccine and/or severe allergic 
reaction (eg, anaphylaxis) to any component of the study intervention(s).
3. 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.
4. Immunocompromised individuals with known or suspected immunodeficiency, as 
determined by history and/or laboratory/physical examination.
5. Bleeding diathesis or condition associated with prolonged bleeding that would, in the 
opinion of the investigator, contraindicate intramuscular injection.
6. Women who are pregnant or breastfeeding.
Prior/Concomitant Therapy:
7. Individuals who receive treatment with radiotherapy or immunosuppressive therapy, 
including cytotoxic agents or systemic corticosteroids (if systemic corticosteroids are 
administered for ≥14 days at a dose of ≥20 mg/day of prednisone or equivalent), eg, for 
cancer or an autoimmune disease, or planned receipt throughout the study.  
Inhaled/nebulized, intra-articular, intrabursal, or topical (skin or eyes) corticosteroids are 
permitted.

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8. Receipt of blood/plasma products, immunoglobulin, or monoclonal antibodies, from 
60 days before study intervention administration, or receipt of any passive antibody 
therapy specific to COVID-19, from 90 days before study intervention administration, or 
planned receipt throughout the study.
Prior/Concurrent Clinical Study Experience:
9. Cohorts 1 and 2: prior receipt of any COVID-19 vaccine other than BNT162b2.
10. Cohort 3 only: prior receipt of any COVID-19 vaccine.
Other Exclusions:
11. Investigator site staff or Pfizer-BioNTech employees directly involved in the conduct of 
the study, site staff otherwise supervised by the investigator, and their respective family 
members.
12. Receipt of medications intended to prevent COVID-19.
13. Participation in other studies involving study intervention within 28 days prior to study
entry through and including 28 days after the last dose of study intervention, with the 
exception of non-Pfizer interventional studies for prevention of COVID-19, which are 
prohibited throughout study participation.
10.10.5.3. Lifestyle Considerations
Contraception requirements will apply to Substudy D as detailed in Section 5.3 and
Section 10.4.
10.10.5.4. Screen Failures
See Section 5.4.
10.10.5.5. Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention
See Section 5.5.
10.10.6. Study Intervention(s) and Concomitant Therapy
For the purposes of this substudy, study intervention refers to:

BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S): 
30 µg

BNT162b2 OMI (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the 
P2 S): 30 µg

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10.10.6.1. Study Intervention(s) Administered
See Section 6.1 for details of BNT162b2.
Additional Intervention 
Name
BNT162b2 OMICRON (B.1.1.529)
(BNT162 RNA-LNP vaccine utilizing modRNA)
Type
Vaccine
Dose Formulation
modRNA
Unit Dose Strength(s)
250 µg/0.5 mL
Dosage Level(s) 
30 µg
Route of Administration
Intramuscular injection
Use
Experimental
IMP or NIMP
IMP
Sourcing
Provided centrally by the sponsor
Packaging and Labeling
Study intervention will be provided in a glass vial as open-label supply.  
Each vial will be labeled as required per country requirement.
10.10.6.1.1. Administration
For Cohorts 1 and 2, participants will receive 1 dose of study intervention as allocated by the
IRT at Visit 401 (third or fourth dose) in accordance with the substudy’s SoA 
(Section 10.10.1.3). Group 2 participants will receive a second dose of BNT162b2 OMI at 
Visit 402. Group 3 and Group 4 participants may receive a dose of BNT162b2 OMI at 
Visit 404.
For Cohort 3, COVID-19 vaccine–naïve participants will receive 1 dose of BNT162b2 OMI
at Visit 501 and Visit 502, and 1 dose of BNT162b2 at Visit 506. Vaccination 3 may be 
administered as early as 5 months (150 days) after Vaccination 2.
Study intervention should be administered intramuscularly into the deltoid muscle, preferably 
of the nondominant arm, by an unblinded administrator.
10.10.6.1.2. Preparation and Dispensing
Study intervention will be prepared by qualified unblinded site personnel according to the IP 
manual.  The study intervention will be administered in such a way as to ensure that the 
participants in Cohorts 1 and 2 remain blinded. Cohort 3 is open-labeled.
10.10.6.2. Measures to Minimize Bias: Randomization and Blinding
10.10.6.2.1. Blinding of Site Personnel
In Cohort 1 (Groups 1 and 2b) and Cohort 2, the study staff receiving, storing, dispensing, 
preparing, and administering the study interventions will be unblinded.  All other study and 
site personnel, including the investigator, investigator staff, and participants, will be blinded 
to study intervention assignments.  In particular, the individuals who evaluate participant 
safety will be blinded.

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The PI will assign the responsibility of the unblinded dispensers/administrators to persons 
who will not participate in the evaluation of any study participant.  To ensure adequate 
coverage, at least 2 unblinded dispensers/administrators will be assigned per site.  Members 
of the study site staff or clinic pharmacy should fulfill these roles.  Contact between the 
unblinded dispensers and study participants should be kept to a minimum.  The investigator, 
study coordinator, and any site staff other than the unblinded dispensers/administrators must 
not be allowed to know the study intervention assigned to any study participant and must not 
be allowed to see the study intervention container contents.  In the event of a Quality 
Assurance audit, the auditor(s) will be allowed access to unblinded study intervention records 
at the site(s) to verify that randomization/dispensing has been done accurately.
The group of participants who will be enrolled to receive a third and fourth dose of 
BNT162b2 OMI (Group 2 of Cohort 1) will remain blinded to whether they will be receiving 
a fourth dose, through 1 month after their first dose of BNT162b2 OMI, but the investigator 
and sponsor will not be blinded.
Participants in Cohort 2 will be unblinded to confirm the vaccine received once they have 
completed Visit 404 (3 months after Substudy D Vaccination 1).
10.10.6.2.2. Blinding of the Sponsor
The majority of sponsor/Pfizer staff will be blinded to study intervention allocation for 
Cohort 1 (Groups 1 and 2b) and Cohort 2.  All laboratory testing personnel performing 
serology assays will remain blinded to study intervention assigned/received throughout the 
study. The following sponsor/Pfizer staff, who will have no part in the blinded conduct of 
the study, will be unblinded (further details will be provided in a data blinding plan):

Those study team members who are involved in ensuring that protocol requirements for 
study intervention preparation, handling, allocation, and administration are fulfilled at the 
site will be unblinded for the duration of the study (eg, unblinded study manager, 
unblinded clinical research associate).

Unblinded clinician(s), who are not direct members of the study team and will not 
participate in any other study-related activities, will review unblinded protocol 
deviations.

An unblinded team supporting interactions with, and analyses for, the DMC 
(see Section 10.9.9.4.2).  This team comprises a statistician, programmer(s), a clinical 
scientist, and a medical monitor. 

An unblinded submissions team will be responsible for preparing unblinded analyses and 
documents to support regulatory activities that may be required while the study is 
ongoing.  With the exception of the statisticians and programmers, who will become 
unblinded at the participant level at the time of the first planned reporting event to 
perform the analyses, other members of this team will only be unblinded at the group 
level and not have access to individual participant assignments.  A separate group of 

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statisticians and programmers will remain blinded and continue supporting the blinded 
conduct of the study after the first planned analysis.
Participants in Cohort 1 (Groups 1 and 2b) may be unblinded to confirm the vaccine received 
once they have completed Visit 404 (3 months after Substudy D Vaccination 1). Cohort 2
participants will be unblinded once they have completed Visit 404. Since these are the only 
participants still blinded at this time, the study team will also become unblinded to all
participants’ original study intervention allocation at this time.
10.10.6.2.3. Breaking the Blind
The IRT will be programmed with blind-breaking instructions.  In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s study 
intervention assignment is warranted.  Participant safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the sponsor prior to 
unblinding a participant’s vaccine assignment unless this could delay further management of 
the participant.  If a participant’s vaccine assignment is unblinded, the sponsor must be 
notified within 24 hours after breaking the blind.  The date and reason that the blind was 
broken must be recorded in the source documentation and CRF.
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
10.10.6.3. Study Intervention Compliance
See Section 6.4.
10.10.6.4. Dose Modification
See Section 6.5.
10.10.6.5. Continued Access to Study Intervention After the End of the Study
See Section 6.6.
10.10.6.6. Treatment of Overdose
See Section 6.7.
10.10.6.7. Concomitant Therapy
See Section 6.8.
10.10.7. Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
See Section 7.

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10.10.8. Study Assessments and Procedures
The total blood sampling volume for individual participants in this study is up to 
approximately 250 mL for those participants who receive 1 dose and 350 mL for those who 
receive 2 doses. Those participants in the subset who consent to additional blood collection 
for isolation of PBMCs will have a total blood sampling volume of up to approximately
735 mL for those participants who receive 1 dose and 785 mL for those who receive 2 doses.
For those participants enrolled in Cohort 3, COVID-19 vaccine–naïve participants who will 
receive 2 doses of BNT162b2 OMI followed by 1 dose of BNT162b2, the total blood 
sampling volume for individual participants is up to approximately 350 mL. Those 
participants in the cohort who consent to additional blood collection for isolation of PBMCs 
will have a total blood sampling volume of up to approximately 1195 mL.
For all participants, other additional blood samples may be taken for safety assessments at 
times specified by Pfizer, provided the total volume taken during the study does not exceed 
550 mL during any period of 60 consecutive days.
10.10.8.1. Surveillance for COVID-19
If, at any time, a participant develops acute respiratory illness (see Section 10.7.8.5.5.1), for 
the purposes of the study he or she will be considered to potentially have COVID-19 illness.  
In this circumstance, the participant should contact the site, an in-person or telehealth visit 
should occur, and assessments should be conducted as specified in the SoA.  The assessments 
will include collection of a nasal (midturbinate) swab, which will be tested at a central 
laboratory using an RT-PCR test (Cepheid; FDA-approved under EUA and Pfizer-validated), 
or other equivalent nucleic acid amplification–based test (ie, NAAT) to detect SARS-CoV-2.  
In addition, clinical information and results from local standard-of-care tests (as detailed in 
Section 10.7.8.5.5.1) will be assessed.  The central laboratory NAAT result will be used for 
the case definition, unless no result is available from the central laboratory, in which case a 
local NAAT result may be used if it was obtained using 1 of the following assays:

Cepheid Xpert Xpress SARS-CoV-2

Roche cobas SARS-CoV-2 real-time RT-PCR test (EUA200009/A001)

Abbott Molecular/RealTime SARS-CoV-2 assay (EUA200023/A001)
Definitions of SARS-CoV-2–related cases, and SARS-CoV-2–related severe cases, will be 
considered as follows (for both, the onset date of the case will be the date that symptoms 
were first experienced by the participant; if new symptoms are reported within 4 days after 
resolution of all previous symptoms, they will be considered as part of a single illness):

Confirmed COVID-19: presence of at least 1 of the following symptoms and 
SARS-CoV-2 NAAT-positive during, or within 4 days before or after, the symptomatic 
period, either at the central laboratory or at a local testing facility (using an acceptable 
test):

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
Fever; 

New or increased cough; 

New or increased shortness of breath; 

Chills; 

New or increased muscle pain; 

New loss of taste or smell;

Sore throat;

Diarrhea;

Vomiting.

Confirmed severe COVID-19 (FDA definition45): confirmed COVID-19 and presence of 
at least 1 of the following:

Clinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per minute, 
HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or PaO2/FiO2
<300 mm Hg);

Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation, 
mechanical ventilation, or ECMO);

Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiring vasopressors);

Significant acute renal, hepatic, or neurologic dysfunction;

Admission to an ICU;

Death.

Confirmed severe COVID-19 (CDC definition46): confirmed COVID-19 and presence of 
at least 1 of the following:

Hospitalization; 

Admission to the ICU;

Intubation or mechanical ventilation; 

Death.

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The DMC may recommend modification of the definition of severe disease according to 
emerging information.
10.10.8.2. Immunogenicity
Serum samples will be obtained for immunogenicity testing at the visits specified in the SoA.
The test to be performed will be the SARS-CoV-2 neutralizing assay (reference strain and 
Omicron strain). Note that all immunogenicity analyses will be based upon samples 
analyzed at the central laboratory.
Additional whole blood samples of ~120 mL will be obtained from a group of up to 
approximately 30 participants in each group for evaluation of boostability and protection 
against Omicron and the reference strain (both BNT162b2-experienced and 
BNT162b2-naïve) at select sites for isolation of PBMCs. These samples will be used to 
describe B-cell and T-cell responses to Omicron and the reference strain. A blood sample of 
~5 mL for HLA typing will also be obtained.
10.10.8.3. Safety Assessments
See Section 8.2.
10.10.8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting
See Section 8.3.
10.10.8.5. Specified Genetics
Some of the blood samples collected for PBMC isolation and HLA typing may be used for 
DNA and/or RNA isolation. The DNA and/or RNA samples from the PBMC isolation may 
be used for sequencing of participants’ antibody and/or BCR heavy- and light-chain genes, 
TCR genes, and/or mRNAs, for understanding the B-cell, T-cell, and antibody repertoires. 
The DNA and/or RNA samples from the blood sample for HLA typing may be used to 
further characterize HLA type. 
See Appendix 16 for information regarding genetic research. Details on processes for 
collection and shipment of these samples will be provided separately.
10.10.8.6. Substudy D Procedures
10.10.8.6.1. Administration of Additional Dose(s) of BNT162b2 or BNT162b2 OMI
(Cohort 1)
10.10.8.6.1.1. Visit 401 – Substudy D Vaccination (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written, 
study-specific informed consent will be obtained from the participant.  Each signature on the 
ICD must be personally dated by the signatory.  The investigator or his or her designee will 
also sign the ICD.  A copy of the signed and dated ICD must be given to the participant.  The 
source data must reflect that the informed consent was obtained before participation in the 
study.

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It is anticipated that the procedures below will be conducted in a stepwise manner.  The visit 
may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and 
exclusion criteria onwards must be conducted on the same day.

Assign a single participant number using the IRT system.

Obtain the participant’s prior study and participant number (if applicable) and record this 
in the CRF.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).  
The full date of birth will be collected to critically evaluate the immune response and 
safety profile by age.

Obtain any medical history of clinical significance.  For participants who are 
HIV-positive, record the HIV viral load and CD4 count results from the most recent test 
performed in the previous 6 months.

Perform a clinical assessment.  If the clinical assessment indicates that a physical 
examination is necessary to comprehensively evaluate the participant, perform a physical 
examination and record any findings in the source documents and, if clinically 
significant, record any findings on the medical history CRF.

Measure the participant’s height and weight.

Measure the participant’s body temperature.

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 5.3.

Record nonstudy vaccinations as described in Section 6.8.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Record AEs as described in Section 8.3.

Collect a blood sample for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation 
and a further blood sample (approximately 5 mL) for HLA typing.

Obtain a nasal (midturbinate) swab (collected by site staff).

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As Cohort 1 is observer-blinded, the blinded and unblinded roles should still be 
maintained to ensure the integrity of the blind:

Blinded site staff will obtain the participant’s randomization number using the IRT 
system. The randomization confirmation report with the study intervention allocation will 
only be sent to the unblinded site staff member. 

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into 
the deltoid muscle of the preferably nondominant arm.  Please refer to the IP manual for 
further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study 
intervention administration for any acute reactions.  Record any acute reactions 
(including time of onset) in the participant’s source documents and on the AE page of the 
CRF, and on an SAE form as applicable.

Provide a measuring device to measure local reactions at the injection site and a 
thermometer for recording daily temperatures and fever (COVID-19 surveillance) and 
provide instructions on their use.

Explain the e-diary technologies available for this study (see Section 8.2.4), and assist the 
participant in downloading the study application onto the participant’s own device or 
issue a provisioned device if required.

Provide instructions on reactogenicity e-diary completion and ask the participant to 
complete the reactogenicity e-diary from Day 1 through Day 7, with Day 1 being the day 
of vaccination.

Provide instructions on COVID-19 illness e-diary completion and ask the participant to 
complete the COVID-19 illness e-diary if the participant is diagnosed with COVID-19 or 
has possible new or increased symptoms, and when he/she receives a reminder, at least 
weekly.  See Section 10.10.8.6.4 for further details. Provide a self-swab kit in case of 
COVID-19 symptoms and provide instructions on self-collection of nasal swabs.

Ask the participant to contact the site staff or investigator immediately if the participant 
experiences any of the following from Day 1 through Day 7 after vaccination 
(where Day 1 is the day of vaccination) to determine if an unscheduled reactogenicity 
visit is required: 

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units).

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
Severe pain at the injection site.

Any severe systemic event.

Ask the participant to contact the site staff or investigator if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.10.8.6.7).

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 10.10.8.6.4.1.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the reactogenicity e-diary to the next visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs and an unblinded 
dispenser/administrator updates the study intervention accountability records.

The investigator or appropriately qualified designee reviews the reactogenicity e-diary 
data online following vaccination to evaluate participant compliance and as part of the 
ongoing safety review. Daily review is optimal during the active diary period.
10.10.8.6.1.2. Visit 402 – 1-Month Follow-Up Visit (After Substudy D Vaccination 1) 
(28 to 35 Days After Visit 401)

Record AEs as described in Section 8.3.

Review the participant’s reactogenicity e-diary data. Collect stop dates of any 
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary was 
completed and record stop dates in the CRF if required.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Discuss contraceptive use as described in Section 5.3.

Collect a blood sample for immunogenicity testing.

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
If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.
Only if the participant is to receive a second dose of BNT162b2 OMI (Substudy D 
Vaccination 2):

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Measure the participant’s body temperature.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met.
Note: a positive SARS-CoV-2 NAAT result without symptoms or a COVID-19 diagnosis 
(based on signs/symptoms only or signs/symptoms and a positive SARS-CoV-2 NAAT 
result) should not result in discontinuation of study intervention.  Please see Section 7.1.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of BNT162b2 OMI into 
the deltoid muscle of the preferably nondominant arm.  Please refer to the IP manual for 
further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study 
intervention administration for any acute reactions.  Record any acute reactions 
(including time of onset) in the participant’s source documents and on the AE page of the 
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection 
site and a thermometer for recording daily temperatures.

Ensure the participant has a self-swab kit.

Remind the participant of the e-diary technologies available for this study 
(see Section 10.10.8.6.5).  Provide instructions on e-diary completion and ask the 
participant to complete the reactogenicity e-diary from Day 1 through Day 7, with Day 1 
being the day of vaccination, and, if utilized, the COVID-19 illness e‑diary (to be 
completed if the participant is diagnosed with COVID-19 or has possible new or 
increased symptoms, and when he/she receives a reminder, at least weekly).

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
Ask the participant to contact the site staff or investigator immediately if he or she 
experiences any of the following from Day 1 through Day 7 after vaccination (where 
Day 1 is the day of vaccination) to determine if an unscheduled reactogenicity visit is 
required (see Section 10.10.8.6.8):

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units).

Severe pain at the injection site.

Any severe systemic event.

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 10.10.8.6.4.1.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

The investigator or appropriately qualified designee reviews the reactogenicity e-diary 
data online following vaccination to evaluate participant compliance and as part of the 
ongoing safety review. Daily review is optimal during the active diary period.
10.10.8.6.1.3. Visit 403 – 1-Month Follow-Up Visit (After Substudy D Vaccination 2)
(28 to 35 Days After Visit 402): Only for Those Participants Who Receive Substudy D 
Vaccination 2

Record AEs as described in Section 8.3.

Review the participant’s reactogenicity e-diary data. Collect stop dates of any 
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary was 
completed and record stop dates in the CRF if required.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 5.3.

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
Collect a blood sample for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 10.10.8.6.4.1.

Ensure the participant has a self-swab kit.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
10.10.8.6.1.4. Visit 404 – 3-Month Follow-Up Visit (85 to 95 Days After Visit 401, or 
85 to 95 Days After Visit 402 for Those Participants Who Receive Substudy D 
Vaccination 2) 

Collect a blood sample for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 10.10.8.6.4.1.

Ensure the participant has a self-swab kit.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

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
Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3.

Participants in Cohort 1 (Groups 1 and 2b) may be unblinded to confirm the vaccine
received once they have completed Visit 404 (3 months after Substudy D Vaccination 1). 
Since these are the only participants still blinded at this time, the study team will also 
become unblinded to all participants’ original study intervention allocation at this time.
10.10.8.6.1.5. Visit 405 – 6-Month Follow-Up Visit (175 to 189 Days After Visit 401, or 
175 to 189 Days After Visit 402 for Those Participants Who Receive Substudy D 
Vaccination 2)
For participants who have already completed V405 at the time of protocol amendment 11, 
they will be informed by the investigator site staff of study completion and that no further 
visits are required.

Record AEs as described in Section 8.3

Collect a blood sample for immunogenicity testing.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 10.10.8.6.4.1.

Schedule an appointment for the participant to return for the next study visit.

Collect the participant’s e-diary or assist the participant to remove the study application 
from his or her own personal device.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3.
10.10.8.6.2. Administration of Additional Dose(s) of BNT162b2 or BNT162b2 OMI 
(Cohort 2)
Participants who do not provide consent to receive a dose of BNT162b2 OMI at Visit 404 
will remain on the single-dose visit schedule.

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10.10.8.6.2.1. Visit 401 – Substudy D Vaccination (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written, 
study-specific informed consent will be obtained from the participant.  Each signature on the 
ICD must be personally dated by the signatory.  The investigator or his or her designee will 
also sign the ICD.  A copy of the signed and dated ICD must be given to the participant.  The 
source data must reflect that the informed consent was obtained before participation in the 
study.
It is anticipated that the procedures below will be conducted in a stepwise manner.  The visit 
may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and 
exclusion criteria onwards must be conducted on the same day.

Assign a single participant number using the IRT system.

Obtain the participant’s prior study and participant number (if applicable) and record this 
in the CRF.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).  
The full date of birth will be collected to critically evaluate the immune response and 
safety profile by age.

Obtain any medical history of clinical significance.  For participants who are 
HIV-positive, record the HIV viral load and CD4 count results from the most recent test 
performed in the previous 6 months.

Perform a clinical assessment.  If the clinical assessment indicates that a physical 
examination is necessary to comprehensively evaluate the participant, perform a physical 
examination and record any findings in the source documents and, if clinically 
significant, record any findings on the medical history CRF.

Measure the participant’s height and weight.

Measure the participant’s body temperature.

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 5.3.

Record nonstudy vaccinations as described in Section 6.8.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

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
Record AEs as described in Section 8.3.

Collect a blood sample for immunogenicity testing. 

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation 
and a further blood sample (approximately 5 mL) for HLA typing.

Obtain a nasal (midturbinate) swab (collected by site staff).
As Cohort 2 is observer-blinded, the blinded and unblinded roles should still be 
maintained to ensure the integrity of the blind:

Blinded site staff will obtain the participant’s randomization number using the IRT 
system. The randomization confirmation report with the study intervention allocation will 
only be sent to the unblinded site staff member. 

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into 
the deltoid muscle of the preferably nondominant arm.  Please refer to the IP manual for 
further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study 
intervention administration for any acute reactions.  Record any acute reactions 
(including time of onset) in the participant’s source documents and on the AE page of the 
CRF, and on an SAE form as applicable.

Provide a measuring device to measure local reactions at the injection site and a 
thermometer for recording daily temperatures and fever (COVID-19 surveillance) and 
provide instructions on their use.

Explain the e-diary technologies available for this study (see Section 8.2.4), and assist the 
participant in downloading the study application onto the participant’s own device or 
issue a provisioned device if required.

Provide instructions on reactogenicity e-diary completion and ask the participant to 
complete the reactogenicity e-diary from Day 1 through Day 7, with Day 1 being the day 
of vaccination.

Provide instructions on COVID-19 illness e-diary completion and ask the participant to 
complete the COVID-19 illness e-diary if the participant is diagnosed with COVID-19 or 
has possible new or increased symptoms, and when he/she receives a reminder, at least 
weekly.  See Section 10.10.8.6.4 for further details. Provide a self-swab kit in case of 
COVID-19 symptoms and provide instructions on self-collection of nasal swabs.

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Ask the participant to contact the site staff or investigator immediately if the participant 
experiences any of the following from Day 1 through Day 7 after vaccination 
(where Day 1 is the day of vaccination) to determine if an unscheduled reactogenicity 
visit is required: 

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units).

Severe pain at the injection site.

Any severe systemic event.

Ask the participant to contact the site staff or investigator if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.10.8.6.7).

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 10.10.8.6.4.1.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the reactogenicity e-diary to the next visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs and an unblinded 
dispenser/administrator updates the study intervention accountability records.

The investigator or appropriately qualified designee reviews the reactogenicity e-diary 
data online following vaccination to evaluate participant compliance and as part of the 
ongoing safety review. Daily review is optimal during the active diary period.
10.10.8.6.2.2. Visit 402 – 1-Month Follow-Up Visit (After Substudy D Vaccination 1) 
(28 to 35 Days After Visit 401)

Record AEs as described in Section 8.3.

Review the participant’s reactogenicity e-diary data. Collect stop dates of any 
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary was 
completed and record stop dates in the CRF if required.

Record nonstudy vaccinations as described in Section 6.8.

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
Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Discuss contraceptive use as described in Section 5.3.

Collect a blood sample for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 10.10.8.6.4.1.

Ensure the participant has a self-swab kit.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
10.10.8.6.2.3. Visit 404 – 3-Month Follow-Up Visit (85 to 95 Days After Visit 401, or 
85 to 123 Days After Visit 401 for Those Participants Who Consent to Receive Substudy 
D Vaccination 2)
NOTE: Participants in Cohort 2 will be unblinded to confirm the vaccine received once they 
have COMPLETED Visit 404 (3 months after Substudy D Vaccination 1).  Since these will 
be the only participants still blinded at this time, the study team will also become unblinded 
to all participants’ original study intervention allocation at this time.

Collect a blood sample for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

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
Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 10.10.8.6.4.1.

Ensure the participant has a self-swab kit.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 10.10.8.6.4.1.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
Only if the participant consents to receive a dose of BNT162b2 OMI (Substudy D 
Vaccination 2):
NOTE: Voluntary, written, study-specific informed consent will be obtained from the 
participant before the participant receives a dose of BNT162b2 OMI at Visit 404.  Each 
signature on the ICD must be personally dated by the signatory.  The investigator or his or 
her designee will also sign the ICD.  A copy of the signed and dated ICD must be given to 
the participant.  The source data must reflect that the informed consent was obtained before 
the participant receives a dose of BNT162b2 OMI.
NOTE: Participants who do not provide consent to receive a dose of BNT162b2 OMI at 
Visit 404 will remain on the single-dose visit schedule.

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 5.3.

Measure the participant’s body temperature.

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
Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met.
Note: a positive SARS-CoV-2 NAAT result without symptoms or a COVID-19 diagnosis 
(based on signs/symptoms only or signs/symptoms and a positive SARS-CoV-2 NAAT 
result) should not result in discontinuation of study intervention.  Please see Section 7.1.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Obtain a nasal (midturbinate) swab (collected by site staff).

Unblinded site staff member(s) will dispense/administer 1 dose of BNT162b2 OMI into 
the deltoid muscle of the preferably nondominant arm.  Please refer to the IP manual for 
further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study 
intervention administration for any acute reactions.  Record any acute reactions 
(including time of onset) in the participant’s source documents and on the AE page of the 
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection 
site and a thermometer for recording daily temperatures.

Ensure the participant has a self-swab kit.

Remind the participant of the e-diary technologies available for this study 
(see Section 10.10.8.6.5).  Provide instructions on e-diary completion and ask the 
participant to complete the reactogenicity e-diary from Day 1 through Day 7, with Day 1 
being the day of vaccination, and, if utilized, the COVID-19 illness e‑diary (to be 
completed if the participant is diagnosed with COVID-19 or has possible new or 
increased symptoms, and when he/she receives a reminder, at least weekly).

Ask the participant to contact the site staff or investigator immediately if he or she 
experiences any of the following from Day 1 through Day 7 after vaccination (where 
Day 1 is the day of vaccination) to determine if an unscheduled reactogenicity visit is 
required (see Section 10.10.8.6.8):

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units).

Severe pain at the injection site.

Any severe systemic event.

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
Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 10.10.8.6.4.1.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

The investigator or appropriately qualified designee reviews the reactogenicity e-diary 
data online following vaccination to evaluate participant compliance and as part of the 
ongoing safety review. Daily review is optimal during the active diary period.

Participants in Cohort 2 will be unblinded to confirm the vaccine received once they have 
completed Visit 404 (3 months after Substudy D Vaccination 1).  Since these are the only 
participants still blinded at this time, the study team will also become unblinded to all 
participants’ original study intervention allocation at this time.
10.10.8.6.2.4. Visit 404a – 7-Day Follow-Up Visit (After Substudy D Vaccination 2) 
(5 to 9 Days After Visit 404): Only for Those Participants Who Receive Substudy D 
Vaccination 2

Record AEs as described in Section 8.3.

Review the participant’s reactogenicity e-diary data.  Collect stop dates of any 
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary was 
completed and record stop dates in the CRF if required.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 5.3.

Collect a blood sample for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.

Ask the participant to contact the site staff or investigator if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.10.8.6.7).

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
Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 10.10.8.6.4.1.

Ensure the participant has a self-swab kit.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
10.10.8.6.2.5. Visit 404b – 1-Month Follow-Up Visit (After Substudy D Vaccination 2) 
(28 to 35 Days After Visit 404): Only for Those Participants Who Receive Substudy D 
Vaccination 2

Record AEs as described in Section 8.3.

Review the participant’s reactogenicity e-diary data.  Collect stop dates of any 
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary was 
completed and record stop dates in the CRF if required.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Discuss contraceptive use as described in Section 5.3.

Collect a blood sample for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 10.10.8.6.4.1.

Ensure the participant has a self-swab kit.

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
Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
10.10.8.6.2.6. Visit 404c – 3-Month Follow-Up Visit (After Substudy D Vaccination 2)
(85 to 95 Days After Visit 404): Only for Those Participants Who Receive Substudy D 
Vaccination 2

Record AEs as described in Section 8.3.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Collect a blood sample for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 10.10.8.6.4.1.

Ensure the participant has a self-swab kit.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
10.10.8.6.2.7. Visit 405 – 6-Month Follow-Up Visit (175 to 189 Days After Visit 401, or 
175 to 189 Days After Visit 404 for Those Participants Who Receive Substudy D 
Vaccination 2) 
For participants who have already completed V405 at the time of protocol amendment 11, 
they will be informed by the investigator site staff of study completion and that no further 
visits are required.

Record AEs as described in Section 8.3.

Collect a blood sample for immunogenicity testing.

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
Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 10.10.8.6.4.1.

Schedule an appointment for the participant to return for the next study visit.

Collect the participant’s e-diary or assist the participant to remove the study application 
from his or her own personal device.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3.
10.10.8.6.3. Administration of BNT162b2 OMI to COVID-19 Vaccine–Naïve 
Participants (Cohort 3)
To further describe potential homologous and heterologous protection against emerging 
SARS-CoV-2 VOCs, a new group of participants will be enrolled who are COVID-19 
vaccine-naïve and have not experienced COVID-19. They will receive 2 doses (primary 
series) of BNT162b2 OMI, separated by 21 days, with a third dose approximately 5 months 
later.
10.10.8.6.3.1. Visit 501 – Vaccination 1 (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written,
study-specific informed consent will be obtained from the participant. Each signature on the 
ICD must be personally dated by the signatory. The investigator or his or her designee will 
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The 
source data must reflect that the informed consent was obtained before participation in the 
study.
It is anticipated that the procedures below will be conducted in a stepwise manner. The visit 
may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and 
exclusion criteria onwards must be conducted on the same day.

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
Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).  
The full date of birth will be collected to critically evaluate the immune response and 
safety profile by age.

Obtain any medical history of clinical significance. For participants who are 
HIV-positive, record the HIV viral load and CD4 count results from the most recent test 
performed in the previous 6 months.

Perform a clinical assessment. If the clinical assessment indicates that a physical 
examination is necessary to comprehensively evaluate the participant, perform a physical 
examination and record any findings in the source documents and, if clinically 
significant, record on the medical history CRF.

Measure the participant’s height and weight.

Measure the participant’s body temperature.

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 5.3.

Record nonstudy vaccinations as described in Section 6.8.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Record AEs as described in Section 8.3.

Collect a blood sample for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation 
and a further blood sample (approximately 5 mL) for HLA typing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Obtain the participant’s vaccine vial allocation using the IRT system.

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
Site staff member(s) will dispense/administer 1 dose of BNT162b2 OMI into the deltoid 
muscle of the preferably nondominant arm. Please refer to the IP manual for further 
instruction on this process.

Site staff must observe the participant for at least 30 minutes after study intervention 
administration for any acute reactions.  Record any acute reactions (including time of 
onset) in the participant’s source documents and on the AE page of the CRF, and on an 
SAE form as applicable.

Provide a measuring device to measure local reactions at the injection site and a 
thermometer for recording daily temperatures and fever (COVID-19 surveillance) and 
provide instructions on their use.

Explain the e-diary technologies available for this study (see Section 10.10.8.6.5), and 
assist the participant in downloading the study application onto the participant’s own 
device or issue a provisioned device if required. 

Provide instructions on reactogenicity e-diary completion and ask the participant to 
complete the reactogenicity e-diary from Day 1 through Day 7, with Day 1 being the day 
of vaccination.

Provide instructions on COVID-19 illness e-diary completion and ask the participant to 
complete the COVID-19 illness e-diary if the participant is diagnosed with COVID-19 or 
has possible new or increased symptoms, and when he/she receives a reminder, at least 
weekly.  See Section 10.10.8.6.4 for further details. Provide a self-swab kit in case of 
COVID-19 symptoms and provide instructions on self-collection of nasal swabs.

Ask the participant to contact the site staff or investigator immediately if the participant 
experiences any of the following from Day 1 through Day 7 after vaccination (where 
Day 1 is the day of vaccination) to determine if an unscheduled reactogenicity visit is 
required: 

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units).

Severe pain at the injection site.

Any severe systemic event.

Ask the participant to contact the site staff or investigator if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.10.8.6.7).

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

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
Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 10.10.8.6.4.1.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs and the study intervention 
accountability records.

The investigator or appropriately qualified designee reviews the reactogenicity e-diary 
data online following vaccination to evaluate participant compliance and as part of the 
ongoing safety review. Daily review is optimal during the active diary period.
10.10.8.6.3.2. Visit 502 – Vaccination 2 (19 to 23 Days After Visit 501)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensure 
that procedures listed prior to administration of the vaccine are conducted prior to 
vaccination.

Record AEs as described in Section 8.3.

Review the participant’s reactogenicity e-diary data.  Collect stop dates of any 
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary was 
completed and record stop dates in the CRF if required.

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 5.3.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met.  If not, the participant may not receive further study intervention but will remain 
in the study to be evaluated for safety, immunogenicity, and efficacy (see 
Section 10.10.5).
Note: a positive SARS-CoV-2 NAAT result without symptoms or a COVID-19 diagnosis 
(based on signs/symptoms only or signs/symptoms and a positive SARS-CoV-2 NAAT 
result) should not result in discontinuation of study intervention.  Please see Section 7.1.

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
Measure the participant’s body temperature.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 10.10.5.5.

Obtain a nasal (midturbinate) swab (collected by site staff).

Obtain the participant’s vaccine vial allocation using the IRT system.

Site staff member(s) will dispense/administer 1 dose of BNT162b2 OMI into the deltoid 
muscle of the preferably nondominant arm.  Please refer to the IP manual for further 
instruction on this process.

Site staff must observe the participant for at least 30 minutes after study intervention 
administration for any acute reactions.  Record any acute reactions (including time of 
onset) in the participant’s source documents and on the AE page of the CRF, and on an 
SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection 
site and a thermometer for recording daily temperatures.

Ensure the participant remains comfortable with the chosen e-diary platform, confirm
instructions on e-diary completion, and ask the participant to complete the reactogenicity 
e-diary from Day 1 through Day 7, with Day 1 being the day of vaccination.

Ask the participant to contact the site staff or investigator immediately if the participant 
experiences any of the following from Day 1 through Day 7 after vaccination (where 
Day 1 is the day of vaccination) to determine if an unscheduled reactogenicity visit is 
required: 

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units).

Severe pain at the injection site.

Any severe systemic event.

Ask the participant to contact the site staff or investigator if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.10.8.6.7).

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

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
Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 10.10.8.6.4.1.

Ensure the participant has a self-swab kit.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the e-diary to the next visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs and the study intervention 
accountability records.

