A STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND IMMUNOGENICITY OF COMBINED VACCINE CANDIDATE(S) AGAINST INFECTIOUS RESPIRATORY ILLNESSES, INCLUDING COVID-19 AND RSV, IN HEALTHY INDIVIDUALS
Phase: PHASE2
Conditions: Healthy Participants
Sponsor: Pfizer

PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 1
A STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND 
IMMUNOGENICITY OF COMBINED VACCINE CANDIDATE(S) AGAINST
INFECTIOUS RESPIRATORY ILLNESSES, INCLUDING COVID-19 AND RSV, IN 
HEALTHY INDIVIDUALS
Study Intervention Number:
PF-07960613
Study Intervention Name:
Combination COVID-19 and RSV Vaccine
US IND Number:
29521
EU CT Number:
NA
ClinicalTrials.gov ID:
NCT05886777
Pediatric Investigational Plan Number:
NA
Protocol Number:
C5481001
Phase:
1/2
Sponsor Legal Address:
Pfizer Inc.
66 Hudson Boulevard East
New York, NY 10001
Brief Title:
A Study to Learn About Combined Vaccine(s) Against Infectious Respiratory Illnesses,
Including COVID-19 and RSV
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.
090177e19fb526e9\Approved\Approved On: 19-Jan-2024 09:51 (GMT)

PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 2
Document History
Document 
Version Date
Amendment 2
18 January 2024
Amendment 1
19 October 2023
Original protocol
22 April 2023
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any protocol administrative change 
letter(s).
Protocol Amendment Summary of Changes Table
Amendment 2 (18 January 2024)
Overall Rationale for the Amendment: 
Following a review of the needs of the overall development program, Substudy B was
removed from the protocol.
Description of Change
Brief Rationale
Section # and Name
Substantial Modification(s)
Removed Substudy B
Following a review of 
the needs of the overall 
development program,
Substudy B was
removed from the 
protocol
Section 10.12 Appendix 12: 
Substudy B (Phase 1/2)
Nonsubstantial Modification(s)
Removed text in the 
body of protocol that 
was specific to 
Substudy B
Following a review of 
the needs of the overall 
development program,
Substudy B was
removed from the 
protocol
Section 1.1 Synopsis
Section 2.1 Study Rationale
Section 2.2 Background
Section 2.3 Benefit/Risk Assessment
Section 4.2.2 Rationale for 
Comparator
Section 4.3 Justification for Dose
Section 8.4.1 Time Period and 
Frequency for Collecting AE and 
SAE Information
090177e19fb526e9\Approved\Approved On: 19-Jan-2024 09:51 (GMT)

PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 3
Description of Change
Brief Rationale
Section # and Name
Section 8.4.8 Adverse Events of 
Special Interest
Removed references that 
were specific to 
Substudy B
Following a review of 
the needs of the overall 
development program,
Substudy B was
removed from the 
protocol
Sections 1 through 9
Section 10.1.5.1 Data Monitoring 
Committee
Section 10.2 Appendix 2: Clinical 
Laboratory Tests
Section 10.5 Appendix 5: Genetics
090177e19fb526e9\Approved\Approved On: 19-Jan-2024 09:51 (GMT)

PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 4
TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................11
1. PROTOCOL SUMMARY...................................................................................................12
1.1. Synopsis ..................................................................................................................12
1.2. Schema ....................................................................................................................16
1.3. Schedule of Activities .............................................................................................16
2. INTRODUCTION ...............................................................................................................17
2.1. Study Rationale .......................................................................................................17
2.2. Background .............................................................................................................17
2.2.1. SARS-CoV-2..............................................................................................17
2.2.2. RSV.............................................................................................................19
2.2.3. Clinical Overview.......................................................................................20
2.2.3.1. SARS-CoV-2.............................................................................20
2.2.3.2. RSVpreF Vaccination ...............................................................24
2.3. Benefit/Risk Assessment.........................................................................................26
2.3.1. Risk Assessment.........................................................................................27
2.3.2. Benefit Assessment.....................................................................................30
2.3.3. Overall Benefit/Risk Conclusion................................................................30
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS ...........................................................30
4. STUDY DESIGN.................................................................................................................30
4.1. Overall Design.........................................................................................................30
4.2. Scientific Rationale for Study Design.....................................................................30
4.2.1. Diversity of Study Population ....................................................................31
4.2.2. Rationale for Comparator ...........................................................................31
4.2.3. Choice of Contraception/Barrier Requirements .........................................31
4.3. Justification for Dose ..............................................................................................31
4.3.1. Bivalent BNT162b2 (Original/Omi BA.4/BA.5) .......................................31
4.3.2. RSVpreF .....................................................................................................31
4.3.3. Combined RSVpreF and Bivalent BNT162b2 (Original/Omi 
BA.4/BA.5) Vaccine [RSVpreF+BNT162b2].................................................32
4.4. End of Study Definition ..........................................................................................32
090177e19fb526e9\Approved\Approved On: 19-Jan-2024 09:51 (GMT)

PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 5
5. STUDY POPULATION......................................................................................................32
5.1. Inclusion Criteria.....................................................................................................32
5.2. Exclusion Criteria....................................................................................................32
5.3. Lifestyle Considerations..........................................................................................33
5.3.1. Contraception..............................................................................................33
5.4. Screen Failures ........................................................................................................33
5.5. Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention...........................33
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................33
6.1. Study Intervention(s) Administered........................................................................33
6.1.1. Administration............................................................................................34
6.1.2. Medical Devices .........................................................................................34
6.2. Preparation, Handling, Storage, and Accountability...............................................34
6.2.1. Preparation and Dispensing........................................................................35
6.3. Assignment to Study Intervention...........................................................................35
6.4. Blinding...................................................................................................................36
6.4.1. Blinding of Participants..............................................................................36
6.4.2. Blinding of Site Personnel..........................................................................36
6.4.3. Blinding of the Sponsor..............................................................................36
6.4.4. Breaking the Blind......................................................................................36
6.5. Study Intervention Compliance...............................................................................36
6.6. Dose Modification...................................................................................................36
6.7. Continued Access to Study Intervention After the End of the Study......................37
6.8. Treatment of Overdose............................................................................................37
6.9. Prior and Concomitant Therapy..............................................................................37
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................37
7.1. Discontinuation of Study Intervention ....................................................................37
7.2. Participant Discontinuation/Withdrawal From the Study.......................................37
7.2.1. Withdrawal of Consent...............................................................................38
7.3. Lost to Follow-Up ...................................................................................................38
090177e19fb526e9\Approved\Approved On: 19-Jan-2024 09:51 (GMT)

PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 6
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................39
8.1. Administrative Procedures ......................................................................................39
8.1.1. Telehealth Visits.........................................................................................39
8.2. Efficacy and/or Immunogenicity Assessments .......................................................40
8.2.1. Biological Samples.....................................................................................40
8.3. Safety Assessments .................................................................................................41
8.3.1. Physical Examinations................................................................................41
8.3.2. Vital Signs ..................................................................................................41
8.3.3. Clinical Safety Laboratory Assessments ....................................................42
8.3.4. Electronic Diary..........................................................................................42
8.3.4.1. Grading Scales...........................................................................42
8.3.4.2. Local Reactions.........................................................................42
8.3.4.3. Systemic Events ........................................................................43
8.3.4.4. Fever..........................................................................................44
8.3.4.5. Antipyretic Medication .............................................................45
8.3.5. Stopping Rules............................................................................................45
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................45
8.4.1. Time Period and Frequency for Collecting AE and SAE Information.......46
8.4.1.1. Reporting SAEs to Pfizer Safety...............................................46
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF...................47
8.4.2. Method of Detecting AEs and SAEs ..........................................................47
8.4.3. Follow-Up of AEs and SAEs......................................................................47
8.4.4. Regulatory Reporting Requirements for SAEs...........................................47
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................48
8.4.5.1. Exposure During Pregnancy......................................................48
8.4.5.2. Exposure During Breastfeeding ................................................50
8.4.5.3. Occupational Exposure .............................................................50
8.4.6. Cardiovascular and Death Events...............................................................50
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................51
090177e19fb526e9\Approved\Approved On: 19-Jan-2024 09:51 (GMT)

PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 7
8.4.8. Adverse Events of Special Interest.............................................................51
8.4.8.1. Lack of Efficacy........................................................................52
8.4.9. Medical Device Deficiencies......................................................................52
8.4.9.1. Time Period for Detecting Medical Device Deficiencies .........52
8.4.9.2. Follow-Up of Medical Device Deficiencies..............................52
8.4.9.3. Prompt Reporting of Device Deficiencies to the Sponsor ........52
8.4.9.4. Regulatory Reporting Requirements for Device 
Deficiencies .......................................................................................53
8.4.10. Vaccination Errors....................................................................................53
8.5. Pharmacokinetics ....................................................................................................54
8.6. Genetics...................................................................................................................54
8.7. Biomarkers ..............................................................................................................54
8.8. Immunogenicity Assessments.................................................................................54
8.9. Health Economics ...................................................................................................55
9. STATISTICAL CONSIDERATIONS ................................................................................55
9.1. Statistical Hypotheses .............................................................................................55
9.2. Analysis Sets ...........................................................................................................55
9.3. Statistical Analyses .................................................................................................55
9.3.1. General Considerations...............................................................................55
9.3.1.1. Analyses for Binary Data ..........................................................56
9.3.1.2. Analyses for Continuous Data...................................................56
9.4. Interim Analyses .....................................................................................................57
9.5. Sample Size Determination.....................................................................................57
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................58
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............58
10.1.1. Regulatory and Ethical Considerations ....................................................58
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................58
10.1.2. Financial Disclosure .................................................................................59
10.1.3. Informed Consent Process ........................................................................59
10.1.4. Data Protection .........................................................................................60
090177e19fb526e9\Approved\Approved On: 19-Jan-2024 09:51 (GMT)

PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 8
10.1.5. Committees Structure ...............................................................................60
10.1.5.1. Data Monitoring Committee ...................................................60
10.1.6. Dissemination of Clinical Study Data ......................................................61
10.1.7. Data Quality Assurance ............................................................................62
10.1.8. Source Documents....................................................................................63
10.1.9. Use of Medical Records............................................................................64
10.1.10. Study and Site Start and Closure ............................................................64
10.1.11. Publication Policy...................................................................................65
10.1.12. Sponsor’s Medically Qualified Individual..............................................65
10.2. Appendix 2: Clinical Laboratory Tests .................................................................66
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................67
10.3.1. Definition of AE .......................................................................................67
10.3.2. Definition of an SAE ................................................................................68
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................70
10.3.4. Reporting of SAEs....................................................................................73
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................75
10.4.1. Male Participant Reproductive Inclusion Criteria....................................75
10.4.2. Female Participant Reproductive Inclusion Criteria.................................75
10.4.3. Woman of Childbearing Potential ............................................................76
10.4.4. Contraception Methods.............................................................................77
10.5. Appendix 5: Genetics............................................................................................78
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .......79
10.7. Appendix 7: Kidney Safety Monitoring Guidelines .............................................81
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury..............................................................................81
10.7.2. Age-Specific Kidney Function Calculation Recommendations...............81
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations ...........................................................................................81
10.7.3. Kidney Function Calculation Tools..........................................................82
090177e19fb526e9\Approved\Approved On: 19-Jan-2024 09:51 (GMT)

PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 9
10.7.4. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities...................................................................................................82
10.8. Appendix 8: ECG Findings of Potential Clinical Concern ...................................83
10.9. Appendix 9: Criteria for Allowing Inclusion of Participants With Chronic 
Stable HIV, HCV, or HBV Infection ........................................................................85
10.10. Appendix 10: AEs, ADEs, SAEs, SADEs, USADEs, and Device 
Deficiencies: Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting in Medical Device Studies .............................................86
10.10.1. Definition of AE and ADE .....................................................................86
10.10.2. Definition of SAE, SADE, and USADE ................................................86
10.10.3. Definition of Device Deficiency.............................................................87
10.10.4. Recording/Reporting and Follow-Up of Medical Device 
Deficiencies......................................................................................................87
10.10.5. Reporting of SAEs..................................................................................89
10.10.6. Reporting of SADEs...............................................................................89
10.11. Appendix 11: Substudy A (Phase 1/2) ................................................................90
10.11.1. Synopsis – Substudy A...........................................................................90
10.11.2. Schema – Substudy A (Phase 1/2)..........................................................90
10.11.3. SoA – Substudy A (Phase 1/2) ...............................................................91
10.11.4. Introduction – Substudy A......................................................................93
10.11.4.1. Substudy A Rationale............................................................93
10.11.4.2. Background ...........................................................................93
10.11.4.3. Benefit/Risk Assessment.......................................................93
10.11.5. Objectives, Endpoints, and Estimands – Substudy A.............................94
10.11.6. Substudy A Design .................................................................................97
10.11.6.1. Overall Design.......................................................................97
10.11.6.2. Scientific Rationale for Study Design...................................98
10.11.6.3. Justification for Dose ............................................................98
10.11.6.4. End of Study Definition ........................................................98
10.11.7. Substudy A Population ...........................................................................98
10.11.7.1. Substudy A Inclusion Criteria...............................................98
10.11.7.2. Substudy A Exclusion Criteria..............................................99
090177e19fb526e9\Approved\Approved On: 19-Jan-2024 09:51 (GMT)

PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 10
10.11.7.3. Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study 
Intervention......................................................................................101
10.11.8. Substudy A Intervention and Concomitant Therapy ............................101
10.11.8.1. Study Intervention(s) Administered....................................103
10.11.8.2. Blinding...............................................................................106
10.11.8.3. Study Intervention Compliance...........................................108
10.11.8.4. Dose Modification...............................................................108
10.11.8.5. Continued Access to Study Intervention After the End 
of the Study......................................................................................108
10.11.8.6. Treatment of Overdose........................................................108
10.11.8.7. Prior and Concomitant Therapy..........................................108
10.11.9. Discontinuation of Substudy A Intervention and Participant 
Discontinuation/Withdrawal..........................................................................109
10.11.10. Substudy A Assessments and Procedures...........................................109
10.11.10.1. Immunogenicity Assessments...........................................110
10.11.10.2. N-Binding Antibody Test..................................................110
10.11.10.3. Biological Samples............................................................110
10.11.10.4. Safety Assessments ...........................................................110
10.11.10.5. Stopping Rules ..................................................................110
10.11.10.6. Adverse Events, Serious Adverse Events, and Other 
Safety Reporting..............................................................................111
10.11.10.7. Study Procedures...............................................................111
10.11.11. Statistical Considerations – Substudy A.............................................116
10.11.11.1. Statistical Hypotheses .......................................................116
10.11.11.2. Analysis Sets .....................................................................119
10.11.11.3. Statistical Analyses ...........................................................119
10.11.11.4. Interim Analyses ...............................................................122
10.11.11.5. Sample Size Determination...............................................122
10.12. Appendix 12: Protocol Amendment History.....................................................124
10.13. Appendix 13: Abbreviations .............................................................................127
11. REFERENCES ................................................................................................................131
090177e19fb526e9\Approved\Approved On: 19-Jan-2024 09:51 (GMT)

PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 11
LIST OF TABLES
Table 1.
Local Reaction Grading Scale ..................................................................43
Table 2.
Systemic Event Grading Scale..................................................................44
Table 3.
Scale for Fever..........................................................................................45
Table 4.
Substudy A Enrollment Strata ..................................................................97
Table 5.
Power to Demonstrate Noninferiority (N=135 per Group) ....................123
090177e19fb526e9\Approved\Approved On: 19-Jan-2024 09:51 (GMT)

PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 12
1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: 
A Study to Evaluate the Safety, Tolerability, and Immunogenicity of Combined Vaccine 
Candidate(s) Against Infectious Respiratory Illnesses, Including COVID-19 and RSV, in 
Healthy Individuals
Brief Title:
A Study to Learn About Combined Vaccine(s) Against Infectious Respiratory Illnesses, 
Including COVID-19 and RSV
Regulatory Agency Identification Number(s):
US IND Number:
29521
EU CT Number:
NA
ClinicalTrials.gov ID:
NCT05886777
Pediatric Investigational Plan Number:
NA
Protocol Number:
C5481001
Phase:
1/2
Rationale:
Respiratory syncytial virus (RSV), influenza, and severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) viruses are cocirculating infections, with a tendency to peak in 
winter. Vaccines against influenza and coronavirus disease 2019 (COVID-19) can be 
administered at a single healthcare visit as individual vaccinations, requiring multiple 
injections. The Pfizer RSV vaccine, RSV stabilized prefusion F subunit vaccine (RSVpreF),
was recently found to be efficacious against RSV-associated lower respiratory tract illness 
(LRTI) in older adults (≥60 years of age). Concurrent administration of vaccines against 
these respiratory viral infections could reduce the need for multiple healthcare or pharmacy 
visits and may improve vaccine uptake. A combination vaccine with RSVpreF and Pfizer’s 
COVID-19 vaccine (BNT162b2) would require 1 injection at a healthcare provider visit. A 
study of combined vaccination is required to investigate potential immunological interference 
in addition to safety and tolerability. 
090177e19fb526e9\Approved\Approved On: 19-Jan-2024 09:51 (GMT)

PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 13
The nucleoside-modified messenger ribonucleic acid (modRNA) within BNT162b2 encodes 
the SARS-CoV-2 spike protein and is encapsulated in ribonucleic acid lipid nanoparticles 
(RNA-LNPs).  BNT162b2 has demonstrated potent immunogenicity, high vaccine efficacy 
(VE), and a favorable safety profile in Phase 1, 2, and 3 human trials, as well as in real-world 
usage. At the time of study conduct, the relevant authorized/approved variant-adapted 
version of the BNT162b2 vaccine will be used in the substudy.
RSVpreF is a bivalent RSV prefusion F subunit vaccine developed by Pfizer. The RSV 
F glycoprotein facilitates fusion of the virion and host cell membrane through a dramatic 
transition from an unstable but highly immunogenic prefusion conformation to the more 
stable postfusion state. RSVpreF is composed of engineered, stabilized, trimeric, prefusion F 
glycoproteins matching the 2 subgroups (A and B) to help ensure the broadest coverage 
against RSV illness. RSVpreF efficacy against RSV-associated LRTI with ≥2 and 
≥3 symptoms in older adults (≥60 years of age) was 66.7% and 85.7%, respectively. On 
31 May 2023, the Food and Drug Administration (FDA) approved RSVpreF under the name 
Abrysvo™for the prevention of lower respiratory tract disease caused by RSV in individuals 
60 years of age or older. 
Given that annual vaccine programs against RSV and SARS-CoV-2 may be conducted in the 
future at a similar time of year, when influenza vaccine is also administered, developing 
combined vaccines targeting multiple viruses is likely to generate overall higher vaccination 
rates by allowing for more convenient scheduling than if these vaccinations were to be 
administered separately and/or at different visits. Hence, this study will include the 
following substudy:

Substudy A: A Phase 1/2 substudy in up to approximately 1050 healthy participants 
≥65 years of age to describe the safety, tolerability, and immunogenicity of a 
combined RSVpreF and bivalent BNT162b2 (original/Omi BA.4/BA.5) vaccine
[RSVpreF+BNT162b2], administered concomitantly with a seasonal influenza
vaccine or administered alone.
Objectives, Endpoints, and Estimands
Please refer to the substudy appendix for the objectives and endpoints for the substudy.
Overall Design:
This is a master study to evaluate combined vaccine candidate(s) against infectious
respiratory illnesses, including COVID-19 and RSV. The substudy design is detailed 
separately in the substudy appendix.
090177e19fb526e9\Approved\Approved On: 19-Jan-2024 09:51 (GMT)

PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 14
Substudy A (Phase 1/2)
This is a Phase 1/2 randomized, parallel-group, observer-blinded substudy to assess the 
safety, tolerability, and immunogenicity of a combined RSVpreF and bivalent BNT162b2 
(original/Omi BA.4/BA.5) vaccine [RSVpreF+BNT162b2], administered concomitantly with 
a seasonal influenza vaccine or administered alone. Approximately 1050 healthy participants 
≥65 years of age will be enrolled in Substudy A.
Randomization will be conducted across 2 enrollment strata (see the table below).
Substudy A: Enrollment Strata 
Enrollment 
Stratum
Total Number 
of Participants
Number of 
Participants per 
Vaccine Group
Vaccine 
Group 
Number
Vaccine Group Description
1
750
150
1
[RSVpreF+BNT162b2] administered 
concurrently in the opposite arm to 
licensed QIV 
150
2
[RSVpreF+BNT162b2] administered 
concurrently in the opposite arm to 
placebo
150
3
Bivalent BNT162b2 administered 
concurrently in the opposite arm to 
placebo
150
4
RSVpreF administered concurrently in 
the opposite arm to placebo
150
5
Licensed QIV administered 
concurrently in the opposite arm to 
placebo
2
300
150
6
RSVpreF and bivalent BNT162b2 
(2 injections in the same arm) 
coadministered concurrently in the 
opposite arm to placebo
150
7
RSVpreF and bivalent BNT162b2 
(2 injections in the same arm) 
coadministered concurrently in the 
opposite arm to licensed QIV
All participants will be asked to complete a reactogenicity electronic diary (e-diary) for 
7 days following vaccination.  Blood samples of approximately 50 mL will be collected for 
immunogenicity assessments prior to vaccination at Visit A101 and 1 month after 
vaccination (Visit A102). 
E-diary data from Day 1 through Day 3 for the first 50 participants in Groups 1 to 5, and the 
first 20 participants in Groups 6 and 7, will be evaluated prior to enrollment of the remaining 
participants in each group.
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Adverse events (AEs) will be collected from the signing of informed consent through 
Visit A102 (1-month follow-up visit). Serious adverse events (SAEs) will be collected from 
the signing of informed consent through Visit A103 (6-month telephone contact).
Substudy A will have stopping rules that will apply to groups receiving the combined
RSVpreF and bivalent BNT162b2 (original/Omi BA.4/BA.5) vaccine 
[RSVpreF+BNT162b2] as detailed in the protocol.
The total duration of Substudy A for each participant will be up to approximately 6 months.
Number of Participants:
Substudy A (Phase 1/2)
Up to approximately 1050 participants will be enrolled in Substudy A (750 participants in 
enrollment stratum 1 and 300 participants in enrollment stratum 2).
Note: “Enrolled” means a participant’s, or their legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process.
Study Population: 
Please refer to the substudy appendix for the inclusion and exclusion criteria of the substudy.
Study Arms and Duration:
Please refer to the appendix for the study arms and duration of the substudy.
Statistical Methods:
Statistical methods applicable to the substudy are specified in the body of the protocol. 
Statistical methods specific to the substudy are specified in the substudy appendix.
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.
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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, European MDR 2017/745 for clinical device research, 
and all other applicable local regulations.
1.2. Schema
Please refer to the study-specific appendix for the schema of the substudy. 
1.3. Schedule of Activities
The schedule of activities (SoA) table(s) provides an overview of the protocol visits and 
procedures.  Refer to the STUDY ASSESSMENTS AND PROCEDURES section (Section 8)
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(s), in order to conduct evaluations or assessments required to protect the well-being of 
the participant.
See Section 10.11.3 for the Substudy A SoA.
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2. INTRODUCTION
2.1. Study Rationale
BNT162b2 (Comirnaty®) is an RNA-based vaccine that has been granted full marketing 
authorization, conditional marketing authorization, EUA, or temporary authorization in more 
than 100 countries for the prevention of COVID-19 caused by SARS-CoV-2.1
The modRNA within BNT162b2 encodes the SARS-CoV-2 spike protein and is encapsulated 
in RNA-LNPs.  BNT162b2 has demonstrated potent immunogenicity, high VE, and a 
favorable safety profile in Phase 1, 2, and 3 human trials,2 as well as in real-world usage.3 As 
SARS-CoV-2 continues to circulate at very high levels,4 Pfizer-BioNTech have developed a
bivalent BNT162b2 (original/Omi BA.4/BA.5) vaccine, to further protect against COVID-19 
caused by emergent and potentially more antigenically diverse variants. Bivalent BNT162b2 
(original/Omi BA.4/BA.5), consisting of the original SARS-CoV-2 spike protein mRNA, 
targeting the ancestral strain of the virus, in combination with mRNA encoding the spike 
protein of the Omicron variant (BA.4/BA.5 sublineage), was therefore used in Substudy A.
RSVpreF is a bivalent RSV prefusion F subunit vaccine developed by Pfizer. The RSV 
F glycoprotein facilitates fusion of the virion and host cell membrane through a dramatic 
transition from an unstable but highly immunogenic prefusion conformation to the more 
stable postfusion state. RSVpreF is composed of engineered, stabilized, trimeric, prefusion F 
glycoproteins matching the 2 subgroups (A and B) to help ensure the broadest coverage 
against RSV illness. RSVpreF was recently found to be efficacious against RSV-associated 
LRTI in older adults,5 and on 31 May 2023, the FDA approved RSVpreF under the name 
Abrysvo™ for the prevention of lower respiratory tract disease caused by RSV in individuals 
60 years of age or older.6
RSV and SARS-CoV-2 viruses often cocirculate, with a tendency to peak in winter.7,8,9
In older adults, coadministration of vaccines in a single injection could reduce the need for 
multiple healthcare or pharmacy visits and improve vaccine uptake by reducing missed 
opportunities for a subsequent injection.10 Studies of combination vaccination are required 
to investigate potential immunological interference in addition to safety and tolerability. 
Substudy A will investigate a combined RSVpreF and bivalent BNT162b2 
(original/Omi BA.4/BA.5) vaccine [RSVpreF+BNT162b2] administered concomitantly with 
a seasonal influenza vaccine or administered alone.
2.2. Background
2.2.1. SARS-CoV-2
SARS-CoV-2, a novel β-coronavirus, is a highly transmissible and pathogenic respiratory 
virus responsible for the ongoing COVID-19 pandemic.  Studies of SARS-CoV-2 and 
SARS-CoV, a closely related coronavirus that caused the 2003 SARS pandemic, 
demonstrated that effective antibody protection could be achieved through spike-specific 
antibodies.11,12  Therefore, vaccines targeting the spike protein of SARS-CoV-2 have been 
used as a critical mitigation strategy of the COVID-19 pandemic. However, waning 
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effectiveness of the authorized vaccines has been shown to occur over time and is suspected 
to be due to waning of vaccine-induced immunity as well as the emergence of variants.
A large study conducted in 10 states within the US noted waning mRNA vaccine 
effectiveness against emergency room and urgent care encounters as well as hospitalizations, 
when comparing 2 months versus ≥4 months after receipt of a third dose.  During the 
Omicron period, VE against emergency room or urgent care visits was 87% during the first 
2 months after a third dose and decreased to 66% among those vaccinated 4 to 5 months 
earlier; VE against hospitalizations was 91% during the first 2 months following a third dose 
and decreased to 78% ≥4 months after a third dose.13  In another large study conducted in 
approximately 2.5 million UK adults vaccinated with either ChAdOx1-S, BNT162b2, or 
mRNA-1273, approximately 80% of the participants with SARS-CoV-2 had Omicron variant 
infections and approximately 20% had Delta variant infections.  In those who received 
3 doses of BNT162b2, VE increased to 67.2% at 2 to 4 weeks before declining to 45.7% at 
10 or more weeks.14
A 2021 laboratory study in Israel 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 BNT162b2 was also tested against WT 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 compared to 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.15
The bivalent (original/Omi BA.4/BA.5) vaccine has shown improved neutralization of recent 
Omicron sublineages, which has translated to improved real-world protection against the 
Omicron variant.16 Real-world studies show that bivalent mRNA vaccines increase 
protection relative to original monovalent-only mRNA vaccination against a range of 
COVID-19 outcomes, including symptomatic COVID-19 and severe illness, with higher 
effectiveness seen against more severe outcomes such as hospitalization.17,18,19,20,21,22,23
Further, early evidence suggests that the bivalent vaccine may be more effective than the 
original monovalent mRNA booster in those 12 years of age or older during periods in which 
recent Omicron sublineages, including BA.5, BQ.1/BQ.1.1, and XBB.1 were prevalent.16,21
At that time, Pfizer-BioNTech had developed a bivalent BNT162b2 
(original/Omi BA.4/BA.5) vaccine to further protect against COVID-19 caused by emergent 
and potentially more antigenically diverse variants; this formulation was used in Substudy A.
But at present, Omicron and its sublineages continue to cause the majority of SARS-CoV-2 
infections. The Omicron sublineage XBB.1.5 has been globally dominant since 
February 2023, while the prevalence of other XBB sublineages (ie, XBB.1.16, XBB.1.9.1, 
XBB.1.9.2, and XBB.2.3) is growing.4 Sublineages XBB and XBB.1 are more antigenically 
distant from prior Omicron strain sublineages (eg, BA.2, BA.4/BA.5); more so than the 
distance of these early Omicron sublineages from the ancestral WT strain. They also show 
the greatest magnitude of immune escape that has been observed to date.24,25,26 While the 
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bivalent BNT162b2 (original/Omi BA.4/BA.5)–adapted booster increased neutralizing titers 
against currently dominant strains, XBB.1.5 and XBB.1.16, the GMTs were substantially 
reduced compared to GMTs against the matched Omi BA.4/BA.5. Preclinical data showed 
an Omicron XBB–adapted vaccine (eg, Omicron XBB.1.5), when administered as a booster 
or 2-dose primary series, elicited higher neutralizing responses against Omicron XBB.1.5 and 
XBB.1.16 strains compared to the bivalent BNT162b2 (original/Omi BA.4/BA.5)–adapted 
vaccine. Based on these available data, FDA guidance, VRBPAC recommendation 
(held 15 June 2023),27 and Pfizer/BioNTech strategies for manufacturing and testing using 
the same platforms, a variant-modified formulation targeting Omicron XBB.1.5 
(approved 11 September 2023) for 2023/2024 became commercially available.28
2.2.2. RSV
RSV is a major cause of respiratory infection in all ages, which can result in severe illness in 
both infants and older adults. There are 2 antigenic variants of RSV: subgroups A (RSV A) 
and B (RSV B), which cocirculate.29 Like influenza, RSV infection follows a seasonal 
pattern, causing yearly wintertime epidemics in temperate climates, usually between late 
autumn and early spring. In tropical climates, the outbreaks are generally associated with 
rainy seasons but are more unpredictable and frequently continuous.30 Because of the 
COVID-19 pandemic, which spread worldwide in 2020-2021, the seasonality of several 
pathogens, including RSV, has been disrupted and the shift of peak incidence has been 
observed in a majority of geographic areas. RSV now cocirculates with influenza and 
SARS-CoV-2 and increases the incidence of respiratory infection–related disease.7
Adults ≥60 years of age are at increased risk of RSV infection, which can trigger 
exacerbations of underlying comorbid conditions such as COPD and CHF. RSV infection 
has been associated with up to 22% of acute COPD exacerbations in prospective cohort
studies and 11% of wintertime hospitalizations for COPD exacerbations.31 Current 
epidemiology shows that RSV is responsible for approximately 177,000 hospitalizations and 
14,000 deaths annually in US adults 65 years of age and older.32 Morbidity is significant 
among adults hospitalized with RSV disease, with 18% requiring intensive care, 31%
needing home health services at discharge, and 26% dying within 1 year of hospitalization.33
In the US, RSV disease incidence rates in older adults are approximately half those of 
influenza, with variation year to year.34 Incidence rates and risk for severe complications 
from RSV infection are higher among immunocompromised adults and those with chronic 
conditions (eg, cardiopulmonary or renal disease, hematological malignancies, receipt of 
chemotherapy, or HIV infection).35,36 However, the burden of adult RSV disease could be 
underestimated since testing for RSV is less common in older adults than in children.37 RSV 
disease in adults is also difficult to diagnose based on clinical signs and symptoms alone, 
and, prior to the broader use of more sensitive detection methods, laboratory confirmation of 
RSV in adults was challenging because of low levels of virus shedding.31
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RSV disease management in adults is limited to supportive measures, such as hydration and 
oxygenation. Aerosolized ribavirin has limited evidence of effectiveness and is 
predominantly restricted to severely immunocompromised hospitalized patients because of 
inconvenient administration, teratogenicity, anemia concerns, and high cost.38  As of 
31 May 2023, Abrysvo has been approved for the prevention of lower respiratory tract 
disease caused by RSV in individuals 60 years of age and older by the FDA.6 Abrysvo has 
also been approved for the prevention of lower respiratory tract disease caused by RSV in 
pregnant individuals 32 through 36 weeks gestational age by the FDA.39
2.2.3. Clinical Overview
2.2.3.1. SARS-CoV-2
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.40  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 to evaluate the selected 
vaccine candidate (BNT162b2).
The immunogenicity data from Phase 1 participants showed 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 and 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 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.41
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 
and 6 months after the second dose.42  Furthermore, from the same analysis, BNT162b2 was 
shown to have an efficacy of: 
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
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 was 
prevalent at the time of analysis.
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 included 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.41
A booster dose (Dose 3) of BNT162b2 was administered to 306 Phase 3 participants without 
prior evidence of SARS-CoV-2 infection ~6 months after completing the 2-dose schedule.  
The immune response 1 month after administration of Dose 3 was noninferior to that 
observed 1 month after Dose 2 in the same participants.  Furthermore, from the same 
analysis, among participants without prior evidence of SARS-CoV-2 infection up to 1 month 
after Dose 3, a high proportion of participants (99.5%) had a seroresponse at 1 month after 
Dose 3 compared with 98.0% at 1 month after Dose 2.2
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-19.43 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.44  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.  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.  
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.
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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.45
C4591031 Substudy E is an ongoing Phase 3 trial in approximately 2900 participants 
18 years of age and older who have previously received 3 doses of BNT162b2 (30-μg dose). 
Participants in this substudy received a fourth dose of either BNT162b2 or BNT162b2 
Omicron (BA.1 sublineage) or a combination of both at a total dose level of either 30 μg or 
60 μg. From the available safety data from this study, the tolerability and safety profile of 
bivalent BNT162b2 30 μg, up to 1 month after study vaccination (to the data cutoff date),
was acceptable and consistent with the known safety profile of BNT162b2 and previously 
reported AE profile for Omicron BA.1–modified BNT162b2 vaccines. In participants 
>18 through 55 years of age, the bivalent Omicron-modified vaccine at the 30-μg dose level 
showed a similar local reaction and systemic event reactogenicity profile as the prototype 
BNT162b2 vaccine. From the immunogenicity data, in participants >55 years of age 
without evidence of COVID-19 infection, Omicron BA.1–neutralization activity 
substantially increased with Omicron-modified bivalent vaccines as a fourth dose. 
Additionally, analysis of immunogenicity data from this study demonstrated a robust 
vaccine-elicited immune response to the bivalent Omicron BA.1–modified vaccines when 
administered as a booster (Dose 4) to BNT162b2-experienced participants 18 through 
55 years of age. Bivalent Omicron-modified vaccines (BNT162b2 + BNT162b2 Omi 30 µg 
and 60 µg) met the defined superiority criteria against Omicron BA.1 and noninferiority 
response to the reference strain, in participants within the group >55 years of age. Based on 
the 1-month postdose safety and immunogenicity findings from the C4591031 Substudy E 
>55-year age group, the FDA granted EUA on 31 August 2022 for the bivalent vaccine as a 
single booster dose for individuals 12 years of age and older.46
The SARS-CoV-2 Omicron variant B.1.1.529 emerged in late 2021 and quickly became the 
dominant circulating strain worldwide, replacing earlier strains and variants. In the US, the 
Omicron BA.1 sublineage was replaced by the BA.2 sublineage in April 2022 and 
subsequently was replaced by BA.4 and BA.5 sublineages by July 2022.47  The BA.4 and 
BA.5 sublineages demonstrate substantial immune escape from neutralizing antibodies 
induced by both infection and immunization,48 which has been attributed to the L452R and 
F486V spike mutations within the protein sequence of BA.4 and BA.5.49  Moreover, studies 
have demonstrated that the effectiveness of BNT162b2 against SARS-CoV-2 infection 
and COVID-19 wanes over a period of months, particularly in the context of variants.13,14,50  
In light of the waning effectiveness of the 2-dose primary series of BNT162b2 as well as the 
existence of variants with cumulative mutations in the spike protein that are resilient to the 
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existing immune response, particularly Omicron, an enhanced bivalent vaccine was 
developed. Study C4591044 is currently evaluating bivalent BNT162b2 
(original/Omi BA.4/BA.5) consisting of the LNP-formulated original SARS-CoV-2 spike 
protein mRNA, targeting the ancestral strain of the virus, in combination with 
LNP-formulated mRNA encoding the spike protein of the Omicron variant 
(BA.4/BA.5 sublineage) in approximately 900 participants ≥12 years of age.  Preliminary 
data from this study demonstrate a robust neutralizing immune response 1 month after a 
30-µg booster dose of Omicron BA.4/BA.5–adapted bivalent COVID-19 vaccine 
(Pfizer-BioNTech COVID-19 vaccine, bivalent [original and Omicron BA.4/BA.5]).  
Immune responses against the BA.4/BA.5 sublineages were substantially higher for those 
who received the bivalent vaccine compared to the companies’ original COVID-19 vaccine, 
with a similar safety and tolerability profile between both vaccines.51  
Omicron BA.4/BA.5 remained dominant in the US until October 2022, when they were 
replaced by XBB and BQ.1 sublineages. BQ.1 is a subvariant of BA.5, but XBB is a 
recombinant subvariant, combining BA.2.10.1 and BA.2.75.52  Preliminary data comparing 
immune responses to the monovalent BNT162b2 (original) vaccine and the bivalent 
BNT162b2 (original/Omi BA.4/BA.5) in adults >55 years of age who had received 3 prior 
doses of monovalent BNT162b2 showed that bivalent BNT162b2 (original/Omi BA.4/BA.5) 
induced higher GMFRs against BA.4/BA.5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1, 
suggesting that the bivalent BNT162b2 (original/Omi BA.4/BA.5) vaccine is more 
immunogenic against circulating Omicron sublineages compared with the original 
BNT162b2 monovalent vaccine.53
Data on SARS-CoV-2 evolution indicated that Omicron XBB sublineages accounted for 
more than 95% of the circulating virus variants in the US as of early June 2023. While 
XBB.1.5 has declined to less than 40% of presumed circulating virus in the US, XBB.1.16 is 
on the rise and XBB.2.3 is slowly increasing in proportion.  The current trajectory of virus 
evolution suggests that XBB.1.16 could be dominant by fall 2023. XBB.2.3 and other XBB 
sublineages could also continue to increase in proportion as the virus evolves. Although 
SARS-CoV-2 continues to evolve, the protein sequences of the XBB.1.5, XBB.1.16, and 
XBB.2.3 spike proteins appear similar, with few amino acid differences. Available evidence 
suggests little to no further immune evasion from these new substitutions in the XBB.1.16 
spike protein compared to XBB.1.5. By several measures, including escape from antibody 
neutralization and waning protection, the bivalent COVID-19 (original/Omi BA.4/BA.5) 
vaccines appear less effective against currently circulating variants (eg, XBB-lineage viruses) 
than against previous strains of virus. The totality of available evidence suggested that a 
monovalent XBB-lineage vaccine was warranted for the 2023-2024 update, and the FDA has 
advised that manufacturers seeking to update their COVID-19 vaccines should develop 
vaccines with a monovalent XBB.1.5 composition, which was approved on 
11 September 2023 in US.28,54
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2.2.3.2. RSVpreF Vaccination
RSVpreF is a bivalent RSV prefusion F subunit vaccine developed by Pfizer. The RSV 
F glycoprotein facilitates fusion of the virion and host cell membrane through a dramatic 
transition from an unstable but highly immunogenic prefusion conformation to the more 
stable postfusion state. Preclinical studies show that prefusion F elicits much higher 
neutralizing antibody titers than postfusion F and that the most potent neutralizing antibodies 
from postinfection human sera target the prefusion form. RSVpreF is composed of 
engineered, stabilized, trimeric, prefusion F glycoproteins matching the 2 subgroups 
(A and B) to help ensure the broadest coverage against RSV illness.
RSVpreF is being developed for 2 indications:

Older Adult: Prevention of ARI-RSV and LRTI-RSV in adults 60 years of age and older 
via active immunization.

