A PHASE 1/2 RANDOMIZED STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND IMMUNOGENICITY OF A MODIFIED RNA VACCINE AGAINST INFLUENZA IN HEALTHY INDIVIDUALS
Phase: PHASE1
Conditions: Influenza, Human
Sponsor: Pfizer

PF-07252220 [Influenza modRNA Vaccine] 
Protocol C4781001 
Final Protocol Amendment 5, 03 July 2022 
PFIZER CONFIDENTIAL 
Page 1 
 
 
 
 
 
 
 
A PHASE 1/2 RANDOMIZED STUDY TO EVALUATE THE SAFETY, 
TOLERABILITY, AND IMMUNOGENICITY OF A MODIFIED RNA VACCINE 
AGAINST INFLUENZA IN HEALTHY INDIVIDUALS 
 
Study Intervention Number: 
PF-07252220 
Study Intervention Name: 
Influenza modRNA vaccine 
US IND Number: 
27600 
EudraCT Number: 
N/A 
Protocol Number: 
C4781001 
Phase: 
1/2 
Brief Title: A Study to Evaluate the Safety, Tolerability, and Immunogenicity of a 
Modified RNA Vaccine Against Influenza 
 
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information 
in confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified. 

PF-07252220 [Influenza modRNA Vaccine] 
Protocol C4781001 
Final Protocol Amendment 5, 03 July 2022 
PFIZER CONFIDENTIAL 
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Document History 
 
Document 
Version Date 
Amendment 5 
03 July 2022 
Amendment 4 
08 February 2022 
Amendment 3 
13 January 2022 
Amendment 2 
04 December 2021 
Amendment 1 
14 August 2021 
Original protocol 
27 May 2021 
 
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any protocol administrative 
clarification letter. 
Protocol Amendment Summary of Changes Table 
Amendment 5 (03 July 2022) 
Overall Rationale for the Amendment: 
Two hundred and forty participants 18 to 64 years of age were added to Substudy B and will 
be randomized 1:1 to receive either 1 dose ofCCI  qIRV (encoding 2 A strains and 2 B 
strains at a dose level ofCCI 
or 1 dose ofCCI  qIRV (encoding 2 A strains and 
2 B strains at a dose level of CCI 
). 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1 Protocol 
Summary 
Updated to reflect those 
changes made in the body of the 
protocol below. 
Addition of participants 18 to 64 years of age in 
Substudy B. 
Section 2.1 Study 
Rationale 
Removed reference to age range 
of participants solely being 65 
to 85 years of age, and added 
study intervention details of 
participants 18 to 64 years of 
age. 
Addition of participants 18 to 64 years of age in 
Substudy B. 
Section 4.1 Overall 
Design 
Removed reference to age range 
of participants solely being 65 
to 85 years of age. 
Addition of participants 18 to 64 years of age in 
Substudy B. 
Section 4.3 Justification 
for Dose 
Updated to reflect 
administration of 1 dose of 
CCI  qIRV in Substudy B. 
Addition of participants 18 to 64 years of age in 
Substudy B, who will receive this study 
intervention schedule. 
Section 6.8.1 Prohibited 
During the Study 
Changed timeframe for when 
receipt of nonstudy influenza 
vaccine is prohibited to allow 
for receipt after Visit 207 
(8-week follow-up visit). 
No blood draw to be taken at Visit 208, and 
implementation of the study is close to the 
2022/2023 influenza season. 