The investigator or appropriately qualified designee reviews the reactogenicity e-diary 
data online following vaccination to evaluate participant compliance and as part of the 
ongoing safety review. Daily review is optimal during the active diary period.
10.10.8.6.3.3. Visit 503 – 1-Week Follow-Up Visit (After Vaccination 2) (6 to 8 Days 
After Visit 502): Only for Those Participants Who Are Part of the Group for 
Description of Cell-Mediated Immune Response

Record AEs as described in Section 8.3

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 5.3.

Collect a blood sample for immunogenicity testing.

Collect a blood sample (approximately 120 mL) for PBMC isolation.

Ask the participant to contact the site staff or investigator if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.10.8.6.7).

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 10.10.8.6.4.1.

Ensure the participant has a self-swab kit.

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
Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
10.10.8.6.3.4. Visit 504 – 1-Month Follow-Up Visit (After Vaccination 2) (28 to 35 Days 
After Visit 502)

Record AEs as described in Section 8.3.

Review the participant’s reactogenicity e-diary data. Collect stop dates of any 
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary was 
completed and record stop dates in the CRF if required.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Discuss contraceptive use as described in Section 5.3.

Collect a blood sample for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 10.10.8.6.4.1.

Ensure the participant has a self-swab kit.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

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10.10.8.6.3.5. Visit 505 – 3-Month Follow-Up Visit (After Vaccination 2) (85 to 95 Days 
After Visit 502)

Collect a blood sample for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 10.10.8.6.4.1

Ensure the participant has a self-swab kit.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3.
10.10.8.6.3.6. Visit 506 – 6-Month Follow-Up Visit (After Vaccination 2) (150 to 
199 Days After Visit 502) and Administration of Vaccination 3

Vaccination 3 may be administered as early as 5 months (150 days) after Vaccination 2.

Record AEs as described in Section 8.3.

Collect a blood sample for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

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
Discuss contraceptive use as described in Section 5.3.

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Measure the participant’s body temperature.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met.
Note: a positive SARS-CoV-2 NAAT result without symptoms or a COVID-19 diagnosis 
(based on signs/symptoms only or signs/symptoms and a positive SARS-CoV-2 NAAT 
result) should not result in discontinuation of study intervention.  Please see Section 7.1.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Obtain a nasal (midturbinate) swab (collected by site staff).

Obtain the participant’s vaccine vial allocation using the IRT system.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into 
the deltoid muscle of the preferably nondominant arm.  Please refer to the IP manual for 
further instruction on this process. Vaccination 3 may be administered as early as 
5 months (150 days) after Vaccination 2.

Blinded site staff must observe the participant for at least 30 minutes after study 
intervention administration for any acute reactions.  Record any acute reactions 
(including time of onset) in the participant’s source documents and on the AE page of the 
CRF, and on an SAE form as applicable.

Ensure the participant has a measuring device to measure local reactions at the injection 
site and a thermometer for recording daily temperatures.

Remind the participant of the e-diary technologies available for this study 
(see Section 10.10.8.6.5).  Provide instructions on e-diary completion and ask the 
participant to complete the reactogenicity e-diary from Day 1 through Day 7, with Day 1 
being the day of vaccination, and, if utilized, the COVID-19 illness e‑diary (to be 
completed if the participant is diagnosed with COVID-19 or has possible new or 
increased symptoms, and when he/she receives a reminder, at least weekly).

Ask the participant to contact the site staff or investigator immediately if he or she 
experiences any of the following from Day 1 through Day 7 after vaccination (where Day 
1 is the day of vaccination) to determine if an unscheduled reactogenicity visit is required 
(see Section 10.8.8.3.7):

Fever ≥39.0°C (≥102.1°F).

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
Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units).

Severe pain at the injection site.

Any severe systemic event.

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 10.10.8.6.4.1.

Ensure the participant has a self-swab kit.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3.
10.10.8.6.3.7. Visit 507 – 1-Month Follow-Up Visit (After Vaccination 3) (28 to 35 Days 
After Visit 506)

Record AEs as described in Section 8.3.

Review the participant’s reactogenicity e-diary data. Collect stop dates of any 
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary was 
completed and record stop dates in the CRF if required.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Discuss contraceptive use as described in Section 5.3.

Collect a blood sample for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.

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
Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 10.10.8.6.4.1.

Ensure the participant has a self-swab kit.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.
10.10.8.6.3.8. Visit 508 – 6-Month Follow-Up Visit (After Vaccination 3) (175 to 
189 Days After Visit 506)

Collect a blood sample for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Collect the participant’s e-diary or assist the participant to remove the study application 
from his or her own personal device.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3.
10.10.8.6.4. COVID-19 Surveillance (All Substudy D Participants)
If a participant experiences any of the following (irrespective of perceived etiology or 
clinical significance), he or she is instructed to contact the site immediately and, if 
confirmed, participate in an in-person or telehealth visit as soon as possible, optimally within 
3 days of symptom onset (and at the latest 4 days after symptom resolution).

A diagnosis of COVID-19;

Fever;

New or increased cough; 

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
New or increased shortness of breath; 

Chills; 

New or increased muscle pain; 

New loss of taste/smell;

Sore throat;

Diarrhea;

Vomiting.
Note that:

If new symptoms are reported within 4 days after resolution of all previous symptoms, 
they will be considered as part of a single illness and a second illness visit is not required;

Surveillance of potential COVID-19 symptoms should continue even if a participant has 
a positive SARS-CoV-2 test earlier in the study.
During the 7 days following each vaccination, potential COVID-19 symptoms that overlap 
with specific systemic events (ie, fever, chills, new or increased muscle pain, diarrhea, 
vomiting) should not trigger a potential COVID-19 illness visit unless, in the investigator’s 
opinion, the clinical picture is more indicative of a possible COVID-19 illness than vaccine 
reactogenicity.  If, in the investigator’s opinion, the symptoms are considered more likely to 
be vaccine reactogenicity, but a participant is required to demonstrate that he or she is
SARS-CoV-2–negative, a local SARS-CoV-2 test may be performed: if positive, the 
symptoms should be recorded as a potential COVID-19 illness; if not, the symptoms should 
be recorded as AEs.
Participants may utilize a COVID-19 illness e-diary through an application (see 
Section 10.10.8.6.5) installed on a provisioned device or on the participant’s own personal 
device to prompt him/her to report any symptoms.  Note that this does not substitute for a 
participant’s routine medical care.  Therefore, participants should be encouraged to seek care, 
if appropriate, from their usual provider.

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10.10.8.6.4.1. Potential COVID-19 Illness Visit (Optimally Within 3 Days After 
Potential COVID-19 Illness Onset)
This visit may be conducted as an in-person or telehealth visit; a telehealth visit involves the 
sharing of healthcare information and services via telecommunication technologies 
(eg, audio, video, video-conferencing software) remotely, thus allowing the participant and 
investigator to communicate on aspects of clinical care.
As a participant’s COVID-19 illness may evolve over time, several contacts may be required 
to:

Record AEs, as appropriate as described in Section 8.3.  Note: Potential COVID-19 
illnesses that are consistent with the clinical endpoint definition should not be recorded as 
AEs.  These data will be captured as efficacy assessment data only on the relevant pages 
of the CRF, as these are expected endpoints.

Record details of any of the prohibited medications specified in Section 6.8 received by 
the participant if required for his or her clinical care.

If the visit is conducted in person, obtain a nasal (midturbinate) swab (collected by site 
staff).  Alternatively, if the visit is conducted by telehealth, instruct the participant to 
self-collect a nasal (midturbinate) swab and ship for assessment at the central laboratory.

Collect COVID-19–related standard-of-care clinical and laboratory information.  This 
includes, but is not limited to:

Symptoms and signs, including

Clinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per 
minute, HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or
PaO2/FiO2 <300 mm Hg)

Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiring 
vasopressors)

Significant acute renal, hepatic, or neurologic dysfunction

Respiratory failure (defined as needing high-flow oxygen, noninvasive 
ventilation, mechanical ventilation, or ECMO)

Clinical diagnosis

Local laboratory SARS-CoV-2 test result(s).  Note that if it is routine practice to 
perform a repeat local SARS-CoV-2 test for any reason, then a repeat nasal 
(midturbinate) swab should also be obtained and shipped for assessment at the central 
laboratory.

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
Full blood count

Blood chemistry, specifically creatinine, urea, LFTs, and C-reactive protein

Imaging results (eg, CT or MRI scan) to document neurologic dysfunction

Number and type of any healthcare contact; duration of hospitalization and ICU stay

Death

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
10.10.8.6.5. Communication and Use of Technology
In a study of this nature that requires illness events to be reported outside of scheduled study 
visits, it is vital that communication between the study site and the participant is maintained 
to ensure that endpoint events are not missed.  This study will employ various methods, 
tailored to the individual participant, to ensure that communication is maintained and study 
information can be transmitted securely.  Using appropriate technology, such as a study 
application, a communication pathway between the participant and the study site staff will be 
established.  The participant may be able to utilize his or her own devices to access this 
technology, or use a device provided by the sponsor.  Traditional methods of telephone 
communication will also be available.  The technology solution may facilitate the following:

Contact with the investigator, including the ability of the participant to report whether or 
not the participant has experienced symptoms that could represent a potential COVID-19 
illness (COVID-19 illness e-diary).

An alert in the event that the participant is hospitalized.

Visit reminders.

Messages of thanks and encouragement from the study team.

If a participant is not actively completing the COVID-19 illness e-diary, the investigator 
or designee is required to contact the participant to ascertain why and also to obtain 
details of any missed events.

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10.10.8.6.6. SARS-CoV-2 NAAT Results
Nasal (midturbinate) swabs for SARS-CoV-2 NAAT are obtained at:

Visits 401, 402 (for Group 2 participants who receive a second dose of BNT162b2 OMI 
only), 404 (for Group 3 and Group 4 participants who receive a dose of BNT162b2 OMI 
at Visit 404 only), 501, 502, and 506: To determine whether a participant will be included 
in immunogenicity analyses of those with no serological or virological evidence (up to 
1 month after receipt of the third, fourth, or fifth dose to 
BNT162b2-experienced participants, or as a 2-dose series to COVID-19 vaccine–naïve 
participants) of past SARS-CoV-2 infection.

Potential COVID-19 illness visits: To determine whether symptoms experienced by the 
participant fulfill the COVID-19 case definition.
Research laboratory–generated positive results from the Visit 401 and Visit 501 swabs, and 
all results from the illness visit swabs, will be provided to the site once available, but this will 
not be in real time and cannot be relied upon to direct clinical care.  Therefore, the participant 
should be directed to seek additional testing through his/her primary healthcare providers at a 
licensed clinical laboratory when exhibiting potential COVID-19 symptoms or otherwise 
receiving a positive result and counseled on whether to take any precautionary measures 
pending confirmatory testing.
10.10.8.6.7. Additional Procedures for Monitoring of Potential Myocarditis or 
Pericarditis
Any study participant who reports acute chest pain, shortness of breath, palpitations, or any 
other symptom(s) that might be indicative of myocarditis or pericarditis within 4 weeks after 
a study vaccination should be specifically evaluated, preferably by a cardiologist, for possible 
myocarditis or pericarditis. In addition to a clinical evaluation, the following should be 
performed:

ECG and

Measurement of the troponin level
If myocarditis or pericarditis is suspected based upon the initial evaluation, the following 
should also be performed:

Cardiac echocardiogram and/or

Cardiac magnetic resonance study
Details of the symptoms reported, and results of the investigations performed, will be 
recorded in the CRF.

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10.10.8.6.8. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction
If a Grade 3 local reaction (Section 8.2.4.2), systemic event (Section 8.2.4.3), or fever 
(Section 8.2.4.4) is reported in the reactogenicity e-diary, a telephone contact should occur to 
ascertain further details and determine whether a site visit is clinically indicated. If suspected 
Grade 4 local reaction (Section 8.2.4.2), systemic event (Section 8.2.4.3), or fever 
(Section 8.2.4.4) is reported in the reactogenicity e-diary, a telephone contact or site visit 
should occur to confirm whether the event meets the criteria for Grade 4.
A site visit must be scheduled as soon as possible to assess the participant unless any of the 
following is true:

The participant is unable to attend the unscheduled visit.

The local reaction/systemic event is no longer present at the time of the telephone 
contact.

The participant recorded an incorrect value in the reactogenicity e-diary (confirmation 
of a reactogenicity e-diary data entry error).

The PI or authorized designee determined it was not needed.
This telephone contact will be recorded in the participant’s source documentation and the 
CRF.
If the participant is unable to attend the unscheduled visit, or the PI or authorized designee 
determined that it was not needed, any ongoing local reactions/systemic events must be 
assessed at the next study visit.
During the unscheduled visit, the reactions should be assessed by the investigator or a 
medically qualified member of the study staff such as a study physician or a study nurse, as 
applicable to the investigator’s local practice, who will:

Measure body temperature (°F/°C).

Measure minimum and maximum diameters of redness (if present).

Measure minimum and maximum diameters of swelling (if present).

Assess injection site pain (if present) in accordance with the grades provided in
Section 8.2.4.2.

Assess systemic events (if present) in accordance with the grades provided in
Section 8.2.4.3.

Assess for other findings associated with the reaction and record on the AE page of 
the CRF, if appropriate.

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The investigator or an authorized designee will complete the unscheduled visit assessment 
page of the CRF.
10.10.9. Statistical Considerations for Substudy D
See Section 9 for master protocol statistical considerations and substudy specifics below.
10.10.9.1. Statistical Hypotheses
10.10.9.1.1. Estimands
The estimands corresponding to the primary and secondary objectives are described in the 
table in Section 10.10.3.
In the primary safety objective evaluations, missing AE start dates will be imputed according 
to Pfizer safety rules.  No other missing information will be imputed in the safety analysis.
10.10.9.1.2. Statistical Hypotheses
The primary immunogenicity objectives for Cohort 2 and Cohort 3 are to assess the 
superiority with respect to level of neutralizing titer and noninferiority with respect to 
seroresponse rate of the anti-Omicron immune response induced by BNT162b2 OMI relative
to the anti-Omicron immune response elicited by BNT162b2. Each primary objective for 
Cohort 2 and Cohort 3 will be evaluated by the following 2 hypotheses:

The first null hypothesis (H0) is
H0: ln() – ln() ≤ln(1) vs H1: ln() – ln() > ln(1)
where ln(1) corresponds to a 1-fold margin for superiority and 
o
Ln() is the natural log of the geometric mean of SARS-CoV-2 
Omicron-neutralizing titers measured 1 month after BNT162b2 OMI;
o
Ln() is the natural log of the geometric mean of SARS-CoV-2 
Omicron-neutralizing titers measured 1 month after BNT162b2.

The second null hypothesis (H0) is
H0:  − ≤−0.05 vs   − > −0.05
where -5% is the noninferiority margin for seroresponse and 
o
 is the percentage of participants with seroresponse to the Omicron strain at 
1 month after BNT162b2 OMI;
o
 is the percentage of participants with seroresponse to the Omicron strain at 
1 month after BNT162b2.

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Seroresponse is defined as achieving a ≥4-fold rise from baseline (before the first dose of 
study vaccination).  If the baseline measurement is below the LLOQ, the postvaccination 
measure of ≥4 × LLOQ is considered seroresponse. 
Superiority based on GMR will be declared if the lower limit of the 2-sided 95% CI for the 
GMR is greater than 1; noninferiority based on seroresponse will be declared if the lower 
limit of the 2-sided 95% CI for the difference in percentages of participants with 
seroresponse is >-5%.
The secondary objectives of “super” superiority will be evaluated using a 1.5-fold margin for 
GMR. “Super” superiority for GMR will be established if the lower limit of the 2-sided 95% 
CI for the GMR is greater than 1.5.
10.10.9.1.3. Multiplicity Adjustment
The immunogenicity objectives for BNT162b2-experienced participants who completed a 
2-dose primary series of BNT162b2 prior to enrollment in this study (Cohort 1), 
BNT162b2-experienced participants who completed a 2-dose primary series and a booster 
dose of BNT162b2 prior to enrollment in this study (Cohort 2), and COVID-19 
vaccine–naïve participants (Cohort 3) will be evaluated independently.  The 3 cohorts 
(2-dose BNT162b2-experienced, 3-dose BNT162b2-experienced, and COVID-19 
vaccine–naïve individuals) are different populations with different objectives.  The 
3 populations are included in the same study to improve operational efficiency.  
Therefore, no type I error adjustments will be applied to the immunogenicity assessments of 
the 3 populations.
No multiplicity adjustment is needed for Cohort 1 as there is no statistical hypothesis in 
Cohort 1.
For each population in Cohort 2 and Cohort 3, the objectives will be evaluated in sequential 
order as listed below using a 1-sided alpha of 0.025:
Cohort 2 (Groups 3 and 4): G3vG4A ® G3vG4B 
Cohort 3 (Group 5): G5A ® G5B

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For objectives involving 2 hypotheses, hypotheses based on GMR and seroresponse rate 
difference will be assessed sequentially in the order as stated. Both hypotheses within the 
objective must be established before assessing the next objective in the sequence. Therefore, 
the overall type I error is fully controlled for each of these 2 populations.
10.10.9.2. Analysis Sets
For the purpose of analysis, the following analysis sets are defined for this substudy:
Population
Description
Enrolled
All participants who have a signed ICD.
Randomized/assigned
All participants who are assigned a randomization number in the 
IWR system.
Evaluable 
immunogenicity
All eligible randomized/assigned participants who receive the
study intervention(s) to which they are randomized or assigned, 
have a valid and determinate immunogenicity result from the 
blood sample collected within an appropriate window, and have 
no other important protocol deviations as determined by the 
clinician.
All-available 
immunogenicity
All randomized/assigned participants who receive at least 1 dose 
of the study intervention with a valid and determinate
immunogenicity result after vaccination.
Safety
All participants who receive at least 1 dose of the study 
intervention.
10.10.9.3. Statistical Analyses
The SAP will be developed and finalized for this substudy before any analyses are performed
and will describe the analyses and procedures for missing, unused, and spurious data.  This 
section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.
10.10.9.3.1. General Considerations
Refer to Section 9.3.1 for general considerations of statistical analyses.

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10.10.9.3.2. Primary Endpoint(s)/Estimand(s) Analysis
Endpoint
Statistical Analysis Methods
Safety

Descriptive statistics will be provided for each reactogenicity
endpoint for each vaccine group. Local reactions and systemic
events from Day 1 through Day 7 after each study vaccination
(where Day 1 is the day of vaccination) will be presented by severity 
and cumulatively across severity levels. Descriptive summary 
statistics will include counts and percentages of participants with the 
indicated endpoint and the associated Clopper-Pearson 95% CIs.

AEs and SAEs will be categorized according to MedDRA terms.  
Counts, percentages, and associated Clopper-Pearson 95% CIs of 
AEs within 1 month and SAEs within 6 months after the last study 
vaccination will be provided for each vaccine group.  
Immunogenicity
For each primary immunogenicity estimand described in 
Section 10.10.3

GMRs and the associated 2-sided 95% CIs will be calculated using 
the method described in Section 9.3.1.2.3.

The percentages of participants with seroresponse for each group
will be provided. The difference in percentages of participants with 
seroresponse and the associated 2-sided 95% CIs will be calculated 
using the Miettinen and Nurminen method (see Section 9.3.1.1).

For Cohort 1, only participants with evidence of past SARS-CoV-2 
infection will be included in the analysis. For Cohort 2, only 
participants with no serological or virological evidence (up to 
1 month after receipt of 1 dose of study intervention) of past 
SARS-CoV-2 infection will be included in the analysis.

For Cohort 2 and Cohort 3, superiority based on GMR will be 
established if the lower bound of the 2-sided 95% CI for the GMR is 
>1; noninferiority based on seroresponse rate difference will be 
established if the lower bound of the 2-sided 95% CI for the 
difference in percentage is greater than -5%.

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10.10.9.3.3. Secondary Endpoint(s)/Estimand(s) Analysis
Endpoint
Statistical Analysis Methods
Immunogenicity
For each secondary immunogenicity estimand described in 
Section 10.10.3

GMR and the associated 2-sided 95% CIs, the percentages of 
participants with seroresponse, and the difference in percentages of 
participants with seroresponse and the associated 2-sided 95% CIs 
will be calculated using same method as for the primary 
immunogenicity objectives.

“Super” superiority will be evaluated using criteria described in 
Section 10.10.9.1.2 and Section 10.10.9.1.3.
10.10.9.3.4. Exploratory Endpoint(s) Analysis
Endpoint
Statistical Analysis Methods
Immunogenicity
GMTs and GMFRs of SARS-CoV-2 Omicron- or reference-strain–
neutralizing titers
Percentages of participants with seroresponse to Omicron or the
reference strain
Cohort 1: At baseline, 1 month after the first study vaccination, and 
1 month after the second study vaccination (Group 2 only),
Cohort 2: At baseline, 1 month and 3 months after the first study 
vaccination, and 1 month, 3 months, and 6 months after the last study 
vaccination,
Cohort 3: At baseline, 1 month and 6 months after Dose 2, and 1 month 
and 6 months after Dose 3,

GMTs at each of the above time points and GMFRs of SARS-CoV-
2 Omicron- or reference-strain–neutralizing titers from baseline 
(before the first study vaccination received in this study) to each of 
the above postvaccination time points, along with the associated 
2-sided 95% CIs, will be provided for each vaccine group using the 
statistical method described in Section 9.3.1.2.1 and 
Section 9.3.1.2.2.

The percentages of participants with seroresponse at each time point 
and the associated Clopper-Pearson 95% CIs will be provided for 
each vaccine group.

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Endpoint
Statistical Analysis Methods
GMTs and GMFRs of SARS-CoV-2 reference strain and VOCs for 
the subset of 30 participants per group
Percentages of participants with seroresponse to reference strain 
and VOCs for the subset of 30 participants per group

GMTs, GMFRs, and percentages of participants with seroresponse
for the subset of 30 participants per group, along with the associated 
95% CIs, will be calculated using same method as described above.
GMTs for any VOCs not already specified, after any dose of 
BNT162b2 OMI or BNT162b2

GMTs of VOC-neutralizing titers, along with the associated 
2-sided 95% CIs, will be provided at specific time points for each 
group. GMFRs and GMRs of VOC-neutralizing titers to reference-
strain–neutralizing titers may also be calculated along with the 
associated 2-sided 95% CIs.
COVID-19 cases
Confirmed COVID-19 cases, confirmed severe COVID-19 cases, and 
strain sequencing of the COVID-19 cases will be summarized.
Cell-mediated 
immune response
The cell-mediated immune response and additional humoral immune 
response parameters to the reference strain and Omicron will be 
summarized at each time point for the subset of participants with PBMC 
samples collected in each group.
10.10.9.4. Interim Analyses
No formal interim analysis will be conducted for this study. Statistical analyses will be 
carried out when the final data for specified objectives are available while the study is 
ongoing.  The timing of these planned analysis and reporting events is described in the 
section below.
10.10.9.4.1. Analysis Timing
Statistical analyses will be carried out when the following data are available:

Safety data through 1 month after the first study vaccination received in this study for 
Groups 1, 2b, 3, and 4 or through 1 month after the second study vaccination received in 
this study for Groups 2 and 5.

Immunogenicity data for the subset of 30 participants per group.

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
Immunogenicity data through 1 month after the first study vaccination (for Groups 1, 2b, 
3, and 4) or 1 month after the second study vaccination (for Groups 2 and 5) received in 
this study for participants enrolled in this study and through 1 month after Dose 2 for the 
comparator group from the C4591001 study.

Complete safety and immunogenicity analysis approximately 6 months after the last
study vaccination for each group.
Certain analyses may be combined as 1 regulatory submission report if the data become 
available around the same time.  Additional analyses may be conducted if required for 
regulatory purposes. All analyses conducted while the study is ongoing will be performed by 
an unblinded team.
10.10.9.4.2. Data Monitoring Committee or Other Independent Oversight Committee
The study will utilize a DMC. The DMC is independent of the study team and includes only 
external members.  The DMC charter describes the role of the DMC in more detail. The 
DMC will be responsible for ongoing monitoring of the safety data throughout the study 
according to the charter.
The recommendations made by the DMC will be forwarded to the appropriate Pfizer 
personnel for final decision.  Pfizer will forward such decisions, which may include 
summaries of aggregate analyses of safety data, to regulatory authorities, investigators as 
appropriate.
10.10.9.5. Sample Size Determination
The sample size for Groups 3 and 4 is based on consideration of an acceptable safety 
database. A subset of 30 participants from each group may be selected as a sentinel group
for separate assessment of immune response defined in an exploratory objective. The subset 
may be the first 30 participants selected for operational expedience or a random sample 
selection depending on the enrollment status. A random sample of approximately 
100 participants with evidence of past SARS-CoV-2 infection from each of Groups 1, 2, and 
2b selected from the remaining approximately 175 participants will be used for evaluation of 
the primary immunogenicity objectives in each group for Cohort 1. A random sample of 
175 participants from each of Groups 3 and 4 selected from the remaining approximately 
270 participants, and the remaining approximately 175 participants in Group 5, will be used
for evaluation of the primary and secondary immunogenicity objectives in each group for 
Cohort 2 and Cohort 3. The same number of participants for Group 5 will be selected from 
the C4591001 study as a control group for the immunogenicity evaluation.
Assuming a 35% nonevaluable and prior SARS-CoV-2 infection rate, approximately 
114 evaluable participants in each group will contribute to the immunogenicity evaluation. 
The superiority and noninferiority evaluation based on GMR and seroresponse rate 
difference will each be performed at 1-sided alpha level of 0.025 as described in 
Section 10.10.9.1.3.

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Superiority Immunogenicity Objectives
For comparisons based on GMR, common assay standard deviations at 1 month after the 
third or fourth dose or 1 month after Dose 2 in log scale is assumed to be 0.93 based on data 
observed in the C4591001 study.  If the true GMR of Omicron-neutralizing titer after 
BNT162b2 OMI to after BNT162b2 is 1.5, 114 evaluable participants per group will provide 
90.6% power to declare superiority. If the true GMR is 2.5, the study will have 98.5% power 
to declare “super” superiority using a 1.5-fold margin.
For comparisons based on seroresponse rate difference, if the seroresponse rate is 80% in the
BNT162b2 OMI group and 60% in the BNT162b2 group, the study has 98.6% power to 
demonstrate noninferiority using a 5% margin. 
For safety outcomes, Table 11 shows the probability of observing at least 1 AE for a given 
true event rate of a particular AE, for various sample sizes. For example, if the true AE rate 
is 1%, with 300 participants in a vaccine group, there is 95% probability of observing at least 
1 AE.
Table 11.
Probability of Observing at 1 Least AE by Assumed True Event Rates 
With Different Sample Sizes
Assumed True Event 
Rate of an AE
N=30
N=205
N=300
N=915
N=1420
0.01%
0.003
0.02
0.03
0.09
0.13
0.02%
0.006
0.04
0.06
0.17
0.25
0.05%
0.01
0.10
0.14
0.37
0.51
0.10%
0.03
0.19
0.26
0.60
0.76
0.20%
0.06
0.34
0.45
0.84
0.94
0.50%
0.14
0.64
0.78
0.99
>0.99
1.00%
0.26
0.87
0.95
>0.99
>0.99
2.00%
0.45
0.98
>0.99
>0.99
>0.99
5.00%
0.79
>0.99
>0.99
>0.99
>0.99
10.0%
0.96
>0.99
>0.99
>0.99
>0.99

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10.11. Appendix 11: Substudy E
10.11.1. Substudy Summary
10.11.1.1. Substudy Synopsis
See Section 1.1 for a synopsis of Substudy E.

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10.11.1.2. Schema
Visit Number
Screening
601
601A
602
603
604
605
Visit Description
Screeninga
4th Dose of 
BNT162b2,
BNT162b2 OMI,
or Combination 
BNT162b2 and
BNT162b2 OMI
3 Days After 4th
Vaccinationa
7 Days After 
4th
Vaccination
1 Month After 
4th Vaccination
3 Months After 
4th Vaccination
6 Months After 
4th Vaccination
ONLY FOR 
SENTINEL-
COHORT 
PARTICIPANTS 
IN GROUPS 7, 8, 
AND 9
ONLY FOR 
SENTINEL-
COHORT 
PARTICIPANTS 
IN GROUPS 7, 
8, AND 9
Participants having 
received 3 prior doses of 
30 µg BNT162b2 5-12 
months prior to 
randomization
30-µg OR 60-µg dose
Blood draw for 
immunogenicity
assessment/PBMC 
isolationb
50 mL/120 mL
50 mL/120 mL
50 mL/120 mL
50 mL/120 mL
50 mL/120 mL
Blood draw for troponin 
levels
10 mL
10 mL
a.
Only for sentinel-cohort participants 18 to 55 years of age (Groups 7 to 9).
b.
Additional 120 mL for PBMC isolation (and 5 mL for HLA typing at Visit 601) is for select expanded-enrollment participants (~30 per group for Groups 
1 to 6, and ~90 across all groups for Groups 7 to 9) at select sites only. Sentinel-cohort participants will not have samples collected for PBMC 
isolation/HLA typing. See Section 10.11.8.2.

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10.11.1.3. Schedule of Activities for Substudy E
Visit Number
Screening
601
601A
602
603
604
605
Unplanned
Visit Description
Screeninga
Vaccination 3-Day Follow-Up 
Visit After 
Vaccinationa
1-Week
Follow-Up 
Visit After 
Vaccination
1-Month
Follow-Up 
Visit After 
Vaccination
3-Month
Follow-Up 
Visit After 
Vaccination
6-Month
Follow-Up 
Visit After 
Vaccination
Potential 
COVID-19 
Illness Visitb
Visit Window (Days)
0 to 14 Days 
Before Visit 601
Day 1c
2 to 4 Days After 
Visit 601
6 to 8 Days 
After Visit 
601
28 to 35 Days 
After Visit 
601
85 to 95 
Days After 
Visit 601
175 to 189 
Days After 
Visit 601
Optimally 
Within 3 
Days After 
Potential 
COVID-19 
Illness Onset
ONLY FOR 
SENTINEL-
COHORT 
PARTICIPANTS 
IN GROUPS 7, 
8, AND 9
ONLY FOR 
SENTINEL-
COHORT 
PARTICIPANTS 
IN GROUPS 7, 
8, AND 9
Obtain informed consent
X
Xd
Obtain the participant’s prior study and 
participant number 
(if applicable)
X
Xd
Assign participant number 
X
Xd
Obtain demography and medical history data
X
Xd
Perform clinical assessmente
X
X
Measure height and weight
X
X
Measure temperature (body)
X
Perform urine pregnancy test (if appropriate)
X
X
Confirm use of contraceptives (if appropriate)
X
X
X
X
X
Collect nonstudy vaccine information 
X
X
X
X
X
X
X
Collect prohibited medication use
X
X
X
X
X
X
For participants who are HIV-positive, record 
latest CD4 count and HIV viral load
X
Xd
X
X
X
Confirm eligibility
X
X
Review temporary delay criteria
X

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Visit Number
Screening
601
601A
602
603
604
605
Unplanned
Visit Description
Screeninga
Vaccination 3-Day Follow-Up 
Visit After 
Vaccinationa
1-Week
Follow-Up 
Visit After 
Vaccination
1-Month
Follow-Up 
Visit After 
Vaccination
3-Month
Follow-Up 
Visit After 
Vaccination
6-Month
Follow-Up 
Visit After 
Vaccination
Potential 
COVID-19 
Illness Visitb
Visit Window (Days)
0 to 14 Days 
Before Visit 601
Day 1c
2 to 4 Days After 
Visit 601
6 to 8 Days 
After Visit 
601
28 to 35 Days 
After Visit 
601
85 to 95 
Days After 
Visit 601
175 to 189 
Days After 
Visit 601
Optimally 
Within 3 
Days After 
Potential 
COVID-19 
Illness Onset
ONLY FOR 
SENTINEL-
COHORT 
PARTICIPANTS 
IN GROUPS 7, 
8, AND 9
ONLY FOR 
SENTINEL-
COHORT 
PARTICIPANTS 
IN GROUPS 7, 
8, AND 9
Collect blood sample for immunogenicity 
assessment
~50 mL
~50 mL
~50 mL
~50 mL
~50 mL
Collect blood sample for PBMC isolationf
~120 mL
~120 mL
~120 mL
~120 mL
~120 mL
Collect blood sample for HLA typingf
~5 mL
Collect a blood sample for troponin testing
10 mL
10 mL
Obtain nasal (midturbinate) swab
X
X
Obtain the participant’s vaccine vial allocation 
using the IRT system
X
Administer study intervention
X
Assess acute reactions for at least 30 minutes 
after study intervention administration
X
Explain/review participant communication 
methods (including for e-diary completion), 
assist the participant with downloading the 
app, or issue provisioned device, if required
X
Provide/ensure the participant has a
thermometer and measuring device
X
Review reactogenicity e-diary data (daily 
review is optimal during the active diary 
period)
X
X
X

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Visit Number
Screening
601
601A
602
603
604
605
Unplanned
Visit Description
Screeninga
Vaccination 3-Day Follow-Up 
Visit After 
Vaccinationa
1-Week
Follow-Up 
Visit After 
Vaccination
1-Month
Follow-Up 
Visit After 
Vaccination
3-Month
Follow-Up 
Visit After 
Vaccination
6-Month
Follow-Up 
Visit After 
Vaccination
Potential 
COVID-19 
Illness Visitb
Visit Window (Days)
0 to 14 Days 
Before Visit 601
Day 1c
2 to 4 Days After 
Visit 601
6 to 8 Days 
After Visit 
601
28 to 35 Days 
After Visit 
601
85 to 95 
Days After 
Visit 601
175 to 189 
Days After 
Visit 601
Optimally 
Within 3 
Days After 
Potential 
COVID-19 
Illness Onset
ONLY FOR 
SENTINEL-
COHORT 
PARTICIPANTS 
IN GROUPS 7, 
8, AND 9
ONLY FOR 
SENTINEL-
COHORT 
PARTICIPANTS 
IN GROUPS 7, 
8, AND 9
Review ongoing reactogenicity e-diary 
symptoms and obtain stop dates
X
X
X
Collect AEs and SAEs as appropriate
X
X
X
X
Xg
Xg
Xg
X
Collect e-diary or assist the participant to 
delete application
X
Collection of COVID-19–related clinical and 
laboratory information (including local 
diagnosis)
X

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Visit Number
Screening
601
601A
602
603
604
605
Unplanned
Visit Description
Screeninga
Vaccination 3-Day Follow-Up 
Visit After 
Vaccinationa
1-Week
Follow-Up 
Visit After 
Vaccination
1-Month
Follow-Up 
Visit After 
Vaccination
3-Month
Follow-Up 
Visit After 
Vaccination
6-Month
Follow-Up 
Visit After 
Vaccination
Potential 
COVID-19 
Illness Visitb
Visit Window (Days)
0 to 14 Days 
Before Visit 601
Day 1c
2 to 4 Days After 
Visit 601
6 to 8 Days 
After Visit 
601
28 to 35 Days 
After Visit 
601
85 to 95 
Days After 
Visit 601
175 to 189 
Days After 
Visit 601
Optimally 
Within 3 
Days After 
Potential 
COVID-19 
Illness Onset
ONLY FOR 
SENTINEL-
COHORT 
PARTICIPANTS 
IN GROUPS 7, 
8, AND 9
ONLY FOR 
SENTINEL-
COHORT 
PARTICIPANTS 
IN GROUPS 7, 
8, AND 9
Provide/ensure the participant has a nasal self-
swab kit and instructions on self-collection of 
nasal swabs
X
X
X
X
Abbreviations: HIV = human immunodeficiency virus; HLA = human leukocyte antigen; IRT = interactive response technology; PBMC = peripheral blood 
mononuclear cell.
a.
Only for sentinel-cohort participants 18 to 55 years of age in Groups 7 to 9. The Screening Visit can occur over more than 1 day.
b.
The COVID-19 illness visit may be conducted as an in-person or telehealth visit.
c.
The visit may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and exclusion criteria onwards must be conducted on the 
same day.
d.
These Visit 601 procedures are not required for the Group 7, 8, and 9 sentinel-cohort participants, as they will be completed at the screening visit.
e.
Including, if indicated, a physical examination.
f.
Additional 120 mL for PBMC isolation (and 5 mL for HLA typing at Visit 601) is for select expanded-enrollment participants (~30 per group for Groups 1 
to 6, and ~90 across all groups for Groups 7 to 9) at select sites only. Sentinel-cohort participants will not have samples collected for PBMC isolation/HLA 
typing. See Section 10.11.8.2.
g.
Any AEs occurring up to 48 hours after the blood draw must be recorded (see Section 8.3.1).