Maternal: Prevention of LRTI-RSV and severe LRTI-RSV in infants by active 
immunization of pregnant women.
As of September 2023, RSVpreF has been studied in healthy adults and pregnant women.  
RSVpreF was shown to be well tolerated, with an acceptable safety profile, and highly 
efficacious in older adults and infants of women vaccinated during pregnancy.

In the Phase 1/2 study C3671001, 1233 healthy adults 18 through 49 and 50 through
85 years of age received 3 dose levels of RSVpreF (60 µg, 120 µg, and 240 µg), with or 
without Al(OH)3, or placebo, administered with or without concomitant influenza
vaccine. The results have shown that the vaccine was well tolerated and immunogenic in 
both age groups. RSVpreF elicited robust neutralizing responses against RSV A and 
RSV B 1 month after vaccination for both age groups across all vaccine dose levels and 
formulations; these responses remained high through the 12 months after vaccination. 
In 616 vaccinated participants in the 50- through 85-year age group, RSV 50% NT 
GMFRs were high across all study groups, ranging from 9 to 13 from before vaccination 
through 1 month after vaccination, and from 3 to 4 from before vaccination through
12 months for RSV A and RSV B. RSVpreF was safe and well tolerated when 
administered alone or with SIIV, with no major differences observed across all dose 
levels and formulations. Most reported local reactions or systemic events were mild or 
moderate in severity.
The proportions of participants reporting AEs were generally similar across RSVpreF 
groups, and no SAEs were considered related to the investigational vaccine.

Phase 1/2 study C3671002, in 313 older adults 65 through 85 years of age, studied the 
3 dose levels of RSVpreF with Al(OH)3, or CpG/Al(OH)3 (60 µg, 120 µg, and 240 µg), 
given as a single dose or on a schedule of 2 doses administered 2 months apart. 
All RSVpreF doses and formulations elicited high RSV A– and RSV B–neutralizing 
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antibody GMTs 1 month after vaccination (GMFRs ranging from 4.8 to 11.6 and 4.5 to 
14.1, respectively). CpG-containing formulations did not further increase neutralizing 
GMTs compared to RSVpreF with or without Al(OH)3. GMTs in all groups declined but 
remained higher than baseline (before vaccination) and placebo (SIIV only) at 12 months 
after vaccination (GMFRs ranging from 2.1 to 3.5 and 2.2 to 4.3, respectively). 
No increase in GMTs was observed 1 month after Vaccination 2 (GMFR of 0.9). 
All doses and formulations were safe and well tolerated. 

Study C3671014 is a completed Phase 3, multicenter, parallel-group, placebo-controlled, 
randomized, double-blind lot-consistency study in a population of up to 1000 healthy 
adults 18 to ≤49 years of age. The study examined the immune response and the safety 
and tolerability profiles across 3 manufactured lots of RSVpreF when administered as a 
single 120-µg dose to healthy adults. The primary analyses showed that the ratios of 
neutralizing GMTs for each of the 3 manufactured RSVpreF lots 1 month after 
vaccination are equivalent, and that the 120-μg dose of RSVpreF is well tolerated and has 
an acceptable safety profile.

A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Safety, Immunogenicity and Efficacy of a Respiratory Syncytial Virus Vaccine 
(RSVpreF) in a Virus Challenge Model in Healthy Adults (NCT04785612) was 
conducted by hVIVO in 70 healthy participants 18 to 50 years of age. Participants
received a single dose of either 120 μg RSVpreF or placebo and 4 weeks later underwent 
intranasal challenge with RSV A Memphis 37b virus. The immunogenicity and efficacy 
of RSVpreF vaccination on virus replication, clinical symptoms, and incidence of 
symptomatic RSV infection following the intranasal challenge were evaluated. The 
primary analysis of the human challenge study showed that a 120-μg dose of RSVpreF 
was well tolerated and has an acceptable safety profile. The study demonstrated 
100% efficacy of RSVpreF against RT-PCR–confirmed symptomatic infection.

C3671013 is an ongoing Phase 3, multicenter, randomized, double-blind, 
placebo-controlled study to assess the safety, immunogenicity, and efficacy of Pfizer’s 
RSVpreF in prevention of RSV-associated LRTI in adults 60 years of age and older. 
Both healthy adults and adults with stable chronic cardiopulmonary conditions are 
included. Approximately 10% of participants with stable chronic cardiopulmonary 
conditions such as COPD, asthma, or CHF are being enrolled. The study enrolled over 
37,000 participants, randomized to receive RSVpreF or placebo in a 1:1 ratio. This is an 
event-driven study with a target of 59 first episodes of evaluable RSV-associated LRTI 
cases. Interim analysis results in August 2022 showed protection against LRTI-RSV 
defined by 2 or more symptoms demonstrated VE: 66.7%. VE of 85.7% was observed in 
participants with a more severe disease primary endpoint of LRTI-RSV defined by 
analysis of 3 or more RSV-associated symptoms. The vaccine was well tolerated, with 
no safety concerns.
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
C3671006 is a completed Phase 3, multicenter, parallel-group, placebo-controlled, 
randomized, double-blind study designed to assess the safety and immunogenicity of 
RSVpreF when coadministered with SIIV compared to sequential administration of the 
vaccines when given 1 month apart (SIIV followed by RSVpreF). Approximately 
1400 healthy adults ≥65 years of age were randomized 1:1 to either a coadministration 
group or a sequential-administration group.  The intention was to demonstrate that the 
immune responses generated with a 120-µg RSVpreF dose coadministered with SIIV 
were noninferior to the immune responses when these products were administered 
4 weeks apart. The safety and tolerability of RSVpreF were also examined. Results 
demonstrated noninferiority of the RSVpreF and SIIV immune responses when RSVpreF 
was coadministered with SIIV. The results of this study support the acceptability of 
coadministration of RSVpreF and SIIV in an older adult population.

C3671016 is Phase 1/2/3 study in participants 2 to <18 years of age at high risk of RSV 
disease initiated in June 2023.55  The study consists of 2 phases: Phase 1 and Phase 2/3. 
Phase 1 is an open-label, age descending, dose-finding study and Phase 2/3 is a
placebo-controlled, randomized, double-blinded study to evaluate the safety, tolerability, 
and immunogenicity of RSVpreF. Both the 120-µg dose level and a 60-µg dose level will 
be evaluated. Approximately 120 participants will be enrolled in the Phase 1 cohort and 
up to 1860 participants will be enrolled in the Phase 2/3 cohort.

C3671023 is a Phase 3 study to evaluate the safety, tolerability, and immunogenicity of 
RSVpreF in adults at high risk of severe RSV disease. The study is divided into 
2 substudies: Substudy A and Substudy B. Substudy A is a double-blinded, randomized, 
placebo-controlled trial, enrolling participants ≥18 to <60 years of age who are at high 
risk for severe RSV disease due to underlying medical conditions, such as COPD, 
asthma, and CHF, or due to living in a skilled-nursing facility. Participants (N=675) will 
be randomized 2:1 to 1 dose of RSVpreF or placebo and followed for 6 months.
Substudy B is an open-label trial which has completed enrollment of participants age 
18 years and older with immunocompromising conditions. Participants (approximately 
N=200) received 2 doses (1 month apart) of RSVpreF and were followed for 6 months 
after the last dose.
RSVpreF is also being studied in the maternal program, which includes Phase 2b and
Phase 3 studies in pregnant women and a Phase 2b study in nonpregnant women. Details of 
each of these studies are provided in the RSVpreF IB.
2.3. Benefit/Risk Assessment
The available safety, immunogenicity, and effectiveness data from ongoing clinical trials for 
RSVpreF and BNT162b2 support a favorable benefit/risk profile and support clinical 
development of a vaccine combining these components. The stability of RSVpreF and LNP 
mRNA formulation has been assessed, and there is no observed difference in stability profile 
of RSVpreF as a result of mixing with LNP.
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Taking into account the measures to minimize risk to study participants, the potential risks 
identified in association with the study intervention are justified by the anticipated benefits 
that may be afforded to healthy participants.
Clinical investigation is justified, given:

The threat posed by continuous new outbreaks of SARS-CoV-2 infections worldwide.

The threat posed by the SARS-CoV-2 variants emerging worldwide.

The potential need for enhancing immune responses to overcome waning immunity.

The potential advantages and convenience to individuals in developing a combined 
vaccine against RSV and SARS-CoV-2 that would align with the recent FDA 
recommendations for an annual COVID-19 vaccination approach.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of bivalent BNT162b2 (original/Omi BA.4/BA.5) and RSVpreF may be found 
in their IBs, which are the SRSDs for this study. The SRSD for QIV is the Fluzone HD
USPI. Refer to the Study Intervention(s) table in Section 6 for a complete description of 
SRSDs.
2.3.1. Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Study Intervention(s): [RSVpreF+BNT162b2]
The potential risks for the combination 
vaccine are expected to be similar to 
the potential risks for the individual 
components as detailed below.
It is anticipated that common 
adverse reactions seen with 
the individual components 
will also be seen with the 
combination vaccine, as 
detailed below.
The mitigations for the combination 
vaccine will be similar to the 
mitigations for the individual 
components as detailed below.
Study Intervention(s): BNT162b2, BNT162b2 Omicron (BA.4/BA.5 Sublineage)
For BNT162b2 Omicron (BA.4/BA.5 
sublineage):
These vaccines have the same 
modRNA platform (with sequence 
changes limited to those that are 
Omicron specific) and LNP 
formulation as BNT162b2; therefore, 
the safety profile is expected to be 
similar to that of BNT162b2, ie, local 
reactions, such as injection site 
redness, injection site swelling, and 
These are common adverse 
reactions seen with other 
vaccines as well as the 
COVID-19 vaccine.
Data available from the 
C4591001 study (with 
BNT162b2) showed low 
incidence of severe or serious 
events and no clinically 
concerning safety 
observations across the safety 
The study employs the use of a 
reactogenicity e-diary, which allows 
the investigator to monitor local 
reactions and systemic events in real 
time through an electronic portal. 
Severe reactions will require an 
unscheduled telephone call, and visit 
if required, to be conducted per 
protocol.
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
injection site pain, and systemic 
events, such as fever, fatigue, 
headache, chills, muscle pain, and 
joint pain.
Other key risks identified for 
BNT162b2 are lymphadenopathy; 
hypersensitivity reactions, such as 
rash, pruritus, urticaria, angioedema, 
and anaphylaxis; and myocarditis and 
pericarditis.
population and within 
demographic subgroups based 
on age, sex, race/ethnicity, 
country, and baseline 
SARS-CoV-2 status.41
Anaphylaxis: Frequency not 
known.
Myocarditis and pericarditis: 
Very rare cases of myocarditis 
and pericarditis have been 
reported following 
vaccination with mRNA 
COVID-19 vaccines.
Typically, the cases have 
occurred more often in 
younger men and after the 
second dose of the vaccine 
and within 14 days after 
vaccination. These cases are 
generally mild, 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.
Postauthorization safety data 
surveillance has confirmed 
the safety profile observed in 
Study C4591001 and has 
resulted in identification of 
some additional adverse 
reactions (risks) as noted in 
the SRSD.
AEs will be collected from the 
signing of informed consent through 
Visit 2 (1-month follow-up visit).
SAEs will be collected from the 
signing of informed consent through 
Visit 3 (6-month telephone contact). 
Specific references to risks and events 
of interest are made within the ICD, 
with reporting instructions if a case is 
suspected.
Study Intervention(s): RSVpreF
For RSVpreF: Pfizer has identified 
the most common risks for RSVpreF 
as local reactions, such as injection 
site redness, injection site swelling, 
and injection site pain, and systemic 
events, such as fatigue, headache, 
diarrhea, joint pain, nausea, vomiting, 
muscle pain, and fever.39
These are common adverse 
reactions seen with other 
vaccines as well as 
RSVpreF.57
Data available from 
completed and ongoing 
studies showed a low 
incidence of severe or serious 
events, and no clinically 
The study employs the use of a 
reactogenicity e-diary, which allows 
the investigator to monitor local 
reactions and systemic events in real 
time through an electronic portal. 
Severe reactions will require an 
unscheduled telephone call, and visit 
if required, to be conducted per 
protocol.
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Guillain-Barré syndrome has been 
identified as a potential risk for 
RSVpreF.
Other events of interest include atrial 
fibrillation, polyneuropathy, preterm 
birth (delivery at <37 0/7 weeks’ 
gestation), and hypertensive disorders 
of pregnancy.56
The identified adverse reactions in 
local product labels may vary 
depending on the requirements of the 
respective regulatory authorities 
(eg, EU SmPC and USPI).
concerning events. The 
vaccine appears to be safe and 
well tolerated across the 
safety population and within 
demographic subgroups based 
on age, sex, and 
race/ethnicity.58
In Study C3671013, 
conducted in adults 60 years 
of age and older, there was 
1 case of Guillain-Barré
syndrome and 1 case of Miller 
Fisher syndrome (both with a 
plausible temporal 
relationship with vaccination).
Both cases had confounding 
factors or an alternative 
etiology. 
In Study C3671013, 
conducted in adults 60 years 
of age and older, there was a 
nonsignificant numerical 
imbalance in the number of 
cases of atrial fibrillation 
reported for individuals who 
received RSVpreF compared 
to individuals who received 
the placebo. Most of the 
participants who had atrial 
fibrillation and received 
RSVpreF had a preexisting 
medical history of atrial 
fibrillation and/or cardiac 
disease.59
All study participants will be 
observed for at least 30 minutes after 
vaccination.
AEs will be collected from the 
signing of informed consent through 
Visit 2 (1-month follow-up visit).
SAEs will be collected from the 
signing of informed consent through 
Visit 3 (6-month telephone contact). 
Specific references to risks and events 
of interest are made within the ICD, 
with reporting instructions if a case is 
suspected.
Study Intervention(s): QIV
Local and systemic reactions to the 
vaccine may occur.
The following summary 
represents an example QIV 
safety profile.
In adults 65 years of age and 
older, the most commonly 
reported injection-site adverse 
reaction was pain (41.3%).
The most commonly reported 
systemic adverse reactions 
were myalgia (22.7%), 
The study employs the use of a 
reactogenicity e-diary, which allows 
the investigator to monitor local 
reactions and systemic events in real 
time through an electronic portal.  
Severe reactions will require an 
unscheduled telephone call, and visit 
if required, to be conducted per 
protocol.
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Potential Risk of Clinical 
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Summary of Data/Rationale 
for Risk
Mitigation Strategy
headache (14.4%), and 
malaise (13.2%).60
All study participants will be 
observed for at least 30 minutes after 
vaccination.
AEs will be collected from signing of 
the ICD through 1 month and SAEs 
through 6 months after study 
vaccination.
Study Procedures
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 10.11.4.3.
2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures to minimize risk to study participants, the potential risks 
identified in association with RSVpreF and BNT162b2 RNA-based COVID-19 vaccines are 
justified by the anticipated benefits that may be afforded to healthy participants.
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS
See Section 10.11.5 for the Substudy A objectives, endpoints, and estimands.
4. STUDY DESIGN
4.1. Overall Design
See Section 10.11.6 for the Substudy A design.
4.2. Scientific Rationale for Study Design
See Section 2.1.
See the substudy appendix for the rationale supporting the substudy.
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4.2.1. Diversity of Study Population 
The team will follow best practices for diverse study population enrollment and retention,
which will include engaging with sites that have historically been shown to recruit diverse 
participants and/or are geographically located in diverse communities. Early and ongoing 
site interactions will include diversity discussions, and diversity materials will be provided to 
support the sites’ participant engagements.
4.2.2. Rationale for Comparator
Active comparators to the combination vaccine [RSVpreF+BNT162b2] have been chosen for 
Substudy A, including individual injections of RSVpreF and bivalent BNT162b2. The doses 
for these comparators were chosen based on the doses that demonstrated efficacy in the 
pivotal Phase 3 study (RSVpreF) and the dose granted with an EUA by the FDA (bivalent 
BNT162b2 [original/Omi BA.4/BA.5]).
4.2.3. Choice of Contraception/Barrier Requirements
Abrysvo (for the prevention of lower respiratory tract disease caused by RSV in individuals 
60 years and older) has not been studied in pregnant individuals less than 24 weeks 
gestational age and in those at increased risk for preterm birth, and available data on 
Comirnaty (for the prevention of COVID-19 caused by SARS-CoV-2) administered to 
pregnant women are insufficient to inform vaccine-associated risks in pregnancy. The use of 
a highly effective method of contraception is required for sexual intercourse involving a 
WOCBP (see Section 10.4.3).
4.3. Justification for Dose
4.3.1. Bivalent BNT162b2 (Original/Omi BA.4/BA.5)
The FDA has granted EUA for the use of bivalent BNT162b2 (original/Omi BA.4/BA.5) at a 
dose level of 30 µg (15 µg original BNT162b2 and 15 µg BNT162b2 Omicron [B.1.1.529 
sublineage BA.4/BA.5]) in individuals ≥12 years of age,61 and this dose level is being used 
when bivalent BNT162b2 (original/Omi BA.4/BA.5) is administered alone and as part of the 
RSVpreF and bivalent BNT162b2 (original/Omi BA.4/BA.5) vaccine 
[RSVpreF+BNT162b2] administered in Substudy A.
4.3.2. RSVpreF
The 120-μg dose, without any adjuvants, was the dose that demonstrated efficacy in the 
pivotal Phase 3 study in adults 60 years of age and older. This dose has been shown to be 
well tolerated. This dose also demonstrated no interference when administered concurrently 
with a seasonal influenza vaccine (Study C3671006).5
The dose and formulation for Substudy A is 120 μg RSVpreF without any adjuvants.
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4.3.3. Combined RSVpreF and Bivalent BNT162b2 (Original/Omi BA.4/BA.5) Vaccine 
[RSVpreF+BNT162b2]
The dose and formulation for Substudy A is based on the combination of the individual 
components of the vaccine as detailed in Section 10.11.8.
4.4. End of Study Definition
The end of the substudy is defined as the date of the last visit of the last participant in the 
substudy.
A participant is considered to have completed the substudy if they have completed all periods 
of the substudy, including the last visit.
The end of the overall study is the last visit of the last participant in the substudy to be 
completed.
5. STUDY POPULATION
The substudy can fulfill the objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds.  If a 
prescreening tool is utilized for study recruitment purposes, it 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 substudy 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.
Note: “Enrolled” means a participant’s, or their legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process.
5.1. Inclusion Criteria
See Section 10.11.7.1 for the Substudy A inclusion criteria.
5.2. Exclusion Criteria
See Section 10.11.7.2 for the Substudy A exclusion criteria.
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5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or their designee, in consultation with the participant, will confirm that the 
participant is utilizing an appropriate method of contraception for the individual participant 
and their partner(s) from the permitted list of contraception methods (see Section 10.4) and 
will confirm that the participant has been instructed in its consistent and correct use. The 
investigator or designee will advise the participant to seek advice about the donation and 
cryopreservation of germ cells prior to the start of study intervention, if applicable.
At time points indicated in the SoA(s), the investigator or designee will inform the 
participant of the need to use acceptable 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 and document the requirement to use an 
alternate protocol-specified method, including if the participant will no longer use abstinence 
as the selected contraception method, 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 enrolled in the study.  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, and any SAEs.
Individuals who do not meet the criteria for participation in the substudy (screen failures) 
may be rescreened.
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Administration of 
Study Intervention
See Section 10.11.7.3 for temporary delay criteria for Substudy A.
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
See Section 10.11.8 for study intervention(s) and concomitant therapy for Substudy A.
6.1. Study Intervention(s) Administered
See Section 10.11.8.1 for study interventions to be administered during Substudy A.
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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 must be available in accordance with local guidelines for standard 
immunization practices.
Administration of study interventions will be performed by an unblinded appropriately 
qualified, 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 10.11.8.1.1 (Substudy A) for study intervention administration details.
6.1.2. Medical Devices
In this study, medical devices being deployed are for the reconstitution diluent for some of 
the study interventions. 
All medical device deficiencies (including malfunction, use error, and inadequate labeling) 
shall be documented and reported by the investigator throughout the clinical investigation 
(see Section 8.4.9) and appropriately managed by the sponsor.
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm that appropriate conditions (eg, temperature) 
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, prepare, and/or administer study intervention.
3. 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 upon return to 
business.
4. Any excursions from the study intervention label storage conditions should be reported to 
Pfizer upon discovery along with actions taken.  The site should actively pursue options 
for returning the study intervention to labeled storage conditions, 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 
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the excursion definition and information to report for each excursion will be provided to 
the site in the IPM.
5. Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the label.  See the IPM for storage conditions of the prepared study intervention.
6. Study interventions should be stored in their original containers.
7. The investigator, institution, head of the medical institution (where applicable), or 
authorized site staff 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 IPM.  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 IPM.
6.2.1. Preparation and Dispensing
See the IPM for instructions on how to prepare the study intervention for administration.  
Study intervention should be prepared and dispensed by an unblinded 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 unblinded staff member will verify the dispensing.
See Section 10.11.8.1.3.1 for further details regarding preparation and dispensing for 
Substudy A.
6.3. Assignment to Study Intervention
Allocation (randomization) of participants to vaccine groups will proceed through the use of 
an IRT system (IWR).  The site personnel (study coordinator or specified designee) will be 
required to enter or select information including, but not limited to, the user’s ID and 
password, the protocol number, and the participant number.  The site personnel will then be 
provided with a randomization number*.  The IRT system will provide a confirmation report 
containing the participant number, randomization number, and study intervention allocation 
assigned.  This report will be provided to blinded or unblinded site staff as appropriate on the 
role/permission the user is granted and must be stored in the site’s blinded or unblinded files 
as appropriate.
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* Do not randomize until eligibility is confirmed and the participant is present.
Study intervention will be dispensed at the study visits summarized in the SoA(s). 
6.4. Blinding
See Section 10.11.8.2 for Substudy A blinding arrangements.
6.4.1. Blinding of Participants
Substudy A blinding arrangements for participants are detailed in Section 10.11.8.2.1.
6.4.2. Blinding of Site Personnel
Substudy A blinding arrangements for site personnel are detailed in Section 10.11.8.2.2.
6.4.3. Blinding of the Sponsor
Substudy A blinding arrangements for the sponsor are detailed in Section 10.11.8.2.3.
6.4.4. Breaking the Blind 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s study 
intervention assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the study medical monitor
prior to unblinding a participant’s study intervention assignment unless this could delay 
further management of the participant. If a participant’s study intervention 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 IPM will provide the contact information and 
further details on the use of the IRT system.
6.5. 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.
6.6. Dose Modification
Dose modification is NA to this protocol.
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6.7. Continued Access to Study Intervention After the End of the Study
No study intervention will be provided to participants at the end of their study participation.
It is expected that participants will be treated as required with standard-of-care treatments, as 
advised by their usual care physician.
6.8. 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 study medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities as 
medically appropriate and at least until the next scheduled follow-up.
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.
6.9. Prior and Concomitant Therapy
See Section 10.11.8.7 for Substudy A prior and concomitant therapy.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
Since this is a single-dose study, this section is NA.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at their own request.  Reasons for 
discontinuation from the study include the following:

Refused further study procedures

Lost to follow-up

Death

Study terminated by sponsor
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
AEs

Participant request 

Investigator request
If a participant withdraws from the study, they 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 will be performed, and no 
additional data will be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
When a participant is withdrawn from the study, the investigator will complete the 6-month 
telephone contact if the participant has received study intervention.
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 them or persons previously authorized by the participant to provide this information.  
Participants should notify the investigator in writing of the decision to withdraw consent 
from future follow-up, whenever possible.  The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of study intervention or also from study procedures and/or postvaccination 
study follow-up, and entered on the appropriate CRF page. In the event that vital status 
(whether the participant is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law.
7.3. Lost to Follow-Up
A participant will be considered lost to follow-up if the participant 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 return to the clinic for 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.
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
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, the participant will be considered to 
have withdrawn from the study.
8. STUDY ASSESSMENTS AND PROCEDURES
8.1. Administrative Procedures
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.
Study procedures and their timing are summarized in the SoA(s).  Protocol waivers or 
exemptions are not allowed.
Adherence to the study design requirements, including those specified in the SoA(s), 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 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 they have 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.
8.1.1. Telehealth Visits
If in-clinic study visits cannot be conducted, every effort should be made to follow up on the 
safety of study participants.
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In the event that a clinic visit cannot be conducted, telehealth visits may be used to assess 
participant safety and collect data points. Telehealth includes the exchange of healthcare 
information and services via telecommunication technologies (eg, audio, video, 
videoconferencing 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 study intervention(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact. Refer to Section 10.3.3.

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

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 Section 10.4.

Study participants must be reminded to promptly notify site staff about any change in 
their health status.
Additionally, for Substudy A:

Obtain stop dates for previously reported AEs and SAEs. 

Obtain stop dates for any reactogenicity events reported as present on the last day of 
e-diary completion.

Record the use of prohibited medications in the CRF as noted in Section 10.11.8.7.1.

Record the use of any new nonstudy vaccines in the CRF.
8.2. Efficacy and/or Immunogenicity Assessments
See Section 10.11.10.1 for Substudy A immunogenicity assessments.
8.2.1. Biological Samples
Blood samples will be used only for scientific research.  Each sample will be labeled with a 
code so that the laboratory analyst testing the samples will not know the participant’s 
identity, study visit, or study cohort associated with the sample.  Samples that remain after 
performing assays outlined in the protocol may be stored by Pfizer.  Unless a time limitation 
is required by local regulations or ethical requirements, the samples will be stored for up to 
15 years after the end of the study and then destroyed.  If allowed by the ICD, stored samples 
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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 DNA will be performed.
The participant may request that their samples, if still identifiable, be destroyed at any time; 
however, any data already collected from those samples will still be used for this research.  
The biological samples may be shared with other researchers as long as confidentiality is 
maintained and no testing of the participant’s DNA is performed.
8.3. Safety Assessments
Planned time points for all safety assessments are provided in the SoA(s).  Unscheduled 
safety 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 8.4.
Acute reactions within the first 30 minutes after administration of the study intervention will 
be assessed and documented in the AE CRF.
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 8.3.4.
8.3.1. Physical Examinations
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 (Section 10.3) must be reported according to the processes in 
Sections 8.4.1 to 8.4.3.
For details, refer to the substudy appendix.
8.3.2. Vital Signs
Any untoward vital sign findings that are identified during the active collection period and 
meet the definition of an AE or SAE (Section 10.3) must be reported according to the 
processes in Sections 8.4.1 to 8.4.3.
For details, refer to the substudy appendix.
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8.3.3. Clinical Safety Laboratory Assessments
Clinical safety laboratory assessments will not be collected in this study. Measurement of 
troponin will be performed locally for potential myocarditis/pericarditis evaluation. 
For details, refer to the substudy appendix.
8.3.4. Electronic Diary
All participants will be required to complete a reactogenicity e-diary after each vaccination 
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 use of antipyretic medication 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.  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.
8.3.4.1. 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.57
8.3.4.2. 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.  In Substudy A, local reactions will be assessed at the injection site on 
the right arm.
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.
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Participants will be provided with a measuring device.  Redness and swelling will be 
measured and recorded in measuring device units (range: 1 to 21) and then categorized 
during analysis as absent, mild, moderate, or severe based on the grading scale in Table 1.  
Measuring device units can be converted to centimeters according to the following formula: 
1 measuring device unit = 0.5 cm.  Pain at the injection site will be assessed by the 
participant as absent, mild, moderate, or severe according to the grading scale in Table 1.
If a Grade 3 local reaction is reported in the reactogenicity e-diary, a telephone contact 
should occur to ascertain further details and determine whether a site visit is clinically 
indicated.  Only an investigator or medically qualified person is able to classify a 
participant’s local reaction as Grade 4.  If a participant experiences a confirmed Grade 4 local 
reaction, the investigator must immediately notify the sponsor.
Table 1.
Local Reaction Grading Scale
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially 
Life-Threatening 
(Grade 4)
Pain at the 
injection site
Does not interfere 
with activity
Interferes with activity
Prevents daily 
activity 
Emergency room visit 
or hospitalization for 
severe pain
Redness
>2.0 cm to 5.0 cm 
(5 to 10 measuring 
device units)
>5.0 cm to 10.0 cm 
(11 to 20 measuring 
device units)
>10 cm 
(≥21 measuring 
device units)
Necrosis or exfoliative 
dermatitis
Swelling
>2.0 cm to 5.0 cm 
(5 to 10 measuring 
device units)
>5.0 cm to 10.0 cm 
(11 to 20 measuring 
device units)
>10 cm 
(≥21 measuring 
device units)
Necrosis
8.3.4.3. Systemic Events
During the reactogenicity e-diary reporting period, participants will be asked to assess 
vomiting, diarrhea, headache, fatigue, chills, new or worsened muscle pain, and new or 
worsened joint pain and to record the symptoms in the reactogenicity e-diary.  The symptoms 
will be assessed by the participant as absent, mild, moderate, or severe according to the 
grading scale in Table 2.
If a systemic event 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.
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 
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to be related to the administration of the study intervention, further vaccinations will be 
discontinued in that participant.
Table 2.
Systemic Event Grading Scale
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially 
Life-Threatening 
(Grade 4)
Vomiting
1-2 times in 
24 hours
>2 times in 
24 hours
Requires IV 
hydration
Emergency room visit 
or hospitalization for 
hypotensive shock
Diarrhea
2 to 3 loose stools 
in 24 hours
4 to 5 loose stools 
in 24 hours
6 or more loose stools 
in 24 hours
Emergency room visit 
or hospitalization for 
severe diarrhea
Headache
Does not interfere 
with activity
Some interference 
with activity
Prevents daily routine 
activity
Emergency room visit 
or hospitalization for 
severe headache
Fatigue/tiredness
Does not interfere 
with activity
Some interference 
with activity
Prevents daily routine 
activity
Emergency room visit 
or hospitalization for 
severe fatigue
Chills
Does not interfere 
with activity
Some interference 
with activity
Prevents daily routine 
activity
Emergency room visit 
or hospitalization for 
severe chills
New or worsened 
muscle pain
Does not interfere 
with activity
Some interference 
with activity
Prevents daily routine 
activity
Emergency room visit 
or hospitalization for 
severe new or worsened 
muscle pain
New or worsened 
joint pain
Does not interfere 
with activity
Some interference 
with activity
Prevents daily routine 
activity
Emergency room visit 
or hospitalization for 
severe new or worsened 
joint pain
8.3.4.4. 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 ≥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 3 during analysis.
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If a fever of ≥39.0°C (≥102.1°F) is reported in the reactogenicity e-diary, a telephone contact 
should occur to ascertain further details and determine whether a site visit is clinically 
indicated.  Only an investigator or medically qualified person is able to confirm a 
participant’s fever as >40.0°C (>104.0°F).  If a participant experiences a confirmed fever 
>40.0°C (>104.0°F), the investigator must immediately notify the sponsor and, if it is 
determined to be related to the administration of the study intervention, further vaccinations
(if applicable) will be discontinued in that participant.
Table 3.
Scale for Fever
≥38.0-38.4°C (100.4-101.1°F)
>38.4-38.9°C (101.2-102.0°F)
>38.9-40.0°C (102.1-104.0°F)
>40.0°C (>104.0°F)
8.3.4.5. Antipyretic Medication
The use of antipyretic medication to treat symptoms associated with study intervention 
administration will be recorded in the reactogenicity e-diary daily during the reporting period 
(Day 1 through Day 7).
8.3.5. Stopping Rules
Stopping rules will be employed in Substudy A; see Section 10.11.10.5.
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Section 10.3.
The definitions of device-related safety events (ADEs and SADEs) can be found in 
Sections 10.10.1 and 10.10.2. Device deficiencies are covered in Section 10.10.3.
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 (see Section 7.1).
During the active collection period as described in Section 8.4.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner.
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In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.4.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant 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 A102 (1-month follow-up visit), per the SoA in the substudy appendix. 
Record any AEs that occur within the 48 hours after the blood draw. 
SAEs will be collected from the time the participant provides informed consent through and 
including Visit A103 (6-month follow-up visit), per the SoA in the substudy appendix.
Follow-up by the investigator continues throughout the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator.
When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the investigator continues until the AE or SAE or its sequelae resolve or 
stabilize at a level acceptable to the investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study 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 they 
consider 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.
8.4.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in
Section 8.4.1 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
Section 10.3.4.  The investigator will submit any updated SAE data to the sponsor within 
24 hours of its being available.
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8.4.1.2. 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 8.4.1, 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.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.4.2. 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 Section 10.3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.4.3. 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 provided in Section 10.3.
8.4.4. 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.
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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.
8.4.5. 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 EDP, EDB, and occupational exposure.
Any such exposures to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.4.5.1. 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 
inseminates a female partner.

A female nonparticipant is found to be pregnant while being exposed or having been 
exposed to study intervention because of 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 inseminates his female partner 
prior to or around the time of conception.
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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/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 study intervention.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the Vaccine SAE Reporting Form and EDP 
Supplemental Form.  Since the exposure information does not pertain to the 
participant enrolled in the study, the information is not recorded on a CRF; however, 
a copy of the completed Vaccine SAE Reporting Form is maintained in the 
investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs.  If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly), the investigator should follow the procedures 
for reporting SAEs.  Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion, including miscarriage and missed abortion, should be reported 
as an SAE;

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.
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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.
8.4.5.2. Exposure During Breastfeeding
An EDB occurs if:

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female nonparticipant is found to be breastfeeding while being exposed or having 
been exposed to study intervention (ie, environmental exposure).  An example of 
environmental EDB 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 EDB 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 EDB occurs in the setting of environmental 
exposure, the exposure information does not pertain to the participant enrolled in the study, 
so the information is not recorded on a CRF.  However, a copy of the completed Vaccine 
SAE Reporting Form is maintained in the investigator site file.
An EDB report is not created when a Pfizer drug specifically approved for use in 
breastfeeding women (eg, vitamins) is administered in accordance with authorized use.  
However, if the infant experiences an SAE associated with such a drug, the SAE is reported 
together with the EDB.
8.4.5.3. 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.
8.4.6. Cardiovascular and Death Events
Deaths will be recorded throughout the study as detailed in Section 8.4.1.
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8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.4.8. Adverse Events of Special Interest
The following events are considered AESIs:

Confirmed diagnosis of influenza.

Confirmed diagnosis of RSV infection.

Confirmed diagnosis of myocarditis or pericarditis occurring within 4 weeks after 
vaccination.  See Section 10.11.10.7.5.

Confirmed COVID-19 diagnosis (clinical signs/symptoms per the CDC62 and positive 
SARS-CoV-2 NAAT or rapid antigen test result).

Diagnosis of Guillain-Barré syndrome.

Diagnosis of acute polyneuropathy without an underlying etiology.

Diagnosis of atrial fibrillation.

Preterm delivery (delivery at <37 0/7 weeks’ gestation).

Diagnosis of a hypertensive disorder of pregnancy.

Details of the AESIs listed above are further defined in the investigator site file.
AESIs are examined as part of routine safety data review procedures throughout the clinical 
trial and as part of signal detection processes.  Should an aggregate analysis indicate that 
these prespecified events occur more frequently than expected, eg, based on epidemiological 
data, literature, or other data, then this will be submitted and reported in accordance with 
Pfizer’s safety reporting requirements.  Aggregate analyses of safety data will be performed 
on a regular basis per internal SOPs.
All AESIs must be reported as an AE or SAE following the procedures described in
Sections 8.4.1 through 8.4.3.  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.
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8.4.8.1. 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.
8.4.9. Medical Device Deficiencies
Medical devices being provided for use in this study are those listed in Section 6.1.2.  In 
order to fulfill regulatory reporting obligations worldwide, the unblinded site staff is 
responsible for the detection and documentation of events meeting the definitions of device 
deficiency that occur during the study with such devices.
The definition of a medical device deficiency can be found in Section 10.10.
Note: AEs and/or SAEs that are associated with a medical device deficiency will follow the 
same processes as other AEs or SAEs, as outlined in Sections 8.4.1 through 8.4.3 and 
Section 10.3.
8.4.9.1. Time Period for Detecting Medical Device Deficiencies
Medical device deficiencies that result in an incident will be detected, documented, and 
reported during all periods of the study in which the medical device is used.
Importantly, reportable device deficiencies are not limited to problems with the device itself 
but also include incorrect or improper use of the device and even intentional misuse, etc.
If the unblinded site staff learns of any device deficiency at any time after a participant has 
been discharged from the study, and such deficiency is considered reasonably related to a 
medical device provided for the study, the unblinded site staff will promptly notify the 
sponsor.
The method of documenting medical device deficiencies is provided in Section 10.10.
8.4.9.2. Follow-Up of Medical Device Deficiencies
Follow-up applies to all participants, including those who discontinue study intervention.
The unblinded site staff is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency.
New or updated information will be recorded on a follow-up form with all changes signed 
and dated by the unblinded site staff.
8.4.9.3. Prompt Reporting of Device Deficiencies to the Sponsor
When a device deficiency occurs: 
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1. The unblinded site staff notifies the sponsor by a contact method as detailed in the IPM 
within 1 business day of determining that the incident meets the protocol definition of a 
medical device deficiency.
2. The device deficiency must be recorded on the Medical Device Complaint form.
3. If an AE (either serious or nonserious) associated with the device deficiency occurs, then 
the AE must be entered into the AE section of the CRF.
4. If an SAE associated with the device deficiency is brought to the attention of the 
unblinded site staff, the unblinded site staff must immediately notify Pfizer Safety of 
the SAE (see Section 8.4.1.1).  All relevant details related to the role of the device 
in the event must be included in the Vaccine SAE Reporting Form as outlined in 
Sections 8.4.1.1 and 8.4.1.2.
The sponsor will be the contact for the receipt of device deficiency information.
8.4.9.4. Regulatory Reporting Requirements for Device Deficiencies
The unblinded site staff will promptly report all device deficiencies occurring with any 
medical device provided for use in the study in order for the sponsor to fulfill the legal 
responsibility to notify appropriate regulatory authorities and other entities about certain 
safety information relating to medical devices being used in clinical studies.
The unblinded site staff, or responsible person according to local requirements (eg, the head 
of the medical institution), will comply with the applicable local regulatory requirements 
relating to the reporting of device deficiencies to the IRB/EC.
8.4.10. Vaccination Errors
Vaccination 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.
Vaccination errors are recorded and reported as follows:
Recorded on the 
Vaccination Error Page 
of the CRF
Recorded on the 
Adverse Event Page 
of the CRF
Reported on the Vaccine 
SAE Reporting Form to 
Pfizer Safety Within 
24 Hours of Awareness
All (regardless of whether 
associated with an AE)
Any AE or SAE associated 
with the vaccination error
Only if associated with an 
SAE
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Vaccination errors include:

Vaccination errors involving participant exposure to the study intervention;