PF-07252220 [Influenza modRNA Vaccine] 
Protocol C4781001 
Final Protocol Amendment 5, 03 July 2022 
PFIZER CONFIDENTIAL 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.2.5 Pregnancy 
Testing 
Added pregnancy testing 
requirement for WOCBP. 
Addition of participants 18 to 64 years of age in 
Substudy B. 
Section 9.3.1.2.4 
Reverse Cumulative 
Distribution Curves 
Updated language to be 
consistent with other influenza 
studies. 
Revision to add a bit more details about drawing 
RCDCs. 
Section 9.5 Sample Size 
Determination 
Updated sample size 
information to reflect the 
addition of 240 participants 
18 to 64 years of age in 
Substudy B. 
Addition of participants 18 to 64 years of age in 
Substudy B. 
Section 10.4.2 Female 
Participant Reproductive 
Inclusion Criteria 
Added these standard criteria 
for participants 18 to 64 years 
of age. 
Addition of participants 18 to 64 years of age in 
Substudy B. 
Section 10.10.1 SoA – 
Substudy B (Phase 1/2) 
Added urine pregnancy test for 
WOCBP. 
Addition of participants 18 to 64 years of age in 
Substudy B. 
Section 10.10.2.1 
Substudy Rationale 
Added study intervention 
details of participants 18 to 
64 years of age. 
Addition of participants 18 to 64 years of age in 
Substudy B. 
Section 10.10.3 
Objectives, Endpoints, 
and Estimands 
(Substudy B) 
Updated primary safety and 
secondary/exploratory 
immunogenicity objectives to 
reflect the addition of 
participants 18 to 64 years of 
age in Substudy B. 
Removed estimands relating to 
seroconversion and HAI ≥1:40 
for all heterologous strains. 
Addition of participants 18 to 64 years of age in 
Substudy B. 
Heterologous strains may not all be seasonally 
related. 
Section 10.10.4.1 
Overall Design 
Added details relating to the 
inclusion of participants 18 to 
64 years of age in Substudy B, 
and updated to reflect prior 
protocol administrative change 
letter. 
Addition of participants 18 to 64 years of age in 
Substudy B. 
Section 10.10.5.1 
Substudy B Inclusion 
Criteria 
Updated inclusion criterion 
1 and removed inclusion 
criterion 4 to reflect the 
addition of participants 18 to 
64 years of age in Substudy B. 
Addition of participants 18 to 64 years of age in 
Substudy B. 
Section 10.10.5.2 
Substudy B Exclusion 
Criteria 
Added exclusion criterion 12. 
Substudy B enrollment may continue into the 
2022 northern hemisphere influenza season. 
Section 10.10.6.1.1 
Administration 
Added study intervention 
details for participants 18 to 
64 years of age in Substudy B, 
and updated to reflect prior 
protocol administrative change 
letter. 
Addition of participants 18 to 64 years of age in 
Substudy B. 

PF-07252220 [Influenza modRNA Vaccine] 
Protocol C4781001 
Final Protocol Amendment 5, 03 July 2022 
PFIZER CONFIDENTIAL 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.10.8.6 
Stopping Rules 
Updated stopping rules, such 
that each study intervention 
dose level will be judged 
independently and study pauses 
were applied to the impacted 
(and higher, if applicable) dose 
level. 
To allow for independent pausing of groups by 
dose level. 
Section 10.10.8.8.1 
Screening (0 to 28 Days 
Before Visit 201) 
Section 10.10.8.8.2 Visit 
201 – Vaccination 1 
(Day 1) 
Added urine pregnancy test for 
WOCBP. 
Addition of participants 18 to 64 years of age in 
Substudy B. 
Section 10.10.9.3.2 
Primary 
Endpoint(s)/Estimand(s) 
Analysis 
Section 10.10.9.3.3 
Secondary 
Endpoint(s)/Estimand(s) 
Analysis 
Section 10.10.9.3.4 
Tertiary/Exploratory 
Endpoint(s) 
Updated primary safety and 
secondary/exploratory 
immunogenicity estimands to 
reflect addition of participants 
18 to 64 years of age in 
Substudy B. 
Removed estimands relating to 
seroconversion and HAI ≥1:40 
for all heterologous strains. 
Addition of participants 18 to 64 years of age in 
Substudy B. 
Heterologous strains may not all be seasonally 
related. 

PF-07252220 [Influenza modRNA Vaccine] 
Protocol C4781001 
Final Protocol Amendment 5, 03 July 2022 
PFIZER CONFIDENTIAL 
Page 5 
 