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10.11.2. Introduction
10.11.2.1. Study Rationale
The SARS-CoV-2 variant B.1.1.529, also known as Omicron, is currently the dominant 
variant in many countries and within the US is responsible for 98.3% of sequenced 
COVID-19 cases as of 08 January 2022.25 Current data note that the vaccine effectiveness 
against hospitalization is 88% (78%-93%) for Omicron after 3 doses of vaccine.26  However, 
even with 3 vaccine doses, neutralization against the Omicron variant was lower (by a factor 
of 4) than that against the Delta variant. The addition of a higher dose booster may improve 
protection, particularly in older individuals, with increased longevity of an immune response, 
provided it has a tolerable safety profile.27 Therefore, Substudy E has been designed to 
evaluate high-dose BNT162b2 OMI (60 µg), high-dose BNT162b2 (60 µg), and a high-dose 
combination of BNT162b2 OMI and BNT162b2 (30 µg of each), compared to 
BNT162b2 OMI 30 µg, BNT162b2 30 µg, and a combination of BNT162b2 OMI and 
BNT162b2 (15 µg of each), given as a fourth dose.
See Section 2.2 for the study background.
10.11.2.2. Benefit/Risk Assessment
A tolerability profile of a 60-µg dose of BNT162b2 has yet to be established. However, 
BNT162b1 (a candidate RNA-LNP vaccine tested in clinical trial C4591001 utilizing a 
nucleoside-modified messenger RNA similar to BNT162b2 but instead of encoding the 
SARS-CoV-2 full-length, P2 mutant, prefusion spike glycoprotein, BNT162b1 encodes the 
trimerized SARS-CoV-2 spike glycoprotein receptor-binding domain) was studied in adults 
18 to 55 years of age at dose levels of 50 µg, 60 µg, and 100 µg. In one study, 60 
participants were vaccinated with BNT162b1. Twelve participants for each of the dose level 
groups (1 µg, 10 µg, 30 µg, 50 µg, and 60 µg) were to receive the first dose on Day 1 and a 
second dose on Day 22. Due to the tolerability observed in participants after 2 doses of 
50 µg and after reviewing the totality of the data available, including the local and systemic 
reactogenicity data (such as the increasing number of severe [Grade 3] systemic reactions 
reported with ascending dose), a second dose of 60 µg was not administered.37,47 Another 
study investigated BNT162b1 at 10 µg, 30 µg, and 100 µg. Participants in this study were 
not administered the second dose of 100 µg because of the increased reactogenicity profile 
seen after a single dose at 100 µg and in participants who received 2 doses of 30 µg.38 In 
light of better tolerability of BNT162b2 (compared to BNT162b1), and better tolerability in 
older adults (compared to younger adults), the potential benefit of a 60-µg dose of 
BNT162b2 is likely to outweigh the risk.
10.11.2.2.1. Benefit Assessment
Benefits to individual participants enrolled in Substudy E may be:

Receipt of a fourth dose of an efficacious or potentially efficacious COVID-19 vaccine 
that may convey a longer duration of protection during a global pandemic, particularly 
against new variant-associated infection and disease.

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
Contributing to research to help others in a time of global pandemic.
10.11.3. Objectives, Estimands, and Endpoints
Objectives
Estimands
Endpoints
Primary Safety

To describe the safety and 
tolerability profile of BNT162b2 
(30 µg or 60 µg), 
BNT162b2 OMI (30 µg or 60 
µg), and bivalent BNT162b2 and 
BNT162b2 OMI (30 µg or 60 µg) 
given as a fourth dose to 
BNT162b2-experienced 
participants >55 years of age
In participants receiving at least 1 dose of study 
intervention, the percentage of participants 
reporting:

Local reactions for up to 7 days following 
the study vaccination

Systemic events for up to 7 days following 
the study vaccination

AEs from the study vaccination through
1 month after the study vaccination

SAEs from the study vaccination through
6 months after the study vaccination

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 OMI 60 µg and
bivalent BNT162b2 and 
BNT162b2 OMI (30 µg or 60 µg) 
given as a fourth dose to 
BNT162b2-experienced 
participants 18-55 years of age
In participants receiving at least 1 dose of study 
intervention, the percentage of participants 
reporting:

Local reactions for up to 7 days following 
the study vaccination

Systemic events for up to 7 days following 
the study vaccination

AEs from the study vaccination through
1 month after the study vaccination

SAEs from the study vaccination through 
6 months after the study vaccination

Percentage of participants with elevated 
troponin I levels before and 3 days after 
study vaccination (sentinel cohort only)

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

Troponin I level (sentinel 
cohort only)
Primary Immunogenicity
G3vG1A: To demonstrate the 
superiority with respect to level of 
neutralizing titer and noninferiority 
with respect to seroresponse rate of 
anti-Omicron immune response after 
1 dose of BNT162b2 OMI at 30 µg
compared to after 1 dose of 
BNT162b2 at 30 µg given as a fourth 
dose in BNT162b2-experienced 
participants >55 years of age
In participants complying with the key protocol 
criteria (evaluable participants) and no 
serological or virological evidence (up to 
1 month after receipt of 1 dose of study 
intervention given as a fourth dose) of past 
SARS-CoV-2 infection:

GMR of the Omicron-neutralizing titers at 
1 month after 1 dose of BNT162b2 OMI at 
30 µg to those at 1 month after 1 dose of 
BNT162b2 at 30 µg given as a fourth dose
in BNT162b2-experienced participants

The difference in percentages of 
participants with seroresponsea to the 
Omicron strain at 1 month after 1 dose of 
BNT162b2 OMI 30 µg and at 1 month after 
1 dose of BNT162b2 at 30 µg given as a 
fourth dose in BNT162b2-experienced 
participants

SARS-CoV-2 
Omicron-neutralizing 
titers

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Objectives
Estimands
Endpoints
G4vG1A: To demonstrate the 
superiority with respect to level of 
neutralizing titer and noninferiority 
with respect to seroresponse rate of 
anti-Omicron immune response after 
1 dose of BNT162b2 OMI at 60 µg
compared to after 1 dose of 
BNT162b2 at 30 µg given as a fourth 
dose in BNT162b2-experienced 
participants >55 years of age
In participants complying with the key protocol 
criteria (evaluable participants) and no 
serological or virological evidence (up to 
1 month after receipt of 1 dose of study 
intervention given as a fourth dose) of past 
SARS-CoV-2 infection:

GMR of the Omicron-neutralizing titers at 
1 month after 1 dose of BNT162b2 OMI at 
60 µg to those at 1 month after 1 dose of 
BNT162b2 at 30 µg given as a fourth dose
in BNT162b2-experienced participants

The difference in percentages of 
participants with seroresponsea to the 
Omicron strain at 1 month after 1 dose of 
BNT162b2 OMI 60 µg and at 1 month after 
1 dose of BNT162b2 at 30 µg given as a 
fourth dose in BNT162b2-experienced 
participants

SARS-CoV-2 
Omicron-neutralizing 
titers
G5vG1A: To demonstrate the 
superiority with respect to level of 
neutralizing titer and noninferiority 
with respect to seroresponse rate of 
anti-Omicron immune response after 1 
dose of bivalent BNT162b2 and 
BNT162b2 OMI at 30 µg compared to 
after 1 dose of BNT162b2 at 30 µg 
given as a fourth dose in BNT162b2-
experienced participants >55 years of 
age
In participants complying with the key protocol 
criteria (evaluable participants) and no 
serological or virological evidence (up to 
1 month after receipt of 1 dose of study 
intervention given as a fourth dose) of past 
SARS-CoV-2 infection:

GMR of the Omicron-neutralizing titers at 
1 month after 1 dose of bivalent BNT162b2 
and BNT162b2 OMI at 30 µg to those at
1 month after 1 dose of BNT162b2 at 30 µg
given as a fourth dose in BNT162b2-
experienced participants

The difference in percentages of 
participants with seroresponsea to the 
Omicron strain at 1 month after 1 dose of 
bivalent BNT162b2 and BNT162b2 OMI at 
30 µg and at 1 month after 1 dose of 
BNT162b2 at 30 µg given as a fourth dose 
in BNT162b2-experienced participants

SARS-CoV-2 
Omicron-neutralizing 
titers
G6vG1A: To demonstrate the 
superiority with respect to level of 
neutralizing titer and noninferiority 
with respect to seroresponse rate of 
anti-Omicron immune response after 
1 dose of bivalent BNT162b2 and 
BNT162b2 OMI at 60 µg compared to 
after 1 dose of BNT162b2 at 30 µg 
given as a fourth dose in BNT162b2-
experienced participants >55 years of 
age
In participants complying with the key protocol 
criteria (evaluable participants) and no 
serological or virological evidence (up to 
1 month after receipt of 1 dose of study 
intervention given as a fourth dose) of past 
SARS-CoV-2 infection:

GMR of the Omicron-neutralizing titers at 
1 month after 1 dose of bivalent BNT162b2 
and BNT162b2 OMI at 60 µg to those at
1 month after 1 dose of BNT162b2 at 30 µg
given as a fourth dose in BNT162b2-
experienced participants

The difference in percentages of 
participants with seroresponsea to the 
Omicron strain at 1 month after 1 dose of 
bivalent BNT162b2 and BNT162b2 OMI at 
60 µg and at 1 month after 1 dose of 
BNT162b2 at 30 µg given as a fourth dose 
in BNT162b2-experienced participants

SARS-CoV-2 
Omicron-neutralizing 
titers

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Objectives
Estimands
Endpoints
Secondary Immunogenicity
G5vG1B: To demonstrate the 
noninferiority of anti-reference-strain
immune response after 1 dose of 
bivalent BNT162b2 and BNT162b2
OMI at 30 µg compared to after 1 dose 
of BNT162b2 at 30 µg given as a
fourth dose in BNT162b2-experienced 
participants >55 years of age
In participants complying with the key protocol 
criteria (evaluable participants) and no 
serological or virological evidence (up to 
1 month after receipt of 1 dose of study 
intervention given as a fourth dose) of past 
SARS-CoV-2 infection:

GMR of the reference-strain–neutralizing 
titers at 1 month after 1 dose of bivalent
BNT162b2 and BNT162b2 OMI at 30 µg
to those at 1 month after 1 dose of 
BNT162b2 at 30 µg given as a fourth dose
in BNT162b2-experienced participants

SARS-CoV-2 reference-
strain–neutralizing titers
G6vG1B: To demonstrate the 
noninferiority of anti–reference strain
immune response after 1 dose of 
bivalent BNT162b2 and 
BNT162b2 OMI at 60 µg compared to 
after 1 dose of BNT162b2 at 30 µg 
given as a fourth dose in BNT162b2-
experienced participants >55 years of 
age
In participants complying with the key protocol 
criteria (evaluable participants) and no 
serological or virological evidence (up to 
1 month after receipt of 1 dose of study 
intervention given as a fourth dose) of past 
SARS-CoV-2 infection:

GMR of the reference-strain–neutralizing 
titers at 1 month after 1 dose of bivalent
BNT162b2 and BNT162b2 OMI at 60 µg
to those at 1 month after 1 dose of 
BNT162b2 at 30 µg given as a fourth dose
in BNT162b2-experienced participants

SARS-CoV-2 reference-
strain–neutralizing titers
To demonstrate the “super” superiority 
of anti-Omicron immune responses
after 1 dose of BNT162b2 OMI at 
30 µg (G3vG1B), BNT162b2 OMI at 
60 µg (G4vG1B), bivalent BNT162b2 
and BNT162b2 OMI at 30 µg
(G5vG1C), or bivalent BNT162b2 and 
BNT162b2 OMI at 60 µg (G6vG1C) 
compared to after 1 dose of 
BNT162b2 at 30 µg given as a fourth 
dose in BNT162b2-experienced 
participants >55 years of age
Same as GMR estimand of G3vG1A, G4vG1A, 
G5vG1A, G6vG1A

SARS-CoV-2 
Omicron-neutralizing 
titers

Exploratory
To describe the immune response to 
BNT162b2 (30 µg or 60 µg), 
BNT162b2 OMI (30 µg or 60 µg), and 
bivalent BNT162b2 and 
BNT162b2 OMI (30 µg or 60 µg)
given as a fourth dose in BNT162b2-
experienced participants >55 years of
age

GMT at each time point

GMFRs from before the study vaccination 
to subsequent time points

Percentages of participants with 
seroresponsea at each time point 

SARS-CoV-2 
Omicron-neutralizing 
titers

SARS-CoV-2 reference-
strain–neutralizing titers
To describe the immune response to
bivalent BNT162b2 and 
BNT162b2 OMI (30 µg or 60 µg), 
BNT162b2 OMI 60 µg, and 
BNT162b2 30 µgb given as a fourth 
dose in BNT162b2-experienced 
participants 18 to 55 years of age

GMT at each time point

GMFRs from before the study vaccination 
to subsequent time points

Percentages of participants with 
seroresponsea at each time point

SARS-CoV-2 
Omicron-neutralizing 
titers

SARS-CoV-2 reference-
strain–neutralizing titers

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Objectives
Estimands
Endpoints
To describe the immune response to 
the reference strain and VOCs for 
participantsc in sentinel cohorts of 
each age group

SARS-CoV-2 
neutralizing titers for 
the reference strain and 
VOCs
To describe the immune response to 
any VOCs not already specified in 
each age group

SARS-CoV-2
neutralizing titers for 
any VOCs not already 
specified
To describe confirmed COVID-19 and 
severe COVID-19 cases in each age 
group

Confirmed COVID-19 
cases

Confirmed severe 
COVID-19 cases

Strain sequencing of 
COVID-19 cases
To describe the cell-mediated immune 
response, and additional humoral 
immune response parameters, to the 
reference strain and Omicron in a 
subset of participants with PBMC 
samples collected in each group for 
each age group
a.
Seroresponse is defined as achieving ≥4-fold rise from baseline (before the first dose of study vaccination).  If the 
baseline measurement is below the LLOQ, the postvaccination measure of ≥4 × LLOQ is considered seroresponse.
b.
A subset of the youngest 150 participants from the >55-year-old group in Substudy E who have received bivalent 
BNT162b2 30 µg as a fourth dose will be selected for this objective.
c.
This subset of participants will not contribute to the assessment of primary immunogenicity objectives.
10.11.4. Study Design
10.11.4.1. Overall Design
This is a randomized, observer-blinded substudy to evaluate the safety, tolerability, and 
immunogenicity of high-dose BNT162b2 (60 µg), high-dose BNT162b2 OMI (60 µg), and a 
high-dose combination of BNT162b2 and BNT162b2 OMI at 60 µg (30 µg each), given as a 
single dose. Approximately 1920 participants >55 years of age and 990 participants 18 to 
55 years of age who have received 3 prior doses of BNT162b2 (30-µg doses), with the most 
recent dose being 5 to 12 months (150 to 360 days) prior to randomization, will be enrolled at 
investigator sites in the US only. Participants >55 years of age will be randomized at a ratio 
of 1:1:1:1:1:1 to receive BNT162b2 at 30 µg, BNT162b2 at 60 µg, BNT162b2 OMI at 30 µg, 
BNT162b2 OMI at 60 µg, a combination of BNT162b2 and BNT162b2 OMI at 30 µg (15 µg
each), or a combination of BNT162b2 and BNT162b2 OMI at 60 µg (30 µg each) at 
Visit 601 as a fourth dose. Participants 18 to 55 years of age will be randomized to receive
bivalent BNT162b2 and BNT162b2 OMI at 60 µg (30 µg each), bivalent BNT162b2 and 
BNT162b2 OMI at 30 µg (15 µg each), or BNT162b2 OMI at 60 µg at Visit 601 as a fourth 
dose.

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Initially, for participants >55 years of age, sentinel cohorts (sponsor open-label) of 
20 participants per group will be enrolled. E-diary data from Day 1 and Day 2 for the first 
30 participants enrolled in the sentinel cohort (5 per group) will be evaluated prior to 
enrollment of the remaining 90 sentinel-cohort participants. An IRC will review all reported 
AEs and reactogenicity e-diary data from the sentinel cohorts collected through Day 7 to 
allow expanded enrollment of an additional 300 participants per group upon confirmation of 
an acceptable safety assessment. If the safety assessment is considered not to be acceptable, 
the protocol may be amended to include a further sentinel cohort employing 50-µg dose 
levels of BNT162b2, BNT162b2 OMI, and a combination of BNT162b2 and BNT162b2 
OMI (25 µg each).
For participants 18 to 55 years of age, sentinel cohorts (sponsor open-label) of 30 participants 
per group will be enrolled. E-diary data from Day 1 and Day 2 for the first 15 participants 
enrolled in the sentinel cohort (5 per group) will be evaluated prior to enrollment of the 
remaining 75 sentinel-cohort participants. An IRC will review all reported AEs,
reactogenicity e-diary data, and troponin levels from the sentinel cohorts collected through 
Day 7 to allow expanded enrollment upon confirmation of an acceptable safety assessment. 
An additional 900 participants will be enrolled and randomized in a 3:1:2 ratio to receive 
bivalent BNT162b2 and BNT162b2 OMI at 60 µg (30 µg each), bivalent BNT162b2 and 
BNT162b2 OMI at 30 µg (15 µg each), and BNT162b2 OMI at 60 µg.
Table 12 and Table 13 describe the enrollment of the sentinel cohorts and steps to progress to 
expanded enrollment for the >55-year age groups and 18- to 55-year age groups, 
respectively.

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Table 12.
Substudy E – Participants >55 Years of Age – Sentinel and Expanded 
Enrollment
Initial-Sentinel Enrollmenta
Group
Study Intervention
Number of 
Participants
1
BNT162b2 30 µg (participants >55 years of age)
5
2
BNT162b2 60 µg (participants >55 years of age)
5
3
BNT162b2 OMI 30 µg (participants >55 years of age)
5
4
BNT162b2 OMI 60 µg (participants >55 years of age)
5
5
Combination of BNT162b2 and BNT162b2 OMI 30 µg (15 µg each)b
(participants >55 years of age)
5
6
Combination of BNT162b2 and BNT162b2 OMI 60 µg (30 µg each)b
(participants >55 years of age)
5
Study team review of Day 1 and Day 2 e-diary reactogenicity data from sentinel-cohort participants
Expanded-Sentinel Enrollmenta
Group
Study Intervention
Number of 
Participants
1
BNT162b2 30 µg (participants >55 years of age)
15
2
BNT162b2 60 µg (participants >55 years of age)
15
3
BNT162b2 OMI 30 µg (participants >55 years of age)
15
4
BNT162b2 OMI 60 µg (participants >55 years of age)
15
5
Combination of BNT162b2 and BNT162b2 OMI 30 µg (15 µg each)b
(participants >55 years of age)
15
6
Combination of BNT162b2 and BNT162b2 OMI 60 µg (30 µg each)b
(participants >55 years of age)  
15
IRC review of all reported AE and reactogenicity e-diary data from the sentinel cohorts collected through Day 7. 
Expanded enrollment to commence upon confirmation of an acceptable safety assessment.
Expanded Enrollmentc
Group
Study Intervention
Number of 
Participants
1
BNT162b2 30 µg (participants >55 years of age)
300
2
BNT162b2 60 µg (participants >55 years of age)
300
3
BNT162b2 OMI 30 µg (participants >55 years of age)
300
4
BNT162b2 OMI 60 µg (participants >55 years of age)
300
5
Bivalent BNT162b2 and BNT162b2 OMI 30 µg (15 µg each)d
(participants >55 years of age)
300
6
Bivalent BNT162b2 and BNT162b2 OMI 60 µg (30 µg each)d
(participants >55 years of age)
300
Abbreviation: IRC = independent review committee.
a.
Sentinel cohorts will be sponsor open-label.
b.
Initial- and expanded-sentinel enrollment participants randomized to combination BNT162b2 and 
BNT162b2 OMI 30 µg and 60 µg will receive doses that are prepared at the investigator site from 1 vial 
each of diluted BNT162b2 vaccine and BNT162b2 OMI vaccine.
c.
If the IRC’s safety assessment is considered not to be acceptable, the protocol may be amended to include 
a further sentinel cohort employing 50-µg dose levels of BNT162b2, BNT162b2 OMI, and a combination 
of BNT162b2 and BNT162b2 OMI (25 µg each).
d.
Expanded-enrollment participants randomized to bivalent BNT162b2 and BNT162b2 OMI 30 µg and 
60 µg will receive the doses from a single 100-µg/mL vial of BNT162b2 bivalent [Wild Type and 
Omicron (B.1.1.529)] preformulated vaccine suspension for injection. No dilution is required.

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Table 13.
Substudy E – Participants 18 to 55 Years of Age – Sentinel and Expanded 
Enrollment
Initial-Sentinel Enrollmenta,b
Group Study Intervention
Number of 
Participants
7
Bivalent BNT162b2 and BNT162b2 OMI 60 µg (30 µg each) 
(participants 18 to 55 years of age)
5
8
Bivalent BNT162b2 and BNT162b2 OMI 30 µg (15 µg each) 
(participants 18 to 55 years of age)
5
9
BNT162b2 OMI 60 µg (participants 18 to 55 years of age)
5
Study team review of Day 1 and Day 2 e-diary reactogenicity data from sentinel-cohort participants
Expanded-Sentinel Enrollment
Group Study Intervention
Number of 
Participants
7
Bivalent BNT162b2 and BNT162b2 OMI 60 µg (30 µg each) 
(participants 18 to 55 years of age)
25
8
Bivalent BNT162b2 and BNT162b2 OMI 30 µg (15 µg each) 
(participants 18 to 55 years of age)
25
9
BNT162b2 OMI 60 µg (participants 18 to 55 years of age)
25
IRC review of all reported AE and reactogenicity e-diary data from the sentinel cohorts collected through 
Day 7. Expanded enrollment to commence upon confirmation of an acceptable safety assessment.
Expanded Enrollmentc
Group Study Intervention
Number of 
Participants
7
Bivalent BNT162b2 and BNT162b2 OMI 60 µg (30 µg each) 
(participants 18 to 55 years of age)
450
8
Bivalent BNT162b2 and BNT162b2 OMI 30 µg (15 µg each) 
(participants 18 to 55 years of age)
150
9
BNT162b2 OMI 60 µg (participants 18 to 55 years of age)
300
Abbreviation: IRC = internal review committee.
a.
Sentinel cohorts will be sponsor open-label.
b.
Participants randomized to bivalent BNT162b2 and BNT162b2 OMI 30 µg and 60 µg will receive the 
doses from a single 100-µg/mL vial of BNT162b2 bivalent ([Wild Type and Omicron [(B.1.1.529])] 
preformulated vaccine suspension for injection. No dilution is required.
c.
If the IRC’s safety assessment is considered not to be acceptable, the protocol may be amended to include 
a further sentinel cohort employing 50-µg dose levels of BNT162b2, BNT162b2 OMI, and a combination 
of BNT162b2 and BNT162b2 OMI (25 µg each).
10.11.4.2. Scientific Rationale for Substudy E Design
See Section 10.11.2.1.
10.11.4.2.1. Diversity of Study Population 
Reasonable attempts will be made to enroll participants who align with the US population 
distribution (Census-based), to ensure that the study population is representative of patient 
populations that will benefit from a COVID-19 vaccine in clinical practice.

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10.11.4.3. Justification for Dose
See Section 4.3 for a justification of the BNT162b2 and BNT162b2 OMI dose used in 
Substudy E.
10.11.4.4. End of Study Definition
See Section 4.4.
10.11.5. Study Population
Details of the master and Substudy E eligibility criteria are shown in Section 5.  Participants 
must meet all of the general inclusion and exclusion criteria as specified for the master 
protocol as well as Substudy E–specific inclusion and exclusion criteria.
10.11.5.1. Inclusion Criteria
Participants are eligible to be included in Substudy E only if all of the following criteria 
apply:
Age and Sex:
1. Groups 1 to 6: Male or female participants 55 years of age
or
Groups 7 to 9: Male or female participants 18 to 55 years of age
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, vaccination 
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Healthy participants who are determined by medical history, physical examination
(if required), and clinical judgment of the investigator to be eligible for inclusion in the 
study.
Note: Healthy participants with preexisting stable disease, defined as disease not 
requiring significant change in therapy or hospitalization for worsening disease during 
the 6 weeks before enrollment, can be included.  Specific criteria for participants with 
known stable infection with HIV, HCV, or HBV can be found in Section 10.15.

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Informed Consent:
4. Capable of giving personal signed informed consent as described in Appendix 1, which
includes compliance with the requirements and restrictions listed in the ICD and in this 
protocol.
Other Inclusions:
5. Participants who have received 3 prior doses of 30 µg BNT162b2, with the third dose 
being 5 to 12 months (150 to 360 days) before Visit 601 (Day 1).
Documented confirmation of prior BNT162b2 receipt must be obtained prior to 
randomization.
6. Groups 7 to 9 (sentinel participants): Screening troponin levels must be within normal 
range prior to randomization.
10.11.5.2. Exclusion Criteria
Participants are excluded from Substudy E if any of the following criteria apply:
Medical Conditions:
1. Other medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for the 
study.
2. History of severe adverse reaction associated with a vaccine and/or severe allergic 
reaction (eg, anaphylaxis) to any component of the study intervention(s).
3. 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.
4. Immunocompromised individuals with known or suspected immunodeficiency, as 
determined by history and/or laboratory/physical examination.
5. Bleeding diathesis or condition associated with prolonged bleeding that would, in the 
opinion of the investigator, contraindicate intramuscular injection.
6. Women who are pregnant or breastfeeding.

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Prior/Concomitant Therapy:
7. Individuals who receive treatment with radiotherapy or immunosuppressive therapy, 
including cytotoxic agents or systemic corticosteroids (if systemic corticosteroids are 
administered for ≥14 days at a dose of ≥20 mg/day of prednisone or equivalent), eg, for 
cancer or an autoimmune disease, or planned receipt throughout the study.  
Inhaled/nebulized, intra-articular, intrabursal, or topical (skin or eyes) corticosteroids are 
permitted.
8. Receipt of blood/plasma products, immunoglobulin, or monoclonal antibodies, from 
60 days before study intervention administration, or receipt of any passive antibody 
therapy specific to COVID-19, from 90 days before study intervention administration, or 
planned receipt throughout the study.
Prior/Concurrent Clinical Study Experience:
9. Prior receipt of any COVID-19 vaccine other than BNT162b2.
Other Exclusions:
10. Investigator site staff or Pfizer-BioNTech employees directly involved in the conduct of 
the study, site staff otherwise supervised by the investigator, and their respective family 
members.
11. Receipt of medications intended to prevent COVID-19.
12. Participation in other studies involving study intervention within 28 days prior to study
entry through and including 28 days after the dose of study intervention, with the 
exception of non-Pfizer interventional studies for prevention of COVID-19, which are 
prohibited throughout study participation.
10.11.5.3. Lifestyle Considerations
Contraception requirements will apply to Substudy E as detailed in Section 5.3 and
Section 10.4.
10.11.5.4. Screen Failures
See Section 5.4.
10.11.5.5. Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention
See Section 5.5.

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10.11.6. Study Intervention(s) and Concomitant Therapy
For the purposes of this substudy, study intervention refers to:

BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S): 
30 µg or 60 µg.

BNT162b2 OMI (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the 
P2 S): 30 µg or 60 µg.

Combination of BNT162b2 and BNT162b2 OMI (BNT162 RNA-LNP vaccine utilizing 
modRNA and encoding the P2 S): 30 µg or 60 µg (site-prepared dosing suspension from 
1 vial each of diluted BNT162b2 and BNT162b2 OMI for the sentinel-cohort participants 
in Groups 1 to 6, or a preformulated bivalent mixture [no dilution required] in a single 
vial for the expanded-enrollment participants in Groups 1 to 6 and for all cohorts in 
Groups 7 to 9).
Note: If the IRC’s safety assessment is considered not to be acceptable, then the 60-µg dose 
levels for BNT162b2, BNT162b2 OMI, and the combination of BNT162b2 and 
BNT162b2 OMI may be replaced by 50-µg dose levels for the expanded enrollment
(combination of BNT162b2 and BNT162b2 OMI at 25 µg each).
10.11.6.1. Study Intervention(s) Administered
Additional 
Intervention 
Name
BNT162b2 
(BNT162 RNA-LNP 
Vaccine Utilizing 
modRNA)
(Dilution Required)
BNT162b2 OMI 
(B.1.1.529)
(BNT162 RNA-LNP 
Vaccine Utilizing 
modRNA)
(Dilution Required)
Combination 
BNT162b2 and 
BNT162b2 OMI
(B.1.1.529)
(BNT162 RNA-LNP 
Vaccine Utilizing 
modRNA)
Site-Prepared Dosing 
Suspension Using 
2 Vials
(Dilution Required)
Combination
BNT162b2 Bivalent 
[Wild Type and 
Omicron (B.1.1.529)]
Preformulated as a 
Single Vial
(No Dilution 
Required)
Type
Vaccine
Vaccine
Vaccine
Vaccine
Dose 
Formulation
modRNA
modRNA
modRNA
modRNA
Unit Dose 
Strength(s)
10 µg/0.1 mL
10 µg/0.1 mL
10 µg/0.1 mL
10 µg/0.1 mL
Dosage 
Level(s) 
30-µg or 60-µga
30-µg or 60-µga
30-µg (15-µg each) or 
60-µg (30-µg each)a
30-µg (15-µg each) or 
60-µg (30-µg each)a
Route of 
Administration
Intramuscular injection Intramuscular injection Intramuscular injection Intramuscular injection
Use
Experimental
Experimental
Experimental
Experimental
IMP or NIMP IMP
IMP
IMP
IMP
Sourcing
Provided centrally by 
the sponsor
Provided centrally by 
the sponsor
Provided centrally by 
the sponsorb
Provided centrally by 
the sponsorc

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Additional 
Intervention 
Name
BNT162b2 
(BNT162 RNA-LNP 
Vaccine Utilizing 
modRNA)
(Dilution Required)
BNT162b2 OMI 
(B.1.1.529)
(BNT162 RNA-LNP 
Vaccine Utilizing 
modRNA)
(Dilution Required)
Combination 
BNT162b2 and 
BNT162b2 OMI
(B.1.1.529)
(BNT162 RNA-LNP 
Vaccine Utilizing 
modRNA)
Site-Prepared Dosing 
Suspension Using 
2 Vials
(Dilution Required)
Combination
BNT162b2 Bivalent 
[Wild Type and 
Omicron (B.1.1.529)]
Preformulated as a 
Single Vial
(No Dilution 
Required)
Packaging and 
Labeling
Study intervention will 
be provided in a glass 
vial as open-label 
supply.  Each vial will 
be labeled as required 
per country 
requirement
Study intervention will 
be provided in a glass 
vial as open-label 
supply.  Each vial will 
be labeled as required 
per country 
requirement
Study intervention will 
be provided in a glass 
vial as open-label 
supply.  Each vial will 
be labeled as required 
per country 
requirement
Study intervention will 
be provided in a glass 
vial as open-label 
supply.  Each vial will 
be labeled as required 
per country 
requirement
a.
If the IRC’s safety assessment is considered not to be acceptable, then the protocol may be amended to 
include a further sentinel cohort employing 50-µg dose levels of BNT162b2, BNT162b2 OMI, and a 
combination of BNT162b2 and BNT162b2 OMI (25 µg each).
b.
The combination of BNT162b2 and BNT162b2 OMI for the sentinel-cohort participants in Groups 1 to 6
will be a dosing suspension prepared at the investigator site from 1 vial each of diluted BNT162b2 vaccine 
and BNT162b2 OMI vaccine at the dose levels shown in this table.
c.
The bivalent formulation of BNT162b2 and BNT162b2 OMI for the expanded-cohort participants in 
Groups 1 to 6 and for all cohorts in Groups 7 to 9 will be provided as a preformulated suspension for 
injection in a single vial. No dilution is required.
10.11.6.1.1. Administration
Participants will receive 1 dose of study intervention as allocated by the IRT at Visit 601 in 
accordance with the substudy’s SoA (Section 10.11.1.3).
Study intervention should be administered intramuscularly into the deltoid muscle, preferably 
of the nondominant arm, by an unblinded administrator.
10.11.6.1.2. Preparation and Dispensing
Study intervention will be prepared by qualified unblinded site personnel according to the IP 
manual.  The study intervention will be administered in such a way as to ensure that the 
participants remain blinded.
10.11.6.2. Measures to Minimize Bias: Randomization and Blinding
10.11.6.2.1. Blinding of Site Personnel
Study staff receiving, storing, dispensing, preparing, and administering the study 
interventions will be unblinded.  All other study and site personnel, including the 
investigator, investigator staff, and participants, will be blinded to study intervention 
assignments.  In particular, the individuals who evaluate participant safety will be blinded.

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The PI will assign the responsibility of the unblinded dispensers/administrators to persons 
who will not participate in the evaluation of any study participant.  To ensure adequate 
coverage, at least 2 unblinded dispensers/administrators will be assigned per site.  Members 
of the study site staff or clinic pharmacy should fulfill these roles.  Contact between the 
unblinded dispensers and study participants should be kept to a minimum.  The investigator, 
study coordinator, and any site staff other than the unblinded dispensers/administrators must 
not be allowed to know the study intervention assigned to any study participant and must not 
be allowed to see the study intervention container contents.  In the event of a Quality 
Assurance audit, the auditor(s) will be allowed access to unblinded study intervention records 
at the site(s) to verify that randomization/dispensing has been done accurately.
10.11.6.2.2. Blinding of the Sponsor
The sponsor will be unblinded to the study intervention allocation for the sentinel cohorts. 
For the expanded-enrollment part of the study, the majority of sponsor/Pfizer staff will be 
blinded to study intervention allocation. All laboratory testing personnel performing 
serology assays will remain blinded to study intervention assigned/received throughout the 
study.  The following sponsor/Pfizer staff, who will have no part in the blinded conduct of 
the study, will be unblinded (further details will be provided in a data blinding plan):

Those study team members who are involved in ensuring that protocol requirements for 
study intervention preparation, handling, allocation, and administration are fulfilled at the 
site will be unblinded for the duration of the study (eg, unblinded study manager, 
unblinded clinical research associate).

Unblinded clinician(s), who are not direct members of the study team and will not 
participate in any other study-related activities, will review unblinded protocol 
deviations.

An unblinded team supporting interactions with, and analyses for, the DMC and IRC
(see Section 10.11.9.4.2).  This team comprises a statistician, programmer(s), a clinical 
scientist, and a medical monitor. 

An unblinded submissions team will be responsible for preparing unblinded analyses and 
documents to support regulatory activities that may be required while the study is 
ongoing.  With the exception of the statisticians and programmers, who will become 
unblinded at the participant level at the time of the first planned reporting event to 
perform the analyses, other members of this team will only be unblinded at the group 
level and not have access to individual participant assignments.  A separate group of 
statisticians and programmers will remain blinded and continue supporting the blinded 
conduct of the study after the first planned analysis.
When a participant has completed their 3-month visit (Visit 604), they may be unblinded to 
confirm the vaccine and dose received.  The study team will also become unblinded to the 
participant’s original study intervention allocation at this time.

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10.11.6.2.3. Breaking the Blind
The IRT will be programmed with blind-breaking instructions.  In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s study 
intervention assignment is warranted.  Participant safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the sponsor prior to 
unblinding a participant’s vaccine assignment unless this could delay further management of 
the participant.  If a participant’s vaccine assignment is unblinded, the sponsor must be 
notified within 24 hours after breaking the blind.  The date and reason that the blind was 
broken must be recorded in the source documentation and CRF.
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
10.11.6.3. Study Intervention Compliance
See Section 6.4.
10.11.6.4. Dose Modification
See Section 6.5.
10.11.6.5. Continued Access to Study Intervention After the End of the Study
See Section 6.6.
10.11.6.6. Treatment of Overdose
See Section 6.7.
10.11.6.7. Concomitant Therapy
See Section 6.8.
10.11.7. Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
See Section 7.
10.11.8. Study Assessments and Procedures
The total blood sampling volume for individual participants in this study is up to 
approximately 250 mL. Sentinel-cohort participants in Groups 7, 8, and 9 will also have 
20 mL of blood drawn for troponin measurements. Those participants in the subset who 
consent to additional blood collection for isolation of PBMCs will have a total blood 
sampling volume of up to approximately 855 mL.
For all participants, other additional blood samples may be taken for safety assessments at 
times specified by Pfizer, provided the total volume taken during the study does not exceed 
550 mL during any period of 60 consecutive days.