Potential vaccination 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 vaccination errors occurring to a study participant are to be captured on the vaccination 
error page of the CRF, which is a specific version of the AE page.
Whether or not the vaccination error is accompanied by an AE, as determined by the 
investigator, the vaccination error is recorded on the vaccination error page of the CRF and, 
if applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of 
the CRF.
In the event of a vaccination dosing error, the sponsor should be notified within 24 hours.
Vaccination errors should be reported to Pfizer Safety within 24 hours on a Vaccine SAE 
Reporting Form only when associated with an SAE.
8.5. Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.6. Genetics
NA for Substudy A.
8.7. Biomarkers
Biomarkers are not evaluated in this study.
8.8. Immunogenicity Assessments
See Section 10.11.10.1 for Substudy A.
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8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in Substudy A.
9. STATISTICAL CONSIDERATIONS
Methodology for summary and statistical analyses of the data collected in this study is 
described here and further detailed in the 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
Refer to Section 10.11.11.1 for statistical hypotheses for Substudy A.
9.2. Analysis Sets
Refer to Section 10.11.11.2 for analysis sets in Substudy A.
9.3. Statistical Analyses
The SAP will be developed and finalized 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 planned statistical analyses of the primary and secondary 
endpoints.
Statistical analyses for Substudy A are detailed in Section 10.11.11.3.
9.3.1. General Considerations
Unless stated otherwise, “vaccine group” in this section refers to the study intervention
group. 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 actually received. In general,
completely missing reactogenicity e-diary data (ie, all 7 days of e-diary collection were 
missing) will not be imputed. For partially complete e-diary data (ie, 1-6 days of 
reactogenicity data are available), it is assumed that no reactions or events were experienced 
on missing days based on the e-diary data source. Missing AE dates will be handled 
according to the Pfizer safety rules.
The estimands to evaluate the immunogenicity objective are based on the evaluable 
immunogenicity population. These estimands estimate the immune response after study 
intervention in the hypothetical setting where participants follow the study schedules and 
protocol requirements as directed. For all the immunogenicity endpoints, the analysis will be 
based on the evaluable immunogenicity population.  An additional analysis may be 
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performed based on the mITT immunogenicity population if there is a large enough 
difference in sample size between the mITT immunogenicity population and the evaluable 
immunogenicity population.  Participants will be summarized according to the vaccine group 
to which they were randomized.  Missing immunogenicity results will not be imputed. 
Immunogenicity results that are below the LLOQ will be set to 0.5 × LLOQ in the analysis; 
this may be adjusted once additional data on the assay characteristics become available.
9.3.1.1. Analyses for Binary Data
Descriptive statistics for binary 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).
The 95% CI for the difference in the proportions will be computed using the Miettinen and
Nurminen method. The 95% CI will be presented in terms of percentage.
9.3.1.2. Analyses for Continuous Data
Unless otherwise stated, descriptive statistics for continuous variables are n, mean, median, 
SD, minimum, and maximum.
CIs for the mean of the continuous variables will be constructed by the standard method 
based on the Student t distribution.
9.3.1.2.1. Geometric Mean 
Continuous immunogenicity endpoints will be logarithmically transformed for analysis. 
Geometric means and associated 2-sided 95% CIs will be derived by calculating group 
means and CIs on the natural log scale based on the t distribution, and then exponentiating 
the results.
9.3.1.2.2. Geometric Mean Fold Rises
Fold rises are defined as ratios of the results after vaccination to the results before 
vaccination.  The calculations of fold rises 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 the Student t 
distribution for the mean difference on the logarithm scale and exponentiating the confidence 
limits.
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9.3.1.2.3. Geometric Mean Ratios
The GMRs will be calculated as the mean of the difference of logarithmically transformed 
assay results between 2 vaccine groups and exponentiating the mean. Two-sided CIs will be 
obtained by calculating CIs using the Student 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 the line first going down and then to the right to 
the next assay value.
9.4. Interim Analyses
Details for interim analyses will be provided in Section 10.11.11.4 for Substudy A.
9.5. Sample Size Determination
Refer to Section 10.11.11.5 for sample size determination related to Substudy A.
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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, European MDR 2017/745 for clinical device research, and all other applicable 
local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately. 
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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 the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions regarding the 
study.  The participant should be given sufficient time and opportunity to ask questions and 
to decide whether or not to participate in the trial.
Participants must be informed that their participation is voluntary.  Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB/EC or study center.
The investigator must ensure that each participant is fully informed about the nature and 
objectives of the study, the sharing of data related to the study, and possible risks associated 
with participation, including the risks associated with the processing of the participant’s 
personal data.
The participant must be informed that their personal study-related data will be used by the 
sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the participant.
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about their 
right to access and correct their personal data and to withdraw consent for the processing of 
their 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.
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Participants must be reconsented to the most current version of the IRB/EC-approved ICD(s) 
during their participation in the study as required per local regulations.
A copy of the ICD(s) must be provided to the participant.
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 their 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.
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access.
The sponsor maintains SOPs on how to respond in the event of unauthorized access, use, or 
disclosure of sponsor information or systems.
10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee 
Substudy A will use an IRC.  The IRC is independent of the study team and includes only 
internal members.  The IRC charter describes the role of the IRC in more detail.
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The IRC will be responsible for ongoing monitoring of the safety of participants in the study 
according to the charter.  The recommendations made by the IRC 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 and investigators, as appropriate.
The responsibilities of the IRC will include at a minimum:

Review of safety data in the case of a stopping rule being met in Substudy A.
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/CTIS, and/or 
www.pfizer.com, and other public registries and websites 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.
EudraCT/CTIS
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer-sponsored interventional studies 
in accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized.
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Documents within marketing applications
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized.
Data sharing
Pfizer provides researchers secure access to participant-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 
18 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized.
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.
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 CSR.
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.
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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 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant’s medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.8. 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 Source 
Document Locator, which is maintained by the sponsor.
Description of the use of the computerized system is documented in the data management 
plan, which is maintained by the sponsor.
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The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The sponsor or designee will perform monitoring 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. Use of Medical Records
Not applicable.
10.1.10. Study and Site Start and Closure
The study start date is the date of the first participant’s first visit.
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, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment.  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;

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.
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10.1.11. Publication Policy
For multicenter trials, the primary publication will be a joint publication developed by the 
investigator and Pfizer reporting the primary endpoint(s) of the study covering all study sites.  
The investigator agrees to refer to the primary publication in any subsequent publications.  
Pfizer will not provide any financial compensation for the investigator’s participation in the 
preparation of the primary congress abstract, poster, presentation, or primary manuscript for 
the study.
Investigators are free to publish individual center results that they deem to be clinically 
meaningful after publication of the overall results of the study or 12 months after primary 
completion date or study completion at all sites, whichever occurs first, subject to the other 
requirements described in this section.
The investigator will provide Pfizer an opportunity to review any proposed publication or 
any other type of disclosure of the study results (collectively, “publication”) before it is 
submitted or otherwise disclosed and will submit all publications to Pfizer 30 days before 
submission.  If any patent action is required to protect intellectual property rights, the 
investigator agrees to delay the disclosure for a period not to exceed an additional 60 days 
upon request from Pfizer.  This allows Pfizer 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 intervention or Pfizer-related 
information necessary for the appropriate scientific presentation or understanding of the 
study results.  For joint publications, should there be disagreement regarding interpretation 
and/or presentation of specific analysis results, resolution of, and responsibility for, such 
disagreements will be the collective responsibility of all authors of the publication.
For all publications relating to the study, the investigator and Pfizer will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors.  The investigator will 
disclose any relationship with Pfizer and any relevant potential conflicts of interest, including 
any financial or personal relationship with Pfizer, in any publications.  All authors will have 
access to the relevant statistical tables, figures, and reports (in their original format) required 
to develop the publication.
10.1.12. Sponsor’s Medically Qualified Individual 
The contact information for the sponsor’s MQI for the study is documented in the study 
contact list located in the supporting study documentation/study portal or other electronic 
system.
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To facilitate access to their investigator and the sponsor’s MQI for study-related medical 
questions or problems from nonstudy healthcare professionals, 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 participant and their investigator and site staff, and between the investigator and 
sponsor study team.  The ECC is only to be used by healthcare professionals not involved in 
the research study, as a means of reaching the investigator or site staff related to the care of a 
participant.  The Pfizer Call Center number is to be used when the investigator and site staff 
are unavailable.  The Pfizer Call Center number is not for use by the participant directly; if a 
participant calls that number directly, they will be directed back to the investigator site.
10.2. Appendix 2: Clinical Laboratory Tests
Routine clinical laboratory tests are NA to Substudy A.
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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 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 an 
increase in either 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 
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suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.
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 
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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.
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 nonpathogenic  
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.
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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; 
(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 EDP or EDB
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 nonparticipant (not 
involving EDP or EDB)
None.  Exposure to a study 
nonparticipant 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.
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
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.

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.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
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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 their assessment.

For each AE or SAE, the investigator must document in the medical notes that they 
have reviewed the AE or SAE and have 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 their 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 DCT

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic DCT (eg, eSAE or PSSA).

If the electronic system is unavailable, then the site will use the paper SAE report 
form (see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic DCT (eg, eSAE or PSSA) or 
paper form (as applicable) as soon as the data become available.

After the study is completed at a given site, the electronic DCT 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 DCT 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 the 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, an alternative method should 
be used, eg, secured (Transport Layer Security) or password-protected email.  If 
none of these methods can be used, 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 
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 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 and should also be advised of the benefit for a 
female partner to use a highly effective method of contraception as a condom may 
break or leak when having sexual intercourse with a WOCBP who is not currently 
pregnant.
OR

Be vasectomized, with the absence of sperm having been confirmed.
10.4.2. Female Participant Reproductive Inclusion Criteria
The criteria below are part of inclusion criterion 1 (Age and Sex; Section 5.1) and specify the 
reproductive requirements for including female participants. Refer to Section 10.4.4 for a 
complete list of contraceptive methods permitted in the study.
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 agrees to use an acceptable contraceptive method 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.
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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.
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to a medical cause other than the above
(eg, mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview.  The method of documentation should be recorded in the participant’s medical 
record for the study.
2. Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  In addition:

A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years of age and not using hormonal 
contraception or HRT.

A female on HRT and whose menopausal status is in doubt will be required to use 
one of the highly effective nonestrogen hormonal contraception methods if she 
wishes to continue her HRT during the study.  Otherwise, she 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.
The following contraceptive methods are appropriate for this study:
Highly Effective Methods That Have Low User Dependency
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner:

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP 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.
Highly Effective Methods That Are User Dependent
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 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.
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Other Effective Methods
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).
10.5. Appendix 5: Genetics
NA for Substudy A.
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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome.  These participants fail to adapt and therefore are 
“susceptible” to progressive and serious liver injury, commonly referred to as DILI.  
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “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 T bili elevations 
(>2 × ULN) by several days or weeks.  The increase in T bili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and T bili values will be elevated 
within the same laboratory sample).  In rare instances, by the time T bili 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 T bili 
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 T bili baseline values within the normal range who 
subsequently present with AST OR ALT values ≥3 × ULN AND a T bili 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 T bili 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:
o
Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values ≥2 times the baseline values AND ≥3 × ULN; or ≥8 × ULN (whichever is 
smaller).
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o
Preexisting values of T bili above the normal range: T bili level increased from 
baseline value by an amount of ≥1 × ULN or if the value reaches ≥3 × ULN 
(whichever is smaller).
Rises in AST/ALT and T bili 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 T bili 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 
T bili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
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10.7. Appendix 7: Kidney Safety Monitoring Guidelines
10.7.1. Laboratory Assessment of Change in Kidney Function and Detection of Kidney 
Injury
Standard kidney safety monitoring requires assessment of baseline and postbaseline Screat
measurement to estimate eGFR (Screat-based eGFR) or creatinine clearance (eCrCl).  
Baseline and postbaseline Scys makes it feasible to distinguish AKI from other causes of 
Screat increase.  If Screat increase is confirmed after baseline, then reflex measurement of 
Scys is indicated (for adult and for pediatric participants). Screat and reflex Scys values are 
needed to estimate the combined Screat-Scys eGFR calculation to ascertain whether eGFR 
change from baseline is comparable for 2021 CKD-EPI eGFR Screat-only and for 
2021 CKD-EPI eGFR combined Screat plus Scys (for adult participants only).
Regardless of whether kidney function monitoring tests are required as a routine safety 
monitoring procedure in the study, if the investigator or sponsor deems it necessary to further 
assess kidney safety and quantify kidney function, then these test results should be managed 
and followed per standard of care.
10.7.2. Age-Specific Kidney Function Calculation Recommendations
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI Equations
eGFR (mL/min/1.73m²)
2021 CKD-EPI Equationsa
2021 CKD-EPI
Screat Only
Screat
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤0.7
NA
eGFR = 143 × (Screat/0.7)-0.241 × (0.9938)Age
Female
if >0.7
NA
eGFR = 143 × (Screat/0.7)-1.200 × (0.9938)Age
Male
if ≤0.9
NA
eGFR = 142 × (Screat/0.9)-0.302 × (0.9938)Age
Male
if >0.9
NA
eGFR = 142 × (Screat/0.9)-1.200 × (0.9938)Age
2021 CKD-EPI
Screat-Scys 
Combined
Screat
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤0.7
if ≤0.8
eGFR = 130 × (Screat/0.7)-0.219 × (Scys/0.8)-0.323 × (0.9961)Age
Female
if ≤0.7
if >0.8
eGFR = 130 × (Screat/0.7)-0.219 × (Scys/0.8)-0.778 × (0.9961)Age
Female
if >0.7
if ≤0.8
eGFR = 130 × (Screat/0.7)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age
Female
if >0.7
if >0.8
eGFR = 130 × (Screat/0.7)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age
Male
if ≤0.9
if ≤0.8
eGFR = 135 × (Screat/0.9)-0.144 × (Scys/0.8)-0.323 × (0.9961)Age
Male
if ≤0.9
if >0.8
eGFR = 135 × (Screat/0.9)-0.144 × (Scys/0.8)-0.778 × (0.9961)Age
Male
if >0.9
if ≤0.8
eGFR = 135 × (Screat/0.9)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age
Male
if >0.9
if >0.8
eGFR = 135 × (Screat/0.9)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age
a.
Inker LA et al. N Engl J Med. 2021;385:1737-49.
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10.7.3. Kidney Function Calculation Tools
The sponsor has provided the following resources to investigational sites when required to 
calculate age-specific kidney function at screening, baseline, and postbaseline visits. Site 
calculations of kidney function can be performed manually, using the age-appropriate 
formulae (see Section 10.7.2) and can use recommended online kidney function calculators 
to reduce the likelihood of a calculation error. 
The US National Kidney Foundation Online Calculators:

Adults (18 years and above) - 2021 CKD-EPI Creatinine Online Calculator (eGFR): 
https://www.kidney.org/professionals/KDOQI/gfr_calculator

Adolescents (12 years to <18 years) - Cockcroft-Gault Formula (eCrCl): 
https://www.kidney.org/professionals/kdoqi/gfr_calculatorCoc
Investigational sites are responsible for ensuring that the accurate age-specific equation is 
selected and that the correct units are used for Screat (mg/dL only), Scys (mg/L only), total 
body weight (kg only), and age (years). Investigators are expected to (i) review and confirm 
correctness of the kidney function calculation results and (ii) evaluate the calculated value 
within the context of historical information available to them in the participant’s medical 
record. Investigators are responsible for the clinical oversight of the participant eligibility 
process, kidney function calculation, and dose selection and adjustments per study protocol.
Investigators are encouraged to direct questions or uncertainties regarding kidney function 
and dosing to the Pfizer clinical team and medical monitor, if needed.
10.7.4. Adverse Event Grading for Kidney Safety Laboratory Abnormalities
AE grading for decline in kidney function (ie, eGFR or eCrCl) will be according to KDIGO
criteria.
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10.8. Appendix 8: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 ms.

New prolongation of QTcF to >480 ms (absolute).

New prolongation of QTcF by >60 ms from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate: 
ie, rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30-second duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 ms.

Absolute value of QTcF >450 ms AND QTcF change from baseline >60 ms.

New ST-T changes suggestive of myocardial ischemia.

New-onset LBBB (QRS complex >120 ms).

New-onset right bundle branch block (QRS complex >120 ms).

Symptomatic bradycardia.

Asystole

In awake, symptom-free participants in sinus rhythm, with documented 
asystolic pauses ≥3 seconds or any escape rate <40 bpm, or with an escape 
rhythm that is below the AV node;

In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more asystolic pauses of at least 5 seconds or longer. 

Atrial flutter or fibrillation, with rapid ventricular response rate: 
rapid = rate >120 bpm.
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
Sustained supraventricular tachycardia (rate >120 bpm) 
(“sustained” = short duration with relevant symptoms or lasting >1 minute).

Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm 
(HR <40 bpm), accelerated idioventricular rhythm (HR 40 bpm to <100 bpm), and 
monomorphic/polymorphic ventricular tachycardia (HR >100 bpm [such as torsades 
de pointes]).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as SAEs

Change in pattern suggestive of new myocardial infarction.

Sustained ventricular tachyarrhythmias (>30-second duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The major events of potential clinical concern listed above are recommended as “alerts” or notifications from 
the core ECG laboratory to the investigator and Pfizer study team, and not to be considered as all-inclusive of 
what is to be reported as AEs/SAEs.
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10.9. Appendix 9: 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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10.10. Appendix 10: AEs, ADEs, SAEs, SADEs, USADEs, and Device Deficiencies:
Definitions and Procedures for Recording, Evaluating, Follow-Up, and Reporting in 
Medical Device Studies
Definitions of a Medical Device Deficiency
The definitions and procedures detailed in this appendix are in accordance with ISO 14155 
and the European MDR 2017/745 for clinical device research (if applicable).
Both the investigator and the sponsor will comply with all local reporting requirements for 
medical devices.
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study (see Section 6.1.2 for the list of sponsor 
medical devices).
10.10.1. Definition of AE and ADE
AE and ADE Definition

An AE is defined in Appendix 3 (Section 10.3.1).

An ADE is defined as an AE related to the use of an investigational medical 
device.  This definition includes any AEs resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, or 
operation, or any malfunction of the investigational medical device as well as 
any event resulting from use error or from intentional misuse of the 
investigational medical device.
10.10.2. Definition of SAE, SADE, and USADE
SAE Definition

An SAE is defined in Appendix 3 (Section 10.3.2).
SADE Definition

An SADE is defined as an ADE that has resulted in any of the consequences 
characteristic of an SAE.

Any device deficiency that might have led to an SAE if appropriate action had 
not been taken, intervention had not occurred, or circumstances had been less 
fortunate.
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USADE Definition

A USADE (also identified as UADE in US Regulation 21 CFR 813.3) is an 
SADE that by its nature, incidence, severity, or outcome has not been identified 
in the current version of the risk analysis management file.
10.10.3. Definition of Device Deficiency
Device Deficiency Definition

A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance.  Device 
deficiencies include malfunctions, use errors, and inadequate information 
supplied by the manufacturer.
10.10.4. Recording/Reporting and Follow-Up of Medical Device Deficiencies
Device Deficiency Recording

When a device deficiency occurs, it is the responsibility of the unblinded site staff to 
review all documentation (eg, hospital progress notes, laboratory reports, and 
diagnostic reports) related to the event.

The unblinded site staff will then record all relevant device deficiency information 
in the participant’s medical records, in accordance with the investigator’s normal 
clinical practice, and will also capture the required information on the Medical 
Device Complaint form.

It is not acceptable for the unblinded site staff to send photocopies of the 
participant’s medical records to Pfizer Safety in lieu of following the reporting 
process described in the Medical Device Complaint form.

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.

If the unblinded site staff determines that the medical device deficiency may have 
injured the participant (ie, the medical device deficiency is associated with an AE or 
SAE), then the unblinded site staff will attempt to establish a diagnosis of the event 
based on signs, symptoms, and/or other clinical information.  Whenever possible, 
the diagnosis will be documented in the participant’s medical record and recorded as 
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the AE or SAE rather than the individual signs/symptoms.  Requirements for 
recording and reporting an AE or SAE are provided in Appendix 3 (Section 10.3.3).

For device deficiencies, it is very important that the unblinded site staff describe any 
corrective or remedial actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of a device 
deficiency.  This includes any amendment to the device design to prevent 
recurrence.
Assessment of Causality Occurring in Conjunction With a Medical Device Deficiency

If an AE or SAE has occurred in conjunction with a medical device deficiency, the 
investigator must assess the relationship between each occurrence of the AE or SAE 
and the medical device deficiency.  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 their assessment.

For each device deficiency, the investigator must document in the medical notes 
that they have reviewed the device deficiency and have 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 their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.
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
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-Up of Medical Device Deficiency

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 device deficiency as fully as 
possible.  This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers.

New or updated information regarding the nature of the device deficiency will be 
recorded in the originally completed Medical Device Complaint form.

New or updated information regarding any SAE that was potentially associated with 
the medical device deficiency will be submitted to Pfizer Safety on the Vaccine SAE 
Reporting Form within 24 hours of receipt of the information, according to the 
requirements provided in Section 10.3.
10.10.5. Reporting of SAEs
Reporting of an SAE to Pfizer Safety must be performed according to the processes 
described in Section 10.3.4.
10.10.6. Reporting of SADEs
SADE Reporting to Pfizer Safety
Note: There are additional reporting obligations for medical device deficiencies that are 
potentially related to SAEs (ie, an SADE) that must fulfill the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety information relating 
to medical devices being used in clinical studies.