 
TABLE OF CONTENTS 
LIST OF TABLES ................................................................................................................... 12 
1. PROTOCOL SUMMARY ................................................................................................... 13 
1.1. Synopsis ................................................................................................................... 13 
1.2. Schema..................................................................................................................... 26 
1.2.1. Substudy A (Phase 1) Schema .................................................................... 26 
1.2.2. Substudy B (Phase 1/2) Schema ................................................................. 28 
1.3. Schedule of Activities .............................................................................................. 29 
2. INTRODUCTION ................................................................................................................ 29 
2.1. Study Rationale ........................................................................................................ 29 
2.2. Background .............................................................................................................. 31 
2.2.1. Influenza...................................................................................................... 31 
2.2.2. Influenza Vaccination ................................................................................. 31 
2.2.2.1. Assessing Influenza Vaccine Immunogenicity .......................... 32 
2.2.3. Nucleoside-Modified mRNA Vaccines ...................................................... 32 
2.2.4. Potential for mRNA Influenza Vaccines ..................................................... 33 
2.3. Benefit/Risk Assessment ......................................................................................... 33 
2.3.1. Risk Assessment ......................................................................................... 33 
2.3.2. Benefit Assessment ..................................................................................... 35 
2.3.3. Overall Benefit/Risk Conclusion ................................................................ 35 
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS ............................................................ 36 
4. STUDY DESIGN ................................................................................................................. 36 
4.1. Overall Design ......................................................................................................... 36 
4.2. Scientific Rationale for Study Design ..................................................................... 36 
4.2.1. Diversity of Study Population ..................................................................... 36 
4.2.2. Choice of Contraception/Barrier Requirements .......................................... 36 
4.3. Justification for Dose ............................................................................................... 36 
4.4. End of Study Definition ........................................................................................... 37 
5. STUDY POPULATION ...................................................................................................... 37 
5.1. Inclusion Criteria ..................................................................................................... 37 
5.2. Exclusion Criteria .................................................................................................... 37 
5.3. Lifestyle Considerations .......................................................................................... 37 

PF-07252220 [Influenza modRNA Vaccine] 
Protocol C4781001 
Final Protocol Amendment 5, 03 July 2022 
PFIZER CONFIDENTIAL 
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5.3.1. Contraception ..............................................................................................37 
5.4. Screen Failures ........................................................................................................38 
5.5. Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention ...........................38 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ..................................38 
6.1. Study Intervention(s) Administered .........................................................................39 
6.1.1. Administration .............................................................................................39 
6.1.2. Medical Devices ..........................................................................................39 
6.2. Preparation, Handling, Storage, and Accountability ...............................................39 
6.2.1. Preparation and Dispensing .........................................................................40 
6.3. Measures to Minimize Bias: Randomization and Blinding .....................................41 
6.3.1. Allocation to Study Intervention .................................................................41 
6.3.2. Blinding Arrangements ...............................................................................41 
6.4. Study Intervention Compliance ...............................................................................41 
6.5. Dose Modification ...................................................................................................41 
6.6. Continued Access to Study Intervention After the End of the Study ......................41 
6.7. Treatment of Overdose ............................................................................................42 
6.8. Concomitant Therapy ..............................................................................................42 
6.8.1. Prohibited During the Study .......................................................................42 
6.8.2. Permitted During the Study ........................................................................43 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................44 
7.1. Discontinuation of Study Intervention .....................................................................44 
7.2. Participant Discontinuation/Withdrawal From the Study .......................................44 
7.2.1. Withdrawal of Consent ...............................................................................45 
7.3. Lost to Follow-Up ...................................................................................................45 
8. STUDY ASSESSMENTS AND PROCEDURES ...............................................................46 
8.1. Efficacy and/or Immunogenicity Assessments ........................................................47 
8.1.1. Biological Samples .....................................................................................47 
8.2. Safety Assessments ..................................................................................................47 
8.2.1. Physical Examinations ................................................................................48 
8.2.2. Vital Signs ...................................................................................................48 
8.2.3. Electronic Diary ..........................................................................................48 