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10.11.8.1. Surveillance for COVID-19
If, at any time, a participant develops acute respiratory illness (see Section 10.11.8.6.8), for 
the purposes of the study, he or she will be considered to potentially have COVID-19 illness.  
In this circumstance, the participant should contact the site, an in-person or telehealth visit 
should occur, and assessments should be conducted as specified in the SoA.  The assessments
will include collection of a nasal (midturbinate) swab, which will be tested at a central 
laboratory using an RT-PCR test (Cepheid Xpert Xpress SARS-CoV-2; authorized by the 
FDA under EUA and Pfizer-validated), or other equivalent nucleic acid amplification–based 
test (ie, NAAT) to detect SARS-CoV-2.  In addition, clinical information and results from 
local standard-of-care tests (as detailed in Section 10.11.8.6.9) will be assessed.  The central 
laboratory NAAT result will be used for the case definition, unless no result is available from 
the central laboratory, in which case a local NAAT result may be used if it was obtained 
using 1 of the following assays:

Cepheid Xpert Xpress SARS-CoV-2

Roche cobas SARS-CoV-2 real-time RT-PCR test (EUA200009/A001)

Abbott Molecular/RealTime SARS-CoV-2 assay (EUA200023/A001)
Definitions of SARS-CoV-2–related cases, and SARS-CoV-2–related severe cases, will be 
considered as follows (for both, the onset date of the case will be the date that symptoms 
were first experienced by the participant; if new symptoms are reported within 4 days after 
resolution of all previous symptoms, they will be considered as part of a single illness):

Confirmed COVID-19: presence of at least 1 of the following symptoms and 
SARS-CoV-2 NAAT-positive during, or within 4 days before or after, the symptomatic 
period, either at the central laboratory or at a local testing facility (using an acceptable 
test):

Fever; 

New or increased cough; 

New or increased shortness of breath; 

Chills; 

New or increased muscle pain; 

New loss of taste or smell;

Sore throat;

Diarrhea;

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
Vomiting.

Confirmed severe COVID-19 (FDA definition45): confirmed COVID-19 and presence of 
at least 1 of the following:

Clinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per minute, 
HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or PaO2/FiO2
<300 mm Hg);

Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation, 
mechanical ventilation, or ECMO);

Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiring vasopressors);

Significant acute renal, hepatic, or neurologic dysfunction;

Admission to an ICU;

Death.

Confirmed severe COVID-19 (CDC definition46): confirmed COVID-19 and presence of 
at least 1 of the following:

Hospitalization; 

Admission to the ICU;

Intubation or mechanical ventilation; 

Death.
The DMC may recommend modification of the definition of severe disease according to 
emerging information.
10.11.8.2. Immunogenicity
Serum samples will be obtained for immunogenicity testing at the visits specified in the SoA.
The test to be performed will be the SARS-CoV-2 neutralizing assay (reference strain and 
Omicron strain). Note that all immunogenicity analyses will be based upon samples 
analyzed at the central laboratory.

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Additional whole blood samples of ~120 mL will be obtained from a group of up to 
approximately 30 participants in each >55-year age group (Groups 1 to 6) and up to 
approximately 90 participants across the 18- to 55-year age groups (Groups 7 to 9) during the 
extended enrollment (no sentinel participants will have this additional blood sample drawn) 
for isolation of PBMCs.  These samples will be used to describe B-cell and T-cell responses 
to Omicron and the reference strain.  A blood sample of ~5 mL for HLA typing will also be 
obtained.
10.11.8.3. Safety Assessments
See Section 8.2.
10.11.8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting
See Section 8.3.
10.11.8.5. Specified Genetics
Some of the blood samples collected for PBMC isolation and HLA typing may be used for 
DNA and/or RNA isolation. The DNA and/or RNA samples from the PBMC isolation may 
be used for sequencing of participants’ antibody and/or BCR heavy- and light-chain genes, 
TCR genes, and/or mRNAs, for understanding the B-cell, T-cell, and antibody repertoires. 
The DNA and/or RNA samples from the blood sample for HLA typing may be used to 
further characterize HLA type.
See Appendix 16 for information regarding genetic research. Details on processes for 
collection and shipment of these samples will be provided separately.
10.11.8.6. Substudy E Procedures
10.11.8.6.1. Screening (0 to 14 Days Before Visit 601) (Only for Sentinel-Cohort 
Participants 18 to 55 Years of Age in Groups 7, 8, and 9)
Before enrollment and before any study-related procedures are performed, voluntary, written,
study-specific informed consent will be obtained from the participant. Each signature on the 
ICD must be personally dated by the signatory. The investigator or his or her designee will 
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The 
source data must reflect that the informed consent was obtained before participation in the 
study.
It is anticipated that the procedures below will be conducted in a stepwise manner; however, 
the visit can occur over more than 1 day.

Assign a single participant number using the IRT system.

Obtain the participant’s prior study and participant number (if applicable) and record this 
in the CRF.

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
Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).  
The full date of birth will be collected to critically evaluate the immune response and 
safety profile by age.

Obtain any medical history of clinical significance.  For participants who are 
HIV-positive, record the HIV viral load and CD4 count results from the most recent test 
performed in the previous 6 months.

Perform a clinical assessment.  If the clinical assessment indicates that a physical 
examination is necessary to comprehensively evaluate the participant, perform a physical 
examination and record any findings in the source documents and, if clinically 
significant, record any findings on the medical history CRF.

Measure the participant’s height and weight.

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 5.3.

Record nonstudy vaccinations as described in Section 6.8.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met.

Record AEs as described in Section 8.3.  

Collect a blood sample (approximately 10 mL) for troponin levels.

Ask the participant to contact the site staff or investigator immediately if any significant 
illness or hospitalization occurs.

Ask the participant to contact the site staff or investigator immediately if he or she 
experiences any respiratory symptoms as detailed in Section 10.11.8.6.9.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

Complete the CRF.
10.11.8.6.2. Visit 601 – Substudy E Vaccination (Day 1)
For Participants >55 Years of Age in Groups 1 to 6 and Expanded-Cohort Participants 
18 to 55 Years of Age in Groups 7 to 9:
Before enrollment and before any study-related procedures are performed, voluntary, written, 
study-specific informed consent will be obtained from the participant.  Each signature on the 

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ICD must be personally dated by the signatory.  The investigator or his or her designee will 
also sign the ICD.  A copy of the signed and dated ICD must be given to the participant.  The 
source data must reflect that the informed consent was obtained before participation in the 
study.
It is anticipated that the procedures below will be conducted in a stepwise manner.  The visit 
may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and 
exclusion criteria onwards must be conducted on the same day.

Assign a single participant number using the IRT system.

Obtain the participant’s prior study and participant number (if applicable) and record this 
in the CRF.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).  
The full date of birth will be collected to critically evaluate the immune response and 
safety profile by age.

Obtain any medical history of clinical significance.  For participants who are 
HIV-positive, record the HIV viral load and CD4 count results from the most recent test 
performed in the previous 6 months.
For All Participants:

Perform a clinical assessment.  If the clinical assessment indicates that a physical 
examination is necessary to comprehensively evaluate the participant, perform a physical 
examination and record any findings in the source documents and, if clinically 
significant, record any findings on the medical history CRF.

Measure the participant’s height and weight.

Measure the participant’s body temperature.

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 5.3.

Record nonstudy vaccinations as described in Section 6.8.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Record AEs as described in Section 8.3.

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
Collect a blood sample for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation 
and a further blood sample (approximately 5 mL) for HLA typing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Blinded site staff will obtain the participant’s randomization number using the IRT 
system. The randomization confirmation report with the study intervention allocation will 
only be sent to the unblinded site staff member.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into 
the deltoid muscle of the preferably nondominant arm.  Please refer to the IP manual for 
further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study 
intervention administration for any acute reactions.  Record any acute reactions 
(including time of onset) in the participant’s source documents and on the AE page of the 
CRF, and on an SAE form as applicable.

Provide a measuring device to measure local reactions at the injection site and a 
thermometer for recording daily temperatures and fever (COVID-19 surveillance) and 
provide instructions on their use.

Explain the e-diary technologies available for this study (see Section 8.2.4), and assist the 
participant in downloading the study application onto the participant’s own device or 
issue a provisioned device if required.

Provide instructions on reactogenicity e-diary completion and ask the participant to 
complete the reactogenicity e-diary from Day 1 through Day 7, with Day 1 being the day 
of vaccination.

Provide instructions on COVID-19 illness e-diary completion and ask the participant to 
complete the COVID-19 illness e-diary if the participant is diagnosed with COVID-19 or 
has possible new or increased symptoms, and when he/she receives a reminder, at least 
weekly. See Section 10.11.8.6.8 for further details. Provide a self-swab kit in case of 
COVID-19 symptoms and provide instructions on self-collection of nasal swabs.

Ask the participant to contact the site staff or investigator immediately if the participant 
experiences any of the following from Day 1 through Day 7 after vaccination 
(where Day 1 is the day of vaccination) to determine if an unscheduled reactogenicity 
visit is required: 

Fever ≥39.0°C (≥102.1°F).

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
Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units).

Severe pain at the injection site.

Any severe systemic event.

Ask the participant to contact the site staff or investigator if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.11.8.6.12).

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 10.11.8.6.9.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the reactogenicity e-diary to the next visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs and an unblinded 
dispenser/administrator updates the study intervention accountability records.

The investigator or appropriately qualified designee reviews the reactogenicity e-diary 
data online following vaccination to evaluate participant compliance and as part of the 
ongoing safety review. Daily review is optimal during the active diary period.
10.11.8.6.3. Visit 601A – 3-Day Follow-Up Visit (2 to 4 Days After Visit 601)  (Only for 
Sentinel-Cohort Participants 18 to 55 Years of Age in Groups 7, 8, and 9)

Record AEs as described in Section 8.3.

Review the participant’s reactogenicity e-diary data. Collect stop dates of any 
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary was 
completed and record stop dates in the CRF if required.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 5.3.

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
Collect a blood sample (approximately 10 mL) for troponin levels (only for sentinel-
cohort participants 18 to 55 years of age in Groups 7, 8, and 9).

Ask the participant to contact the site staff or investigator if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.11.8.6.12).

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 10.11.8.6.9.

Ensure the participant has a self-swab kit.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

The investigator or appropriately qualified designee reviews the reactogenicity e-diary 
data online following vaccination to evaluate participant compliance and as part of the 
ongoing safety review. Daily review is optimal during the active diary period.
10.11.8.6.4. Visit 602 – 1-Week Follow-Up Visit (6-8 Days After Visit 601)

Record AEs as described in Section 8.3.

Review the participant’s reactogenicity e-diary data. Collect stop dates of any 
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary was 
completed and record stop dates in the CRF if required.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 5.3.

Collect a blood sample for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.

Ask the participant to contact the site staff or investigator if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.11.8.6.12).

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
Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 10.11.8.6.9.

Ensure the participant has a self-swab kit.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

The investigator or appropriately qualified designee reviews the reactogenicity e-diary 
data online following vaccination to evaluate participant compliance and as part of the 
ongoing safety review. Daily review is optimal during the active diary period.
10.11.8.6.5. Visit 603 – 1-Month Follow-Up Visit (28 to 35 Days After Visit 601) 

Record AEs as described in Section 8.3.

Review the participant’s reactogenicity e-diary data. Collect stop dates of any 
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary was 
completed and record stop dates in the CRF if required.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Discuss contraceptive use as described in Section 5.3.

Collect a blood sample for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 10.11.8.6.9.

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
Ensure the participant has a self-swab kit.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3.
10.11.8.6.6. Visit 604 – 3-Month Follow-Up Visit (85 to 95 Days After Visit 601)

Record AEs as described in Section 8.3.

Collect a blood sample for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 10.11.8.6.9.

Ensure the participant has a self-swab kit.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3.

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10.11.8.6.7. Visit 605 – 6-Month Follow-Up Visit (175 to 189 Days After Visit 601)

Record AEs as described in Section 8.3.

Collect a blood sample for immunogenicity testing.

If the participant is part of the group for description of cell-mediated immune response 
(select sites only), collect a blood sample (approximately 120 mL) for PBMC isolation.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Collect the participant’s e-diary or assist the participant to remove the study application 
from his or her own personal device.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3.
10.11.8.6.8. COVID-19 Surveillance (All Substudy E Participants)
If a participant experiences any of the following (irrespective of perceived etiology or 
clinical significance), he or she is instructed to contact the site immediately and, if 
confirmed, participate in an in-person or telehealth visit as soon as possible, optimally within 
3 days of symptom onset (and at the latest 4 days after symptom resolution).

A diagnosis of COVID-19;

Fever;

New or increased cough; 

New or increased shortness of breath; 

Chills; 

New or increased muscle pain; 

New loss of taste/smell;

Sore throat;

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
Diarrhea;

Vomiting.
Note that:

If new symptoms are reported within 4 days after resolution of all previous symptoms, 
they will be considered as part of a single illness and a second illness visit is not required;

Surveillance of potential COVID-19 symptoms should continue even if a participant has 
a positive SARS-CoV-2 test earlier in the study.
During the 7 days following each vaccination, potential COVID-19 symptoms that overlap 
with specific systemic events (ie, fever, chills, new or increased muscle pain, diarrhea, 
vomiting) should not trigger a potential COVID-19 illness visit unless, in the investigator’s 
opinion, the clinical picture is more indicative of a possible COVID-19 illness than vaccine 
reactogenicity.  If, in the investigator’s opinion, the symptoms are considered more likely to 
be vaccine reactogenicity, but a participant is required to demonstrate that he or she is
SARS-CoV-2–negative, a local SARS-CoV-2 test may be performed: if positive, the 
symptoms should be recorded as a potential COVID-19 illness; if not, the symptoms should 
be recorded as AEs.
Participants may utilize a COVID-19 illness e-diary through an application (see 
Section 10.11.8.6.10) installed on a provisioned device or on the participant’s own personal 
device to prompt him/her to report any symptoms.  Note that this does not substitute for a 
participant’s routine medical care.  Therefore, participants should be encouraged to seek care, 
if appropriate, from their usual provider.
10.11.8.6.9. Potential COVID-19 Illness Visit (Optimally Within 3 Days After Potential 
COVID-19 Illness Onset)
This visit may be conducted as an in-person or telehealth visit; a telehealth visit involves the 
sharing of healthcare information and services via telecommunication technologies 
(eg, audio, video, video-conferencing software) remotely, thus allowing the participant and 
investigator to communicate on aspects of clinical care.
As a participant’s COVID-19 illness may evolve over time, several contacts may be required 
to:

Record AEs, as appropriate as described in Section 8.3.  Note: Potential COVID-19 
illnesses that are consistent with the clinical endpoint definition should not be recorded as 
AEs.  These data will be captured as efficacy assessment data only on the relevant pages 
of the CRF, as these are expected endpoints.

Record details of any of the prohibited medications specified in Section 6.8 received by 
the participant if required for his or her clinical care.

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

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10.11.8.6.10. Communication and Use of Technology
In a study of this nature that requires illness events to be reported outside of scheduled study 
visits, it is vital that communication between the study site and the participant is maintained 
to ensure that endpoint events are not missed.  This study will employ various methods, 
tailored to the individual participant, to ensure that communication is maintained and study 
information can be transmitted securely.  Using appropriate technology, such as a study 
application, a communication pathway between the participant and the study site staff will be 
established.  The participant may be able to utilize his or her own devices to access this 
technology, or use a device provided by the sponsor.  Traditional methods of telephone 
communication will also be available.  The technology solution may facilitate the following:

Contact with the investigator, including the ability of the participant to report whether or 
not the participant has experienced symptoms that could represent a potential COVID-19 
illness (COVID-19 illness e-diary).

An alert in the event that the participant is hospitalized.

Visit reminders.

Messages of thanks and encouragement from the study team.

If a participant is not actively completing the COVID-19 illness e-diary, the investigator 
or designee is required to contact the participant to ascertain why and also to obtain 
details of any missed events.
10.11.8.6.11. SARS-CoV-2 NAAT Results
Nasal (midturbinate) swabs for SARS-CoV-2 NAAT are obtained at:

Visit 601: To determine whether a participant will be included in efficacy analyses of 
those with no serological or virological evidence of past SARS-CoV-2 infection.

Potential COVID-19 illness visits: To determine whether symptoms experienced by the 
participant fulfill the COVID-19 case definition.
Research laboratory–generated positive results from the Visit 601 swab, and all results from 
the illness visit swabs, will be provided to the site once available, but this will not be in real 
time and cannot be relied upon to direct clinical care.  Therefore, the participant should be 
directed to seek additional testing through his/her primary healthcare providers at a licensed 
clinical laboratory when exhibiting potential COVID-19 symptoms or otherwise receiving a 
positive result and counseled on whether to take any precautionary measures pending 
confirmatory testing.

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10.11.8.6.12. Additional Procedures for Monitoring of Potential Myocarditis or 
Pericarditis
Any study participant who reports acute chest pain, shortness of breath, palpitations, or any 
other symptom(s) that might be indicative of myocarditis or pericarditis within 4 weeks after 
a study vaccination should be specifically evaluated, preferably by a cardiologist, for possible 
myocarditis or pericarditis. In addition to a clinical evaluation, the following should be 
performed:

ECG and

Measurement of the troponin level
If myocarditis or pericarditis is suspected based upon the initial evaluation, the following 
should also be performed:

Cardiac echocardiogram and/or

Cardiac magnetic resonance study
Details of the symptoms reported, and results of the investigations performed, will be 
recorded in the CRF.
10.11.8.6.13. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction
If a Grade 3 local reaction (Section 8.2.4.2), systemic event (Section 8.2.4.3), or fever 
(Section 8.2.4.4) is reported in the reactogenicity e-diary, a telephone contact should occur to 
ascertain further details and determine whether a site visit is clinically indicated. If a 
suspected Grade 4 local reaction (Section 8.2.4.2), systemic event (Section 8.2.4.3), or fever 
(Section 8.2.4.4) is reported in the reactogenicity e-diary, a telephone contact or site visit 
should occur to confirm whether the event meets the criteria for Grade 4.
A site visit must be scheduled as soon as possible to assess the participant unless any of the 
following is true:

The participant is unable to attend the unscheduled visit.

The local reaction/systemic event is no longer present at the time of the telephone 
contact.

The participant recorded an incorrect value in the reactogenicity e-diary (confirmation 
of a reactogenicity e-diary data entry error).

The PI or authorized designee determined it was not needed.
This telephone contact will be recorded in the participant’s source documentation and the 
CRF.

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If the participant is unable to attend the unscheduled visit, or the PI or authorized designee 
determined that it was not needed, any ongoing local reactions/systemic events must be 
assessed at the next study visit.
During the unscheduled visit, the reactions should be assessed by the investigator or a 
medically qualified member of the study staff, such as a study physician or a study nurse, as 
applicable to the investigator’s local practice, who will:

Measure body temperature (°F/°C).

Measure minimum and maximum diameters of redness (if present).

Measure minimum and maximum diameters of swelling (if present).

Assess injection site pain (if present) in accordance with the grades provided in
Section 8.2.4.2.

Assess systemic events (if present) in accordance with the grades provided in
Section 8.2.4.3.

Assess for other findings associated with the reaction and record on the AE page of 
the CRF, if appropriate.
The investigator or an authorized designee will complete the unscheduled visit assessment 
page of the CRF.
10.11.9. Statistical Considerations for Substudy E
See Section 9 for master protocol statistical considerations, and see substudy specifics below.
10.11.9.1. Statistical Hypotheses
10.11.9.1.1. Estimands
The estimands corresponding to the primary and exploratory objectives are described in the 
table in Section 10.11.3.
In the primary safety objective evaluations, missing AE start dates will be imputed according 
to Pfizer safety rules.  No other missing information will be imputed in the safety analysis.
10.11.9.1.2. Statistical Hypotheses
The primary and secondary immunogenicity objectives for participants >55 years of age will
be evaluated by the following statistical hypotheses. The immunogenicity objectives for 
participants 18 through 55 years are descriptive only.

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Superiority and Noninferiority of Anti-Omicron Immune Responses
The primary immunogenicity objectives are to assess the superiority with respect to level of 
neutralizing titer and noninferiority with respect to seroresponse rate of the anti-Omicron
immune response induced by a dose of BNT162b2 OMI (30 µg or 60 µg) or bivalent 
BNT162b2 and BNT162b2 OMI (30 µg or 60 µg) relative to the anti-Omicron immune 
response elicited by a dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-
experienced participants >55 years of age. Each primary objective will be evaluated by the 
following 2 hypotheses:

The first null hypothesis (H0) is
H0: ln() – ln() ≤ln(1) vs H1: ln() – ln() > ln(1)
where ln(2) corresponds to a 1-fold superiority criterion and 
o
ln() is the natural log of the geometric mean of SARS-CoV-2 
Omicron-neutralizing titers measured 1 month after 1 dose of BNT162b2 OMI or 
bivalent BNT162b2 and BNT162b2 OMI given as a fourth dose;
o
ln() is the natural log of the geometric mean of SARS-CoV-2 
Omicron-neutralizing titers measured 1 month after 1 dose of BNT162b2 at 30 µg 
given as a fourth dose (Group 1).

The second null hypothesis (H0) is
H0:  − ≤−0.05 vs   − > −0.05
where -5% is the noninferiority margin for seroresponse and 
o
 is the percentage of participants with seroresponse to the Omicron strain at 
1 month after 1 dose of BNT162b2 OMI or bivalent BNT162b2 and 
BNT162b2 OMI given as a fourth dose;
o
 is the percentage of participants with seroresponse to the Omicron strain at 
1 month after 1 dose of BNT162b2 at 30 µg given as a fourth dose (Group 1).
Seroresponse is defined as achieving a ≥4-fold rise from baseline (before the first dose of 
study vaccination).  If the baseline measurement is below the LLOQ, the postvaccination 
measure of ≥4 × LLOQ is considered seroresponse. 
Superiority will be declared if the lower limit of the 2-sided 95% CI for the GMR is greater 
than 1; noninferiority based on seroresponse will be declared if the lower limit of the 2-sided 
95% CI for the difference in percentages of participants with seroresponse is >-5%.

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The secondary objective of “super” superiority will be evaluated using a 1.5-fold margin for 
GMR.  “Super” superiority for GMR will be established if the lower limit of the 2-sided 95% 
CI for the GMR is greater than 1.5.
Noninferiority of Anti–Reference Strain Immune Responses
The noninferiority immunogenicity objectives on anti–reference strain immune responses are
to assess the noninferiority of the anti–reference strain immune response induced by a dose 
of bivalent BNT162b2 and BNT162b2 OMI (30 µg or 60 µg) relative to the anti–reference
strain immune response elicited by a dose of BNT162b2 at 30 µg given as a fourth dose in 
BNT162b2-experienced participants >55 years of age. Each noninferiority objective will be 
evaluated by the following hypothesis:

The null hypothesis (H0) is
H0: ln() – ln() ≤ln(0.67) vs H1: ln() – ln() > ln(0.67)
where ln(0.67) corresponds to a 1.5-fold margin for noninferiority and 
o
ln() is the natural log of the geometric mean of SARS-CoV-2 
reference-strain–neutralizing titers measured 1 month after 1 dose of bivalent 
BNT162b2 and BNT162b2 OMI (30 µg or 60 µg) given as a fourth dose (Group 5 
or Group 6);
o
ln() is the natural log of the geometric mean of SARS-CoV-2 
reference-strain–neutralizing titers measured 1 month after 1 dose of BNT162b2 
given as a fourth dose (Group 1).
Noninferiority based on the GMR will be declared if the lower limit of the 2-sided 95% CI 
for the GMR is greater than 0.67 (1.5-fold criterion) and the point estimate of the GMR is 
≥0.8.

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10.11.9.1.3. Multiplicity Adjustment
The primary and secondary immunogenicity objectives for participants >55 years of age will 
be assessed using the expanded-enrollment cohort.
The primary and secondary immunogenicity objectives for participants >55 years of age will 
be evaluated in sequential order as listed below using a 1-sided alpha of 0.025:

Superiority in GMR and noninferiority in seroresponse rate for Omicron response: 
G4vG1A (OMI-60) G6vG1A (bivalent-60) G5vG1A (bivalent-30) 

Noninferiority in GMR for reference strain response: G6vG1B (bivalent-60) G5vG1B 
(bivalent-30) 

“Super” superiority in GMR for Omicron response: G4vG1B (OMI-60) G6vG1C 
(bivalent-60) G5vG1C (bivalent-30) 

Superiority in GMR and noninferiority in seroresponse rate for Omicron response: 
G3vG1A (OMI-30) G3vG1B (OMI-30)
For objectives involving 2 hypotheses, hypotheses based on GMR and seroresponse rate 
difference will be assessed sequentially in the order as stated.  Both hypotheses within the 
objective must be established before assessing the next objective in the sequence. Therefore, 
the overall type I error is fully controlled.
The immunogenicity objectives for participants 18 through 55 years of age are descriptive 
only; therefore, no multiplicity adjustment is applied.

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10.11.9.2. Analysis Sets
For the purpose of analysis, the following analysis sets are defined for this substudy:
Population
Description
Enrolled
All participants who have a signed ICD.
Randomized/assigned
All participants who are assigned a randomization number in the 
IWR system.
Evaluable 
immunogenicity
All eligible randomized/assigned participants who receive the
study intervention to which they are randomized or assigned, 
have a valid and determinate immunogenicity result from the 
blood sample collected within an appropriate window, and have 
no other important protocol deviations as determined by the 
clinician.
All-available 
immunogenicity
All randomized/assigned participants who receive the study
intervention with a valid and determinate immunogenicity result 
after vaccination.
Safety
All participants who receive the study intervention.
10.11.9.3. Statistical Analyses
The SAP will be developed and finalized for this substudy before any analyses are performed
and will describe the analyses and procedures for missing, unused, and spurious data.  This 
section is a summary of the planned statistical analyses of the primary and exploratory 
endpoints.
10.11.9.3.1. General Considerations
All analyses will be performed separately for each age group (18-55 years of age, >55 years 
of age).
Refer to Section 9.3.1 for general considerations of statistical analyses.
A sensitivity analysis of GMR and difference in seroresponse rate for between-group 
comparison may be performed. The GMR and associated 95% CI will be calculated by 
exponentiating the difference in least-squares means and the corresponding CIs based on 
analysis of logarithmically transformed assay results using a linear regression model with 
terms of baseline assay results (log scale) and vaccine group. The difference in seroresponse 
rate between 2 vaccine groups and the associated 95% CI will be calculated using the 
stratified Miettinen and Nurminen method adjusting for the corresponding baseline assay 
result category (< median, ≥ median).

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10.11.9.3.2. Primary Endpoint(s)/Estimand(s) Analysis
Endpoint
Statistical Analysis Methods
Safety
For each age group (18-55 years of age, >55 years of age):

Descriptive statistics will be provided for each reactogenicity
endpoint for each vaccine group. Local reactions and systemic
events from Day 1 through Day 7 after the study vaccination (where 
Day 1 is the day of vaccination) will be presented by severity and 
cumulatively across severity levels. Descriptive summary statistics 
will include counts and percentages of participants with the 
indicated endpoint and the associated Clopper-Pearson 95% CIs.

AEs and SAEs will be categorized according to MedDRA terms.  
Counts, percentages, and associated Clopper-Pearson 95% CIs of 
AEs within 1 month and SAEs within 6 months after study 
vaccination will be provided for each vaccine group.  
For sentinel-cohort participants 18 to 55 years of age:

Counts and percentages of participants with elevated troponin I 
levels before and 3 days after study vaccination, and associated 
Clopper-Pearson 95% CIs, will be provided for each vaccine group. 
Immunogenicity
For each primary immunogenicity estimand described in 
Section 10.11.3,

GMRs and the associated 2-sided 95% CIs will be calculated using 
the method described in Section 9.3.1.2.3.

The percentages of participants with seroresponse for each group
will be provided. The difference in percentages of participants with 
seroresponse and the associated 2-sided 95% CIs will be calculated 
using the Miettinen and Nurminen method (see Section 9.3.1.1).

Only participants with no serological or virological evidence (up to 
1 month after receipt of 1 dose of study intervention given as a
fourth dose) of past SARS-CoV-2 infection will be included in the 
analysis.

Superiority based on GMR will be established if the lower bound of 
the 2-sided 95% CI for the GMR is >1. Noninferiority based on 
seroresponse rate difference will be established if the lower bound of 
the 2-sided 95% CI for the difference in percentage is greater than 
-5%.

GMRs and the associated 2-sided 95% CI, and the difference in 
percentages of participants with seroresponse and the associated 
2-sided 95% CIs, may be estimated using the sensitivity analysis 
approach specified in Section 10.11.9.3.1.

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10.11.9.3.3. Secondary Endpoint(s)/Estimand(s) Analysis
Endpoint
Statistical Analysis Methods
Immunogenicity
For each secondary immunogenicity estimand described in 
Section 10.11.3.

GMR and the associated 2-sided 95% CIs will be calculated using 
the same method as for the primary immunogenicity objectives.

Noninferiority of anti–reference strain immune response based on 
the GMR will be declared if the lower limit of the 2-sided 95% CI 
for the GMR is greater than 0.67 (1.5-fold criterion) and the point 
estimate of the GMR is ≥0.8. 

“Super” superiority of anti-Omicron immune response will be 
established if the lower bound of the 2-sided 95% CI for the GMR is 
>1.5.

GMRs and the associated 2-sided 95% CI may be estimated using
the sensitivity analysis approach specified in Section 10.11.9.3.1.
10.11.9.3.4. Exploratory Endpoint(s) Analysis
Endpoint
Statistical Analysis Methods
Immunogenicity
GMTs and GMFRs of SARS-CoV-2 Omicron- or reference-strain–
neutralizing titers
Percentages of participants with seroresponse to Omicron- or 
reference-strain
For each age group (18-55 years of age, >55 years of age):

GMTs at each time point and GMFRs of SARS-CoV-2 Omicron- or 
reference-strain–neutralizing titers from before the study vaccination 
to each subsequent time point after vaccination, along with the 
associated 2-sided 95% CIs, will be provided for each vaccine group 
using the statistical method described in Section 9.3.1.2.1 and 
Section 9.3.1.2.2.

The percentages of participants with seroresponse at each time point 
and the associated Clopper-Pearson 95% CIs will be provided for 
each vaccine group.

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Endpoint
Statistical Analysis Methods

GMRs and the differences in percentages of participants with 
seroresponse between certain vaccine groups of interest may be 
calculated along with the associated 2-sided 95% CIs.
GMTs and GMFRs of SARS-CoV-2 reference-strain– and 
VOC-neutralizing titers for participants in the sentinel cohorts
For each age group (18-55 years of age, >55 years of age):

GMTs at each time point and GMFRs of SARS-CoV-2 reference-
strain– and VOC-neutralizing titers from before the study 
vaccination to each subsequent time point after vaccination, along 
with the associated 2-sided 95% CIs, will be provided for each 
vaccine group for sentinel cohorts.
GMTs for any VOCs not already specified
For each age group (18-55 years of age, >55 years of age):

GMTs of reference-strain or VOC-neutralizing titers, along with the 
associated 2-sided 95% CIs, will be provided at specific time points
for each group. GMFRs and GMRs of VOC-neutralizing titers to 
reference-strain–neutralizing titers may also be calculated along 
with the associated 2-sided 95% CIs.
COVID-19 cases
Confirmed COVID-19 cases, confirmed severe COVID-19 cases, and 
strain sequencing of the COVID-19 cases will be summarized for each 
age group.
Cell-mediated 
immune response
The cell-mediated immune response and additional humoral immune 
response parameters to the reference strain and Omicron will be 
summarized at each time point for the subset of participants with PBMC 
samples collected in each vaccine group for each age group.
10.11.9.4. Interim Analyses
No formal interim analysis will be conducted for this study.  Statistical analyses will be 
carried out when the final data for specified objectives are available while the study is 
ongoing.  The timing of these planned analysis and reporting events is described in the 
section below.

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10.11.9.4.1. Analysis Timing
Statistical analyses will be carried out when the following data are available for each age 
group:

Safety data through 1 month after study vaccination for each group in the sentinel 
cohorts.

Immunogenicity data through 1 month after study vaccination for each group in the 
sentinel cohorts.

Safety data through 1 month after study vaccination for each group in the 
expanded-enrollment cohort.

Immunogenicity data through 1 month after study vaccination for each group in the 
expanded-enrollment cohort.

Complete safety and immunogenicity analysis approximately 6 months after study 
vaccination for each group in the sentinel or expanded-enrollment cohorts.
Certain analyses may be combined as 1 regulatory submission report if the data become 
available around the same time.  Additional analyses may be conducted if required for 
regulatory purposes. All analyses for the expanded-enrollment cohort conducted while the 
study is ongoing will be performed by an unblinded team.
10.11.9.4.2. Data Monitoring Committee or Other Independent Oversight Committee
The study will utilize an IRC and DMC. The IRC is independent of the study team and 
includes only internal members. The DMC is independent of the study team and includes
only external members.  The IRC and DMC charters describe the role of the IRC and DMC 
in more detail.
The responsibilities of the IRC are only for the sentinel cohort and will include:

Review of all reported AEs, e-diary reactogenicity data, and troponin levels collected 
through Day 7 from all sentinel-cohort participants. This safety assessment will be 
conducted to determine if the study team may proceed with expanded enrollment of 
approximately 300 participants per group.
The DMC will be responsible for ongoing monitoring of the safety of participants in the 
study according to the charter.
The recommendations made by the DMC will be forwarded to the appropriate Pfizer 
personnel for review and final decision.  Pfizer will communicate such decisions, which may 
include summaries of aggregate analyses of safety data, to regulatory authorities and
investigators as appropriate.

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10.11.9.5. Sample Size Determination
The sample size in each group is based on consideration of an acceptable safety database.
For the >55-year age group, a random sample of 230 participants will be selected from each 
group in the expanded-enrollment cohort as an immunogenicity subset to evaluate the 
primary and secondary immunogenicity objectives. Assuming a 35% nonevaluable or prior 
infection rate, approximately 150 evaluable participants in each group will contribute to the 
primary immunogenicity evaluation.
Superiority and Noninferiority of Anti-Omicron Immunogenicity Objectives
For comparisons based on GMR, assuming common assay standard deviations of 1.05 in log 
scale based on data observed in the Phase 2 part of the C4591001 study for participants 
56 years of age or older and adjusted for assay variability, if the true GMR is 1.5, with 
150 evaluable participants, the study will have 91.5% power to demonstrate superiority.
If the true GMR is 2.0, the study will have 65.7% power to declare “super” superiority using 
a 1.5-fold margin.
For comparisons based on seroresponse rate difference, if the seroresponse rate is 70% in the 
BNT162b2 OMI (30 µg or 60 µg) or bivalent BNT162b2 and BNT162b2 OMI (30 µg or 
60 µg) group and 55% in the BNT162b2 30 µg group, the study will have 94.9% power to 
demonstrate noninferiority using a 5% margin.
Noninferiority of Anti–Reference Strain Immunogenicity Objectives
For comparisons based on GMR, common assay standard deviations of 1.05 and a GMR of 1 
are assumed for each comparison. With 150 evaluable participants and the stated 
assumptions for the GMR and standard deviation, the study has 90.9% power to demonstrate 
noninferiority based on the GMR using a 1.5-fold margin.
For safety outcomes, Table 14 shows the probability of observing at least 1 AE for a given 
true event rate of a particular AE, for various sample sizes. For example, if the true AE rate is 
1%, with 300 participants in a vaccine group, there is 95% probability of observing at least 
1 AE.
Table 14.
Substudy E – Probability of Observing at Least 1 AE by Assumed True 
Event Rates With Different Sample Sizes
Assumed True Event 
Rate of an AE
N=20
N=300
N=900
N=1920
0.01%
0.002
0.03
0.09
0.17
0.02%
0.004
0.06
0.16
0.32
0.05%
0.01
0.14
0.36
0.62
0.10%
0.02
0.26
0.59
0.85
0.20%
0.04
0.45
0.84
0.98
0.50%
0.10
0.78
0.99
>0.99
1.00%
0.18
0.95
>0.99
>0.99
2.00%
0.33
>0.99
>0.99
>0.99

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Table 14.
Substudy E – Probability of Observing at Least 1 AE by Assumed True 
Event Rates With Different Sample Sizes
Assumed True Event 
Rate of an AE
N=20
N=300
N=900
N=1920
5.00%
0.64
>0.99
>0.99
>0.99
10.0%
0.88
>0.99
>0.99
>0.99
10.12. Appendix 12: Substudy F
10.12.1. Substudy Summary
10.12.1.1. Substudy Synopsis
See Section 1.1 for a synopsis of Substudy F.
10.12.1.2. Schema
Visit Number
701
702
703
704
705
Visit Description
4th Dose of BNT162b2
or BNT162b2 OMI
or Combination 
BNT162b2/BNT162b2 OMI
7 Days After 
4th
Vaccination
1 Month 
After 4th
Vaccination
3 Months 
After 4th
Vaccination
6 Months 
After 4th
Vaccination
Participants having 
received 3 prior 
doses of 30 µg 
BNT162b2 
≥4 months prior to 
randomization
30-µg OR 60-µg dose
Blood draw for 
immunogenicity 
assessmentsa
~25 mL
~25 mL
~25 mL
~25 mL
~25 mL
Blood draw for 
additional 
laboratory testingb
~35 mL
~35 mL
~35 mL
~35 mL
~35 mL
a.
~11 mL for Pfizer central laboratory testing, ~11 mL for Sheba laboratory testing, and ~3 mL for 
BioNTech laboratory testing. See Section 10.12.8.2.
b.
~35 mL collected for PBMC for Sheba and BioNTech as described in Section 10.12.8.2.