Any device deficiency that is associated with an SAE must be reported to the 
sponsor within 24 hours after the investigator determines that the event meets the 
definition of a device deficiency.

The sponsor shall review all device deficiencies and determine and document in 
writing whether they could have led to an SAE.  These shall be reported to the 
regulatory authorities and IRBs/ECs as required by national regulations.
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10.11. Appendix 11: Substudy A (Phase 1/2)
10.11.1. Synopsis – Substudy A
See Section 1.1.
10.11.2. Schema – Substudy A (Phase 1/2) 
Vaccination
1-Month 
Follow-Up 
Visit
6-Month 
Telephone 
Contact
Approximate 
Month
(Visit Window)
0 
(Day 1)
1 
(28 to 35 Days 
After 
Vaccination)
6 
(175 to 189 Days 
After 
Vaccination)
Visit Identifier
Visit A101
Visit A102
Visit A103
Vaccination 1 
(Right Arm)
Vaccination 2
(Left Arm)
Vaccination 3
(Right Arm)
Group 1 
(n=150)
Combination 
[RSVpreF+BNT162b2] 
QIV
Group 2 
(n=150)
Combination 
[RSVpreF+BNT162b2]
Placebo
Group 3 
(n=150)
Bivalent BNT162b2
Placebo
Group 4 
(n=150)
RSVpreF
Placebo
Group 5 
(n=150)
QIV
Placebo
Group 6a
(n=150)
Bivalent BNT162b2
Placebo
RSVpreF
Group 7a
(n=150)
Bivalent BNT162b2
QIV
RSVpreF
a.
Separate administration sites on right arm by 1 inch (2.5 cm).
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10.11.3. SoA – Substudy A (Phase 1/2)
Visit Identifier
A101
A102
A103
Notes
Visit Description
Vaccination
1-Month
Follow-Up 
Visit
6-Month 
Telephone 
Contact
Visit Window (Days)
Day 1
28 to 35
Days After
Visit A101
175 to 189
Days After
Visit A101
Day 1 = Day of Vaccination
Obtain informed consent
X
See Section 10.1.3. 
Assign participant number 
X
See Section 6.3.
Obtain demography and medical history data* (including 
confirmed COVID-19 diagnosis or asymptomatic positive 
SARS-CoV-2 test result [NAAT or antigen test])
X
* Include date of onset and resolution 
(if applicable).
Perform clinical assessment
X
Including, if indicated, a physical 
examination. Examinations and assessments 
must occur prior to vaccination. 
See Section 8.3.1.
Measure height and weight
X
Measure vital signs (including oral temperature)
X
Blood pressure and pulse rate; see 
Section 8.3.2.
Confirm use of contraceptives (if appropriate)
X
X
See Section 10.4.3
Collect prior COVID-19 vaccine information
X
Collect details of any influenza vaccine received in the prior 
12 months 
X
Include product name and date of 
administration.
Collect nonstudy vaccine information 
X
X
X
See Section 10.11.8.7.
Collect prohibited medication use
X
X
See Section 10.11.8.7.1.
Confirm eligibility
X
See Section 10.11.7.
Ensure that the participant meets none of the 
temporary delay criteria as described in 
Section 5.5.
Obtain randomization number and study intervention 
allocation
X
Do not randomize until eligibility is 
confirmed and the participant is present. See 
Section 6.3.
Collect blood sample for immunogenicity assessment 
~50 mL†
~50 mL
† Prior to vaccination. 
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Visit Identifier
A101
A102
A103
Notes
Visit Description
Vaccination
1-Month
Follow-Up 
Visit
6-Month 
Telephone 
Contact
Visit Window (Days)
Day 1
28 to 35
Days After
Visit A101
175 to 189
Days After
Visit A101
Day 1 = Day of Vaccination
Administer study intervention
X
See Section 10.11.8.1.1.
Assess acute reactions for at least 30 minutes after study 
intervention administration
X
Must include time of onset.
Explain to the participant e-diary completion requirements and 
assist the participant with downloading the application or issue 
provisioned device if required
X
See Section 8.3.4.
Provide thermometer and measuring device
X
Review reactogenicity e-diary data (daily review is optimal 
during the active diary period)
X
Days 1 through 7.
Review ongoing reactogenicity e-diary symptoms and obtain 
stop dates 
X
See Section 8.3.4.
Collect AEs and SAEs as appropriate
X
X
X
Collect e-diary or assist the participant with deleting 
application
X
Ensure all e-diary data have been transferred 
prior to e-diary deactivation or removal of 
the app.
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10.11.4. Introduction – Substudy A
10.11.4.1. Substudy A Rationale
This is a Phase 1/2 substudy in up to approximately 1050 healthy participants ≥65 years of 
age to describe the safety, tolerability, and immunogenicity of a combined RSVpreF and 
bivalent BNT162b2 (original/Omi BA.4/BA.5) vaccine [RSVpreF+BNT162b2], 
administered concomitantly with a seasonal influenza vaccine or administered alone.
10.11.4.2. Background
See Section 2.2.
10.11.4.3. Benefit/Risk Assessment
See Section 2.3.1 for overall study risks.  No unique risks are identified for Substudy A.
Benefits to individual participants enrolled in Substudy A may be:

Receipt of a dose of an efficacious or potentially efficacious COVID-19 vaccine.

Receipt of a licensed influenza vaccine at no cost to the participant.

Receipt of a potentially efficacious RSV vaccine at no cost to the participant.

Contributing to research to help others.
Please see Section 2.3 for details of the SRSDs relating to the study interventions used in 
Substudy A.
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10.11.5. Objectives, Endpoints, and Estimands – Substudy A
Substudy A (Phase 1/2)
Objectives
Estimands
Endpoints
Primary
Primary
Primary
To describe the safety and tolerability of 
[RSVpreF+BNT162b2]
In participants receiving study intervention, the percentage of participants 
reporting:

Local reactions within 7 days following vaccination

Systemic events within 7 days following vaccination

AEs from vaccination through 1 month after vaccination

SAEs from vaccination through 6 months after 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 demonstrate that the immune responses elicited by 
[RSVpreF+BNT162b2] when coadministered with QIV 
are noninferior to those elicited by each vaccine alone:
1.
RSVpreF alone (Group 1 vs Group 4)
1.
In participants in compliance with the key protocol criteria 
(evaluable participants for Groups 1 and 4):

GMR of NTs at 1 month after vaccination in Group 1 to 
Group 4 for RSV subgroup A 

GMR of NTs at 1 month after vaccination in Group 1 to 
Group 4 for RSV subgroup B
1.
RSV A and RSV B NTs
2.
Bivalent BNT162b2 alone (Group 1 vs Group 3)
2.
In participants in compliance with the key protocol criteria 
(evaluable participants for Groups 1 and 3):

GMR of NTs at 1 month after vaccination in Group 1 to 
Group 3 for SARS-CoV-2 Omicron BA.4/BA.5

GMR of NTs at 1 month after vaccination in Group 1 to 
Group 3 for SARS-CoV-2 reference strain
2.
SARS-CoV-2 Omicron BA.4/BA.5
and reference-strain NTs
3.
QIV alone (Group 1 vs Group 5)
3.
In participants in compliance with the key protocol criteria 
(evaluable participants for Groups 1 and 5):

GMR of HAI titers at 1 month after vaccination in Group 1 to 
Group 5 for each influenza strain included in the QIV
3.
HAI titers for each strain contained in 
the QIV
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Substudy A (Phase 1/2)
Objectives
Estimands
Endpoints
To demonstrate that the immune responses elicited by 
[RSVpreF+BNT162b2] are noninferior to those elicited 
by each vaccine alone:
1.
RSVpreF alone (Group 2 vs Group 4)
1.
In participants in compliance with the key protocol criteria 
(evaluable participants for Groups 2 and 4):

GMR of NTs at 1 month after vaccination in Group 2 to 
Group 4 for RSV subgroup A 

GMR of NTs at 1 month after vaccination in Group 2 to 
Group 4 for RSV subgroup B
1. RSV A and RSV B NTs
2. Bivalent BNT162b2 alone (Group 2 vs Group 3)
2.
In participants in compliance with the key protocol criteria 
(evaluable participants for Groups 2 and 3):

GMR of NTs at 1 month after vaccination in Group 2 to 
Group 3 for SARS-CoV-2 Omicron BA.4/BA.5

GMR of NTs at 1 month after vaccination in Group 2 to 
Group 3 for SARS-CoV-2 reference strain
2. SARS-CoV-2 Omicron BA.4/BA.5 and 
reference-strain NTs
Secondary
Secondary
Secondary
To demonstrate that the immune responses elicited by
RSVpreF, bivalent BNT162b2, and QIV, when 
administered concomitantly, are noninferior to those 
elicited by each vaccine alone:
1.
RSVpreF (Group 7 vs Group 4)
1.
In participants in compliance with the key protocol criteria 
(evaluable participants for Groups 7 and 4):

GMR of NTs at 1 month after vaccination in Group 7 to 
Group 4 for RSV subgroup A

GMR of NTs at 1 month after vaccination in Group 7 to 
Group 4 for RSV subgroup B
1.
RSV A and RSV B NTs
2. Bivalent BNT162b2 (Group 7 vs Group 3)
2.
In participants in compliance with the key protocol criteria 
(evaluable participants for Groups 7 and 3):

GMR of NTs at 1 month after vaccination in Group 7 to 
Group 3 for SARS-CoV-2 Omicron BA.4/BA.5

GMR of NTs at 1 month after vaccination in Group 7 to 
Group 3 for SARS-CoV-2 reference strain
2.
SARS-CoV-2 Omicron BA.4/BA.5
and reference-strain NTs
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Substudy A (Phase 1/2)
Objectives
Estimands
Endpoints
3. QIV (Group 7 vs Group 5)
3.
In participants in compliance with the key protocol criteria 
(evaluable participants for Groups 7 and 5):

GMR of NTs at 1 month after vaccination in Group 7 to 
Group 5 for each influenza strain included in the QIV
3.
HAI titers for each strain contained in 
the QIV
To demonstrate that the immune responses elicited by 
RSVpreF and bivalent BNT162b2 when administered 
concomitantly are noninferior to those elicited by each 
vaccine alone:
1.
RSVpreF (Group 6 vs Group 4)
1.
In participants in compliance with the key protocol criteria 
(evaluable participants for Groups 6 and 4):

GMR of NTs at 1 month after vaccination in Group 6 to 
Group 4 for RSV subgroup A 

GMR of NTs at 1 month after vaccination in Group 6 to 
Group 4 for RSV subgroup B
1. RSV A and RSV B NTs
2.
Bivalent BNT162b2 (Group 6 vs Group 3)
2.
In participants in compliance with the key protocol criteria 
(evaluable participants for Groups 6 and 3):

GMR of NTs at 1 month after vaccination in Group 6 to 
Group 3 for SARS-CoV-2 Omicron BA.4/BA.5

GMR of NTs at 1 month after vaccination in Group 6 to 
Group 3 for SARS-CoV-2 reference strain
2. SARS-CoV-2 Omicron BA.4/BA.5 and 
reference-strain NTs
Exploratory
Exploratory
Exploratory
To further describe the immune responses elicited by 
[RSVpreF+BNT162b2]
NA
NA
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10.11.6. Substudy A Design
10.11.6.1. Overall Design
This is a Phase 1/2 randomized, parallel-group, observer-blinded substudy to describe the 
safety, tolerability, and immunogenicity of a combined RSVpreF and bivalent BNT162b2 
(original/Omi BA.4/BA.5) vaccine [RSVpreF+BNT162b2], administered concomitantly with 
a seasonal influenza vaccine or administered alone. Approximately 1050 healthy participants
≥65 years of age will be enrolled in Substudy A.
Note: "Enrolled" means a participant's, or their legally authorized representative’s, agreement 
to participate in a clinical study following completion of the informed consent process.
Randomization will be conducted across 2 enrollment strata (see Table 4).
Table 4.
Substudy A Enrollment Strata
Enrollment 
Stratum
Total Number 
of Participants
Number of 
Participants per 
Vaccine Group
Vaccine 
Group 
Number
Vaccine Group Description
1
750
150
1
[RSVpreF+BNT162b2] administered 
concurrently in the opposite arm to 
licensed QIV 
150
2
[RSVpreF+BNT162b2] administered 
concurrently in the opposite arm to 
placebo
150
3
Bivalent BNT162b2 administered 
concurrently in the opposite arm to 
placebo
150
4
RSVpreF administered concurrently 
in the opposite arm to placebo
150
5
Licensed QIV administered 
concurrently in the opposite arm to 
placebo
2
300
150
6
RSVpreF and bivalent BNT162b2 
(2 injections in the same arm) 
coadministered concurrently in the 
opposite arm to placebo
150
7
RSVpreF and bivalent BNT162b2 
(2 injections in the same arm) 
coadministered concurrently in the 
opposite arm to QIV
All participants will be asked to complete a reactogenicity e-diary for 7 days following 
vaccination.  Blood samples of approximately 50 mL will be collected for immunogenicity 
assessments prior to vaccination at Visit A101 and 1 month after vaccination (Visit A102). 
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E-diary data from Day 1 through Day 3 for the first 50 participants in Groups 1 to 5, and the 
first 20 participants in Groups 6 and 7, will be evaluated prior to enrollment of the remaining 
participants in each group.
AEs and SAEs will be collected from the signing of informed consent through Visit A102
(1-month follow-up visit). SAEs will be collected from the signing of informed consent 
through Visit A103 (6-month telephone contact).
Substudy A will have stopping rules that will apply to participants as detailed in
Section 10.11.10.5, with monitoring by designated unblinded sponsor site staff on an ongoing 
basis. If a stopping rule is confirmed, further randomization and study intervention 
administration will be paused while additional information is gathered, and cumulative 
unblinded safety data will be reviewed by the IRC. Participants who have received study 
intervention will continue further study visits and procedures as scheduled. A charter for the 
IRC will be prepared and finalized before the first participant provides informed consent.
The total duration of the study for each participant will be up to approximately 6 months.
10.11.6.2. Scientific Rationale for Study Design
See Section 2.1.
10.11.6.3. Justification for Dose
See Section 4.3.
10.11.6.4. End of Study Definition
See Section 4.4.
10.11.7. Substudy A Population
10.11.7.1. Substudy A 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 ≥65 years of age at Visit 1 (Day 1).

Refer to Section 10.4 for reproductive criteria for male Section 10.4.1 and female 
(Section 10.4.2) participants.
Disease Characteristics:
NA.
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Other Inclusion Criteria:
2. Participants who are willing and able to comply with all scheduled visits, investigational 
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 10.9.
4. Capable of giving signed informed consent as described in the protocol, which includes 
compliance with the requirements and restrictions listed in the ICD and in this protocol.
5. Participants who have received at least 3 prior US-authorized mRNA COVID-19
vaccines, with the last dose being an updated (bivalent) vaccine given at least ≥150 days 
before Visit A101 (Day 1). Any dose of modRNA SARS-CoV-2 vaccine received after 
01 September 2022 in the US may be considered to be a bivalent vaccine.
Note: Documented confirmation of prior doses of COVID-19 vaccines received must be 
obtained prior to randomization.
10.11.7.2. Substudy A Exclusion Criteria
Participants are excluded from Substudy A if any of the following criteria apply:
Medical Conditions:
1. A confirmed diagnosis of COVID-19, RSV infection, or influenza ≤120 days before 
study intervention administration.
2. History of severe adverse reaction associated with any vaccine and/or severe allergic 
reaction (eg, anaphylaxis) to any component of the study intervention(s).
3. Immunocompromised individuals with known or suspected immunodeficiency, as 
determined by history and/or laboratory/physical examination.
4. Bleeding diathesis or condition associated with prolonged bleeding that would, in the 
opinion of the investigator, contraindicate intramuscular injection.
5. Allergy to egg proteins (egg or egg products) or chicken proteins.
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6. Any 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.
Prior/Concomitant Therapy:
7. Receipt of chronic systemic treatment with known immunosuppressant medications 
(including cytotoxic agents or systemic corticosteroids), or radiotherapy, within 60 days 
before enrollment through conclusion of the study.
Note: Systemic corticosteroids are defined as those administered for ≥14 days at a dose 
of ≥20 mg/day of prednisone or equivalent (eg, for cancer or an autoimmune disease).  
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 planned receipt throughout the study.
9. Receipt of any RSV vaccine at any time prior to enrollment, or planned receipt 
throughout the study.
10. Receipt of any influenza vaccine ≤120 days before study enrollment.
Prior/Concurrent Clinical Study Experience:
11. Participation in other studies involving a study intervention within 28 days before 
randomization.
12. Anticipated participation in other studies within 28 days after receipt of study 
intervention in this study.
Diagnostic Assessments:
NA.
Other Exclusion Criteria:
13. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members.
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10.11.7.3. Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention
The following conditions may allow a participant to be randomized once the conditions have 
resolved and the participant is otherwise considered eligible.  Participants meeting these 
criteria at Visit 1 will be considered screen failures if enrollment has closed once the 
condition(s) has/have resolved.
1. A positive SARS-CoV-2 test result (NAAT or rapid antigen test) within the previous 
28 days.
2. Current febrile illness (oral temperature ≥38.0°C [≥100.4°F]) or other acute illness within 
48 hours before study intervention administration.  This includes symptoms that could 
represent a potential COVID-19 illness (refer to Section 8.4.8).
Note: The participant should be directed to seek additional testing through their primary 
healthcare provider 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, as per local guidance.
3. Receipt of any nonstudy vaccine within 28 days before study intervention administration 
at Visit A101.
4. Anticipated receipt of any nonstudy vaccine within 28 days after study intervention 
administration at Visit A101.
5. 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.
10.11.8. Substudy A Intervention and Concomitant Therapy
Study interventions are all prespecified investigational and medical devices, and other 
interventions (eg, surgical and behavioral), intended to be administered to the study 
participants during the study conduct.