PF-07252220 [Influenza modRNA Vaccine] 
Protocol C4781001 
Final Protocol Amendment 5, 03 July 2022 
PFIZER CONFIDENTIAL 
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8.2.3.1. Grading Scales ........................................................................... 49 
8.2.3.2. Local Reactions ......................................................................... 49 
8.2.3.3. Systemic Events ......................................................................... 50 
8.2.3.4. Fever .......................................................................................... 51 
8.2.3.5. Antipyretic Medication .............................................................. 51 
8.2.4. Clinical Safety Laboratory Assessments ..................................................... 52 
8.2.5. Pregnancy Testing ....................................................................................... 52 
8.2.6. Stopping Rules ............................................................................................ 52 
8.2.7. ECGs and Echocardiograms ........................................................................ 52 
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................. 53 
8.3.1. Time Period and Frequency for Collecting AE and SAE Information ....... 54 
8.3.1.1. Reporting SAEs to Pfizer Safety ............................................... 55 
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF ................... 55 
8.3.2. Method of Detecting AEs and SAEs ........................................................... 55 
8.3.3. Follow-Up of AEs and SAEs ...................................................................... 55 
8.3.4. Regulatory Reporting Requirements for SAEs ........................................... 55 
8.3.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure ..................................................... 56 
8.3.5.1. Exposure During Pregnancy ...................................................... 56 
8.3.5.2. Exposure During Breastfeeding ................................................. 58 
8.3.5.3. Occupational Exposure .............................................................. 58 
8.3.6. Cardiovascular and Death Events ................................................................ 58 
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs .............................................................................. 58 
8.3.8. Adverse Events of Special Interest .............................................................. 58 
8.3.8.1. Lack of Efficacy ........................................................................ 59 
8.3.9. Medical Device Deficiencies ...................................................................... 59 
8.3.9.1. Time Period for Detecting Medical Device Deficiencies .......... 59 
8.3.9.2. Follow-Up of Medical Device Deficiencies .............................. 60 
8.3.9.3. Prompt Reporting of Device Deficiencies to the Sponsor ......... 60 
8.3.9.4. Regulatory Reporting Requirements for Device 
Deficiencies........................................................................................ 60 
8.3.10. Medication Errors ...................................................................................... 60 

PF-07252220 [Influenza modRNA Vaccine] 
Protocol C4781001 
Final Protocol Amendment 5, 03 July 2022 
PFIZER CONFIDENTIAL 
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8.4. Pharmacokinetics .....................................................................................................61 
8.5. Genetics ...................................................................................................................62 
8.6. Biomarkers ...............................................................................................................62 
8.7. Immunogenicity Assessments .................................................................................62 
8.8. Health Economics ....................................................................................................62 
9. STATISTICAL CONSIDERATIONS .................................................................................62 
9.1. Statistical Hypotheses ..............................................................................................62 
9.1.1. Estimands ....................................................................................................62 
9.1.2. Multiplicity Adjustment ..............................................................................62 
9.2. Analysis Sets ............................................................................................................63 
9.3. Statistical Analyses ..................................................................................................64 
9.3.1. General Considerations ...............................................................................64 
9.3.1.1. Analyses for Binary Data ...........................................................64 
9.3.1.2. Analyses for Continuous Data ...................................................64 
9.3.2. Safety Analyses ...........................................................................................65 
9.4. Interim Analyses ......................................................................................................65 
9.5. Sample Size Determination .....................................................................................65 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...........................................................................................................67 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ................67 
10.1.1. Regulatory and Ethical Considerations .....................................................67 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP .........................................................................67 
10.1.2. Financial Disclosure ..................................................................................68 
10.1.3. Informed Consent Process ........................................................................68 
10.1.4. Data Protection ..........................................................................................69 
10.1.5. Committees Structure ................................................................................69 
10.1.5.1. Data Monitoring Committee ....................................................69 
10.1.6. Dissemination of Clinical Study Data .......................................................70 
10.1.7. Data Quality Assurance .............................................................................71 
10.1.8. Source Documents ....................................................................................72 
10.1.9. Study and Site Start and Closure ...............................................................73 
10.1.10. Publication Policy ...................................................................................73 