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10.12.1.3. Schedule of Activities for Substudy F
Visit Number
701
702
703
704
705
Unplanned
Visit Description
Vaccination
1-Week
Follow-Up Visit 
After Vaccination
1-Month
Follow-Up Visit 
After Vaccination
3-Month
Follow-Up Visit 
After Vaccination
6-Month
Follow-Up Visit 
After Vaccination
Potential 
COVID-19 Illness 
Visita
Visit Window (Days)
Day 1b
6 to 8 Days After 
Visit 701
28 to 35 Days 
After Visit 701
85 to 95 Days 
After Visit 701
175 to 189 Days 
After Visit 701
Optimally Within 3 
Days After 
Potential 
COVID-19 Illness 
Onset
Obtain informed consent
X
Perform SARS-CoV-2 antigen test 
X
Assign participant number 
X
Obtain demography and medical history data
X
Perform clinical assessmentc
X
Measure height and weight
X
Measure temperature (body)
X
Perform urine pregnancy test (if appropriate)
X
Confirm use of contraceptives (if appropriate)
X
X
X
Collect nonstudy vaccine information 
X
X
X
X
X
Collect prohibited medication use
X
X
X
X
X
For participants who are HIV-positive, record latest CD4
count and HIV viral load
X
X
X
X
Confirm eligibility
X
Review temporary delay criteria
X
Collect blood sample for immunogenicity assessmentsd
~25 mL
~25 mL
~25 mL
~25 mL
~25 mL
Collect blood sample for additional laboratory testinge
~35 mL
~35 mL
~35 mL
~35 mL
~35 mL
Obtain nasal (midturbinate) swab
X
X
Obtain the participant’s vaccine vial allocation using the IRT 
system
X
Administer study intervention
X
Assess acute reactions for at least 30 minutes after study 
intervention administration
X

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Visit Number
701
702
703
704
705
Unplanned
Visit Description
Vaccination
1-Week
Follow-Up Visit 
After Vaccination
1-Month
Follow-Up Visit 
After Vaccination
3-Month
Follow-Up Visit 
After Vaccination
6-Month
Follow-Up Visit 
After Vaccination
Potential 
COVID-19 Illness 
Visita
Visit Window (Days)
Day 1b
6 to 8 Days After 
Visit 701
28 to 35 Days 
After Visit 701
85 to 95 Days 
After Visit 701
175 to 189 Days 
After Visit 701
Optimally Within 3 
Days After 
Potential 
COVID-19 Illness 
Onset
Explain/review participant communication methods 
(including for e-diary completion), assist the participant with 
downloading the app, or issue provisioned device, if required
X
Provide/ensure the participant has a thermometer and 
measuring device
X
Review reactogenicity e-diary data (daily review is optimal 
during the active diary period)
X
X
Review ongoing reactogenicity e-diary symptoms and obtain 
stop dates
X
X
Collect AEs and SAEs as appropriate
X
X
Xf
Xf
Xf
X
Collect e-diary or assist the participant to delete application
X
Collection of COVID-19–related clinical and laboratory 
information (including local diagnosis)
X
Provide/ensure the participant has a nasal self-swab kit and 
instructions on self-collection of nasal swabs
X
X
X
X
Abbreviations: HIV = human immunodeficiency virus; IRT = interactive response technology.
a.
The COVID-19 illness visit may be conducted as an in-person or telehealth visit.
b.
The visit may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and exclusion criteria onwards must be conducted on the 
same day.
c.
Including, if indicated, a physical examination.
d.
~11 mL for Pfizer central laboratory testing, ~11 mL for Sheba laboratory testing, and ~3 mL for BioNTech laboratory testing. See Section 10.12.8.2.
e.
~35 mL collected for PBMC for Sheba and BioNTech as described in Section 10.12.8.2.
f.
Any AEs occurring up to 48 hours after the blood draw must be recorded (see Section 8.3.1).

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10.12.2. Introduction
10.12.2.1. Study Rationale
The SARS-CoV-2 variant B.1.1.529, also known as Omicron, is currently the dominant 
variant in many countries and within the US is responsible for 98.3% of sequenced 
COVID-19 cases as of 08 January 2022.25 Current data note that the vaccine effectiveness 
against hospitalization is 88% (78%-93%) for Omicron after 3 doses of vaccine.26  However, 
even with 3 vaccine doses, neutralization against the Omicron variant was lower (by a factor 
of 4) than that against the Delta variant. The addition of a higher-dose booster may improve 
protection, particularly in older individuals, with increased longevity of an immune response, 
provided it has a tolerable safety profile.27 Therefore, Substudy F has been designed to 
evaluate high-dose BNT162b2 OMI (60 µg), high-dose BNT162b2 (60 µg), and a high-dose 
combination of BNT162b2 OMI and BNT162b2 (30 µg of each), compared to 
BNT162b2 OMI 30 µg, BNT162b2 30 µg, and a combination of BNT162b2 OMI and 
BNT162b2 (15 µg of each), given as a fourth dose.
See Section 2.2 for the study background.
10.12.2.2. Benefit/Risk Assessment
A tolerability profile of a 60-µg dose of BNT162b2 has yet to be established. However, 
BNT162b1 (a candidate RNA-LNP vaccine tested in clinical trial C4591001 utilizing 
nucleoside-modified messenger RNA similar to BNT162b2 but instead of encoding the 
SARS-CoV-2 full-length, P2 mutant, prefusion spike glycoprotein, BNT162b1 encodes the 
trimerized SARS-CoV-2 spike glycoprotein receptor-binding domain) was studied in adults 
18 to 55 years of age at dose levels of 50 µg, 60 µg, and 100 µg. In one study, 60 participants 
were vaccinated with BNT162b1. Twelve participants for each of the dose level groups 
(1 µg, 10 µg, 30 µg, 50 µg, and 60 µg) were to receive the first dose on Day 1 and a second 
dose on Day 22. Due to the tolerability observed in participants after 2 doses of 50 µg and 
after reviewing the totality of the data available, including the local and systemic 
reactogenicity data, such as the increasing number of severe (Grade 3) systemic reactions 
reported with ascending dose, a second dose of 60 µg was not administered.37,47 Another 
study investigated BNT162b1 at 10 µg, 30 µg, and 100 µg. Participants in this study were 
not administered the second dose of 100 µg because of the increased reactogenicity profile 
seen after a single dose at 100 µg and in participants who received 2 doses of 30 µg.38 In 
light of better tolerability of BNT162b2 (compared to BNT162b1), and better tolerability in 
older adults (compared to younger adults), the potential benefit of a 60-µg dose of 
BNT162b2 is likely to outweigh the risk.
10.12.2.2.1. Benefit Assessment
Benefits to individual participants enrolled in Substudy F may be:

Receipt of a fourth dose of an efficacious or potentially efficacious COVID-19 vaccine 
that may convey a longer duration of protection during a global pandemic, particularly 
against new variant-associated infection and disease.

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
Contributing to research to help others in a time of global pandemic.
10.12.3. Objectives, Estimands, and Endpoints
Objectives
Estimands
Endpoints
Primary Safety

To describe the safety and 
tolerability profile of BNT162b2
(30 µg or 60 µg), 
BNT162b2 OMI (30 µg or 60 
µg), and a combination of
BNT162b2 and BNT162b2 OMI 
(30 µg or 60 µg) given as a fourth 
dose to 
BNT162b2-experienced 
participants
In participants receiving at least 1 dose of study 
intervention, the percentage of participants 
reporting:

Local reactions for up to 7 days following 
the study vaccination

Systemic events for up to 7 days following 
the study vaccination

AEs from the study vaccination through
1 month after the study vaccination

SAEs from the study vaccination through
6 months after the study vaccination

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
Primary Immunogenicity
To describe the immune response to 
BNT162b2 (30 µg or 60 µg), 
BNT162b2 OMI (30 µg or 60 µg), and 
a combination of BNT162b2 and 
BNT162b2 OMI (30 µg or 60 µg)
given as a fourth dose in
BNT162b2-experienced participants

GMT at each time point

GMFRs from before the study vaccination 
to subsequent time points

Percentages of participants with 
seroresponsea at each time point 

GMRs at each time point after the study 
vaccination between different vaccine
groups

SARS-CoV-2 
Omicron-neutralizing 
titers
SARS-CoV-2 reference-
strain–neutralizing titers

Exploratory
To describe the immune response to 
any VOCs not already specified

SARS-CoV-2
neutralizing titers for 
any VOCs not already 
specified
To describe the cell-mediated immune
response and additional immune 
response parameters

T-cell (by ELISPOT)
and B-cell 
characterization

RBD binding IgG 

RBD binding IgA
To describe confirmed COVID-19 and 
severe COVID-19 cases

Confirmed COVID-19 
cases

Confirmed severe 
COVID-19 cases

Strain sequencing of 
COVID-19 cases
a.
Seroresponse is defined as achieving ≥4-fold rise from baseline (before the study vaccination). If the baseline 
measurement is below the LLOQ, the postvaccination measure of ≥4 × LLOQ is considered seroresponse.
10.12.4. Study Design
10.12.4.1. Overall Design
This is a randomized, observer-blinded substudy to describe the safety, tolerability, and 
immunogenicity of high-dose BNT162b2 (60 µg), high-dose BNT162b2 OMI (60 µg), and a 
high-dose combination of BNT162b2 and BNT162b2 OMI at 60 µg (30 µg each), given as a 
single dose. Approximately 180 participants ≥60 years of age who have received 3 prior 

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doses of BNT162b2 (30 µg doses) with the most recent dose being ≥4 months prior to 
randomization, will be enrolled in Israel. Participants will be randomized at a ratio of 
1:1:1:1:1:1 to receive BNT162b2 at 30 µg, BNT162b2 at 60 µg, BNT162b2 OMI at 30 µg, 
BNT162b2 OMI at 60 µg, a combination of BNT162b2 and BNT162b2 OMI at 30 µg
(15 µg each), or a combination of BNT162b2 and BNT162b2 OMI at 60 µg (30 µg each) at 
Visit 701 as a fourth dose.
Initially, sentinel cohorts (sponsor open-label) of 5 participants per group will be enrolled. 
An IRC and site representatives will review all reported AEs and reactogenicity e-diary data 
from the sentinel cohorts collected through Day 7 to allow expanded enrollment of an 
additional 25 participants per group upon confirmation of an acceptable safety assessment. If 
the safety assessment is considered not to be acceptable, the protocol may be amended to 
include a further sentinel cohort employing 50-µg dose levels of BNT162b2, 
BNT162b2 OMI, and a combination of BNT162b2 and BNT162b2 OMI (25 µg each).
Table 15 describes the enrollment of the sentinel cohorts and steps to progress to expanded 
enrollment.
Table 15.
Substudy F – Sentinel and Expanded Enrollment
Sentinel Enrollmenta
Study Intervention
Number of Participants
BNT162b2 30 µg
5
BNT162b2 60 µg
5
BNT162b2 OMI 30 µg
5
BNT162b2 OMI 60 µg
5
Combination of BNT162b2 and BNT162b2 OMI 30 µg (15 µg each)
5
Combination of BNT162b2 and BNT162b2 OMI 60 µg (30 µg each)
5
IRC and site representatives’ review of all reported AE and reactogenicity e-diary data from the sentinel 
cohorts collected through Day 7. Expanded enrollment to commence upon confirmation of an acceptable 
safety assessment.
Expanded Enrollmentb
Study Intervention
Number of Participants
BNT162b2 30 µg
25
BNT162b2 60 µg
25
BNT162b2 OMI 30 µg
25
BNT162b2 OMI 60 µg
25
Combination of BNT162b2 and BNT162b2 OMI 30 µg (15 µg each)
25
Combination of BNT162b2 and BNT162b2 OMI 60 µg (30 µg each)
25
a.
Sentinel cohorts will be sponsor open-label.
b.
If the IRC and site representative’s safety assessment is considered not to be acceptable, the protocol may 
be amended to include a further sentinel cohort employing 50-µg dose levels of BNT162b2, 
BNT162b2 OMI, and a combination of BNT162b2 and BNT162b2 OMI (25 µg each).
10.12.4.2. Scientific Rationale for Substudy F Design
See Section 10.12.2.1.

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10.12.4.3. Justification for Dose
See Section 4.3 for a justification of the BNT162b2 and BNT162b2 OMI dose used in 
Substudy F.
10.12.4.4. End of Study Definition
See Section 4.4.
10.12.5. Study Population
Details of the master eligibility criteria are shown in Section 5. Substudy F–specific 
eligibility criteria are listed in Sections 10.12.5.1 and 10.12.5.2.
10.12.5.1. Inclusion Criteria
Participants are eligible to be included in Substudy F only if all of the following criteria 
apply:
Age and Sex:
1. Male or female participants ≥60 years of age:
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, vaccination 
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Healthy participants who are determined by medical history, physical examination
(if required), and clinical judgment of the investigator to be eligible for inclusion in the 
study.
Note: Healthy participants with preexisting stable disease, defined as disease not 
requiring significant change in therapy or hospitalization for worsening disease during 
the 6 weeks before enrollment, can be included.  Specific criteria for participants with 
known stable infection with HIV, HCV, or HBV can be found in Section 10.15.
Informed Consent:
4. Capable of giving personal signed informed consent as described in Appendix 1, which
includes compliance with the requirements and restrictions listed in the ICD and in this 
protocol.
Other Inclusions:
5. Participants who have received 3 prior doses of 30 µg BNT162b2, with the third dose 
being ≥4 months before Visit 701 (Day 1).

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Documented confirmation of prior BNT162b2 receipt must be obtained prior to 
randomization.
10.12.5.2. Exclusion Criteria
Participants are excluded from Substudy F if any of the following criteria apply:
Medical Conditions:
1. Other medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for the 
study.
2. History of severe adverse reaction associated with a vaccine and/or severe allergic 
reaction (eg, anaphylaxis) to any component of the study intervention(s).
3. 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 or positive antigen test for 
SARS-CoV-2 at baseline.
4. Immunocompromised individuals with known or suspected immunodeficiency, as 
determined by history and/or laboratory/physical examination.
5. Bleeding diathesis or condition associated with prolonged bleeding that would, in the 
opinion of the investigator, contraindicate intramuscular injection.
6. Women who are pregnant or breastfeeding.
Prior/Concomitant Therapy:
7. Individuals who receive treatment with radiotherapy or immunosuppressive therapy, 
including cytotoxic agents or systemic corticosteroids (if systemic corticosteroids are 
administered for ≥14 days at a dose of ≥20 mg/day of prednisone or equivalent), eg, for 
cancer or an autoimmune disease, or planned receipt throughout the study.  
Inhaled/nebulized, intra-articular, intrabursal, or topical (skin or eyes) corticosteroids are 
permitted.
8. Receipt of blood/plasma products, immunoglobulin, or monoclonal antibodies, from 
60 days before study intervention administration, or receipt of any passive antibody 
therapy specific to COVID-19, from 90 days before study intervention administration, or 
planned receipt throughout the study.
Prior/Concurrent Clinical Study Experience:
9. Prior receipt of any COVID-19 vaccine other than BNT162b2.

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Other Exclusions:
10. Investigator site staff or Pfizer-BioNTech employees directly involved in the conduct of 
the study, site staff otherwise supervised by the investigator, and their respective family 
members.
11. Receipt of medications intended to prevent COVID-19.
12. Participation in other studies involving study intervention within 28 days prior to study
entry through and including 28 days after the dose of study intervention, with the 
exception of non-Pfizer interventional studies for prevention of COVID-19, which are 
prohibited throughout study participation.
10.12.5.3. Lifestyle Considerations
Contraception requirements will apply to Substudy F as detailed in Section 5.3 and
Section 10.4.
10.12.5.4. Screen Failures
See Section 5.4.
10.12.5.5. Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention
See Section 5.5.
10.12.6. Study Intervention(s) and Concomitant Therapy
For the purposes of this substudy, study intervention refers to:

BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S): 
30 µg or 60 µg.

BNT162b2 OMI (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the 
P2 S): 30 µg or 60 µg.

Combination of BNT162b2 and BNT162b2 OMI (BNT162 RNA-LNP vaccine utilizing 
modRNA and encoding the P2 S): 30 µg or 60 µg.
Note: If the IRC and site representative’s safety assessment is considered not to be 
acceptable, then the 60-µg dose levels for BNT162b2, BNT162b2 OMI, and a combination 
of BNT162b2 and BNT162b2 OMI may be replaced by 50-µg dose levels for the expanded 
enrollment (combination of BNT162b2 and BNT162b2 OMI at 25 µg each).

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10.12.6.1. Study Intervention(s) Administered
Additional 
Intervention 
Name
BNT162b2 
(BNT162 RNA-LNP 
Vaccine Utilizing modRNA)
(Dilution Required)
BNT162b2 OMI (B.1.1.529)
(BNT162 RNA-LNP 
Vaccine Utilizing modRNA)
(Dilution Required)
Combination 
BNT162b2 and 
BNT162b2 OMI (B.1.1.529) 
(BNT162 RNA-LNP 
Vaccine Utilizing modRNA)
Site-Prepared Dosing 
Suspension Using 2 Vials
(Dilution Required)
Type
Vaccine
Vaccine
Vaccine
Dose 
Formulation
modRNA
modRNA
modRNA
Unit Dose 
Strength(s)
10 µg/0.1 mL
10 µg/0.1 mL
10 µg/0.1 mL
Dosage 
Level(s) 
30-µg or 60-µga
30-µg or 60-µga
30-µg (15-µg each) or 60-µg 
(30-µg each)a
Route of 
Administration
Intramuscular injection
Intramuscular injection
Intramuscular injection
Use
Experimental
Experimental
Experimental
IMP or NIMP
IMP
IMP
IMP
Sourcing
Provided centrally by the 
sponsor
Provided centrally by the 
sponsor
Provided centrally by the 
sponsorb
Packaging and 
Labeling
Study intervention will be 
provided in a glass vial as 
open-label supply.  Each vial 
will be labeled as required 
per country requirement
Study intervention will be 
provided in a glass vial as 
open-label supply.  Each vial 
will be labeled as required 
per country requirement
Study intervention will be 
provided in a glass vial as 
open-label supply.  Each vial 
will be labeled as required 
per country requirement
a.
If the IRC’s safety assessment is considered not to be acceptable, then the protocol may be amended to 
include a further sentinel cohort employing 50-µg dose levels of BNT162b2, BNT162b2 OMI, and a 
combination of BNT162b2 and BNT162b2 OMI (25 µg each).
b.
The combination of BNT162b2 and BNT162b2 OMI will be dosing suspension prepared at the 
investigator site from 1 vial each of diluted BNT162b2 Vaccine and BNT162b2 OMICRON (B.1.1.529)
at the dose levels shown in this table.
10.12.6.1.1. Administration
Participants will receive 1 dose of study intervention as allocated by the IRT at Visit 701 in 
accordance with the substudy’s SoA (Section 10.12.1.3).
Study intervention should be administered intramuscularly into the deltoid muscle, preferably 
of the nondominant arm, by an unblinded administrator.
10.12.6.1.2. Preparation and Dispensing
Study intervention will be prepared by qualified unblinded site personnel according to the IP 
manual.  The study intervention will be administered in such a way as to ensure that the 
participants remain blinded.

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10.12.6.2. Measures to Minimize Bias: Randomization and Blinding
10.12.6.2.1. Blinding of Site Personnel
Study staff receiving, storing, dispensing, preparing, and administering the study 
interventions will be unblinded.  All other study and site personnel, including the 
investigator, investigator staff, and participants, will be blinded to study intervention 
assignments.  In particular, the individuals who evaluate participant safety will be blinded.
However, site personnel, separate from the site study team, that will review safety data with 
the IRC will be unblinded to the study intervention allocation for the sentinel cohort.
The PI will assign the responsibility of the unblinded dispensers/administrators to persons 
who will not participate in the evaluation of any study participant.  To ensure adequate 
coverage, at least 2 unblinded dispensers/administrators will be assigned per site.  Members 
of the study site staff or clinic pharmacy should fulfill these roles.  Contact between the 
unblinded dispensers and study participants should be kept to a minimum.  The investigator, 
study coordinator, and any site staff other than the unblinded dispensers/administrators must 
not be allowed to know the study intervention assigned to any study participant and must not 
be allowed to see the study intervention container contents.  In the event of a Quality 
Assurance audit, the auditor(s) will be allowed access to unblinded study intervention records 
at the site(s) to verify that randomization/dispensing has been done accurately.
10.12.6.2.2. Blinding of the Sponsor
The sponsor will be unblinded to the study intervention allocation for the sentinel cohort. For 
the expanded-enrollment part of the study the majority of sponsor/Pfizer staff will be blinded 
to study intervention allocation. All laboratory testing personnel performing serology assays 
will remain blinded to study intervention assigned/received throughout the study.  The 
following sponsor/Pfizer staff, who will have no part in the blinded conduct of the study, will 
be unblinded (further details will be provided in a data blinding plan):

Those study team members who are involved in ensuring that protocol requirements for 
study intervention preparation, handling, allocation, and administration are fulfilled at the 
site will be unblinded for the duration of the study (eg, unblinded study manager, 
unblinded clinical research associate).

Unblinded clinician(s), who are not direct members of the study team and will not 
participate in any other study-related activities, will review unblinded protocol 
deviations.

An unblinded team supporting interactions with, and analyses for, the DMC and IRC
(see Section 10.12.9.4.2).  This team comprises a statistician, programmer(s), a clinical 
scientist, and a medical monitor. 

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
An unblinded submissions team will be responsible for preparing unblinded analyses and 
documents to support regulatory activities that may be required while the study is 
ongoing.  With the exception of the statisticians and programmers, who will become 
unblinded at the participant level at the time of the first planned reporting event to 
perform the analyses, other members of this team will only be unblinded at the group 
level and not have access to individual participant assignments.  A separate group of 
statisticians and programmers will remain blinded and continue supporting the blinded 
conduct of the study after the first planned analysis.
When a participant has completed their 3-month visit (Visit 704), they may be unblinded to 
confirm the vaccine and dose received.  The study team will also become unblinded to the 
participant’s original study intervention allocation at this time.
10.12.6.2.3. Breaking the Blind
The IRT will be programmed with blind-breaking instructions.  In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s study 
intervention assignment is warranted.  Participant safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the sponsor prior to 
unblinding a participant’s vaccine assignment unless this could delay further management of 
the participant.  If a participant’s vaccine assignment is unblinded, the sponsor must be 
notified within 24 hours after breaking the blind.  The date and reason that the blind was 
broken must be recorded in the source documentation and CRF.
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
10.12.6.3. Study Intervention Compliance
See Section 6.4.
10.12.6.4. Dose Modification
See Section 6.5.
10.12.6.5. Continued Access to Study Intervention After the End of the Study
See Section 6.6.
10.12.6.6. Treatment of Overdose
See Section 6.7.
10.12.6.7. Concomitant Therapy
See Section 6.8.

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10.12.7. Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
See Section 7.
10.12.8. Study Assessments and Procedures
The total blood sampling volume for individual participants in this study is up to 
approximately 300 mL. For all participants, other additional blood samples may be taken for 
safety assessments at times specified by Pfizer, provided the total volume taken during the 
study does not exceed 550 mL during any period of 60 consecutive days.
10.12.8.1. Surveillance for COVID-19
If, at any time, a participant develops acute respiratory illness (see Section 10.12.8.5.6), for 
the purposes of the study he or she will be considered to potentially have COVID-19 illness.  
In this circumstance, the participant should contact the site, an in-person or telehealth visit 
should occur, and assessments should be conducted as specified in the SoA.  The assessments 
will include collection of a nasal (midturbinate) swab, which will be tested at a central 
laboratory using an RT-PCR test (Cepheid Xpert Xpress SARS-CoV-2; authorized by the 
FDA under EUA and Pfizer-validated), or other equivalent nucleic acid amplification–based
test (ie, NAAT) to detect SARS-CoV-2.  In addition, clinical information and results from 
local standard-of-care tests (as detailed in Section 10.12.8.5.7) will be assessed.  The central 
laboratory NAAT result will be used for the case definition, unless no result is available from 
the central laboratory, in which case a local NAAT result may be used if it was obtained 
using 1 of the following assays:

Cepheid Xpert Xpress SARS-CoV-2

Roche cobas SARS-CoV-2 real-time RT-PCR test (EUA200009/A001)

Abbott Molecular/RealTime SARS-CoV-2 assay (EUA200023/A001)
Definitions of SARS-CoV-2–related cases, and SARS-CoV-2–related severe cases, will be 
considered as follows (for both, the onset date of the case will be the date that symptoms 
were first experienced by the participant; if new symptoms are reported within 4 days after 
resolution of all previous symptoms, they will be considered as part of a single illness):

Confirmed COVID-19: presence of at least 1 of the following symptoms and 
SARS-CoV-2 NAAT-positive during, or within 4 days before or after, the symptomatic 
period, either at the central laboratory or at a local testing facility (using an acceptable 
test):

Fever; 

New or increased cough; 

New or increased shortness of breath; 

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
Chills; 

New or increased muscle pain; 

New loss of taste or smell;

Sore throat;

Diarrhea;

Vomiting.

Confirmed severe COVID-19 (FDA definition45): confirmed COVID-19 and presence of 
at least 1 of the following:

Clinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per minute, 
HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or PaO2/FiO2
<300 mm Hg);

Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation, 
mechanical ventilation, or ECMO);

Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiring vasopressors);

Significant acute renal, hepatic, or neurologic dysfunction;

Admission to an ICU;

Death.

Confirmed severe COVID-19 (CDC definition46): confirmed COVID-19 and presence of 
at least 1 of the following:

Hospitalization; 

Admission to the ICU;

Intubation or mechanical ventilation; 

Death.
The DMC may recommend modification of the definition of severe disease according to 
emerging information.

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10.12.8.2. Immunogenicity
Blood samples (~11 mL for Pfizer, ~11 mL for Sheba, and ~3 mL for BioNTech) for serum 
collection will be obtained for immunogenicity testing at each visit as specified in the SoA. 
The tests to be performed will be the SARS-CoV-2 neutralizing assays (reference strain and 
Omicron strain).
Additional whole blood samples (~20 mL for Sheba and ~15 mL for BioNTech) will be 
collected for PBMC isolation at each visit as specified in the SoA.  The testing priority will 
be ~5 mL for T-cell analysis for Sheba, ~15 mL for B-cell analysis for BioNTech, and 
~15 mL for B-cell analysis for Sheba.
10.12.8.3. Safety Assessments
See Section 8.2.
10.12.8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting
See Section 8.3.
10.12.8.5. Substudy F Procedures
10.12.8.5.1. Visit 701 – Substudy F Vaccination (Day 1)
Before enrollment and before any study-related procedures are performed, voluntary, written, 
study-specific informed consent will be obtained from the participant.  Each signature on the 
ICD must be personally dated by the signatory.  The investigator or his or her designee will 
also sign the ICD.  A copy of the signed and dated ICD must be given to the participant.  The 
source data must reflect that the informed consent was obtained before participation in the 
study.
It is anticipated that the procedures below will be conducted in a stepwise manner.  The visit 
may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and 
exclusion criteria onwards must be conducted on the same day.

Perform a SARS-CoV-2 antigen test and confirm that the participant is negative. Record 
the result in the source documents only.

Assign a single participant number using the IRT system.

Obtain the participant’s demography (including date of birth, sex, race, and ethnicity).  
The full date of birth will be collected to critically evaluate the immune response and 
safety profile by age.

Obtain any medical history of clinical significance.  For participants who are 
HIV-positive, record the HIV viral load and CD4 count results from the most recent test 
performed in the previous 6 months.

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
Perform a clinical assessment.  If the clinical assessment indicates that a physical 
examination is necessary to comprehensively evaluate the participant, perform a physical 
examination and record any findings in the source documents and, if clinically 
significant, record any findings on the medical history CRF.

Measure the participant’s height and weight.

Measure the participant’s body temperature.

Perform urine pregnancy test on WOCBP as described in Section 8.2.5.

Discuss contraceptive use as described in Section 5.3.

Record nonstudy vaccinations as described in Section 6.8.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Record AEs as described in Section 8.3.

Collect a blood sample for immunogenicity assessments.

Collect a whole blood sample for additional laboratory testing.

Obtain a nasal (midturbinate) swab (collected by site staff).

Blinded site staff will obtain the participant’s randomization number using the IRT 
system. The randomization confirmation report with the study intervention allocation 
will only be sent to the unblinded site staff member.

Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into 
the deltoid muscle of the preferably nondominant arm.  Please refer to the IP manual for 
further instruction on this process.

Blinded site staff must observe the participant for at least 30 minutes after study 
intervention administration for any acute reactions.  Record any acute reactions 
(including time of onset) in the participant’s source documents and on the AE page of the 
CRF, and on an SAE form as applicable.

Provide a measuring device to measure local reactions at the injection site and a 
thermometer for recording daily temperatures and fever (COVID-19 surveillance) and 
provide instructions on their use.

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
Explain the e-diary technologies available for this study (see Section 8.2.4), and assist the 
participant in downloading the study application onto the participant’s own device or 
issue a provisioned device if required.

Provide instructions on reactogenicity e-diary completion and ask the participant to 
complete the reactogenicity e-diary from Day 1 through Day 7, with Day 1 being the day 
of vaccination.

Provide instructions on COVID-19 illness e-diary completion and ask the participant to 
complete the COVID-19 illness e-diary if the participant is diagnosed with COVID-19 or 
has possible new or increased symptoms, and when he/she receives a reminder, at least 
weekly. See Section 10.12.8.5.6 for further details. Provide a self-swab kit in case of 
COVID-19 symptoms and provide instructions on self-collection of nasal swabs.

Ask the participant to contact the site staff or investigator immediately if the participant 
experiences any of the following from Day 1 through Day 7 after vaccination (where 
Day 1 is the day of vaccination) to determine if an unscheduled reactogenicity visit is 
required: 

Fever ≥39.0°C (≥102.1°F).

Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units).

Severe pain at the injection site.

Any severe systemic event.

Ask the participant to contact the site staff or investigator if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.12.8.5.10).

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 10.12.8.5.7.

Schedule an appointment for the participant to return for the next study visit.

Remind the participant to bring the reactogenicity e-diary to the next visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs and an unblinded 
dispenser/administrator updates the study intervention accountability records.

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
The investigator or appropriately qualified designee reviews the reactogenicity e-diary 
data online following vaccination to evaluate participant compliance and as part of the 
ongoing safety review. Daily review is optimal during the active diary period.
10.12.8.5.2. Visit 702 – 1-Week Follow-Up Visit (6-8 Days After Visit 701)

Record AEs as described in Section 8.3.

Review the participant’s reactogenicity e-diary data. Collect stop dates of any 
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary was 
completed and record stop dates in the CRF if required.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

Discuss contraceptive use as described in Section 5.3.

Collect a blood sample for immunogenicity assessments.

Collect a whole blood sample for additional laboratory testing. 

Ask the participant to contact the site staff or investigator if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.12.8.5.10).

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 10.12.8.5.7.

Ensure the participant has a self-swab kit.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

The investigator or appropriately qualified designee reviews the reactogenicity e-diary 
data online following vaccination to evaluate participant compliance and as part of the 
ongoing safety review. Daily review is optimal during the active diary period.

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10.12.8.5.3. Visit 703 – 1-Month Follow-Up Visit (28 to 35 Days After Visit 701) 

Record AEs as described in Section 8.3.

Review the participant’s reactogenicity e-diary data. Collect stop dates of any 
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary was 
completed and record stop dates in the CRF if required.

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Discuss contraceptive use as described in Section 5.3.

Collect a blood sample for immunogenicity assessments.

Collect a whole blood sample for additional laboratory testing.

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if the participant experiences any respiratory 
symptoms as detailed in Section 10.12.8.5.7.

Ensure the participant has a self-swab kit.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3.
10.12.8.5.4. Visit 704 – 3-Month Follow-Up Visit (85 to 95 Days After Visit 701)

Record AEs as described in Section 8.3.

Collect a blood sample for immunogenicity assessments.

Collect a whole blood sample for additional laboratory testing.

Record nonstudy vaccinations as described in Section 6.8.

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
Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Ask the participant to contact the site staff or investigator (this could be via the 
COVID-19 illness e-diary) immediately if he or she experiences any respiratory 
symptoms as detailed in Section 10.12.8.5.7.

Ensure the participant has a self-swab kit.

Schedule an appointment for the participant to return for the next study visit.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3.
10.12.8.5.5. Visit 705 – 6-Month Follow-Up Visit (175 to 189 Days After Visit 701)

Record AEs as described in Section 8.3.

Collect a blood sample for immunogenicity assessments.

Collect a whole blood sample for additional laboratory testing. 

Record nonstudy vaccinations as described in Section 6.8.

Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care.

For participants who are HIV-positive, record the latest CD4 count and HIV viral load.

Collect the participant’s e-diary or assist the participant to remove the study application 
from his or her own personal device.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.

Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3.

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10.12.8.5.6. COVID-19 Surveillance (All Substudy F Participants)
If a participant experiences any of the following (irrespective of perceived etiology or 
clinical significance), he or she is instructed to contact the site immediately and, if 
confirmed, participate in an in-person or telehealth visit as soon as possible, optimally within 
3 days of symptom onset (and at the latest 4 days after symptom resolution).

A diagnosis of COVID-19;

Fever;

New or increased cough; 

New or increased shortness of breath; 

Chills; 

New or increased muscle pain; 

New loss of taste/smell;

Sore throat;

Diarrhea;

Vomiting.
Note that:

If new symptoms are reported within 4 days after resolution of all previous symptoms, 
they will be considered as part of a single illness and a second illness visit is not required;

Surveillance of potential COVID-19 symptoms should continue even if a participant has 
a positive SARS-CoV-2 test earlier in the study.
During the 7 days following each vaccination, potential COVID-19 symptoms that overlap 
with specific systemic events (ie, fever, chills, new or increased muscle pain, diarrhea, 
vomiting) should not trigger a potential COVID-19 illness visit unless, in the investigator’s 
opinion, the clinical picture is more indicative of a possible COVID-19 illness than vaccine 
reactogenicity.  If, in the investigator’s opinion, the symptoms are considered more likely to 
be vaccine reactogenicity, but a participant is required to demonstrate that he or she is
SARS-CoV-2–negative, a local SARS-CoV-2 test may be performed: if positive, the 
symptoms should be recorded as a potential COVID-19 illness; if not, the symptoms should 
be recorded as AEs.

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Participants may utilize a COVID-19 illness e-diary through an application (see 
Section 10.12.8.5.8) installed on a provisioned device or on the participant’s own personal 
device to prompt him/her to report any symptoms.  Note that this does not substitute for a 
participant’s routine medical care.  Therefore, participants should be encouraged to seek care, 
if appropriate, from their usual provider.
10.12.8.5.7. Potential COVID-19 Illness Visit (Optimally Within 3 Days After Potential 
COVID-19 Illness Onset)
This visit may be conducted as an in-person or telehealth visit; a telehealth visit involves the 
sharing of healthcare information and services via telecommunication technologies 
(eg, audio, video, video-conferencing software) remotely, thus allowing the participant and 
investigator to communicate on aspects of clinical care.
As a participant’s COVID-19 illness may evolve over time, several contacts may be required 
to:

Record AEs, as appropriate as described in Section 8.3.  Note: Potential COVID-19 
illnesses that are consistent with the clinical endpoint definition should not be recorded as 
AEs.  These data will be captured as efficacy assessment data only on the relevant pages 
of the CRF, as these are expected endpoints.