Combined RSVpreF and bivalent BNT162b2 (original*/Omi BA.4/BA.5) vaccine 
[RSVpreF+BNT162b2] 0.8 mL, which is a combination of the following:
o
120 µg RSVpreF containing 2 stabilized RSV prefusion F antigens, in equal 
amounts (60 µg per strain) from virus subgroups A and B
o
30 µg Bivalent BNT162b2 (15 µg original/Omi BA.4/BA.5), which contains 
original BNT162b2 and BNT162b2 Omicron (15 µg B.1.1.529 sublineage 
BA.4/BA.5)
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
120 µg RSVpreF containing 2 stabilized RSV prefusion F antigens, in equal amounts
(60 µg per strain) from virus subgroups A and B

Licensed QIV

30 µg Bivalent BNT162b2 (15 µg original/Omi BA.4/BA.5), which contains original 
BNT162b2 and BNT162b2 Omicron (15 µg B.1.1.529 sublineage BA.4/BA.5)

Normal saline (0.9% sodium chloride solution for injection) 0.8 mL
*Original refers to the ancestral strain (Wuhan-Hu-1; USA-WA1/2020), also referred to in 
this protocol as the reference strain.
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10.11.8.1. Study Intervention(s) Administered
Study interventions for Substudy A will include the following:
Substudy A Study Interventions
Intervention Name
Combination 
[RSVpreF+BNTb162b2]
Bivalent BNT162b2 
(Originala/Omi
BA.4/BA.5)
RSVpreF
QIV
Normal Saline Placebo
Arm Name
(group of participants receiving a 
specific study intervention or no 
study intervention)
Groups 1, 2: 
Combination 
[RSVpreF+BNT162b2]
Groups 3, 6, 7:
Bivalent BNT162b2 
(originala/Omi BA.4/BA.5)
(30 µg)
Groups 4, 6, 7:
RSVpreF (120 µg)
Groups 1, 5, 7:
QIV
Groups 2, 3, 4, 5, 6:
Placebo
Targeted Influenza Strains
NA
NA
NA
For each season, 
strains as 
recommended by 
WHO
NA
Type
Vaccine
modRNA vaccine
Vaccine
Vaccine
Placebo
Dose Formulation
Suspension for
injection
Suspension for
injection
Powder for solution 
for injection
Suspension for 
injection
Normal saline
(0.9% sodium chloride 
solution for injection)
Unit Dose Strength(s)
As detailed in the IPM
As detailed in the IPM
As detailed in the 
IPM
As detailed in the IPM NA
Dosage Level(s) or Volume
RSVpreF 120 µg
Bivalent BNT162b2 30 µg
30 µg
120 µg
0.7 mL
0.8 mL
Route of Administration
Intramuscular injection
Intramuscular injection
Intramuscular 
injection
Intramuscular 
injection
Intramuscular injection
Use
Experimental
Comparator (Group 3) 
Experimental (Groups 6 and 
7)
Comparator (Group 4) 
Experimental 
(Groups 6 and 7)
Comparator (Group 5)
Experimental 
(Groups 1 and 7)
Placebo for blinding
IMP or NIMP/AxMP
IMP
IMP
IMP
IMP
IMP
Sourcing
Provided centrally by Pfizer
Provided centrally by Pfizer
Provided centrally by 
Pfizer
Provided centrally by 
Pfizer
Provided centrally by 
Pfizer
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PF-07960613 (Combination COVID-19 and RSV Vaccine)
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Substudy A Study Interventions
Intervention Name
Combination 
[RSVpreF+BNTb162b2]
Bivalent BNT162b2 
(Originala/Omi
BA.4/BA.5)
RSVpreF
QIV
Normal Saline Placebo
Packaging and Labeling
Study intervention will be 
generated by mixing the 
following at the site at the 
dose-level combinations 
detailed below:

RSVpreF 

Bivalent BNT162b2 
(originala/Omi 
BA.4/BA.5) 
Each vial will be labeled per 
country requirement.
Study intervention will be 
provided in a glass vial as 
open-label supply. Each 
vial will be
labeled per country 
requirement.
Study intervention 
will be provided in a 
glass vial as 
open-label supply. It 
is reconstituted with a 
PFS of sterile water 
diluent for injection 
(supplied).  Each vial 
and PFS will be 
labeled per country 
requirement.
Study intervention 
will be provided as a 
PFS as open-label 
supply. Each carton 
will be labeled per 
country requirement.
Study intervention will be 
provided as either a PFS 
or a glass/plastic vial as 
open-label supply. Each 
PFS or vial will be labeled 
per country requirement.
SRSD
IB
IB
IB
USPI
NA
a.
Original refers to the ancestral strain (Wuhan-Hu-1; USA-WA1/2020).
Substudy A Study Arms
Group Number
1
2
3
4
5
6
7
Arm Title
Combination 
[RSVpreF+BNT162b2 
(0.8 mL)] + QIV
Combination 
[RSVpreF+BNT162b2
(0.8 mL)] + placebo
Bivalent 
BNT162b2 (30 µg) 
+ placebo
RSVpreF (120 µg) 
+
placebo
QIV + placebo Coadministration  
RSVpreF + 
bivalent 
BNT162b2 + 
placebo
Coadministration
RSVpreF + bivalent 
BNT162b2 + QIV
Arm Type
Experimental
Experimental
Comparator
Comparator
Comparator
Experimental
Experimental
Arm Description
Participants will receive 
combination [RSVpreF 
(120 µg) + BNT162b2 
(30 µg)] + QIV
Participants will receive 
combination [RSVpreF 
(120 µg) + BNT162b2 
(30 µg)] + placebo
Participants will 
receive BNT162b2 
(30 µg) + placebo
Participants will 
receive RSVpreF 
(120 µg) + 
placebo
Participants 
will receive 
QIV + placebo
Participants will 
receive 
coadministered 
RSVpreF (120 µg) 
+ BNT162b2 
(30 µg) + placebo
Participants will 
receive 
coadministered 
RSVpreF (120 µg) 
+ BNT162b2 
(30 µg) + QIV
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PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
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TMF Doc ID: 164.01
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Substudy A Study Arms
Group Number
1
2
3
4
5
6
7
Associated 
Intervention 
Labels
[RSVpreF (120 µg) + 
BNT162b2 (30 µg)] + QIV
[RSVpreF (120 µg) + 
BNT162b2 (30 µg)] + 
placebo
BNT162b2 (30 µg) 
+ placebo
RSVpreF (120 µg) 
+ placebo
QIV + placebo RSVpreF (120 µg) 
+ BNT162b2 
(30 µg) + placebo
RSVpreF (120 µg) 
+ BNT162b2 
(30 µg) + QIV
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TMF Doc ID: 164.01
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10.11.8.1.1. Administration
See Section 10.11.8.1.
During Substudy A, all study interventions are to be administered as an intramuscular
injection into the deltoid muscle of the arm, in accordance with the schema (Section 10.11.2)
and the SoA (Section 10.11.3).
10.11.8.1.2. Medical Devices 
See Section 6.1.2.
10.11.8.1.3. Preparation, Handling, Storage, and Accountability
See Section 6.2.
10.11.8.1.3.1. Preparation and Dispensing
See Section 6.2.1.
During Substudy A, study intervention will be prepared and dispensed by an unblinded 
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 unblinded staff member will 
verify the dispensing.
10.11.8.1.4. Allocation to Study Intervention
See Section 6.3.
Allocation of study intervention at Visit A101 in Substudy A will be conducted via the IRT.
E-diary data from Day 1 through Day 3 for the first 50 participants in Groups 1 to 5, and the 
first 20 participants in Groups 6 and 7, will be evaluated prior to enrollment of the remaining 
participants in each group. Initial enrollment will be controlled through the IRT system to 
manage this approach.
10.11.8.2. Blinding
This is an observer-blinded study.
10.11.8.2.1. Blinding of Participants
Participants will be blinded to their assigned study intervention. When the 1-month analysis 
has been performed, and when directed by the sponsor (anticipated to be between Visit A102 
and Visit A103), participants may be unblinded to confirm the vaccine received.  The study 
team will also become unblinded to the participant’s study intervention allocation at this 
time.
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10.11.8.2.2. Blinding of Site Personnel
The study staff receiving, storing, dispensing, preparing, and administering the study 
interventions will be unblinded. All other study and site personnel, including the investigator 
and investigator staff, will be blinded to assignment of study intervention. In particular, the 
individuals who evaluate participant safety will be blinded. Because there are differences in 
physical appearance between study interventions, study interventions will be administered in 
a manner that prevents the participants from identifying the study intervention 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 nursing/medical staff or clinic pharmacy will 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.
10.11.8.2.3. Blinding of the Sponsor
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 will support interactions with and analyses for the IRC (see
Section 10.1.5).  This team comprises a statistician, programmer(s), a clinical scientist, 
and a medical monitor. 
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When the 1-month analysis has been performed, and when directed by the sponsor 
(anticipated to be between Visit A102 and Visit A103), participants may be unblinded to 
confirm the vaccine received.  The study team will also become unblinded to the 
participant’s study intervention allocation at this time.
10.11.8.2.4. Breaking the Blind
See Section 6.4.4.
10.11.8.3. Study Intervention Compliance
See Section 6.5.
10.11.8.4. Dose Modification 
NA.
10.11.8.5. Continued Access to Study Intervention After the End of the Study
See Section 6.7.
10.11.8.6. Treatment of Overdose
See Section 6.8.
10.11.8.7. Prior and Concomitant Therapy
For Substudy A, the following concomitant medications and vaccinations will be recorded in 
the CRF:

Prior receipt of any COVID-19 vaccine.

Influenza vaccine*, if received during the 12 months prior to enrollment.

*Include product name and date of administration.

Any vaccinations received from 28 days prior to study enrollment until the last visit 
(A103).

Prohibited medications listed in Section 10.11.8.7.1, if taken, will be recorded and 
include start and stop dates, name of the medication, dose, unit, route, and frequency.
10.11.8.7.1. 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; however, it is 
anticipated that the participant would not be withdrawn from the study (see Section 7).
Medications should not be withheld if required for a participant’s medical care.
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
Unless considered medically necessary, no vaccines other than study intervention should 
be administered within 28 days before and 28 days after study vaccination at Visit 1.

Licensed or nonstudy investigational coronavirus vaccine from enrollment through 
31 August 2023.

Licensed or nonstudy investigational influenza vaccine from enrollment through 
31 August 2023.

Licensed or nonstudy investigational RSV vaccine from enrollment through
31 August 2023.

Receipt of chronic systemic treatment with known immunosuppressant medications, or 
radiotherapy, within 60 days before enrollment through conclusion of the study is 
prohibited.

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 study intervention.

Receipt of blood/plasma products, immunoglobulins, or monoclonal antibodies, from 
60 days before study intervention administration through conclusion of the study.

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.
10.11.8.7.2. Permitted During the Study

Medication other than that described as prohibited in Section 10.11.8.7.1 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.
10.11.9. Discontinuation of Substudy A Intervention and Participant 
Discontinuation/Withdrawal
See Section 7.
10.11.10. Substudy A Assessments and Procedures
For Substudy A, the minimal blood sampling volume for all individual participants in this 
study is approximately 100 mL.
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For all participants in Substudy A, other additional blood samples may be taken for safety 
assessments, provided the total volume taken during the study does not exceed 550 mL 
during any period of 60 consecutive days.
10.11.10.1. Immunogenicity Assessments
Samples will be collected at time points as specified in Section 10.11.3 from all applicable 
participants, and the following assays will be performed:

HAI titers for the matched seasonal strains (2×A, 2×B) recommended by WHO for 
Groups 1, 5, and 7.

SARS-CoV-2 neutralization assay (reference strain) for Groups 1, 2, 3, 6, and 7.

SARS-CoV-2 neutralization assays (Omicron BA.4, Omicron BA.5; other variants, 
including other Omicron sublineages, may also be evaluated) for Groups 1, 2, 3, 6, and 7.

RSV A and RSV B serum NTs for Groups 1, 2, 4, 6, and 7.
10.11.10.2. N-Binding Antibody Test
The N-binding antibody test will be performed by the central laboratory on each blood 
sample to establish prior exposure to SARS-CoV-2 up to each time point.  
10.11.10.3. Biological Samples
See Section 8.2.1.
10.11.10.4. Safety Assessments
See Section 8.3.
10.11.10.5. Stopping Rules
The following stopping rules are in place for Substudy A participants, based on review of 
AEs, ECG, and laboratory data, and apply to study vaccination (Day 1) through Day 28.  
These data will be monitored on an ongoing basis by the investigator (or medically qualified 
designee) and sponsor in order to promptly identify and flag any event that potentially 
contributes to a stopping rule. In the event that sponsor personnel confirm that a stopping
rule is met, the following actions will commence:

The IRC will review all appropriate data.

The stopping rule will PAUSE randomization and any further study intervention 
administration.
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
For all participants already vaccinated, all other routine study conduct activities, 
including ongoing data entry, reporting of AEs, participant e-diary completion, blood 
sample collection, and participant follow-up, will continue during the pause.
A stopping rule is met if any of the following criteria occur within 28 days after study 
intervention administration. 
Stopping Rule Criteria:
If any participant vaccinated with the combined RSVpreF and bivalent BNT162b2
(original/Omi BA.4/BA.5) vaccine [RSVpreF+BNT162b2] develops:
1. A new ECG abnormality that a cardiologist judges consistent with probable or possible 
myocarditis or pericarditis, including:

Sustained atrial or ventricular arrhythmias

Second-degree Mobitz Type II or worse AV block, new bundle branch block

Diffuse ST-segment elevation or PR-segment inversion, compatible with pericarditis
2. An abnormal troponin value that is confirmed abnormal on repeat testing, assessed as 
related to study intervention by the investigator.
3. If ≥1 participant vaccinated with any [RSVpreF+BNT162b2] combination develops 
confirmed myocarditis or pericarditis.
4. If any participant vaccinated with any [RSVpreF+BNT162b2] combination dies.
A charter for the IRC will be prepared and finalized before the first participant provides
consent.
10.11.10.6. Adverse Events, Serious Adverse Events, and Other Safety Reporting
See Section 8.4.
10.11.10.7. Study Procedures
10.11.10.7.1. Visit A101 – 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 their 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.

Assign a 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 (as permitted by local regulations) to critically 
evaluate the immune response and safety profile by age.

Obtain medical history data*, including confirmed COVID-19 diagnosis (see 
Section 8.4.8) or asymptomatic positive SARS-CoV-2 test result (NAAT or antigen test), 
and any other medical history of clinical significance.

*Include date of onset and resolution (if applicable).

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 or on the AE CRF as per Section 10.3.

Measure the participant’s height and weight.

Measure the participant’s vital signs, including oral temperature, pulse rate, and seated 
blood pressure.

Discuss contraceptive use as described in Section 5.3.1.

Review documentation of all prior COVID-19 vaccinations. Record prior receipt of any 
COVID-19 vaccine as described in Section 10.11.8.7.

Record details of any influenza vaccine received in the prior 12 months, as described in 
Section 10.11.8.7.

Record nonstudy vaccinations as described in Section 10.11.8.7.

Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met.

Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5.

Obtain the participant’s randomization number and study intervention allocation using 
the IRT system.

Collect a blood sample (approximately 50 mL), before administration of study 
intervention, for immunogenicity assessment.
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
Unblinded site staff member(s) will dispense/administer study intervention into the 
deltoid muscle of the arm as described in Section 10.11.8.  Please refer to the IPM for 
further instruction on this process.

Site staff must observe the participant for at least 30 minutes after study intervention 
administration for any acute reactions.  Record any acute reactions (including time of 
onset) in the participant’s source documents and on the AE page of the CRF, and on an 
SAE form as applicable.

Issue a measuring device to measure local reactions at the injection site and a 
thermometer for recording daily temperatures and provide instructions on their use.

Explain the e-diary completion requirement to the participant and assist the participant 
with downloading the study application onto the participant’s own device or issue a 
provisioned device if required.  Provide instructions on e-diary completion and ask the 
participant to complete the reactogenicity e-diary from Day 1 through Day 7, with Day 1 
being the day of vaccination.

Ask the participant to contact the site staff or investigator immediately if they experience 
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.

Record AEs as described in Section 8.4.1.

Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs.

Ask the participant to contact the site staff or investigator immediately if the participant 
experiences acute chest pain, shortness of breath, or palpitations (see
Section 10.11.10.7.5).

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.
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
The investigator or an authorized designee completes the CRFs and 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.
10.11.10.7.2. Visit A102 – 1-Month Follow-Up Visit (After Vaccination) – 28 to 35 Days 
After Visit A101

Record AEs as described in Section 8.4.

Record nonstudy vaccinations as described in Section 10.11.8.7.

Record prohibited medication use as described in Section 10.11.8.7.1.

Verify understanding of and compliance with protocol requirements for contraception as 
described in Section 5.3.1.

Collect a blood sample of approximately 50 mL for immunogenicity testing.

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.

If not already completed, collect the participant’s e-diary or assist the participant with 
removing the study application from their own personal device.
o
Ensure all e-diary data have been transferred prior to e-diary deactivation or removal 
of the app.

Record any AEs that occur within the 48 hours after the blood draw as described in
Section 8.4.1.
10.11.10.7.3. Visit A103 – 6-Month Telephone Contact – 175 to 189 Days After 
Visit A101

Contact the participant by telephone.

Record SAEs as described in Section 8.4.

Record nonstudy vaccinations as described in Section 10.11.8.7.

Record prohibited medication use as described in Section 10.11.8.7.1.
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
Complete the source documents.

The investigator or an authorized designee completes the CRFs.
10.11.10.7.4. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction
If a Grade 3 local reaction (Section 8.3.4.2), systemic event (Section 8.3.4.3), or fever of 
≥39.0°C (≥102.1°F) (Section 8.3.4.4) 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 8.3.4.2), systemic event 
(Section 8.3.4.3), or fever (Section 8.3.4.4) is reported in the reactogenicity e-diary, a 
telephone contact or site visit should occur to confirm whether the event meets Grade 4 
criteria.
A site visit must be scheduled as soon as possible to assess the participant unless any of the 
following is true:

The participant is unable to attend the unscheduled visit.

The local reaction/systemic event is no longer present at the time of the telephone 
contact.

The participant recorded an incorrect value in the reactogenicity e-diary (confirmation of 
a reactogenicity e-diary data entry error).

The PI or authorized designee determined it was not needed.
This telephone contact will be recorded in the participant’s source documentation and the 
CRF.
If the participant is unable to attend the unscheduled visit, or the PI or authorized designee 
determined it was not needed, any ongoing local reactions/systemic events must be assessed 
at the next study visit.
During the unscheduled visit, the reactions 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 8.3.4.2.
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
Assess systemic events (if present) in accordance with the grades provided in 
Section 8.3.4.3.

Assess other findings associated with the reaction and record this 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.
10.11.10.7.5. 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 28 days after 
study vaccination must be specifically evaluated 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:

Evaluation by a cardiologist,

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.
10.11.11. Statistical Considerations – Substudy A
Methodology for summary and statistical analyses of the data collected in this substudy is 
described here and further detailed in the 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.
10.11.11.1. Statistical Hypotheses
The estimands corresponding to the primary and secondary objectives are described in the 
table in Section 10.11.5.
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Both primary and secondary immunogenicity objectives are hypothesis-testing objectives. 
The subsections below describe details of hypotheses to be tested for each objective.
10.11.11.1.1. Statistical Hypotheses for Combined Vaccine Coadministered With QIV
A total of 8 hypotheses will be tested for the first primary immunogenicity objective as 
described below for each vaccine component.
1. The null hypothesis (H0) to assess noninferiority of the response with respect to RSVpreF 
will be evaluated by the following hypothesis for both RSV A and RSV B as measured 
by NT:
H0: ln(µ1) - ln(µ4) ≤ln(0.5)
where ln(0.5) corresponds to a 2-fold margin for noninferiority, and ln(µ1) and ln(µ4) are 
the natural log of the geometric mean of NT at 1 month after vaccination for Group 1 and 
Group 4, respectively. 
2. The null hypothesis (H0) to assess noninferiority of the response with respect to 
BNT162b2 will be evaluated by the following hypothesis for both the SARS-CoV-2 
Omicron BA.4/BA.5 strain and the reference strain as measured by NT:
H0: ln(µ1) - ln(µ3) ≤ln(0.5) 
where ln(0.5) corresponds to a 2-fold margin for noninferiority, and ln(µ1) and ln(µ3) are 
the natural log of the geometric mean of NT at 1 month after vaccination for Group 1 and 
Group 3, respectively. 
3. The null hypothesis (H0) to assess noninferiority of the response with respect to QIV will 
be evaluated by the following hypothesis for each of the 4 strains included in QIV as 
measured by HAI titer:
H0: ln(µ1) - ln(µ5) ≤ln(0.5) 
where ln(0.5) corresponds to a 2-fold margin for noninferiority, and ln(µ1) and ln(µ5) are 
the natural log of the geometric mean of HAI titers at 1 month after vaccination for 
Group 1 and Group 5, respectively. 
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10.11.11.1.2. Statistical Hypotheses for Combined Vaccine Alone
A total of 4 hypotheses will be tested for the second primary immunogenicity objective as 
described below for each vaccine component.
1. The null hypothesis (H0) to assess noninferiority of the response with respect to RSVpreF 
will be evaluated by the following hypothesis for both RSV A and RSV B as measured 
by NT:
H0: ln(µ2) - ln(µ4) ≤ln(0.5) 
where ln(0.5) corresponds to a 2-fold margin for noninferiority and ln(µ2) and ln(µ4) are 
the natural log of the geometric mean of NT at 1 month after vaccination for Group 2 and 
Group 4, respectively. 
2. The null hypothesis (H0) to assess noninferiority of the response with respect to 
BNT162b2 will be evaluated by the following hypothesis for both the SARS-CoV-2 
Omicron BA.4/BA.5 strain and the reference strain as measured by NT:
H0: ln(µ2) - ln(µ3) ≤ln(0.5) 
where ln(0.5) corresponds to a 2-fold margin for noninferiority and ln(µ2) and ln(µ3) are 
the natural log of the geometric mean of NT at 1 month after vaccination for Group 2 and 
Group 3, respectively. 
10.11.11.1.3. Statistical Hypotheses for Coadministration of 3 Individual Vaccines
A total of 8 hypotheses will be tested for the first of the secondary objectives similar to
Section 10.11.11.1.1, except that Group 1 will be replaced with Group 7.
10.11.11.1.4. Statistical Hypotheses for Coadministration of 2 Individual Vaccines
A total of 4 hypotheses will be tested for the second of the secondary objectives similar to
Section 10.11.11.1.2, except that Group 2 will be replaced with Group 6.
10.11.11.1.5. Multiplicity Adjustment
Type I error of 5% is equally split between the 2 primary immunogenicity objectives (2-sided 
2.5% for each). The first primary immunogenicity objective will be achieved if all 8 null
hypotheses are rejected. The second primary immunogenicity objective will be achieved if 
all 4 null hypotheses are rejected. The study is considered successful if either primary 
immunogenicity objective is achieved.
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The secondary immunogenicity objectives will be tested sequentially after the primary 
objective(s) is achieved as described in the schema below.
10.11.11.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined in Substudy A:
Population
Description
Enrolled
All participants who sign the ICD.
Randomized population
All participants who are assigned a randomization number in the IWR 
system regardless of whether the study intervention was administered.
Safety population
All participants who receive the study intervention.
mITT immunogenicity
population
All randomized participants who receive the study intervention and have at 
least 1 valid and determinate assay result after vaccination.
Evaluable immunogenicity
population
All participants who are eligible, receive the study intervention to which 
they were randomized, have the 1-month postvaccination blood collection
within an appropriate window, have no major protocol violations from 
randomization through the 1-month postvaccination blood draw, and have 
at least 1 valid and determinate assay result at the 1-month postvaccination 
visit.
10.11.11.3. Statistical Analyses
10.11.11.3.1. General Considerations
Refer to Section 9 for general considerations of statistical analyses.
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10.11.11.3.2. Primary Endpoint(s)/Estimand(s) Analysis
Endpoint
Statistical Analysis Methods
Safety

Descriptive statistics will be provided for each reactogenicity 
endpoint in each vaccine group (Group 1 to Group 7 individually). 
Local reactions (pain at the injection site, redness, and swelling) 
and systemic events (fever, fatigue, headache, chills, vomiting, 
diarrhea, new or worsened muscle pain, and new or worsened joint 
pain) from Day 1 through Day 7 after vaccination will be presented 
by maximum severity and any severity.  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).