Record details of any of the prohibited medications specified in Section 6.8 received by 
the participant if required for his or her clinical care.

If the visit is conducted in person, obtain a nasal (midturbinate) swab (collected by site 
staff).  Alternatively, if the visit is conducted by telehealth, instruct the participant to 
self-collect a nasal (midturbinate) swab and ship for assessment at the central laboratory.

Collect COVID-19–related standard-of-care clinical and laboratory information.  This 
includes, but is not limited to:

Symptoms and signs, including

Clinical signs at rest indicative of severe systemic illness (RR ≥30 breaths per 
minute, HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or 
PaO2/FiO2 <300 mm Hg);

Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiring 
vasopressors);

Significant acute renal, hepatic, or neurologic dysfunction;

Respiratory failure (defined as needing high-flow oxygen, noninvasive 
ventilation, mechanical ventilation, or ECMO).

Clinical diagnosis.

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
Local laboratory SARS-CoV-2 test result(s).  Note that if it is routine practice to 
perform a repeat local SARS-CoV-2 test for any reason, then a repeat nasal 
(midturbinate) swab should also be obtained and shipped for assessment at the central 
laboratory.

Full blood count.

Blood chemistry, specifically creatinine, urea, LFTs, and C-reactive protein.

Imaging results (eg, CT or MRI scan) to document neurologic dysfunction.

Number and type of any healthcare contact; duration of hospitalization and ICU stay.

Death.

Complete the source documents.

The investigator or an authorized designee completes the CRFs.
10.12.8.5.8. Communication and Use of Technology
In a study of this nature that requires illness events to be reported outside of scheduled study 
visits, it is vital that communication between the study site and the participant is maintained 
to ensure that endpoint events are not missed.  This study will employ various methods, 
tailored to the individual participant, to ensure that communication is maintained and study 
information can be transmitted securely.  Using appropriate technology, such as a study 
application, a communication pathway between the participant and the study site staff will be 
established.  The participant may be able to utilize his or her own devices to access this 
technology, or use a device provided by the sponsor.  Traditional methods of telephone 
communication will also be available.  The technology solution may facilitate the following:

Contact with the investigator, including the ability of the participant to report whether or 
not the participant has experienced symptoms that could represent a potential COVID-19 
illness (COVID-19 illness e-diary).

An alert in the event that the participant is hospitalized.

Visit reminders.

Messages of thanks and encouragement from the study team.

If a participant is not actively completing the COVID-19 illness e-diary, the investigator 
or designee is required to contact the participant to ascertain why and also to obtain 
details of any missed events.

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10.12.8.5.9. SARS-CoV-2 NAAT Results
Nasal (midturbinate) swabs for SARS-CoV-2 NAAT are obtained at:

Visit 701: To determine whether a participant will be included in efficacy analyses of 
those with no serological or virological evidence of past SARS-CoV-2 infection.

Potential COVID-19 illness visits: To determine whether symptoms experienced by the 
participant fulfill the COVID-19 case definition.
Research laboratory–generated positive results from the Visit 701 swab, and all results from 
the illness visit swabs, will be provided to the site once available, but this will not be in real 
time and cannot be relied upon to direct clinical care.  Therefore, the participant should be 
directed to seek additional testing through his/her primary healthcare providers at a licensed 
clinical laboratory when exhibiting potential COVID-19 symptoms or otherwise receiving a 
positive result and counseled on whether to take any precautionary measures pending 
confirmatory testing.
10.12.8.5.10. Additional Procedures for Monitoring of Potential Myocarditis or 
Pericarditis
Any study participant who reports acute chest pain, shortness of breath, palpitations, or any 
other symptom(s) that might be indicative of myocarditis or pericarditis within 4 weeks after 
a study vaccination should be specifically evaluated, preferably by a cardiologist, for possible 
myocarditis or pericarditis. In addition to a clinical evaluation, the following should be 
performed:

ECG and

Measurement of the troponin level
If myocarditis or pericarditis is suspected based upon the initial evaluation, the following 
should also be performed:

Cardiac echocardiogram and/or

Cardiac magnetic resonance study
Details of the symptoms reported, and results of the investigations performed, will be 
recorded in the CRF.
10.12.8.5.11. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction
If a Grade 3 local reaction (Section 8.2.4.2), systemic event (Section 8.2.4.3), or fever 
(Section 8.2.4.4) is reported in the reactogenicity e-diary, a telephone contact should occur to 
ascertain further details and determine whether a site visit is clinically indicated. If a 
suspected Grade 4 local reaction (Section 8.2.4.2), systemic event (Section 8.2.4.3), or fever 

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(Section 8.2.4.4) is reported in the reactogenicity e-diary, a telephone contact or site visit 
should occur to confirm whether the event meets the criteria for Grade 4.
A site visit must be scheduled as soon as possible to assess the participant unless any of the 
following is true:

The participant is unable to attend the unscheduled visit.

The local reaction/systemic event is no longer present at the time of the telephone 
contact.

The participant recorded an incorrect value in the reactogenicity e-diary (confirmation of 
a reactogenicity e-diary data entry error).

The PI or authorized designee determined it was not needed.
This telephone contact will be recorded in the participant’s source documentation and the 
CRF.
If the participant is unable to attend the unscheduled visit, or the PI or authorized designee 
determined that it was not needed, any ongoing local reactions/systemic events must be 
assessed at the next study visit.
During the unscheduled visit, the reactions should be assessed by the investigator or a 
medically qualified member of the study staff, such as a study physician or a study nurse, as 
applicable to the investigator’s local practice, who will:

Measure body temperature (°F/°C).

Measure minimum and maximum diameters of redness (if present).

Measure minimum and maximum diameters of swelling (if present).

Assess injection site pain (if present) in accordance with the grades provided in
Section 8.2.4.2.

Assess systemic events (if present) in accordance with the grades provided in
Section 8.2.4.3.

Assess for other findings associated with the reaction and record on the AE page of 
the CRF, if appropriate.
The investigator or an authorized designee will complete the unscheduled visit assessment 
page of the CRF.

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10.12.9. Statistical Considerations for Substudy F
See Section 9 for master protocol statistical considerations, and see substudy specifics below.
10.12.9.1. Statistical Hypotheses
10.12.9.1.1. Estimands
The estimands corresponding to the primary and exploratory objectives are described in the 
table in Section 10.12.3.
In the primary safety objective evaluations, missing AE start dates will be imputed according 
to Pfizer safety rules.  No other missing information will be imputed in the safety analysis.
10.12.9.1.2. Statistical Hypotheses
All objectives in this substudy are descriptive.  No hypothesis testing is planned.
10.12.9.1.3. Multiplicity Adjustment
No multiplicity adjustment is needed for the study as there is no statistical hypothesis.
10.12.9.2. Analysis Sets
For the purpose of analysis, the following analysis sets are defined for this substudy:
Population
Description
Enrolled
All participants who have a signed ICD.
Randomized/assigned
All participants who are assigned a randomization number in the 
IWR system.
Evaluable 
immunogenicity
All eligible randomized/assigned participants who receive the
study intervention to which they are randomized or assigned, 
have a valid and determinate immunogenicity result from the 
blood sample collected within an appropriate window, and have 
no other important protocol deviations as determined by the 
clinician.
All-available 
immunogenicity
All randomized/assigned participants who receive the study
intervention with a valid and determinate immunogenicity result 
after vaccination.
Safety
All participants who receive the study intervention.
10.12.9.3. Statistical Analyses
The SAP will be developed and finalized for this substudy before any analyses are performed
and will describe the analyses and procedures for missing, unused, and spurious data.  This 
section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.

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10.12.9.3.1. General Considerations
Refer to Section 9.3.1 for general considerations of statistical analyses.
Adjusted Comparison of Antibody Levels
The relative difference in antibody levels between different vaccine groups, using the 
BNT162b2 30-µg group as the reference, will be estimated using an ANCOVA model. For 
each time point after the baseline, log-antibody levels will be modeled using a linear 
regression with the vaccine group as the exposure and the baseline antibody levels as a 
covariate. The GMR and associated 95% CI will be calculated by exponentiating the 
difference in least-squares mean and the corresponding CIs.
10.12.9.3.2. Primary Endpoint(s)/Estimand(s) Analysis
Endpoint
Statistical Analysis Methods
Safety

Descriptive statistics will be provided for each reactogenicity
endpoint for each vaccine group. Local reactions and systemic
events from Day 1 through Day 7 after the study vaccination (where 
Day 1 is the day of vaccination) will be presented by severity and 
cumulatively across severity levels. Descriptive summary statistics 
will include counts and percentages of participants with the 
indicated endpoint and the associated Clopper-Pearson 95% CIs.

AEs and SAEs will be categorized according to MedDRA terms.  
Counts, percentages, and associated Clopper-Pearson 95% CIs of 
AEs within 1 month and SAEs within 6 months after study 
vaccination will be provided for each vaccine group.  
Immunogenicity
GMTs and GMFRs of SARS-CoV-2 Omicron- or reference-strain–
neutralizing titers
Percentages of participants with seroresponse to Omicron- or 
reference-strain
GMRs between different vaccine groups

GMTs at each time point and GMFRs of SARS-CoV-2 Omicron- or 
reference-strain–neutralizing titers from before the study vaccination 
to each subsequent time point after vaccination, along with the 
associated 2-sided 95% CIs, will be provided for each vaccine group 
using the statistical method described in Section 9.3.1.2.1 and 
Section 9.3.1.2.2.

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Endpoint
Statistical Analysis Methods

The percentages of participants with seroresponse at each time point 
and the associated Clopper-Pearson 95% CIs will be provided for 
each vaccine group.

Model-based GMRs at each time point after the study vaccination, 
along with the associated 2-sided 95% CIs, will be provided for each 
vaccine group (using the BNT162b2 30-µg group as the reference) 
using the statistical method described in Section 10.12.9.3.1
10.12.9.3.3. Exploratory Endpoint(s) Analysis
Endpoint
Statistical Analysis Methods
Immunogenicity
GMTs and GMFRs for any VOCs not already specified
GMTs of reference-strain– or VOC-neutralizing titers and GMFRs from 
before the study vaccination to each subsequent time point after 
vaccination, along with the associated 2-sided 95% CIs, will be 
provided at specific time points for each group.
Model-based GMRs of neutralizing titers for VOCs not already 
analyzed as a primary outcome at a specific time point after the study 
vaccination, along with the associated 2-sided 95% CIs, may be 
provided for each vaccine group (using the BNT162b2 30-µg group as 
the reference) using the statistical method described in 
Section 10.12.9.3.1.
Cell-mediated immune response and additional immune response 
parameters
The cell-mediated immune response and additional immune response 
parameters will be summarized at each time point.
COVID-19 cases
Confirmed COVID-19 cases, confirmed severe COVID-19 cases, and 
strain sequencing of the COVID-19 cases will be summarized using the 
statistical method described in Section 9.3.1.1.
10.12.9.4. Interim Analyses
No formal interim analysis will be conducted for this study.  Statistical analyses will be 
carried out when the final data for specified objectives are available while the study is 
ongoing.  The timing of these planned analysis and reporting events is described in the 
section below.

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10.12.9.4.1. Analysis Timing
Statistical analyses will be carried out when the following data are available:

Safety data through 1 month after study vaccination for each group.

Immunogenicity data through 1 month after study vaccination for each group.

Safety and immunogenicity data through 3 months after study vaccination for each group.

Complete safety and immunogenicity analysis approximately 6 months after study 
vaccination for each group.
Certain analyses may be combined into a single regulatory submission report if the data 
become available around the same time.  Additional analyses may be conducted if required 
for regulatory purposes. All analyses for the expanded-enrollment cohort conducted while 
the study is ongoing will be performed by an unblinded team.
10.12.9.4.2. Data Monitoring Committee or Other Independent Oversight Committee
The study will utilize an IRC and DMC. The IRC is independent of the study team and 
includes internal members and site representatives. The DMC is independent of the study 
team and includes only external members.  The IRC and DMC charters describe the role of 
the IRC and DMC in more detail.
The responsibilities of the IRC and site representatives are only for the sentinel cohort and 
will include:

Review of all reported AE and e-diary reactogenicity data collected through Day 7 from 
all sentinel-cohort participants. This safety assessment will be conducted to determine if 
the study team may proceed with expanded enrollment of approximately 25 additional
participants per group.
The DMC will be responsible for ongoing monitoring of the safety of participants in the 
study according to the charter.
The recommendations made by the DMC will be forwarded to the appropriate Pfizer 
personnel for review and final decision.  Pfizer will communicate such decisions, which may 
include summaries of aggregate analyses of safety data, to regulatory authorities and
investigators as appropriate.
10.12.9.5. Sample Size Determination
The study size is not based on any formal hypothesis test. All statistical analyses will be 
descriptive.
Table 16 shows the probability of observing at least 1 AE for a given true event rate of a 
particular AE, for various sample sizes. For example, if the true AE rate is 1%, with 
30 participants in a vaccine group, there is 26% probability of observing at least 1 AE.

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Table 16.
Substudy F - Probability of Observing at Least 1 AE by Assumed True 
Event Rates With Different Sample Sizes
Assumed True Event 
Rate of an AE
N=30
N=90
N=180
0.01%
0.003
0.01
0.02
0.02%
0.006
0.02
0.04
0.05%
0.01
0.04
0.09
0.10%
0.03
0.09
0.16
0.20%
0.06
0.16
0.30
0.50%
0.14
0.36
0.59
1.00%
0.26
0.60
0.84
2.00%
0.45
0.84
0.97
5.00%
0.79
0.99
>0.99
10.0%
0.96
>0.99
>0.99

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10.13. Appendix 13: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the table of contents.  The protocol amendment summary of changes tables 
for past amendment(s) can be found below:
Amendment 11 (20 Sep 2022)
Overall Rationale for the Amendment:
As part of protocol amendment 11, progression beyond the 12 through 17 years age group in 
Substudy C will not occur and no further participants will be enrolled. Active participants at 
the time of this amendment will also only be followed for 6 months after their last study 
vaccination. Their final visit will be V304. 
Active participants in Cohort 1 and Cohort 2 in Substudy D at the time of protocol 
amendment 11 will also only be followed for 6 months after their last study vaccination, the 
protocol-specified safety reporting period. Their final visit will be V405. 
The endpoints and statistical considerations were updated for Substudy F to further clarify 
the testing and analyses.
Protocol Amendment Summary of Changes Table
Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Synopsis – Substudy C 
Design
Confirmation that 
progression beyond the 
12 through 17 years age 
group in Substudy C will not 
occur and no further 
participants will be enrolled
A third dose of 
COVID-19 vaccine has 
been recommended for 
all age groups for a 
considerable period of 
time and, for Fall 2022, 
the recommended booster 
vaccine will switch to a 
bivalent 
original/Omicron-
modified vaccine, making 
age escalation 
operationally unfeasible.
Substantial
Synopsis – Substudy D 
Design
Confirmed that participants 
in Cohort 1 and Cohort 2 
will only be followed for 
6 months after their last 
study vaccination
The safety follow-up 
period is 6 months after 
the last dose; therefore, a 
longer study duration is 
not required.  
Substantial
Synopsis – Number of 
Participants 
(Substudy C)
Confirmed up to 
150 participants will be 
enrolled
Progression beyond the 
12 through 17 years age 
group will not occur.
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Synopsis – DMC
Clarified that DMC will only 
review safety and 
immunogenicity data in the 
first approximately 
100 participants 7 days after 
the third dose
Progression beyond the 
12 through 17 years age 
group will not occur.
Substantial
Section 10.8.2.3.1
Benefit Assessment
Updated to include reference 
to a fourth dose 
Protocol clarification.
Nonsubstantial
Section 10.9.1.2
Schema (Substudy C) 
Removed the 12-month 
follow-up visit and the 
20-mL blood sample for 
participants ≥18 years of age
The safety follow-up 
period is 6 months after 
the last dose, therefore a 
longer study duration is 
not required.  
Substantial
Section 10.9.1.3
Schedule of Activities 
(Substudy C)
Removed the 12-month 
follow-up visit and the 
20-mL blood sample for 
participants ≥18 years of age
The safety follow-up 
period is 6 months after 
the last dose, therefore a 
longer study duration is 
not required.  
Substantial
Section 10.9.2.1
Study Rationale 
(Substudy C)
Confirmation that 
progression beyond the 
12 through 17 years age 
group in Substudy C will not 
occur, and that the final visit 
will be 6 months after the 
last dose
A third dose of 
COVID-19 vaccine has 
been recommended for 
all age groups for a 
considerable period of 
time and, for Fall 2022, 
the recommended booster 
vaccine will switch to a 
bivalent 
original/Omicron-
modified vaccine, making 
age escalation 
operationally unfeasible.
The safety follow-up 
period is 6 months after 
the last dose, therefore a 
longer study duration is 
not required.  
Substantial
Section 10.9.3
Objectives, Estimands, 
and Endpoints 
(Substudy C)
Updated objectives in 
response to change in study 
design
A third dose of 
COVID-19 vaccine has 
been recommended for 
all age groups for a 
considerable period of 
time and, for Fall 2022, 
the recommended booster 
vaccine will switch to a 
bivalent 
original/Omicron-
modified vaccine, making 
age escalation 
operationally unfeasible.
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 10.9.4.1
Overall Design 
(Substudy C)
Confirmation that 
progression beyond the 
12 through 17 years age 
group in Substudy C will not 
occur, and no further 
subjects will be enrolled
A third dose of 
COVID-19 vaccine has 
been recommended for 
all age groups for a 
considerable period of 
time and, for Fall 2022, 
the recommended booster 
vaccine will switch to a 
bivalent 
original/Omicron-
modified vaccine, making 
age escalation 
operationally unfeasible.
The safety follow-up 
period is 6 months after 
the last dose, therefore a 
longer study duration is 
not required.  
Substantial
Section 10.9.4.1
Overall Design 
(Substudy C)
Removed reference to blood 
sample collection at the 
12-month visit
Due to decreased study 
duration.
Substantial
Section 10.9.8
Study Assessments and 
Procedures (Substudy C)
Clarified total blood 
sampling volume
The volume reduced as 
progression beyond the 
12 through 17 years age 
group will not occur, and 
the 12-month visit was 
removed.
Substantial
Section 10.9.8.4.1
Visit 301 (Substudy C)
Amended blood sample 
wording
Progression beyond the 
12 through 17 years age 
group will not occur.
Substantial
Section 10.9.8.4.2
Visit 302 (Substudy C)
Amended blood sample 
wording
Progression beyond the 
12 through 17 years age 
group will not occur.
Substantial
Section 10.9.8.4.3
Visit 303 (Substudy C)
Amended blood sample 
wording
Progression beyond the 
12 through 17 years age 
group will not occur.
Substantial
Section 10.9.8.4.4
Visit 304 (Substudy C)
Clarified for participants that 
have already completed 
V304 at the time of protocol 
amendment 11 that they will 
be informed by the 
investigator site staff of 
study completion
Due to removal of the 
12-month follow-up visit.
Substantial
Section 10.9.8.4.4
Visit 304 (Substudy C)
Amended blood sample 
wording
Progression beyond the 
12 through 17 years age 
group will not occur.
Substantial
Section 10.9.8.4.5
Visit 305 (Substudy C)
12-month follow-up visit 
removed
The safety follow-up 
period is 6 months after 
the last dose, therefore a 
longer study duration is 
not required.  
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 10.9.9.1.2
Statistical Hypotheses 
(Substudy C)
Clarified there is no formal 
hypotheses testing
Due to change in overall 
substudy design.
Substantial
Section 10.9.9.1.3
Multiplicity Adjustment 
(Substudy C)
Clarified no multiplicity 
adjustment is needed for the 
study
Due to change in overall 
substudy design.
Substantial
Section 10.9.9.3.2
Primary 
Endpoint(s)/Estimand(s) 
Analysis (Substudy C)
Updated objectives in 
response to change in study 
design
A third dose of 
COVID-19 vaccine has 
been recommended for 
all age groups for a 
considerable period of 
time and, for Fall 2022, 
the recommended booster 
vaccine will switch to a 
bivalent 
original/Omicron-
modified vaccine, making 
age escalation 
operationally unfeasible.
Substantial
Section 10.9.9.3.3
Secondary 
Endpoint(s)/Estimand(s) 
Analysis (Substudy C)
Updated objectives in 
response to change in study 
design
A third dose of 
COVID-19 vaccine has 
been recommended for 
all age groups for a 
considerable period of 
time and, for Fall 2022, 
the recommended booster 
vaccine will switch to a 
bivalent 
original/Omicron-
modified vaccine, making 
age escalation
operationally unfeasible.
Substantial
Section 10.9.9.3.4
Exploratory Endpoint(s) 
Analysis (Substudy C)
Updated objective in 
response to change in study 
design
A third dose of 
COVID-19 vaccine has 
been recommended for 
all age groups for a 
considerable period of 
time and, for Fall 2022, 
the recommended booster 
vaccine will switch to a 
bivalent 
original/Omicron-
modified vaccine, making 
age escalation 
operationally unfeasible.
Substantial
Section 10.9.9.4
Interim Analyses 
(Substudy C)
Confirmed the 
administrative interim 
analysis for 12 through 
17 years of age was 
completed
Protocol clarification.
Nonsubstantial

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Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 10.9.9.4.1
Analysis Timing 
(Substudy C)
Updated timing of analysis 
Due to change in overall 
substudy design.
Substantial
Section 10.9.9.5
Sample Size 
Determination 
(Substudy C)
Confirmed the sample size is 
not based on any formal 
hypothesis test
Due to change in overall 
substudy design.
Substantial
Section 10.9.9.5
Sample Size 
Determination 
(Substudy C)
Updated Table 9 based on 
revised enrollment 
Due to change in overall 
substudy design.
Substantial
Section 10.10.1.2.1
Schema Cohort 1 
(Substudy D)
12-month follow-up visit 
removed
The safety follow-up 
period is 6 months after 
the last dose, therefore a 
longer study duration is 
not required.  
Substantial
Section 10.10.1.2.2
Schema Cohort 2 
(Substudy D)
12-month follow-up visit 
removed
The safety follow-up 
period is 6 months after 
the last dose, therefore a 
longer study duration is 
not required.  
Substantial
Section 10.10.1.3.1
Schedule of Activities 
Cohort 1 (Substudy D)
12-month follow-up visit 
removed
The safety follow-up 
period is 6 months after 
the last dose, therefore a 
longer study duration is 
not required.  
Substantial
Section 10.10.1.3.2
Schedule of Activities 
Cohort 2 (Substudy D)
12-month follow-up visit 
removed
The safety follow-up 
period is 6 months after 
the last dose, therefore a 
longer study duration is 
not required.  
Substantial
Section 10.10.2.1
Study Rationale 
(Substudy D)
Confirmed active 
participants in Cohort 1 and 
Cohort 2 at the time of this 
amendment will only be 
followed for 6 months after 
their last study vaccination.
Their final visit will be 
V405. For participants who
have already completed 
V405 at the time of protocol 
amendment 11, they will be 
informed by the investigator 
site staff of study completion 
and that no further visits are 
required
The safety follow-up 
period is 6 months after 
the last dose, therefore a 
longer study duration is 
not required.  
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 10.10.3
Objectives, Estimands, 
and Endpoints 
(Substudy D)
Confirmed participants will 
not be age-matched to 
participants in C4591001, 
but will include similar 
percentage of participants 
with baseline-positive 
SARS-CoV-2 infection 
status as Group 5 of 
Substudy D, whenever 
feasible
In response to feedback 
received from CBER.
Nonsubstantial
Section 10.10.4.1
Study Design 
(Substudy D)
Confirmed active 
participants in Cohort 1 and 
Cohort 2 at the time of this 
amendment will only be 
followed for 6 months after 
their last study vaccination. 
Their final visit will be V405
The safety follow-up 
period is 6 months after 
the last dose, therefore a 
longer study duration is 
not required.  
Substantial
Section 10.10.8
Study Assessments and 
Procedures (Substudy D)
Clarified total blood 
sampling volume
Volume reduced due to 
removal of 12-month 
follow-up visit.
Substantial
Section 10.10.8.6.1.5
Visit 405 (Substudy D)
Clarified for participants 
who have already completed 
V405 at the time of protocol 
amendment 11 that they will 
be informed by the 
investigator site staff of 
study completion
The safety follow-up 
period is 6 months after 
the last dose, therefore a 
longer study duration is 
not required and V406 
was removed. 
Substantial
Section 10.10.8.6.1.5
Visit 405 (Substudy D)
Confirmed the e-diary will 
be collected or the 
participant assisted to 
remove the study application 
from his or her own personal 
device, and reference to 
ensuring the participant has a 
self-swab kit was removed 
V405 is now the final 
study visit for Cohort 1 
and Cohort 2 as they will 
now only be followed for 
the safety reporting 
period of 6 months after 
the last dose.
Substantial
Section 10.10.8.6.1.6
Visit 406 (Substudy D)
12-month follow-up visit 
removed
The safety follow-up 
period is 6 months after 
the last dose, therefore a 
longer study duration is 
not required.  
Substantial
Section 10.10.8.6.2.7
Visit 405 (Substudy D)
Clarified for participants 
who have already completed 
V405 at the time of protocol 
amendment 11 that they will 
be informed by the 
investigator site staff of 
study completion
The safety follow-up 
period is 6 months after 
the last dose, therefore a 
longer study duration is 
not required and V406 
was removed.
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 10.10.8.6.2.7
Visit 405 (Substudy D)
Confirmed the e-diary will 
be collected or the 
participant assisted to 
remove the study application 
from his or her own personal 
device, and reference to 
ensuring the participant has a 
self-swab kit was removed
V405 is now the final 
study visit for Cohort 1 
and Cohort 2 as they will 
now only be followed for 
the safety reporting 
period of 6 months after 
the last dose.
Substantial
Section 10.10.8.6.2.8
Visit 406 (Substudy D)
12-month follow-up visit
removed
The safety follow-up 
period is 6 months after 
the last dose, therefore a 
longer study duration is 
not required.  
Substantial
Section 10.10.9.4.1
Analysis Timing 
(Substudy D)
Deleted the safety and 
immunogenicity analysis 
12 months after the last 
study vaccination
The safety follow-up 
period is 6 months after 
the last dose, therefore a 
longer study duration is 
not required.  
Substantial
Section 10.11.8.6.1
Screening (Substudy E)
Deleted reference to AEs 
that occur prior to dosing 
being recorded on the 
medical history CRF
For consistency with 
Section 8.3.
Nonsubstantial
Section 10.12.3
Objectives, Endpoints, 
and Estimands 
(Substudy F)
Updated the seroresponse 
definition to achieving 
≥4-fold rise from baseline 
(before the study 
vaccination). If the baseline 
measurement is below the 
LLOQ, the postvaccination 
measure of ≥4 × LLOQ is 
considered seroresponse
To align with the 
definition used in other 
substudies within 
C4591031.
Nonsubstantial
Section 10.12.3
Objectives, Endpoints, 
and Estimands 
(Substudy F) 
Clarified that PBMC 
analysis will include B-cell 
characterization, and that 
RBD binding IgG and RBD 
binding IgA will also be 
tested
To further clarify the 
testing to be performed.
Nonsubstantial
Section 10.12.3
Objectives, Endpoints, 
and Estimands 
(Substudy F)
Added the following 
endpoint: GMRs at each 
time point after the study 
vaccination between 
different vaccine groups
To further clarify the 
analyses to be performed.
Substantial
Section 10.12.8.2
Immunogenicity 
(Substudy F)
Removed details on PBMC 
analysis as the analyses to be 
performed are detailed in  
Section 10.12.9
To further clarify the 
testing to be performed.
Nonsubstantial
Section 10.12.9.3.1
General Considerations 
(Substudy F)
Added a section, “Adjusted 
Comparisons of Antibody 
Levels”
To further clarify the 
analyses to be performed.
Nonsubstantial

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Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 10.12.9.3.2
Primary 
Endpoint(s)/Estimand(s) 
Analysis (Substudy F)
Added the following 
analysis: model-based
GMRs at each time point 
after the study vaccination, 
along with the associated 
2-sided 95% CIs, will be 
provided for each vaccine 
group (using the BNT162b2 
30-µg group as the 
reference)
To further clarify the 
analyses to be performed.
Nonsubstantial
Section 10.12.9.3.3
Exploratory 
Endpoint(s)/Estimand(s) 
Analysis (Substudy F)
Added the following 
analysis: model-based
GMRs of neutralizing titers 
for VOCs not already 
analyzed as a primary 
outcome at a specific time 
point after the study 
vaccination, along with the 
associated 2-sided 95% CIs, 
may be provided for each 
vaccine group (using the 
BNT162b2 30-µg group as 
the reference)
To further clarify the 
analyses to be performed.
Nonsubstantial
Section 10.12.9.4.1
Analysis Timing 
(Substudy F)
Added safety and 
immunogenicity data 
analysis through 3 months
after study vaccination for 
each group
To further clarify the 
analyses to be performed.
Nonsubstantial
Amendment 10 (22 July 2022)
Overall Rationale for the Amendment:
Initial immunogenicity data reviewed from Cohort 3 Substudy D at 1 month after Dose 2 
demonstrated a more pronounced antibody response against the Omicron variant versus the 
Wild Type and Delta variants. Therefore, the third dose for participants in Cohort 3 of 
Substudy D has been changed from BNT162b2 OMI 30 µg to BNT162b2 30 µg to provide 
participants with wider protection against the different SARS-CoV-2 variants, in addition to 
the protection they will already have against the Omicron variant from their first 2 
vaccinations.

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Protocol Amendment Summary of Changes Table
Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 1.1 – Synopsis
and Section 10.10.4.1 –
Overall Design 
(Substudy D)
Confirmed that if participants do 
not consent to receive 
BNT162b2 as a third dose, they 
will not receive a third dose
Protocol clarification
Substantial
Section 10.10.6.1.1 –
Administration 
(Substudy D)
Clarified that participants in 
Cohort 3 will receive BNT162b2 
rather than BNT162b2 OMI as 
their third dose
Protocol clarification
Substantial
Section 10.10.8 – Study 
Assessments and 
Procedures (Substudy D)
Clarified that participants in 
Cohort 3 will receive BNT162b2 
rather than BNT162b2 OMI as 
their third dose
Protocol clarification
Substantial
Section 10.10.1.3.3 –
Cohort 3 schedule of 
activities (Substudy D)
Confirmed that the vaccine 
received at Visit 506 is 
BNT162b2
Protocol clarification
Substantial
Section 10.10.2.1 – Study 
Rationale (Substudy D)
Clarified that participants in 
Cohort 3 will receive BNT162b2 
rather than BNT162b2 OMI as 
their third dose
Protocol clarification
Substantial
Section 10.8.8.3.5 – Visit 
205 – 1 Month Follow-Up 
Visit (After Vaccination 
2) (28-35 Days After Visit 
203) (Substudy B)
Confirmed that a participant may 
be unblinded at Visit 205, 1 
month after receiving their 
second study vaccination, to 
confirm the date of BNT162b2 
receipt
Protocol clarification
Substantial
Section 10.10.1.2.3 –
Participants in Cohort 3 
schema (Substudy D)
Confirmed that the vaccine 
received at the 6-month visit is 
BNT162b2
Protocol clarification
Substantial
Section 1.1 – Synopsis, 
Section 10.10.1.2 –
Schema, Section 
10.10.1.3 – Schedule of 
Activities for Substudy D, 
Section 10.10.2.1 – Study 
Rationale, 
Section 10.10.4 – Study 
Design,
Section 10.10.6.1.1 –
Administration, and
Section 10.10.8 – Study 
Assessments and 
Procedures (Substudy D)
Clarified that participants in 
Cohort 3 will receive BNT162b2 
rather than BNT162b2 OMI as 
their third dose
Protocol clarification
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 1.1 – Synopsis, 
Section 10.8.1.2 –
Schema,
Section 10.8.1.3 –
Schedule of Activities for 
Substudy B, 
Section 10.8.2.1 – Study 
Rationale,
Section 10.8.4 – Study 
Design, Section 10.8.5.1 –
Inclusion Criteria, and
Section 10.8.8.3 –
Substudy B Procedures 
(Substudy B)
Added the number of days since
the last dose, in parentheses after 
the number of months
Protocol clarification
Nonsubstantial
Section 1.1 – Synopsis, 
Section 10.9.1.2 –
Schema, 
Section 10.9.1.3 –
Schedule of Activities for 
Substudy C, 
Section 10.9.2.1 – Study 
Rationale,
Section 10.9.4 – Study 
Design, and Section 
10.9.8.4 – Substudy C 
Procedures 
(Substudy C)
Added the number of days since 
the last dose, in parentheses after 
the number of months
Protocol clarification
Nonsubstantial
Section 1.1 – Synopsis, 
Section 10.11.4 – Study 
Design, and Section 
10.11.5.1 – Inclusion 
Criteria 
(Substudy E)
Added the number of days since 
the last dose, in parentheses after 
the number of months
Protocol clarification
Nonsubstantial
Section 10.7.3 –
Objectives, Estimands, 
and Endpoints 
(Substudy A)
Deleted the objective for 
efficacy against asymptomatic 
SARS-CoV-2 infection
Protocol clarification
Nonsubstantial
Section 10.7.8.1.2 –
Efficacy Against 
Asymptomatic
SARS-CoV-2 Infection 
(Substudy A)
Deleted the section on efficacy 
against asymptomatic
SARS-CoV-2 infection 
Protocol clarification
Nonsubstantial
Section 10.7.9.3.3 –
Secondary 
Endpoints(s)/Estimand(s) 
Analysis (Substudy A)
Deleted the objective for 
efficacy against asymptomatic 
SARS-CoV-2 infection
Protocol clarification
Nonsubstantial
Section 10.8.5.2 –
Exclusion Criteria, Other 
Exclusions (Substudy B)
Clarified that prior receipt of 
more than 3 doses of BNT162b2 
30 µg is an exclusion
Protocol clarification
Nonsubstantial

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Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 10.8.8.3.3 – Visit 
203 –Vaccination 2 (28 to 
35 Days After Visit 201) 
(Substudy B)
Confirmed that a positive 
SARS-CoV-2 NAAT result 
without symptoms, or a COVID-
19 diagnosis, should not result in 
discontinuation of study 
intervention
Protocol clarification
Nonsubstantial
Section 10.10.1.3.3 –
Cohort 3 schedule of 
activities (Substudy D)
Extended the visit window by 
7 days to 199 days after Visit 
502
Protocol clarification
Nonsubstantial
Section 10.10.3 –
Objectives, Estimands, 
and Endpoints 
(Substudy D)
Added Group 5 to the objectives 
and clarified the estimands to 
include those with or without 
serological or virological 
evidence of past SARS-CoV-2 
infection
Clarified objectives and 
estimands
Nonsubstantial
Section 10.10.8.6.1.2 –
Visit 402 – 1-Month 
Follow-Up Visit (After 
Substudy D Vaccination 
1) (28 to 35 Days After 
Visit 401) (Substudy D)
Confirmed that a positive 
SARS-CoV-2 NAAT result 
without symptoms, or a 
COVID-19 diagnosis, should not 
result in discontinuation of study 
intervention
Protocol clarification
Nonsubstantial
Section 10.10.8.6.2.3 –
Visit 404 – 3-Month 
Follow-Up Visit (85 to 95 
Days After Visit 401, or 
85 to 123 Days After Visit 
401 for Those Participants 
Who Consent to Receive 
Substudy D Vaccination 
2) (Substudy D)
Confirmed that a positive 
SARS-CoV-2 NAAT result 
without symptoms, or a COVID-
19 diagnosis, should not result in 
discontinuation of study 
intervention
Protocol clarification
Nonsubstantial
Section 10.10.8.6.3.2 –
Visit 502 –  Vaccination 2 
(19 to 23 Days After Visit 
501) (Substudy D)
Confirmed that a positive 
SARS-CoV-2 NAAT result 
without symptoms, or a 
COVID-19 diagnosis, should not 
result in discontinuation of study 
intervention
Protocol clarification
Nonsubstantial
Section 10.10.8.6.3.6 –
Visit 506 – 6-Month 
Follow-Up Visit (After 
Vaccination 2) (150 to 
199 Days After Visit 502) 
and Administration of 
Vaccination 3 
(Substudy D)
Confirmed that a positive 
SARS-CoV-2 NAAT result 
without symptoms, or a 
COVID-19 diagnosis, should not 
result in discontinuation of study 
intervention
Protocol clarification
Nonsubstantial
Section 10.10.9.3.2 –
Primary 
Endpoint(s)/Estimand(s) 
Analysis (Substudy D)
Updated an immunogenicity 
endpoint to specify the Cohort 1 
and 2 participants to be used in 
analysis  
Clarified primary 
endpoints
Nonsubstantial

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Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 10.11.3 –
Objectives, Estimands, 
and Endpoints 
(Substudy E)
Clarified an exploratory 
objective’s footnote to specify 
that the subset taken will be from 
the youngest 150 participants in 
Substudy E who received 
bivalent BNT162b2
Clarified the subset of 
participants to be 
selected for the 
exploratory objective
Nonsubstantial
Section 10.11.9.1.2 –
Statistical Hypotheses 
(Substudy E)
Clarified that the primary and 
secondary immunogenicity 
objectives for participants 
>55 years of age will be 
evaluated by the statistical 
hypotheses described in the 
section, and the immunogenicity 
objectives for participants 18
through 55 years of age are 
descriptive only 
Clarified the statistical 
hypotheses
Nonsubstantial
Section 10.11.9.1.3 –
Multiplicity Adjustment 
(Substudy E)
Clarified the age ranges for the 
objectives
To clarify the age 
ranges to use 
multiplicity adjustments
Nonsubstantial
Section 10.11.9.3 –
Statistical Analyses 
(Substudy E)
Confirmed that a sensitivity 
analysis of GMR and difference 
in seroresponse rate for between-
group comparison may be 
performed
Clarified additional 
analyses being 
performed
Nonsubstantial
Amendment 9 (03 May 2022)
Overall Rationale for the Amendment:
The inclusion criteria for Substudy B have been updated to allow participants who have 
received a third dose of BNT162b2 at least 4 months prior to randomization, to support 
enrollment and to align with current recommendations.
Substudy E  has been amended to obtain data on bivalent BNT162b2 and BNT162b2 OMI at 
60 µg (30 µg each), bivalent BNT162b2 and BNT162b2 OMI at 30 µg (15 µg each), and 
BNT162b2 OMI at 60 µg in participants 18 to 55 years of age.

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Protocol Amendment Summary of Changes Table
Section # and Name
Description of Change
Brief Rationale
Section 1.1 Synopsis, Substudy B
Added text to allow inclusion of 
participants who have received a 
booster (third) dose of BNT162b2 
at least 4 months prior to 
randomization. Timing of prior 
BNT162b2 for participants with 2 
prior doses updated to 4 months 
prior to randomization.
To support enrollment and to align 
with current recommendations.
Section 1.1 – Synopsis, Substudy E
Added sentinel and expanded 
cohorts of participants 18 to 55 
years of age in Substudy E and 
updated the number of participants 
to 2910 for Substudy E.
To obtain data on bivalent 
BNT162b2 and BNT162b2 OMI at 
60 µg (30 µg each), bivalent 
BNT162b2 and BNT162b2 OMI at 
30 µg (15 µg each), and 
BNT162b2 OMI at 60 µg in 18- to 
55-year-olds. 
Section 10.8.1.2 – Schema for 
Substudy B
Added text to allow inclusion of 
participants who have received a 
booster (third) dose of BNT162b2 
at least 4 months prior to 
randomization. Timing of prior 
BNT162b2 for participants with 2 
prior doses updated to 4 months 
prior to randomization.
To support enrollment and to align 
with current recommendations.
Section 10.8.1.3 – SoA for 
Substudy B 
Added text to allow inclusion of 
participants who have received a 
booster (third) dose of BNT162b2 
at least 4 months prior to 
randomization. Timing of prior 
BNT162b2 for participants with 2 
prior doses updated to 4 months 
prior to randomization.
To support enrollment and to align 
with current recommendations.
Section 10.8.2.1 – Study Rationale 
for Substudy B
Added text to allow inclusion of 
participants who have received a 
booster (third) dose of BNT162b2 
at least 4 months prior to 
randomization. Timing of prior 
BNT162b2 for participants with 2 
prior doses updated to 4 months 
prior to randomization.
To support enrollment and to align 
with current recommendations.
Section 10.8.4.1 – Overall Design 
for Substudy B
Added text to allow inclusion of 
participants who have received a 
booster (third) dose of BNT162b2 
at least 4 months prior to 
randomization. Timing of prior 
BNT162b2 for participants with 2 
prior doses updated to 4 months 
prior to randomization.
To support enrollment and to align 
with current recommendations.

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Section # and Name
Description of Change
Brief Rationale
Section 10.8.5.1 – Inclusion 
Criteria for Substudy B
Updated criteria to allow inclusion 
of participants who have received a 
booster (third) dose of BNT162b2 
at least 4 months prior to 
randomization. Timing of prior 
BNT162b2 for participants with 2 
prior doses updated to 4 months 
prior to randomization.
To support enrollment and to align 
with current recommendations.
Section 10.8.8.3.1 – Visit 201 for 
Substudy B
Added text to allow inclusion of 
participants who have received a 
booster (third) dose of BNT162b2 
at least 4 months prior to 
randomization. Timing of prior 
BNT162b2 for participants with 2 
prior doses updated to 4 months 
prior to randomization.
To support enrollment and to align 
with current recommendations.
Section 10.10.8.6.2.3 – Visit 404 
for Substudy D
Moved the following text and 
changed it from a procedure to a 
note: Participants in Cohort 2 will 
be unblinded to confirm the 
vaccine received once they have 
COMPLETED Visit 404 (3 
months after Substudy D 
Vaccination 1).  Since these are the 
only participants still blinded at this 
time, the study team will also 
become unblinded to all 
participants’ original study 
intervention allocation at this time.
To prevent sites from unblinding 
participants prematurely.
Section 10.11.1.2 – Schema for 
Substudy E
Added sentinel and expanded 
cohorts of participants 18 to 55 
years of age in Substudy E.
To obtain data on bivalent 
BNT162b2 and BNT162b2 OMI at 
60 µg (30 µg each), bivalent 
BNT162b2 and BNT162b2 OMI at 
30 µg (15 µg each), and 
BNT162b2 OMI at 60 µg in 18- to 
55-year-olds.
Section 10.11.1.3 – SoA for 
Substudy E
Added sentinel and expanded 
cohorts of participants 18 to 55 
years of age in Substudy E.
To obtain data on bivalent 
BNT162b2 and BNT162b2 OMI at 
60 µg (30 µg each), bivalent 
BNT162b2 and BNT162b2 OMI at 
30 µg (15 µg each), and 
BNT162b2 OMI at 60 µg in 18- to 
55-year-olds.
Section 10.11.3 – Objectives, 
Estimands, and Endpoints for 
Substudy E 
Updated the primary and secondary 
objectives with respect to 
noninferiority of the seroresponse 
rate and updated the definition of 
seroresponse and added text and 
objectives for the 18- to 55-year-
olds.
To align with regulatory 
requirements and to describe the 
analysis of data from 18- to 55-
year-olds.

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Section # and Name
Description of Change
Brief Rationale
Section 10.11.4 – Overall Design 
for Substudy E
Added text to include sentinel and 
expanded cohorts of participants 18 
to 55 years of age in Substudy E.
To obtain data on bivalent 
BNT162b2 and BNT162b2 OMI at 
60 µg (30 µg each), bivalent 
BNT162b2 and BNT162b2 OMI at 
30 µg (15 µg each), and 
BNT162b2 OMI at 60 µg in 18- to 
55-year-olds.
Section 10.11.5.1 – Inclusion 
Criteria for Substudy E
Updated inclusion criterion 1 for 
sentinel and expanded cohorts of 
participants 18 to 55 years of age in 
Substudy E. 
Added a new exclusion criterion 
for sentinel participants in 
Groups 7 to 9 requiring that 
screening troponin levels must be 
within normal range prior to 
randomization.
To obtain data on bivalent 
BNT162b2 and BNT162b2 OMI at 
60 µg (30 µg each), bivalent 
BNT162b2 and BNT162b2 OMI at 
30 µg (15 µg each), and 
BNT162b2 OMI at 60 µg in 18- to 
55-year-olds.
Section 10.11.6 – Study 
Intervention(s) and Concomitant 
Therapy for Substudy E
Added text to include sentinel and 
expanded cohorts of participants 18 
to 55 years of age in Substudy E.
To obtain data on bivalent 
BNT162b2 and BNT162b2 OMI at 
60 µg (30 µg each), bivalent 
BNT162b2 and BNT162b2 OMI at 
30 µg (15 µg each), and 
BNT162b2 OMI at 60 µg in 18- to 
55-year-olds.
Section 10.11.8 – Study 
Assessments and Procedures for 
Substudy E
Added text to specify that sentinel 
cohort participants in Groups 7, 8, 
and 9 will also have 20 mL of 
blood drawn for troponin levels.
Troponin levels will be obtained at 
screening and on Day 3.
Section 10.11.8.2 –
Immunogenicity for Substudy E
Added text to specify that up to 
approximately 90 participants 
across the 18- to 55-year-old 
groups (Groups 7 to 9) will 
contribute to PBMC sample 
collection.
To obtain data on bivalent 
BNT162b2 and BNT162b2 OMI at 
60 µg (30 µg each), bivalent 
BNT162b2 and BNT162b2 OMI at 
30 µg (15 µg each), and 
BNT162b2 OMI at 60 µg in 18- to 
55-year-olds.
Section 10.11.8.6 – Substudy E 
Procedures
Added text to include sentinel and 
expanded cohorts of participants 18 
to 55 years of age in Substudy E.
To obtain data on bivalent 
BNT162b2 and BNT162b2 OMI at 
60 µg (30 µg each), bivalent 
BNT162b2 and BNT162b2 OMI at 
30 µg (15 µg each), and 
BNT162b2 OMI at 60 µg in 18- to 
55-year-olds.
Section 10.11.9 – Statistical 
Considerations for Substudy E
Updated hypotheses, multiplicity, 
analysis, and sample size 
calculation related to changes in 
objectives and added text and 
objectives for the 18- to 55-year-
olds.
To align with regulatory 
requirements and to describe the 
analysis of data from 18- to 55-
year-olds.

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Amendment 8 (31 Mar 2022)
Overall Rationale for the Amendment:
Added language to permit early discontinuation of participants in Substudy A for reasons 
including (but not limited to) access and availability of BNT162b2 in the real world, 
reducing the need for participant involvement and observation in this clinical trial.
Substudy B was updated to clarify that participants may be unblinded to confirm the dose of 
BNT162b2 received at Visit 205, 1 month after receiving their second study vaccination.  
This amendment will allow for collection of data after a dose of BNT162b2 OMI at Visit 404 
in Substudy D Group 3 and Group 4 participants who received 3 prior doses of BNT162b2 
and a fourth dose of either BNT162b2 or BNT162b2 OMI. Substudy D updates also include 
changes to the statistical considerations to align with CBER feedback.
Protocol Amendment Summary of Changes Table
Section # and Name
Description of Change
Brief Rationale
Section 1.1 – Synopsis, Rationale
Updated text to state that to date, 
more than 455 million people have 
been infected with SARS-CoV-2 
and >6 million have died.
To provide the most current 
information.
Section 1.1 – Synopsis, Substudy A
Design
Added language to permit early 
discontinuation of participants in 
Substudy A.
Due to access and availability of 
BNT162b2 in the real world, and 
for participants who are offered the 
possibility to participate in a future 
study within the Pfizer/BioNTech 
COVID-19 vaccine development 
program. 
Section 1.1 – Synopsis, Substudy D
Design
Added text for Cohort 2 to clarify 
that participants will be offered a 
dose of BNT162b2 OMI at 
Visit 404 (3-month follow-up). 
Removed text stating that Group 4 
may not be enrolled.
To allow for collection of data after 
a dose of BNT162b2 OMI at Visit 
404 in participants who received 
3 prior doses of BNT162b2 and a 
fourth dose of either BNT162b2 or 
BNT162b2 OMI.
Group 4 was enrolled.
Section 2.2 – Background
Updated text to state that to date, 
more than 455 million people have 
been infected with SARS-CoV-2 
and >6 million have died.
To provide the most current 
information.
Section 8.3.1 – Time Period and 
Frequency for Collecting AE and 
SAE Information, Substudy D
Added text to clarify the AE 
collection time period for Group 3 
and Group 4 participants who will 
receive a dose of BNT162b2 OMI
at Visit 404.
To account for a dose of 
BNT162b2 OMI administered to 
Group 3 and Group 4 participants 
at Visit 404.

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Section # and Name
Description of Change
Brief Rationale
Section 10.7.4 – Study Design for 
Substudy A
Added language to permit early 
discontinuation of participants in 
Substudy A.
Due to access and availability of 
BNT162b2 in the real world, and 
for participants who are offered the 
possibility to participate in a future 
study within the Pfizer/BioNTech 
COVID-19 vaccine development 
program.
Section 10.8.6.2.2 – Blinding of the 
Sponsor for Substudy B
Added text to clarify that the 
participant may be unblinded to 
confirm the dose of BNT162b2 
received at Visit 205, 1 month after 
receiving their second study 
vaccination.  The study team will 
also become unblinded to the 
participant’s original study 
intervention allocation at this time.
To allow participants to add the 
vaccination details to their national 
vaccination record cards.
Section 10.8.8.3.3 - Visit 203 –
Vaccination 2 (28 to 35 Days After 
Visit 201) for Substudy B
Addition of the step to measure the 
participant’s body temperature.
Protocol clarification.
Section 10.9.8.4.3 Visit 303 –
1 Month After Booster Vaccination
(28 to 35 Days After Visit 301) for 
Substudy C
Deleted the request to ask the 
participant or his/her parent(s)/legal 
guardian to contact the site staff or 
investigator if the participant 
experiences acute chest pain, 
shortness of breath, or palpitations.
Protocol clarification as outside of 
the reporting period.
Section 10.9.3 – Objectives, 
Estimands, and Endpoints for 
Substudy C
Corrected the age group ranges in 
the second primary 
immunogenicity objective: 
18 through 30 years of age and 
31 through 55 years of age.
To correct a typographical error in 
the previous version.
Section 10.9.9.3.4 – Exploratory 
Endpoint(s) Analysis for 
Substudy C
Removed “anti” from anti-VOC 
neutralizing titers, as the term 
“anti” in this context is extraneous.
To correct a typographical error in 
the previous version.
Section 10.10.1.2.1 – Schema for 
Substudy D
Added a row to confirm the 
participant’s prior study and 
participant number (if applicable) 
should be recorded in the CRF.
Protocol clarification.
Section 10.10.1.2.2 – Schema for 
Substudy D
Added a separate schema for 
Cohort 2 participants.
To account for the second dose of 
BNT162b2 OMI administered to 
Group 3 and 4 participants.
Section 10.10.1.3 – Schedule of 
Activities for Substudy D
Added a separate schedule of 
activities for Cohort 2 participants.
To account for the second dose of 
BNT162b2 OMI administered to 
Group 3 and 4 participants.
Section 10.10.3 – Objectives, 
Estimands, and Endpoints for 
Substudy D 
Updated the primary and secondary 
objectives with respect to 
noninferiority of the seroresponse 
rate and updated the definition of 
seroresponse. 
To align with regulatory 
requirements.

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Section # and Name
Description of Change
Brief Rationale
Section 10.10.4.1 – Study Design 
for Substudy D
Added text for Cohort 2 
participants to clarify that they will 
be offered a dose of 
BNT162b2 OMI at Visit 404 
(3-month follow-up). 
Removed text stating that Group 4 
may not be enrolled.
To allow for collection of data after 
a dose of BNT162b2 OMI at 
Visit 404 in participants who 
received 3 prior doses of 
BNT162b2 and either a fourth dose 
of BNT162b2 or BNT162b2 OMI.
Group 4 was enrolled.
Section 10.10.6.1.1 –
Administration for Substudy D
Added text to indicate that Group 3 
and Group 4 participants may 
receive a dose of BNT162b2 OMI 
at Visit 404.
To account for a dose of 
BNT162b2 OMI administered to 
Group 3 and Group 4 participants 
at Visit 404.
Section 10.10.6.2.1 – Blinding of 
the Site Personnel for Substudy D
Added text to allow Cohort 2 to be 
unblinded at Visit 404.
To allow participants to add the 
vaccination details to their national 
vaccination record cards.
Section 10.10.6.2.2 – Blinding of 
the Sponsor for Substudy D
Added text to allow Cohort 2 to be 
unblinded at Visit 404.
To allow participants to add the 
vaccination details to their national 
vaccination record cards.
Section 10.10.8.6 – Substudy D 
Procedures
Added a subsection of procedures 
for Cohort 2.
To account for a dose of 
BNT162b2 OMI administered to 
Group 3 and Group 4 participants.
Section 10.10.8.6.1.2 Visit 402 –
1-Month Follow-Up Visit (After 
Substudy D Vaccination 1) 
(28 to 35 Days After Visit 401) for 
Substudy D
Deleted the request to ask the 
participant or his/her parent(s)/legal 
guardian to contact the site staff or 
investigator if the participant 
experiences acute chest pain, 
shortness of breath, or palpitations.
Protocol clarification as outside of 
the reporting period.
Section 10.10.8.6.1.3 Visit 403 –
1-Month Follow-Up Visit (After 
Substudy D Vaccination 2) 
(28 to 35 Days After Visit 402) for 
Substudy D
Deleted the request to ask the 
participant or his/her parent(s)/legal 
guardian to contact the site staff or 
investigator if the participant 
experiences acute chest pain, 
shortness of breath, or palpitations.
Protocol clarification as outside of 
the reporting period.
Section 10.10.8.6.3.4 Visit 504 –
1-Month Follow-Up Visit (After 
Vaccination 2) (28 to 35 Days 
After Visit 502) for Substudy D
Deleted the request to ask the 
participant or his/her parent(s)/legal
guardian to contact the site staff or 
investigator if the participant 
experiences acute chest pain, 
shortness of breath, or palpitations.
Protocol clarification as outside of 
the reporting period.
Section 10.10.8.6.3.7 Visit 507 –
1-Month Follow-Up Visit (After 
Vaccination 3) (28 to 35 Days 
After Visit 506) for Substudy D
Deleted the request to ask the 
participant or his/her parent(s)/legal 
guardian to contact the site staff or 
investigator if the participant 
experiences acute chest pain, 
shortness of breath, or palpitations.
Protocol clarification as outside of 
the reporting period.

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Section # and Name
Description of Change
Brief Rationale
Section 10.10.8.6.6 – SARS-CoV-2 
NAAT Results for Substudy D
Added Visit 404 (Group 3 and 
Group 4 participants who receive a 
dose of BNT162b2 OMI at Visit 
404) to the list of nasal swab visit 
time points that will be used to 
determine whether a participant 
will be included in the 
immunogenicity analysis.
Clarified the analysis 
(immunogenicity) and time points
of those with no serological or 
virological evidence (up to 1 month
after receipt of the third, fourth, or 
fifth dose for BNT162b2-
experienced participants, or as a 
2-dose series to COVID-19 
vaccine–naïve participants) of past 
SARS-CoV-2 infection.
To account for the dose of 
BNT162b2 OMI administered to 
Group 3 and Group 4 participants 
at Visit 404.
To correct the analysis population 
and time points of past 
SARS-CoV-2 infection.
Section 10.10.9 – Statistical 
Considerations for Substudy D
Updated hypotheses, multiplicity, 
analysis, and sample size 
calculation related to changes in 
objectives.
To align with regulatory 
requirements.
Section 10.10.9.3.4 – Exploratory 
Endpoint(s) Analysis for 
Substudy D
Removed “anti” from anti-VOC 
neutralizing titers, as the term 
“anti” in this context is extraneous.
To correct a typographical error in 
the previous version.
Section 10.11.4.1 – Overall Design 
for Substudy E
Added group number to the 
Sentinel and Expanded Enrollment 
table.
To provide more clarity when 
referring to groups in the Statistical 
Considerations section.
Section 10.11.8.6.5 Visit 603 –
1-Month Follow-Up Visit 
(28 to 35 Days After Visit 601) for 
Substudy E
Deleted the request to ask the 
participant or his/her parent(s)/legal 
guardian to contact the site staff or 
investigator if the participant 
experiences acute chest pain, 
shortness of breath, or palpitations.
Protocol clarification as outside of 
the reporting period.
Section 10.11.9.3.4 – Exploratory 
Endpoint(s) Analysis for 
Substudy E
Removed “anti” from anti-VOC 
neutralizing titers, as the term 
“anti” in this context is extraneous.
To correct a typographical error in 
the previous version.
Section 10.12.8.5.3 Visit 703 –
1-Month Follow-Up Visit 
(28 to 35 Days After Visit 701) for 
Substudy F
Deleted the request to ask the 
participant or his/her parent(s)/legal 
guardian to contact the site staff or 
investigator if the participant 
experiences acute chest pain, 
shortness of breath, or palpitations.
Protocol clarification as outside of 
the reporting period.
Section 10.12.9.3.3 – Exploratory 
Endpoint(s) Analysis for 
Substudy F
Removed “anti” from anti-VOC 
neutralizing titers as the term “anti” 
in this context is extraneous.
To correct a typographical error in 
the previous version.
Section 10.12.9.4.1 – Analysis 
Timing for Substudy F
Removed the analysis for 
immunogenicity data through 
7 days after study vaccination for 
each group and safety data through 
7 days after study vaccination for 
each group.
Data from Substudy E will be used 
to inform decisions at this 
immunogenicity time point. Safety 
data at 7 days after study 
vaccination are covered by the IRC 
review.

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Amendment 7 (17 Feb 2022)
Overall Rationale for the Amendment:
A BNT162b2 bivalent (BNT162b2 Wild Type and BNT162b2 OMI) formulation will be 
available as a preformulated product in Substudy E. The sentinel-cohort participants 
randomized to the combination BNT162b2 and BNT162b2 OMI groups will be administered 
a suspension containing a mixture of BNT162b2 Wild Type and BNT162b2 OMI prepared 
from 2 separate vials at the investigator site. Participants in the expanded cohort who are 
randomized to the combination BNT162b2 and BNT162b2 OMI groups will receive the 
preformulated product containing BNT162b2 Wild Type and BNT162b2 OMI.
Protocol Amendment Summary of Changes Table
Section # and Name
Description of Change
Brief Rationale
Section 10.10.9.3.2 – Primary 
Endpoint(s)/Estimand(s) Analysis
for Substudy D
Updated text to clarify that 
superiority based on GMR will be 
established if the lower bound of 
the 2-sided 97.5% CI for the GMR 
is >1.
To correct a typographical error in 
the previous version.
Section 10.10.6.2 – Measures to 
Minimize Bias: Randomization and 
Blinding for Substudy D
Removed “(Cohort 2 Only)” from 
the header as the text included in 
the subsections referenced Cohort 1 
as well.
To clarify that the section contains 
text for Cohort 1. 
Section 10.9.6.2.2 – Blinding of the 
Sponsor for Substudy D
Added text to clarify sponsor 
blinding to Cohort 1, Groups 1 and 
2b, as specified elsewhere within 
this subsection. 
To clarify and reiterate sponsor 
blinding to Cohort 1, Groups 1 and 
2b.
Section 10.11.4 – Study Design for 
Substudy E
Updated footnotes to clarify that 
the sentinel-cohort participants 
randomized to the combination 
BNT162b2 and BNT162b2 OMI 
groups will receive doses that are 
prepared at the investigator site 
from 1 vial each of diluted
BNT162b2 vaccine and 
BNT162b2 OMI vaccine.
Participants in the expanded cohort 
who are randomized to the 
combination BNT162b2 and 
BNT162b2 OMI groups will 
receive the doses from a single 
100-µg/mL vial of BNT162b2 
bivalent [Wild Type and Omicron 
(B.1.1.529)] preformulated vaccine 
suspension for injection. No 
dilution is required
To study a preformulated 
BNT162b2 bivalent mixture of 
BNT162b2 Wild Type and 
BNT162b2 OMI.

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Section # and Name
Description of Change
Brief Rationale
Section 10.11.6 – Study 
Intervention(s) and Concomitant 
Therapy for Substudy E
Updated text to clarify that the 
sentinel-cohort participants 
randomized to the combination 
BNT162b2 and BNT162b2 OMI 
groups will be administered a 
suspension containing a mixture of 
BNT162b2 Wild Type and 
BNT162b2 OMI prepared from 2 
separate diluted vials at the 
investigator site. Participants in the 
expanded cohort who are 
randomized to the combination 
BNT162b2 and BNT162b2 OMI 
groups will receive the 
preformulated bivalent mixture 
from a single vial (no dilution 
required).
To study a preformulated 
BNT162b2 bivalent mixture of 
BNT162b2 Wild Type and 
BNT162b2 OMI.
Section 10.11.6.1 – Study 
Intervention(s) Administered for 
Substudy E
Added a column to the table to 
account for the preformulated 
BNT162b2 bivalent [Wild Type 
and Omicron (B.1.1.529)] vaccine 
that will be administered to the 
expanded-enrollment participants 
from a preformulated single vial 
(no dilution required).
Clarified text in the footnotes to 
align with the study design section.
To study a preformulated 
BNT162b2 bivalent mixture of 
BNT162b2 Wild Type and 
BNT162b2 OMI.
Administrative change to clarify 
and align with the study design 
section.
Section 10.12.6.1 – Study 
Intervention(s) Administered for 
Substudy F
Clarified text in the footnotes to 
align with the study design section.
Administrative change to clarify 
and align with the study design 
section.
Amendment 6 (08 Feb 2022)
Overall Rationale for the Amendment:
The primary and secondary objectives and statistical parameters for Substudy D will be 
modified to include superiority analyses to align with regulatory requirements.
This amendment also includes updates to the inclusion criteria to both Substudy B and 
Substudy C to reduce the time period of the second dose of prior BNT162b2 to 5 months 
prior to randomization for all participants. Updates to inclusion criteria for Substudy D and 
Substudy E were made to increase the eligible population.

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Protocol Amendment Summary of Changes Table
Section # and Name
Description of Change
Brief Rationale
Section 1.1 – Synopsis, Substudy B 
Design
Updated text to clarify that 
participants may be enrolled if they 
completed a 2-dose primary series 
of BNT162b2 (30-µg doses) at 
least 5 months prior to 
randomization for all participants.
To align with regulatory feedback 
and current recommendations.
Section 1.1 – Synopsis, Substudy C 
Design
Updated text to clarify that 
participants may be enrolled if they 
completed a 2-dose primary series 
of BNT162b2 (30-µg doses) at 
least 5 months prior to 
randomization instead of 6 months 
prior for all participants.
To align with regulatory feedback 
and current recommendations.
Section 1.1 – Synopsis, Substudy D 
Design
Updated text to clarify that 
participants in Cohort 3 may 
receive their third dose of 
BNT162b2 OMI as early as 
5 months after their second dose.
Removed the statement that 
stratification by age will be 
managed by the IRT system to 
ensure a similar distribution of age 
strata across the 3 cohorts.
Updated text to clarify that 
participants in Cohort 1 will have 
completed a 2-dose primary series 
of BNT162b2 (30-µg doses), with 
their last dose 90 to 240 days prior 
to enrollment.
To align with regulatory feedback 
and current recommendations.
Text regarding stratification by age 
was removed as it is already 
included in the descriptions of the 
cohorts.
To increase the eligible population.
Section 1.1 – Synopsis, Substudy E 
Design
Updated text to state that 
participants who have received 
3 prior doses of BNT162b2 (30-µg 
doses), with the most recent dose 
being 5 to 12 months prior to 
randomization, will be enrolled. 
The previous prior BNT162b2 
window was 6 to 12 months.
To increase the eligible population.
Section 10.8.1.2 – Schema for 
Substudy B
Updated text to clarify that 
participants may be enrolled if they 
completed a 2-dose primary series 
of BNT162b2 (30-µg doses) at 
least 5 months prior to 
randomization for all participants.
To align with regulatory feedback 
and current recommendations.
Section 10.8.1.3 – Schedule of 
Activities for Substudy B
Updated text to clarify that 
participants may be enrolled if they 
completed a 2-dose primary series 
of BNT162b2 (30-µg doses) at 
least 5 months prior to 
randomization for all participants.
To align with regulatory feedback 
and current recommendations.

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Section # and Name
Description of Change
Brief Rationale
Section 10.8.2 – Rationale for 
Substudy B
Updated text to clarify that 
participants may be enrolled if they 
completed a 2-dose primary series 
of BNT162b2 (30-µg doses) at 
least 5 months prior to 
randomization for all participants.
To align with regulatory feedback 
and current recommendations.
Section 10.8.4 – Study Design for 
Substudy B
Updated text to clarify that 
participants may be enrolled if they 
completed a 2-dose primary series 
of BNT162b2 (30-µg doses) at 
least 5 months prior to 
randomization for all participants.
To align with regulatory feedback 
and current recommendations.
Section 10.8.5.1 – Inclusion 
Criteria for Substudy B
Updated text to clarify that 
participants may be enrolled if they 
completed a 2-dose primary series 
of BNT162b2 (30-µg doses) at 
least 150 days prior to Visit 201 for 
all participants. Inclusion criterion 
1 was combined into a single bullet 
as this new window applies to all 
age groups in Substudy B.
To align with regulatory feedback 
and current recommendations.
Section 10.8.8.3.1 – Substudy B 
Procedures, Visit 201
Updated text asking to confirm that
the participant has only received 2 
doses of BNT162b2 at least 5
months prior to randomization.
To align with regulatory feedback 
and current recommendations.
Section 10.9.1.2 – Schema for 
Substudy C
Updated text to clarify that 
participants may be enrolled if they 
completed a 2-dose primary series 
of BNT162b2 (30-µg doses) at 
least 5 months prior to 
randomization for all participants.
To align with regulatory feedback 
and current recommendations.
Section 10.9.1.3 – Schedule of 
Activities for Substudy C
Updated text to clarify that 
participants may be enrolled if they 
completed a 2-dose primary series 
of BNT162b2 (30-µg doses) at 
least 5 months prior to 
randomization for all participants.
To align with regulatory feedback 
and current recommendations.
Section 10.9.2 – Rationale for 
Substudy C
Updated text to clarify that 
participants may be enrolled if they 
completed a 2-dose primary series 
of BNT162b2 (30-µg doses) at 
least 5 months prior to 
randomization for all participants.
To align with regulatory feedback 
and current recommendations.
Section 10.9.3 – Objectives, 
Estimands, and Endpoints for 
Substudy C
Updated the control group for 
noninferiority to age-matched 
participants randomly selected 
from C4591001. 
To align with the removal of the 
requirement that participants 12 to 
17 years of age must have received 
2 prior doses of BNT162b2 in 
C4591001.

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Section # and Name
Description of Change
Brief Rationale
Section 10.9.4 – Study Design for 
Substudy C
Updated text to clarify that 
participants may be enrolled if they 
completed a 2-dose primary series 
of BNT162b2 (30-µg doses) at 
least 5 months prior to 
randomization instead of 6 months 
prior for all participants.
To align with regulatory feedback 
and current recommendations.
Section 10.9.5.1 – Inclusion 
Criteria for Substudy C
Updated text to clarify that 
participants may be enrolled if they 
completed a 2-dose primary series 
of BNT162b2 (30-µg doses) at 
least 150 days prior to Visit 301 for 
all participants.
Removed the requirement that 
participants 12 to 17 years of age 
must have received 2 prior doses of 
BNT162b2 in C4591001. 
To align with regulatory feedback 
and current recommendations.
To permit enrollment of 
participants who did not participant 
in C4591001.
Section 10.9.8.4.1 – Substudy C 
Procedures, Visit 301
Updated text asking to confirm the 
participant has only received 
2 doses of BNT162b2 at least 
5 months prior to randomization.
To align with regulatory feedback 
and current recommendations.
Section 10.9.9 – Statistical 
Considerations for Substudy C
Modified the statistical 
considerations including the 
hypothesis, general considerations, 
objectives, estimands, endpoints, 
and comparisons.
To align with the removal of the 
requirement that participants 12 to 
17 years of age must have received 
2 prior doses of BNT162b2 in 
C4591001.
Section 10.10.1.2.1 – Schema for 
Substudy D, Participants in Cohorts 
1 and 2
Updated text to clarify that Cohort
1 participants must have received 
2 doses of BNT162b2 before 
enrollment (3-8 months after last 
dose).
To increase the eligible population.
Section 10.10.1.2.2 – Schema for 
Substudy D, Participants in Cohort 
3
Added a footnote to clarify that 
participants in Cohort 3 may 
receive their third dose of 
BNT162b2 OMI as early as 
5 months after their second dose.
To align with regulatory feedback 
and current recommendations.
Section 10.10.1.3.1 – Schedule of 
Activities for Substudy D, Cohorts 
1 and 2
Added a row for the following 
procedure: Provide/ensure the 
participant has a nasal self-swab kit
and instructions on self-collection 
of nasal swabs.
Updated text to clarify that Cohort 
1 participants must have received 
2 doses of BNT162b2 before 
enrollment (3-8 months after last 
dose).
To provide clarification on 
expectations for site personnel 
regarding self-swabs.
To increase the eligible population.

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Section # and Name
Description of Change
Brief Rationale
Section 10.10.1.3.2 – Schedule of 
Activities for Substudy D, Cohort 3
Added footnote to clarify that 
participants in Cohort 3 may 
receive their third dose of 
BNT162b2 OMI as early as 
5 months after their second dose. 
Updated the early part of the Visit 
506 window to 150 days after 
Vaccination 2.
Added a row for the following 
procedure: Provide/ensure the 
participant has a nasal self-swab kit
and instructions on self-collection 
of nasal swabs.
To align with regulatory feedback 
and current recommendations.
To provide clarification on 
expectations for site personnel 
regarding self-swabs.
Section 10.10.2.1 – Study 
Rationale for Substudy D
Corrected “2 doses” to “3 doses” of 
BNT162b2 OMI.
This was an administrative change 
to correct a typo.
Section 10.10.3 – Objectives, 
Estimands, and Endpoints for 
Substudy D
Updated the primary and secondary 
objectives. Superiority added as a 
primary immunogenicity objective. 
Noninferiority and “super” 
superiority added as secondary 
immunogenicity objectives. 
Exploratory objectives and 
footnotes were modified. 
To align with regulatory 
requirements.
Section 10.10.4 – Study Design for 
Substudy D
Updated text to clarify that 
participants in Cohort 3 may 
receive their third dose of 
BNT162b2 OMI as early as 
5 months after their second dose.
Updated text to clarify that Cohort 
1 participants must have received 2 
prior doses of 30 µg BNT162b2,
with the second dose being 90 to 
240 days before Visit 401 (Day 1).
Removed the statement that 
stratification by age will be 
managed by the IRT system to 
ensure a similar distribution of age 
strata across the 3 cohorts.
To align with regulatory feedback 
and current recommendations.
To increase the eligible population.
Text regarding stratification by age 
was removed as it is already 
included in the descriptions of the 
cohorts.
Section 10.10.5.1 – Inclusion 
Criteria for Substudy D
Updated inclusion criteria for 
Cohort 1 participants to state that 
participants must have received 
2 prior doses of 30 µg BNT162b2,
with the second dose being 90 to 
240 days before Visit 401 (Day 1).
To increase the eligible population.