AEs and SAEs will be categorized according to MedDRA terms. 
All of the AEs reported through the 1-month follow-up visit and 
SAEs reported throughout the study will be descriptively 
summarized with counts, percentages, and associated 
Clopper-Pearson 95% CI for each vaccine group (Section 9.3.1).
Immunogenicity

GMRs of RSV A and RSV B NTs (Group 1 to Group 4), GMRs of 
SARS-CoV-2 Omicron BA.4/BA.5–strain NTs and 
reference-strain NTs (Group 1 to Group 3), influenza 
strain-specific GMRs of HAI titers (Group 1 to Group 5) at 
1 month after vaccination will be provided with 97.5% CIs 
(Section 9.3.1.2.3). Using a 2-fold noninferiority margin, success 
for the first primary immunogenicity objective will be declared if 
the lower bound of the 2-sided 97.5% CI for the GMR is greater 
than 0.5 for both RSV A and RSV B antigens, for both the 
Omicron BA.4/BA.5 and reference strains, and for all 4 QIV
strains.

GMRs of RSV A and RSV B NTs (Group 2 to Group 4) and
GMRs of SARS-CoV-2 Omicron BA.4/BA.5–strain NTs and 
reference-strain NTs (Group 2 to Group 3) at 1 month after 
vaccination will be provided with 97.5% CIs (Section 9.3.1.2.3).
Using a 2-fold noninferiority margin, success for the second
primary immunogenicity objective will be declared if the lower 
bound of the 2-sided 97.5% CI for the GMR is greater than 0.5 for 
both RSV A and RSV B antigens and for both the Omicron 
BA.4/BA.5 and reference strains.
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10.11.11.3.3. Secondary Endpoint(s)/Estimand(s) Analysis
Endpoint
Statistical Analysis Methods
Secondary
immunogenicity

GMRs of RSV A and RSV B NTs (Group 7 to Group 4), GMRs of 
SARS-CoV-2 Omicron BA.4/BA.5–strain NTs and reference-strain
NTs (Group 7 to Group 3), influenza strain-specific GMRs of HAI 
titers (Group 7 to Group 5) at 1 month after vaccination will be 
provided with 97.5% CIs (Section 9.3.1.2.3). Using a 2-fold 
noninferiority margin, success for the first of the secondary
immunogenicity objectives will be declared if the lower bound of 
the 2-sided 97.5% CI for the GMR is greater than 0.5 for both RSV 
A and RSV B antigens, for both the Omicron BA.4/BA.5 and 
reference strains, and for all 4 QIV strains, after the first primary 
immunogenicity objective is achieved.

GMRs of RSV A and RSV B NTs (Group 6 to Group 4) and GMRs 
of SARS-CoV-2 Omicron BA.4/BA.5–strain NTs and 
reference-strain NTs (Group 6 to Group 3) at 1 month after 
vaccination will be provided with 97.5% CIs (Section 9.3.1.2.3).
Using a 2-fold noninferiority margin, success for the second of the 
secondary immunogenicity objectives will be declared if the lower 
bound of the 2-sided 97.5% CI for the GMR is greater than 0.5 for 
both RSV A and RSV B antigens and for both the Omicron 
BA.4/BA.5 and reference strains, after the second primary 
immunogenicity objective is achieved.
10.11.11.3.4. Exploratory Endpoint(s) Analysis
Endpoint
Statistical Analysis Methods
Exploratory

GMTs of NTs for each RSV subgroup (A or B), GMTs of QIV 
strain-specific HAI titers, and GMTs of SARS-CoV-2 strain–
specific NTs will be descriptively summarized with 2-sided 
95% CIs for each applicable vaccine group both before vaccination 
and at the 1-month postvaccination visit (Section 9.3.1).

GMFRs of NTs for each RSV subgroup (A or B), GMFRs of 
influenza strain-specific HAI titers, and GMFRs of SARS-CoV-2
strain–specific NTs from before vaccination to the 1-month
postvaccination visit will be descriptively summarized with 2-sided 
95% CIs for each applicable vaccine group (Section 9.3.1).
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Endpoint
Statistical Analysis Methods

The number and percentage of participants achieving strain-specific 
HAI seroconversion, SARS-CoV-2 strain–specific seroresponse at 
1 month after vaccination, and the number and percentage of 
participants with strain-specific HAI titers ≥1:40 before vaccination
and 1 month after vaccination will be summarized with 2-sided 
Clopper-Pearson 95% CIs for each applicable vaccine group 
(Section 9.3.1).
Note: HAI seroconversion is defined as an HAI titer <1:10 prior to 
vaccination and ≥1:40 at the postvaccination visit, or an HAI titer of 
≥1:10 prior to vaccination with a 4-fold rise at the postvaccination 
visit. SARS-CoV-2 seroresponse is defined as achieving a ≥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.

GMTs may be compared between other vaccine groups (eg, Group 1 
vs Group 2; Group 1 vs Group 7; Group 2 vs Group 6; etc) with 
GMRs and associated 2-sided 95% CIs (Section 9.3.1.2.3).
10.11.11.4. Interim Analyses
No formal interim analysis will be conducted for this study phase.  
The primary analysis will be performed on safety and immunogenicity data through 1 month 
after vaccination (ie, Visit A102); all type I error will be spent at this analysis. Once this 
analysis has been completed, study participants and the study team may be unblinded to
study intervention allocation.
6-Month safety data will be summarized when they become available.
10.11.11.5. Sample Size Determination
Table 5 presents the power to demonstrate the noninferiority for each antigen included in 
Group 1 ([RSVpreF+BNT162b2] + QIV) as well as the power to demonstrate the 
noninferiority for each antigen included in Group 2 ([RSVpreF+BNT162b2] + placebo). The 
power for the secondary objectives is similar to that for the primary objectives as the 
comparisons and assumptions are similar.
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For all assay results, no interference is assumed (ie, GMR=1). The SDs of the log titers are 
based on different reference studies. With 135 evaluable participants per vaccine group, 
there is ~90% power to declare noninferiority for all 8 antigens included in Group 1, and 
~92% power to declare noninferiority for all 4 antigens included in Group 2. Power was 
calculated with PROC POWER in SAS using the TWOSAMPLEMEANS statement.
Assuming 10% of the participants are nonevaluable, approximately 150 participants per 
group need to be enrolled for Groups 1 through 7.
Table 5.
Power to Demonstrate Noninferiority (N=135 per Group)
Vaccine 
Component
(SD Reference 
Study)
Antigen/Endpoint
Common SD 
(Log e Scale) 
Difference
(Log e Scale)
Noninferiority 
Margin
Power to 
Declare 
Noninferiority
(1-Sided Alpha 
= 0.0125)
RSVpreF
(C3671013)
RSV A NT
1.1
0
2-Fold
99.8%
RSV B NT
1.1
0
2-Fold
99.8%
BNT162b2
(C4591044)
SARS-CoV-2 
Omicron 
BA.4/BA.5–strain 
NTs
1.5
0
2-Fold
93.8%
SARS-CoV-2 
reference-strain 
NTs
1.3
0
2-Fold
98.3%
QIV
(C3671006)
H1N1 HAI
1.1
0
2-Fold
99.8%
H3N2 HAI
1.1
0
2-Fold
99.8%
B strain 1 HAI
1.2
0
2-Fold
99.3%
B strain 2 HAI
1.2
0
2-Fold
99.3%
Overall power to reject all 8 tests (Group 1 or 7 vs Group 4, Group 1 or 7 vs Group 3, 
Group 1 or 7 vs Group 5)
90.2%
Overall power to reject all first 4 tests (Group 2 or 6 vs Group 4, Group 2 or 6 vs Group 3)
91.8%
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10.12. Appendix 12: Protocol Amendment History
The protocol amendment summary of changes table for the current amendment is located 
directly before the TOC. The protocol amendment summary of changes tables for past 
amendment(s) can be found below:
Description of Change
Brief Rationale
Section # and Name
Substantial Modification(s)
Added Substudy B
New substudy on 
alternative formulation 
of RSVpreF and 
BNT162b2 
(Omi XBB.1.5) 
combination vaccine 
[RSVpreF+BNT162b2] 
Section 10.12 Appendix 12: 
Substudy B (Phase 1/2)
Non-substantial Modification(s)
Updated/removed text in 
the body of protocol that 
was specific to 
Substudy A 
Substudy-specific text is 
included in substudy 
appendices
Section 1.1 Synopsis
Section 2.3.1 Risk Assessment
Section 7.2 Participant 
Discontinuation/Withdrawal From 
the Study
Section 5.4 Screen Failures
Section 8.3.1 Physical Examinations
Section 8.3.2 Vital Signs
Section 8.3.3 Clinical Safety 
Laboratory Assessments
Section 8.4.1 Time Period and 
Frequency for Collecting AE and 
SAE Information
Section 8.4.8 Adverse Events of 
Special Interest for Substudy A
Section 10.11.4 Introduction –
Substudy A
Updated references and 
text to include 
Substudy B
Changes to align with 
master protocol format
Sections 1 through 9
Section 10.1.5.1 Data Monitoring 
Committee
Section 10.2 Appendix 2: Clinical 
Laboratory Tests
Section 10.5 Appendix 5: Genetics
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Description of Change
Brief Rationale
Section # and Name
Added stopping rule text 
for Substudy B
Consistency with 
Substudy A
Section 1.1 Synopsis
Added IND number and 
clintrials.gov ID
Not available at the time 
of original protocol
Title page
Section 1.1 Synopsis
Updated text on 
anaphylaxis and 
myocarditis assessment 
for RSVpreF
Consolidated the risk 
text from RSV and 
COVID; updated based 
on the recent updates for 
both programs
Section 2.3.1 Risk Assessment
Removed text on 
bivalent BNT162b2 
vaccine approval
Updated formulation 
Section 2.2.3.1 SARS-CoV-2
Removed collection of 
date of birth
New requirement
Section 8.1 Administrative 
Procedures
Added instructions for 
noting COVID-19 
symptoms for 
Substudy A
Editorial change
Section 10.11.3 SoA – Substudy A
“RSV” was updated to 
“RSVpreF” as per 
PACL (26 April 2023)
Correction of 
typographical error 
Section 2.3 Benefit/Risk Assessment
Updated information on 
RSVpreF 
Introductory paragraph 
on clinical studies
Section 2.2.3.2 RSVpreF 
Vaccination
Added/updated text 
Substudy B formulation 
to read “alternative 
formulation of RSVpreF 
and BNT162b2 (Omi 
XBB.1.5) combination 
vaccine
[RSVpreF+BNT162b2]”
Consistency throughout 
the document 
Section 1: Protocol Summary
Section 4.3: Justification for Dose
Section 10.12 Appendix 12: 
Substudy B
Section 10.13 Appendix 13: 
Abbreviations
Added a review of 
e-diary data from Days 1 
through 3 for the first 
50 participants in 
Stratum 1 and the first 
Regulatory 
recommendation since 
there is no prior human 
experience with the 
combined RSVpreF and 
Section 10.11.6.1 Overall Design
Section 10.11.8.1.4 Allocation to 
Study Intervention
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Description of Change
Brief Rationale
Section # and Name
20 participants in 
Stratum 2 prior to
enrollment of the 
remaining participants in 
each group per PACL 
(01 June 2023)
bivalent BNT162b2 
(original/Omi 
BA.4/BA.5) vaccine
Stopping rule #2 
updated from “troponin 
I” to “troponin” per 
PACL (12 July 2023)
To accommodate sites 
not able to measure 
troponin I
Section 10.11.10.5 Stopping Rules
“Licensed influenza 
vaccine” updated to 
“influenza vaccine” per 
PACL (12 July 2023)
To accommodate 
participants that may 
have received 
investigational influenza 
vaccines
Section 10.11.3 SoA – Substudy A 
(Phase 1/2)
Section 10.11.8.7 Prior and 
Concomitant Therapy
Section 10.11.10.7 Study Procedures 
Added volume for 
normal saline placebo 
per PACL 
(26 April 2023)
Addition of text that 
was inadvertently 
omitted in original 
protocol
Section 10.11.8 Substudy A 
Intervention and Concomitant 
Therapy
Section 10.11.8.1 Study 
Intervention(s) Administered
Added volume for QIV
Addition of text that 
was inadvertently 
omitted in original 
protocol
Section 10.11.8.1 Study 
Intervention(s) Administered
Updated barrier 
requirements
New information for 
Comirnaty and Abrysvo
Section 4.2.3 Choice of 
Contraception/Barrier Requirements
Removed text 
inadvertently included 
previously
Typographical errors 
corrected
Section 10.11.7.3 Study Procedures
Section 10.11.11.2 Analysis Sets
Section 10.11.11.3 Statistical 
Analyses
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PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 127
10.13. Appendix 13: Abbreviations
Abbreviation
Term
ADE
adverse device effect
AE
adverse event
AESI
adverse event of special interest
AKI
acute kidney injury
Al(OH)3
aluminum hydroxide
ALT
alanine aminotransferase
ARI-RSV
RSV-associated acute respiratory illness
AST
aspartate aminotransferase
AV
atrioventricular
AxMP
auxiliary medicinal product
BNT162b2
Pfizer’s COVID-19 vaccine
CBER
Center for Biologics Evaluation and Research (United States)
CDC
Centers for Disease Control and Prevention (United States)
CFR
Code of Federal Regulations (United States)
ChAdOx1-S
ChAdOx1-S (recombinant) SARS-CoV-2 vaccine (AstraZeneca)
CHF
congestive heart failure
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
COVID-19
coronavirus disease 2019
CpG
CpG 24555
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CT
clinical trial
CTIS
Clinical Trial Information System
DCT
data collection tool
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid
EC
ethics committee
ECC
emergency contact card
ECG
electrocardiogram
eCrCl
estimated creatinine clearance
eCRF
electronic case report form
EDB
exposure during breastfeeding
090177e19fb526e9\Approved\Approved On: 19-Jan-2024 09:51 (GMT)

PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 128
Abbreviation
Term
e-diary
electronic diary
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
eSAE
electronic safety adverse event
EU
European Union
EUA
emergency use authorization
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database)
FDA
Food and Drug Administration (United States)
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
HAI
hemagglutination inhibition assay
HBe
hepatitis B e
HBeAg
hepatitis B e antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HD
high dose
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
investigator’s brochure
ICD
informed consent document
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ID
identification
IgG
immunoglobulin G
IMP
investigational medicinal product
IND
investigational new drug
INR
international normalized ratio
IPAL
investigational product accountability log
IPM
investigational product manual
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
ISO
International Organization for Standardization
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PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 129
Abbreviation
Term
IV
intravenous(ly)
IWR
interactive Web-based response
KDIGO
Kidney Disease Improving Global Outcomes
LBBB
left bundle branch block
LFT
liver function test
LLOQ
lower limit of quantitation
LNP
lipid nanoparticle
LRTI
lower respiratory tract illness
LRTI-RSV
RSV-associated lower respiratory tract illness
LSLV
last subject last visit
MDR
medical device regulation
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
modRNA
nucleoside-modified messenger ribonucleic acid
MQI
medically qualified individual
mRNA
messenger ribonucleic acid
mRNA-1273
mRNA-1273 SARS-CoV-2 vaccine (Moderna)
NA
not applicable
NAAT
nucleic acid amplification test
N-binding
SARS-CoV-2 nucleoprotein–binding
NIMP
noninvestigational medicinal product
NT
neutralizing titer
Omi
Omicron
PACL
protocol administrative change letter
PFS
prefilled syringe(s)
PI
principal investigator
PSSA
Pfizer’s Serious Adverse Event Submission Assistant
PT
prothrombin time
PVC
premature ventricular contraction
QIV
quadrivalent influenza vaccine
QTcF
QT interval corrected by the Fridericia formula
QTL
quality tolerance limit
RCDC
reverse cumulative distribution curve
RNA
ribonucleic acid
RSV
respiratory syncytial virus
RSV A
respiratory syncytial virus subgroup A
RSV B
respiratory syncytial virus subgroup B
RSVpreF
respiratory syncytial virus stabilized prefusion F subunit vaccine
[RSVpreF+BNT162b2]
Substudy A: combination RSVpreF and bivalent BNT162b2 
(original/Omi BA.4/BA.5) vaccine 
090177e19fb526e9\Approved\Approved On: 19-Jan-2024 09:51 (GMT)

PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 130
Abbreviation
Term
RT-PCR
reverse transcription–polymerase chain reaction
S1
spike protein S1 subunit
SADE
serious adverse device effect
SAE
serious adverse event
SAP
statistical analysis plan
SARS
severe acute respiratory syndrome
SARS-CoV
severe acute respiratory syndrome coronavirus 
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
Screat
serum creatinine
Scys
serum cystatin C
SD
standard deviation
SIIV
seasonal inactivated influenza vaccine
SmPC
summary of product characteristics (European Union)
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
ST-T
ST-segment and T-wave
SUSAR
suspected unexpected serious adverse reaction
TBA
to be advised
T bili
total bilirubin
Th1
T-helper type 1
TOC
table of contents
UADE
unanticipated adverse device effect
UK
United Kingdom
ULN
upper limit of normal
US
United States
USADE
unanticipated serious adverse device effect
USPI
United States package insert
VE
vaccine efficacy
VRBPAC
Center for Biologics Evaluation and Research Vaccines and 
Related Biological Products Advisory Committee (United States)
WHO
World Health Organization
WOCBP
woman/women of childbearing potential
WT
wild type
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PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 131
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PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 132
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PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 133
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PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 134
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PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 135
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PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
Page 136
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PF-07960613 (Combination COVID-19 and RSV Vaccine)
Protocol C5481001
Final Protocol Amendment 2, 18 January 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (14 April 2023)
TMF Doc ID: 164.01
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Accessed: 09 Feb 2023.
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090177e19fb526e9\Approved\Approved On: 19-Jan-2024 09:51 (GMT)
PPD