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Section # and Name
Description of Change
Brief Rationale
Section 10.10.8.6 –Substudy D 
Procedures
Added details regarding the self-
swabs to clarify that sites must 
provide/ensure the participant has a 
nasal self-swab kit and provide 
instructions on self-collection of 
nasal swabs.
To provide clarification on 
expectations for site personnel 
regarding self-swabs.
Section 10.10.6.1.1 –
Administration for Substudy D
Added the following text: 
Vaccination 3 may be administered 
as early as 5 months (150 days) 
after Vaccination 2.
To align with regulatory feedback 
and current recommendations.
Section 10.10.8.6.2 –
Administration of BNT162b2 OMI 
to COVID-19 Vaccine-Naïve 
Participants (Cohort 3) for 
Substudy D
Updated text to clarify that 
participants will receive 2 doses 
(primary series) of 
BNT162b2 OMI, separated by 
21 days, with a third dose 
approximately 5 months later.
Administrative change and to align 
with regulatory feedback and 
current recommendations.
Section 10.10.8.6.2.6 –
Administration of BNT162b2 OMI 
to COVID-19 Vaccine-Naïve 
Participants (Cohort 3), Visit 506 
for Substudy D
Updated text to clarify that 
Vaccination 3 may be administered 
as early as 5 months (150 days) 
after Vaccination 2.
To align with regulatory feedback 
and current recommendations.
Section 10.10.9 – Statistical 
Considerations for Substudy D
Updated the primary and secondary 
objectives to include superiority 
and “super” superiority. Additional 
changes were made to the statistical 
hypothesis, multiplicity adjustment, 
general considerations and 
comparisons.
To align with regulatory 
requirements.
Section 10.11.1.3 – Schedule of 
Activities for Substudy E
Added a row for the following 
procedure: Provide/ensure the 
participant has a nasal self-swab kit 
and instructions on self-collection 
of nasal swabs.
To provide clarification on 
expectations for site personnel 
regarding self-swabs.
Section 10.11.4 – Study Design for 
Substudy E 
Updated text to state that 
participants who have received 
3 prior doses of BNT162b2 (30-µg 
doses), with the most recent dose 
being 5 to 12 months prior to 
randomization, will be enrolled. 
The previous prior BNT162b2 
window was 6 to 12 months.
To increase the eligible population.
Section 10.11.5.1 – Inclusion 
Criteria for Substudy E
Updated inclusion criteria to state  
that participants who have received 
3 prior doses of 30 µg BNT162b2, 
with the third dose being 5 to 12 
months before Visit 601 (Day 1).
The previous prior BNT162b2 
window was 6 to 12 months.
To increase the eligible population.

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Section # and Name
Description of Change
Brief Rationale
Section 10.11.8.6 –Substudy E 
Procedures
Added details regarding the self-
swabs to clarify that sites must 
provide/ensure the participant has a 
nasal self-swab kit and provide 
instructions on self-collection of 
nasal swabs.
To provide clarification on 
expectations for site personnel 
regarding self-swabs.
Section 10.12.1.3 – Schedule of 
Activities for Substudy F
Added a row for the following 
procedure: Provide/ensure the 
participant has a nasal self-swab kit 
and instructions on self-collection 
of nasal swabs.
To provide clarification on 
expectations for site personnel 
regarding self-swabs.
Section 10.12.8.5 –Substudy F 
Procedures
Added details regarding the self-
swabs to clarify that sites must 
provide/ensure the participant has a 
nasal self-swab kit and provide 
instructions on self-collection of 
nasal swabs.
To provide clarification on 
expectations for site personnel 
regarding self-swabs.
Amendment 5 (20 Jan 2022)
Overall Rationale for the Amendment:
The SARS-CoV-2 variant B.1.1.529, also known as Omicron, is currently the dominant 
variant in many countries and within the US is responsible for 95.4% of sequenced 
COVID-19 cases. Current data note that the vaccine effectiveness against hospitalization is 
88% (78%-93%) for Omicron after 3 doses of vaccine.  However, even with 3 vaccine doses, 
neutralization against the Omicron variant was lower (by a factor of 4) than that against the 
Delta variant. The addition of a higher-dose booster may improve protection, particularly in 
older individuals, with increased longevity of an immune response, provided it has a 
tolerable safety profile. Therefore, Substudies E and F have been designed to evaluate 
high-dose BNT162b2 OMI (60 µg), high-dose BNT162b2 (60 µg), and a high-dose 
combination of BNT162b2 OMI and BNT162b2 (30 µg of each) compared to 
BNT162b2 OMI 30 µg, BNT162b2 30 µg, and a combination of BNT162b2 OMI and 
BNT162b2 (15 µg of each), given as a fourth dose.
This amendment also incorporates the addition of a BNT162b2 30-µg dose group (given as a 
third dose) to Cohort 1 in Substudy D. In this group, 205 participants will be enrolled to 
provide a contemporaneous third-dose control group for analyses and comparisons.

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Protocol Amendment Summary of Changes Table
Section # and Name
Description of Change
Brief Rationale
Sections 1 through 9
Cross-reference to sections within 
Substudies E and F added where 
required and throughout.
Substudies E and F have been 
added to evaluate high-dose 
BNT162b2 OMI, high-dose 
BNT162b2, and a high-dose 
combination of BNT162b2 OMI 
and BNT162b2 given as a fourth 
dose.
Section 1.1 – Synopsis, Substudy D 
Design
Addition of description of Group 
2b (1 dose of BNT162b2), updated 
total number of participants to 
1420, updated Cohort 1 participant 
total to 615, and updated the table 
to include Group 2b.
Group 2b has been added to 
Substudy D to provide a 
contemporaneous third-dose 
control group for analyses and 
comparisons.
Section 1.1 – Synopsis, Substudy D 
Number of Participants
Updated the number of participants 
to 615 for Cohort 1.
Group 2b has been added to 
Substudy D to provide a 
contemporaneous third-dose 
control group for analyses and 
comparisons.
Section 1.1 – Synopsis, Overall 
Design
Addition of design of Substudies E 
and F, number of participants, and 
specified that an IRC will be used 
for Substudies E and F.
Substudies E and F have been 
added to evaluate high-dose 
BNT162b2 OMI, high-dose 
BNT162b2, and a high-dose 
combination of BNT162b2 OMI 
and BNT162b2 given as a fourth 
dose.
Section 1.1 – Synopsis, Substudies 
E and F Number of Participants 
Addition of Substudies E and F, 
number of participants.
Substudies E and F have been 
added to evaluate high-dose 
BNT162b2 OMI, high-dose 
BNT162b2, and a high-dose 
combination of BNT162b2 OMI 
and BNT162b2 given as a fourth
dose.
Section 1.1 – Synopsis, Data 
Monitoring Committee or Other 
Independent Data Monitoring 
Committee
Addition of DMC and IRC details 
for Substudies E and F.
Substudies E and F have been 
added to evaluate high-dose 
BNT162b2 OMI, high-dose 
BNT162b2, and a high-dose 
combination of BNT162b2 OMI 
and BNT162b2 given as a fourth
dose.
Section 2.2 – Background
Addition of Substudies E and F.
Substudies E and F have been 
added to evaluate high-dose 
BNT162b2 OMI, high-dose 
BNT162b2, and a high-dose 
combination of BNT162b2 OMI 
and BNT162b2 given as a fourth
dose.

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Section # and Name
Description of Change
Brief Rationale
Section 2.3 – Risk Assessment
Added additional mitigations for 
Substudies E and F and updated 
existing mitigations to align with 
the study designs for Substudies D, 
E, and F.
Substudies E and F have a higher 
dose level of study vaccine, and 
additional mitigations have been 
put in place. Existing mitigations 
were updated to account for the 
dosing schedules for Substudies D, 
E, and F.
Section 4.3 – Justification for Dose
Addition of justification for dose 
levels in Substudies E and F.
Substudies E and F have been 
added to evaluate high-dose 
BNT162b2 OMI, high-dose 
BNT162b2, and a high-dose 
combination of BNT162b2 OMI 
and BNT162b2 given as a fourth
dose.
Section 8.3.1 – Time Period and 
Frequency for Collecting AE and 
SAE Information – Substudy D
Addition of Group 2b. 
Group 2b has been added to 
Substudy D to provide a 
contemporaneous third-dose 
control group for analyses and 
comparisons.
Section 8.3.1 – Time Period and 
Frequency for Collecting AE and 
SAE Information – Substudies E 
and F
Confirmation of the safety 
reporting time periods for 
Substudies E and F.
Substudies E and F have been 
added to evaluate high-dose 
BNT162b2 OMI, high-dose 
BNT162b2, and a high-dose 
combination of BNT162b2 OMI 
and BNT162b2 given as a fourth 
dose.
Sections 10.7.9.4 – Interim 
Analysis and 10.7.9.4.1 – Analysis 
Timing for Substudy A
Removed efficacy and safety 
analysis when all participants 
completed blinded follow-up and 
added that additional analyses may 
be conducted if required for 
regulatory purposes.  
Removed the requirement to 
conduct interim analyses every 
2 months.
This will allow the team to deliver 
the analysis if required for 
regulatory purposes.
Interim analyses are no longer 
needed every 2 months as Substudy 
A has been unblinded.
Section 10.9.6.2.2 – Blinding of the 
Sponsor for Substudy C
Updated timing for unblinding of 
the participant to 3 months after 
study vaccination administration.
This will allow for collection of 
blinded safety data up to 3 months 
after study vaccine administration.
Section 10.9.8.4.3 – Study 
Assessments and Procedures, Visit 
303 for Substudy C
Removed text stating that the 
participant would be unblinded at 
the 1-month after booster 
vaccination visit. 
Participants will now be unblinded 
at 3 months after study vaccine 
administration.
Section 10.9.9.5 – Sample Size 
Determination for Substudy C
Updated the assumed response rate 
for each comparative group at the 
comparative time point from 90% 
to 95%. 
This was a typo in the previous 
version of the protocol.
Section 10.10.1.2.1 Schema for 
Cohorts 1 and 2 in Substudy D
Addition of the PBMC and HLA 
sample collections.
To provide further clarity on all 
blood sample collections to be 
performed during the study.
Section 10.10.1.2.2 Schema for 
Cohort 3 in Substudy D
Addition of the PBMC and HLA 
sample collections.
To provide further clarity on all 
blood sample collections to be 
performed during the study.

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Section # and Name
Description of Change
Brief Rationale
Section 10.10.1.2.1 – Participants 
in Cohorts 1 and 2 for Substudy D
Addition of Group 2b.
Group 2b has been added to 
Substudy D to provide a 
contemporaneous third-dose 
control group for analyses and 
comparisons.
Section 10.10.2.1 – Study 
Rationale for Substudy D
Addition of description of Group 
2b (1 dose of BNT162b2).
Group 2b has been added to 
Substudy D to provide a 
contemporaneous third-dose 
control group for analyses and 
comparisons.
Section 10.10.3 – Objectives, 
Estimands, and Endpoints for 
Substudy D
Addition of objectives, estimands, 
and endpoints for Group 2b.
Group 2b has been added to 
Substudy D to provide a 
contemporaneous third-dose 
control group for analyses and 
comparisons.
Section 10.10.4.1 – Overall Design 
for Substudy D
Addition of description of Group 
2b (1 dose of BNT162b2), updated 
total number of participants to 
1420, updated Cohort 1 participant 
total to 615, and updated the table 
to include Group 2b.
Group 2b has been added to 
Substudy D to provide a 
contemporaneous third-dose 
control group for analyses and 
comparisons.
Section 10.10.6.2.2 – Blinding of 
the Sponsor for Substudy D
Updated timing of participant 
unblinding for Cohort 2 from Visit 
402 to Visit 404 and added that
Cohort 1 (Groups 1 and 2b) may 
also be unblinded at this time.
This will allow for collection of 
blinded safety data up to 3 months 
after study vaccine administration. 
Cohort 1 was added to account for 
Group 2b being added.
Section 10.10.8.2 –
Immunogenicity for Substudy D
Addition of text clarifying that B-
cell responses will also be tested.
Testing for B-cell responses was 
planned but was erroneously not 
specified in the previous protocol 
version.
Section 10.10.8.6.1.2 – Visit 402 
for Substudy D
Moved the text from Visit 402 to 
Visit 404 describing unblinding of 
participants in Cohort 2 and added 
that Cohort 1 (Groups 1 and 2b) 
may also be unblinded at this time.
This will allow for collection of 
blinded safety data up to 3 months 
after study vaccine administration. 
Cohort 1 was added to account for 
Group 2b being added.
Section 10.10.9 – Statistical 
Considerations for Substudy D
Addition of statistical 
considerations throughout this 
section related to Group 2b.
Group 2b has been added to 
Substudy D to provide a 
contemporaneous third-dose 
control group for analyses and 
comparisons.
Section 10.10.9.5 – Sample Size 
Determination for Substudy D
Updated the assumed response rate 
for each comparative group at the 
comparative time point from 90% 
to 95%. 
This was a typographical error in 
the previous version of the 
protocol.
Section 10.11 – Appendix 11: 
Substudy E
Addition of Substudy E.
Substudy E has been added to 
evaluate high-dose 
BNT162b2 OMI, high-dose 
BNT162b2, and a high-dose 
combination of BNT162b2 OMI 
and BNT162b2 given as a fourth 
dose.

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Section # and Name
Description of Change
Brief Rationale
Section 10.12 – Appendix 12: 
Substudy F
Addition of Substudy F.
Substudy F has been added to 
evaluate high-dose 
BNT162b2 OMI, high-dose 
BNT162b2, and a high-dose 
combination of BNT162b2 OMI 
and BNT162b2 given as a fourth 
dose.
Amendment 4 (22 Dec 2021)
Overall Rationale for the Amendment:

On 26 November 2021 and 30 November 2021, the WHO and the US, respectively, 
classified a new SARS-CoV-2 variant, B.1.1.529, a VOC, and named it Omicron. Pfizer 
has developed a new vaccine, BNT162b2 OMICRON (B.1.1.529) (referred to throughout 
the protocol as BNT162b2 OMI), which is a BNT162b2 RNA-LNP vaccine utilizing 
modified RNA and encoding the P2 S containing Omicron B.1.1.529 variant–specific 
mutations. Substudy D has been designed to assess the safety, tolerability, and 
immunogenicity of BNT162b2 OMI.
Section # and Name
Description of Change
Brief Rationale
Sections 1 through 9
Cross-reference to sections within Substudy 
D added where required throughout
Substudy D has been added because 
of the emergence of the new VOC, 
Omicron
Section 1.1 - Synopsis, 
Rationale
Addition of details on current VOCs
Substudy D has been added because 
of the emergence of the new VOC, 
Omicron
Section 1.1 - Synopsis, 
Overall Design
Addition of design of Substudy D and 
number of participants
Substudy D has been added because 
of the emergence of the new VOC, 
Omicron
Section 1.1 - Synopsis, 
Substudy B Design
Updated the inclusion window for 12- to 
17-year-olds from 12 months to 8 months 
after completion of a 2-dose primary series 
of BNT162b2 (30-µg doses) prior to 
randomization in this substudy
This change has been implemented to 
enable these participants to enroll in 
this substudy sooner and because of 
the emergence of the new VOC, 
Omicron
Section 1.1 - Synopsis,  
Substudy C Design
Updated the inclusion window for 12- to 
17-year-olds from 12 months to 8 months 
after completion of a 2-dose primary series 
of BNT162b2 (30-µg doses) prior to 
randomization in this substudy
This change has been implemented to 
enable these participants to enroll in 
this substudy sooner and because of 
the emergence of the new VOC, 
Omicron
Section 2.2 –
Background
Addition of Substudy D
Substudy D has been added because 
of the emergence of the new VOC, 
Omicron
Section 2.2.1 -
Clinical Overview
Details of EUA for a booster dose in the 
US, EU, and other countries as well as 
details of the interim safety and efficacy 
analysis results for C4591031 Substudy A
This change has been implemented to 
reflect current recommendations and 
to provide details of the recent  

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Section # and Name
Description of Change
Brief Rationale
interim safety and efficacy analysis 
results for C4591031 Substudy A
Section 6.6 - Continued 
Access to Study 
Intervention After the 
End of the Study
Confirmation that if the 10-μg dose is found 
to have a suboptimal immune response, as 
determined by the sponsor, this group will 
be offered a single 30-μg dose
To ensure that participants are 
vaccinated with the currently 
approved dose and details can be 
entered on their vaccination records 
(eg, CDC card)
Section 8.1.1 -
Biological Samples
Added detail that no testing of the 
participants’ genetic testing is performed, 
with the exception of those participants who 
have provided specific consent to genetic 
testing samples of the blood for PBMC 
isolation and HLA typing
Inclusion of PBMC and HLA testing 
in Substudy D
Section 8.2.4.2 -
Local Reactions
Confirming that a reaction classified as 
Grade 4 should be reported as an AE in the 
CRF
A confirmed Grade 4 reaction should 
be reported as an AE in the CRF
Section 8.3.1 - Time 
Period and Frequency for 
Collecting AE and SAE 
Information
Confirmation of the safety reporting time 
periods for Substudy D
Substudy D has been added because 
of the emergence of the new VOC, 
Omicron
Section 10.7.8.5.8.3 -
Visit 103
Removal of the request to contact the site 
for any medically attended events or 
respiratory symptoms after the final visit
To remove bullets entered in error
Section 10.8.1.2 -
Schema
Updated the inclusion window for 12- to 
17-year-olds from 12 months to 8 months 
after completion of a 2-dose primary series 
of BNT162b2 (30-µg doses) prior to 
randomization in this substudy
This change has been implemented to 
enable these participants to enroll in 
this substudy sooner and because of 
the emergence of the new VOC, 
Omicron
Section 10.8.1.3 -
Schedule of Activities 
for Substudy B
Updated the inclusion window for 12- to 
17-year-olds from 12 months to 8 months 
after completion of a 2-dose primary series 
of BNT162b2 (30-µg doses) prior to 
randomization in this substudy
This change has been implemented to 
enable these participants to enroll in 
this substudy sooner and because of 
the emergence of the new VOC, 
Omicron
Section 10.8.2.1 -
Study Rationale
Updated the inclusion window for 12- to 
17-year-olds from 12 months to 8 months 
after completion of a 2-dose primary series 
of BNT162b2 (30-µg doses) prior to 
randomization in this substudy
This change has been implemented to 
enable these participants to enroll in 
this substudy sooner and because of 
the emergence of the new VOC, 
Omicron
Section 10.8.4.1 -
Overall Design
Updated the inclusion window for 12- to 
17-year-olds from 12 months to 8 months 
after completion of a 2-dose primary series 
of BNT162b2 (30-µg doses) prior to 
randomization in this substudy
This change has been implemented to 
enable these participants to enroll in 
this substudy sooner and because of 
the emergence of the new VOC, 
Omicron
Section 10.8.5.1 -
Inclusion Criteria
Updated the inclusion window for 12- to 
17-year-olds from 365 days to 240 days 
after completion of a 2-dose primary series 
of BNT162b2 (30-µg doses) prior to 
randomization in this substudy
This change has been implemented to 
enable these participants to enroll in 
this substudy sooner and because of 
the emergence of the new VOC, 
Omicron

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Section # and Name
Description of Change
Brief Rationale
Section 10.8.8.3.1 -
Visit 201 – Vaccination 
(Day 1)
Updated the inclusion window for 12- to 
17-year-olds from 12 months to 8 months 
after completion of a 2-dose primary series 
of BNT162b2 (30-µg doses) prior to 
randomization in this substudy
This change has been implemented to 
enable these participants to enroll in 
this substudy sooner and because of 
the emergence of the new VOC, 
Omicron
Sections 10.8.8.3.7 and 
10.9.8.5.1- Unscheduled 
Visit for a Grade 3 or 
Suspected Grade 4 
Reaction
Deletion of the temperature reference in the 
sections to ensure consistency with 
Section 8.2.4.4
To ensure consistency within the 
protocol
Section 10.9.1.2 -
Schema
Updated the inclusion window for 12- to 
17-year-olds from 12 months to 8 months 
after completion of a 2-dose primary series 
of BNT162b2 (30-µg doses) prior to 
randomization in this substudy
This change has been implemented to 
enable these participants to enroll in 
this substudy sooner and because of 
the emergence of the new VOC, 
Omicron
Section 10.9.1.3 -
Schedule of Activities 
for Substudy C
Updated the inclusion window for 12- to 
17-year-olds from 12 months to 8 months 
after completion of a 2-dose primary series 
of BNT162b2 (30-µg doses) prior to 
randomization in this substudy
This change has been implemented to 
enable these participants to enroll in 
this substudy sooner and because of 
the emergence of the new VOC, 
Omicron
Section 10.9.2.1 -
Study Rationale
Updated the inclusion window for 12- to 
17-year-olds from 12 months to 8 months 
after completion of a 2-dose primary series 
of BNT162b2 (30-µg doses) prior to 
randomization in this substudy
This change has been implemented to 
enable these participants to enroll in 
this substudy sooner and because of 
the emergence of the new VOC, 
Omicron
Section 10.9.3 -
Objectives, Estimands, 
and Endpoints
Added an exploratory objective to describe 
the immune response to VOCs with an 
endpoint of  SARS-CoV-2 neutralizing 
titers for VOCs
To examine the breadth of 
neutralizing titers against VOCs
Section 10.9.4.1 -
Overall Design
Updated the inclusion window for 12- to 
17-year-olds from 12 months to 8 months 
after completion of a 2-dose primary series 
of BNT162b2 (30-µg doses) prior to 
randomization in this substudy
This change has been implemented to 
enable these participants to enroll in 
this substudy sooner and because of 
the emergence of the new VOC, 
Omicron

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Section # and Name
Description of Change
Brief Rationale
Section 10.9.5.1 -
Inclusion Criteria
Updated the inclusion window for 12- to 
17-year-olds from 365 days to 240 days 
after completion of a 2-dose primary series 
of BNT162b2 (30-µg doses) prior to 
randomization in this substudy
This change has been implemented to 
enable these participants to enroll in 
this substudy sooner and because of 
the emergence of the new VOC, 
Omicron
Section 10.9.8.4.1 -
Visit 301 – Vaccination 
(Day 1)
Updated the inclusion window for 12- to 
17-year-olds from 12 months to 8 months 
after completion of a 2-dose primary series 
of BNT162b2 (30-µg doses) prior to 
randomization in this substudy
This change has been implemented to 
enable these participants to enroll in 
this substudy sooner and because of 
the emergence of the new VOC, 
Omicron
Section 10.9.6.2.2 -
Blinding of the Sponsor
Clarification that once a participant has  
completed their 1-month visit, they may be 
unblinded to confirm the dose of BNT162b2 
received. The study team will also become 
unblinded to the participant’s original study 
intervention allocation at this time
If the 10-µg dose is found to have a 
suboptimal immune response, as 
determined by the sponsor, this group 
will be offered a single 30-μg dose to 
ensure that the participant is 
vaccinated with the currently 
approved dose and details can be 
entered on their vaccination records 
(eg, CDC card)
Section 10.9.8.4.3 -
Visit 303
Clarification that once a participant has  
completed their 1-month visit, they may be 
unblinded to confirm the dose of BNT162b2 
received. The study team will also become 
unblinded to the participant’s original study 
intervention allocation at this time
If the 10-µg dose is found to have a 
suboptimal immune response, as 
determined by the sponsor, this group 
will be offered a single 30-µg dose to 
ensure that the participant is 
vaccinated with the currently 
approved dose and details can be 
entered on their vaccination records 
(eg, CDC card)
Section 10.9.8.5 -
Additional Procedures 
for Monitoring of 
Potential Myocarditis or 
Pericarditis
Deletion of reference to troponin blood 
samples collected during the study 
These samples are not collected as 
part of Substudy C 
Section 10.9.9.3.4 -
Exploratory Endpoint(s) 
Analysis
Addition of an exploratory immunogenicity  
objective
To examine the breadth of 
neutralizing titers against VOCs in 
the 2 dose levels
Section 10.10 -
Substudy D
Addition of Substudy D
Newly included substudy
Amendment 3 (28 Oct 2021)
Overall Rationale for the Amendment:

Very rare cases of myocarditis and pericarditis have been reported following vaccination 
with mRNA COVID-19 vaccines. Substudy B is added to assess the safety and 
tolerability of a booster (third) dose of BNT162b2 through the potential analysis of serum 
troponin levels.

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
Substudy C is added to evaluate the safety, tolerability, and immunogenicity of a booster 
(third) dose of BNT162b2 at 10 µg and at 30 µg. The key objective of the study is to 
demonstrate that the immune response induced by a booster (third) dose of BNT162b2 at 
a 10-µg dose is noninferior to the immune response elicited 1 month after the second 
dose of BNT162b2 at 30 µg (ie, having completed a 2-dose primary series of BNT162b2 
[30-µg doses]).
Section # and Name
Description of Change
Brief Rationale
Sections 1 through
Section 9
Cross-reference to sections within 
Substudy B and Substudy C added where 
required throughout
Substudy B and Substudy C have 
been added in response to 
commitments made to CBER
Section 1.1 - Synopsis
Addition of design of Substudy B and 
Substudy C, number of participants, and use 
of a DMC (Substudy C only)
Substudy B and Substudy C have 
been added in response to 
commitments made to CBER
Section 2 - Introduction 
and Section 2.2 -
Background
Addition of text reporting that BNT162b2 
has been fully licensed for use in 
individuals 16 years of age and above in the 
US as of 23 Aug 2021
This change has been implemented to 
reflect current recommendations
Section 2.2 -
Background
Addition of Substudy B and Substudy C
Substudy B and Substudy C have 
been added in response to 
commitments made to CBER
Sections 5.1 and 5.2 -
Inclusion and Exclusion 
Criteria
Addition of inclusion and exclusion criteria 
specific to Substudy B and Substudy C
Substudy B and Substudy C have 
been added in response to 
commitments made to CBER
Section 7.2 -
Participation 
Discontinuation/
Withdrawal From Study
Confirmation that receipt of a nonstudy 
COVID vaccine during study participation 
will result in study withdrawal
This update was implemented to 
clarify participant withdrawal criteria
Section 7.2.1 -
Withdrawal of Consent
Addition of text to confirm that if a 
participant wishes to receive a COVID-19 
vaccine outside of the study, he or she may 
request to know which study intervention he 
or she received without needing to 
reconsent
This update was implemented to 
allow participants to be unblinded if 
they want to receive a COVID-19 
vaccine outside of the study  
Section 8.2.4 - Electronic 
Diary - Applicable Only 
to Substudy B and 
Substudy C
Addition of details for reactogenicity 
e-diary use
This section was added to describe 
the use of a reactogenicity e-diary for 
substudies that will utilize one
Section 8.3.1 - Time 
Period and Frequency for 
Collecting AE and SAE 
Information
Confirmation of the safety reporting time 
periods for Substudy B and Substudy C
Substudy B and Substudy C have 
been added in response to 
commitments made to CBER
Section 8.3.5.1 -
Exposure During 
Pregnancy
Confirmed that any pregnancy that occurs 
28 days after the last dose of study 
intervention will not be considered EDP for 
this study
This change has been implemented  
to align with contraception 
requirements
Section 10.8 -
Substudy B
Addition of Substudy B
Newly included substudy
Section 10.9 -
Substudy C
Addition of Substudy C
Newly included substudy

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Amendment 2 (27 Aug 2021)
Overall Rationale for the Amendment: 

Addition of procedures for monitoring potential myocarditis or pericarditis in response to 
commitments made to CBER and administrative updates. 

Addition of wording that participants randomized to receive placebo at the booster dose 
vaccination visit may be offered the opportunity to receive BNT162b2 at a determined 
time frame at the discretion of the sponsor.
Section # and Name
Description of Change
Brief Rationale
Section 1.1 – Synopsis
Addition of wording on the timing of 
providing booster doses to placebo 
participants
This update was implemented to 
clarify the timing of booster 
vaccination for placebo participants
Section 2.3.1 – Risk 
Assessment
Addition of myocarditis and pericarditis
This update has been implemented in 
response to commitments made to 
CBER
Section 5 – Study 
Population
Addition of wording on diversity of 
recruitment
This addition was implemented for 
the collection of race and ethnicity 
data in prescreeners to reflect the 
enrollment of a diverse participant 
population
Section 5.2 – Exclusion 
Criteria
Exclusion criterion 13 edited to change the 
exclusion timeframe from the duration of 
study participation to within 28 days of 
confirmed receipt of BNT162b2
This criterion was changed to allow 
study participants to enroll in other 
clinical trials before the end of their
study participation
Section 8.2.5–
Pregnancy Testing
Clarified the timing of pregnancy tests
This update addresses discrepancies 
with SoA
Section 8.3.8 – Adverse 
Events of Special 
Interest
Addition of myocarditis and pericarditis 
This update has been implemented in 
response to commitments made to 
CBER
Section 10.1.3 –
Informed Consent 
Process
Clarified that assent must be obtained when 
the participant has the capacity to provide 
assent
This update has been made to ensure 
compliance with IRB./ECs
Section 10.7.1.3.1 –
Administration of 
BNT162b2 to Those 
Originally Assigned to 
Placebo 
Addition of wording on the timing of 
providing booster doses to placebo 
participants
This update was implemented to 
clarify the timing of booster 
vaccination for placebo participants
Section 10.7.4.1 –
Overall Design
Addition of wording on the timing of 
providing booster doses to placebo 
participants
This update was implemented to 
clarify the timing of booster 
vaccination for placebo participants
Section 10.7.6.2.1 –
Blinding of Site 
Personnel
Addition of wording on unblinding 
decisions
This addition was implemented to 
allow the sponsor to be unblinded 
outside of the interim analyses
Section 10.7.6.2.2 –
Blinding of the Sponsor
Addition of wording on unblinding 
decisions
This addition was implemented to 
allow the sponsor to be unblinded 
outside of the interim analyses

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Section # and Name
Description of Change
Brief Rationale
Section 10.7.8.5 – Study 
Procedures
Addition of a procedure to any visit that 
occurs sooner than 1 month after any 
vaccination
This update has been implemented in 
response to commitments made to 
CBER
Section 10.7.8.5.1 –
Visit 1 – Booster 
Vaccination (Day 1)
Clarified wording on site staff roles in 
relation to randomization and study 
intervention allocation number assignment 
This update has been made to ensure 
the blind is maintained by the 
investigator site staff
Section 10.7.8.5.8 –
Procedures for
Administration of 
BNT162b2 to Those 
Originally Assigned to 
Placebo
Addition of wording on the timing of 
providing booster doses to placebo 
participants
This update was implemented to 
clarify the timing of booster 
vaccination for placebo participants
Section 10.7.8.5.9 –
Additional Procedures 
for Monitoring of 
Potential Myocarditis or 
Pericarditis
Addition of an unplanned visit to capture 
data pertaining to myocarditis and 
pericarditis
This visit has been implemented in 
response to commitments made to 
CBER
Section 10.8 – Appendix 
8: Protocol Amendment 
History
Addition of Appendix 8 to include the 
protocol amendment history, and moved the 
Protocol Amendment Summary of Changes 
Table for protocol amendment 1 from the 
beginning of the document to this new 
section
This update has been made to ensure 
only the latest Protocol Amendment 
Summary of Changes Table for the 
current amendment is located directly 
before the table of contents
Amendment 1 (27 May 2021)
Overall Rationale for the Amendment: Correction to exclusion criterion and administrative 
update.
Section # and Name
Description of Change
Brief Rationale
5.2. Exclusion Criteria
Removal of exclusion criterion 9: Previous 
participation in other studies involving 
study intervention containing LNPs.
Included in the original protocol in 
error. C4591031 Substudy A aims to 
enroll participants having previously 
received BNT162b2 in Study 
C4591001.
5.2. Exclusion Criteria
Addition of new exclusion criterion 
(Number 9) to exclude participants having 
previously received a COVID-19 vaccine 
other than BNT162b2.
To exclude participants who have 
received anything more than 2 doses 
of only BNT162b2 COVID-19 
vaccine.
10.7.4.1. Overall Design
Update to cutoff values for age strata from 
≥16 to <55 and ≥55 years of age to ≥16 to 
55 and >55 years of age.
To ensure the age strata match those 
used in Study C4591001.
10.7.9.5. Sample Size 
Determination
Update to the expected number of cases in 
Table 1 from 97 to 98 at 7 days to 6 months 
if nonboosted and IR0 = 0.14/pyr.
To address prior rounding error.

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10.14. Appendix 14: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
2019-nCoV
novel coronavirus 2019
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BCR
B-cell receptor
-hCG
beta-human chorionic gonadotropin
BNT162b2 OMI
BNT162b2 OMICRON (B.1.1.529)
CBER
Center for Biologics Evaluation and Research 
CDC
Centers for Disease Control and Prevention
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CT
computed tomography
DBP
diastolic blood pressure
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
E1, E2, E3, E4
Estimand 1, Estimand 2, Estimand 3, Estimand 4
e-diary
electronic diary
EC
ethics committee
ECC
emergency contact card
ECG
electrocardiogram
ECMO
extracorporeal membrane oxygenation
eCRF
electronic case report form
EDB
exposure during breastfeeding
EDP
exposure during pregnancy
EMA
European Medicines Agency
EU
European Union
EUA
emergency use authorization
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration

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Abbreviation
Term
FiO2
fraction of inspired oxygen
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GMFR
geometric mean fold rise
GMR
geometric mean ratio
GMT
geometric mean titer
HBe
hepatitis B e
HBeAg
hepatitis B e antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HR
heart rate
HRT
hormone replacement therapy
IB
investigator’s brochure
ICD
informed consent document
ICH
International Council for Harmonisation
ICU
intensive care unit
ID
identification
IgA
Immunoglobulin A
IgG
immunoglobulin G
IMP
investigational medicinal product
IND
investigational new drug
INR
international normalized ratio
IP manual
investigational product manual
IPAL
Investigational Product Accountability Log
IRB
institutional review board
IRC 
independent review committee
IRT
interactive response technology
IWR
interactive Web-based response
LFT
liver function test
LLOQ
lower limit of quantitation
LNP
lipid nanoparticle
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare Products Regulatory Agency
mITT
modified intent-to-treat
modRNA
nucleoside-modified messenger ribonucleic acid
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid

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Abbreviation
Term
N
SARS-CoV-2 nucleoprotein
N/A
not applicable
NAAT
nucleic acid amplification test 
NIMP
noninvestigational medicinal product
OMI
Omicron (ie, in BNT162b2 OMI)
P2 S
SARS-CoV-2 full-length, P2 mutant, prefusion spike glycoprotein
PACL
protocol administrative change letter
PaO2
partial pressure of oxygen, arterial
PBMC
peripheral blood mononuclear cell
PI
principal investigator
PPE
personal protective equipment
PT
prothrombin time
QTL
quality tolerance limit
RBD
receptor-binding domain
RCDC
reverse cumulative distribution curve
RNA
ribonucleic acid
RR
respiratory rate
RSV
respiratory syncytial virus
RT-PCR
reverse transcription–polymerase chain reaction
S
spike protein
S1
spike protein S1 subunit
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SBP
systolic blood pressure
SoA
schedule of activities
SOP
standard operating procedure
SpO2
oxygen saturation as measured by pulse oximetry
SRSD
single reference safety document
SSD
Substudy D
SUSAR
suspected unexpected serious adverse reaction
TBili
total bilirubin
TCR
T-cell receptor
UK
United Kingdom
ULN
upper limit of normal
US
United States
VAED
vaccine-associated enhanced disease
VE
vaccine efficacy
VOC
variant of concern
WHO
World Health Organization
WOCBP
woman/women of childbearing potential

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10.15. Appendix 15: Criteria for Allowing Inclusion of Participants With Chronic 
Stable HIV, HCV, or HBV Infection
Potential participants with chronic stable HIV, HCV, or HBV infection may be considered 
for inclusion if they fulfill the following respective criteria:
Known HIV infection

Confirmed stable HIV disease defined as documented viral load <50 copies/mL and CD4 
count >200 cells/mm3 within 6 months before enrollment, and on stable antiretroviral
therapy for at least 6 months.
Known HCV infection

History of chronic HCV with evidence of sustained virological response (defined as 
undetectable HCV RNA) for ≥12 weeks following HCV treatment or without evidence of 
HCV RNA viremia (undetectable HCV viral load).
Known HBV infection
Confirmed inactive chronic HBV infection, defined as HBsAg present for ≥6 months and the 
following:

HBeAg-negative, anti-HBe–positive;

Serum HBV DNA <2000 IU/mL;

Persistently normal ALT and/or AST levels;

In those who have had a liver biopsy performed, findings that confirm the absence of 
significant necroinflammation.

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10.16. Appendix 16: Genetics
Use/Analysis of DNA and/or RNA

Genetic variation may impact a participant’s response to study intervention, as well as 
susceptibility to and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA and/or RNA
analysis.

The results of genetic analyses may be reported in a CSR or in a separate study summary, 
or may be used for internal decision making without being included in a study report.

The sponsor will store the DNA and/or RNA samples in a secure storage space with 
adequate measures to protect confidentiality.

The samples will be retained as indicated:

Samples for specified genetic analysis (see Section 10.10.8.5 and Section 10.11.8.5) 
will be stored for up to 15 years or other period as per local requirements.

Samples for genetic research will be labeled with a code.  The key between the code and 
the participant’s personally identifying information (eg, name, address) will be held 
securely at the study site.

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