PF-07252220 [Influenza modRNA Vaccine] 
Protocol C4781001 
Final Protocol Amendment 5, 03 July 2022 
PFIZER CONFIDENTIAL 
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10.1.11. Sponsor’s Qualified Medical Personnel ..................................................74 
10.2. Appendix 2: Clinical Laboratory Tests .................................................................75 
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ......................................................................76 
10.3.1. Definition of AE ........................................................................................76 
10.3.2. Definition of an SAE .................................................................................77 
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period ............................................................................79 
10.3.4. Reporting of SAEs ....................................................................................82 
10.4. Appendix 4: Contraceptive and Barrier Guidance .................................................83 
10.4.1. Male Participant Reproductive Inclusion Criteria ....................................83 
10.4.2. Female Participant Reproductive Inclusion Criteria .................................83 
10.4.3. Woman of Childbearing Potential .............................................................84 
10.4.4. Contraception Methods .............................................................................85 
10.5. Appendix 5: ECG Findings of Potential Clinical Concern ....................................87 
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments ........89 
10.7. Appendix 7: AEs, ADEs, SAEs, SADEs, USADEs, and Device 
Deficiencies: Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting in Medical Device Studies ..............................................91 
10.7.1. Definition of AE and ADE ........................................................................91 
10.7.2. Definition of SAE, SADE, and USADE ...................................................91 
10.7.3. Definition of Device Deficiency ...............................................................92 
10.7.4. Recording/Reporting and Follow-Up of Medical Device 
Deficiencies ......................................................................................................92 
10.7.5. Reporting of SAEs ....................................................................................94 
10.7.6. Reporting of SADEs .................................................................................94 
10.8. Appendix 8: Alternative Measures During Public Emergencies ...........................95 
10.8.1. Telehealth Visits ........................................................................................95 
10.9. Appendix 9: Substudy A (Phase 1) .......................................................................96 
10.9.1. SoA – Substudy A (Phase 1) .....................................................................96 
10.9.2. Introduction ...............................................................................................99 
10.9.2.1. Substudy Rationale ..................................................................99 
10.9.2.2. Background ..............................................................................99 

PF-07252220 [Influenza modRNA Vaccine] 
Protocol C4781001 
Final Protocol Amendment 5, 03 July 2022 
PFIZER CONFIDENTIAL 
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10.9.2.3. Benefit/Risk Assessment .........................................................99 
10.9.3. Objectives, Endpoints, and Estimands (Substudy A) .............................100 
10.9.4. Substudy A Design..................................................................................104 
10.9.4.1. Overall Design .......................................................................104 
10.9.4.2. Scientific Rationale for Study Design ...................................105 
10.9.4.3. Justification for Dose .............................................................106 
10.9.4.4. End of Study Definition .........................................................106 
10.9.5. Substudy A Population ............................................................................106 
10.9.5.1. Substudy A Inclusion Criteria ...............................................106 
10.9.5.2. Substudy A Exclusion Criteria ..............................................107 
10.9.6. Substudy A Intervention and Concomitant Therapy ...............................108 
10.9.6.1. Study Intervention(s) Administered .......................................108 
10.9.6.2. Measures to Minimize Bias: Randomization and 
Blinding ...........................................................................................110 
10.9.6.3. Study Intervention Compliance .............................................111 
10.9.6.4. Dose Modification .................................................................111 
10.9.6.5. Continued Access to Study Intervention After the End of 
the Study ..........................................................................................111 
10.9.6.6. Treatment of Overdose ..........................................................111 
10.9.6.7. Concomitant Therapy.............................................................111 
10.9.7. Discontinuation of Substudy A Intervention and Participant 
Discontinuation/Withdrawal ...........................................................................111 
10.9.8. Substudy A Assessments and Procedures ...............................................111 
10.9.8.1. Clinical Safety Laboratory Assessments ...............................111 
10.9.8.2. Efficacy and/or Immunogenicity Assessments ......................112 
10.9.8.3. Safety Assessments ................................................................112 
10.9.8.4. Adverse Events, Serious Adverse Events, and Other 
Safety Reporting ..............................................................................112 
10.9.8.5. ECGs ......................................................................................112 
10.9.8.6. Stopping Rules .......................................................................112 
10.9.8.7. Immunogenicity Assessments ................................................113 
10.9.8.8. Substudy A Procedures ..........................................................114 
10.9.9. Substudy A Statistical Considerations ....................................................126 

PF-07252220 [Influenza modRNA Vaccine] 
Protocol C4781001 
Final Protocol Amendment 5, 03 July 2022 
PFIZER CONFIDENTIAL 
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10.9.9.1. Statistical Hypotheses ............................................................126 
10.9.9.2. Analysis Sets ..........................................................................127 
10.9.9.3. Statistical Analyses ................................................................127 
10.9.9.4. Interim Analyses ....................................................................132 
10.9.9.5. Sample Size Determination ...................................................132 
10.10. Appendix 10: Substudy B (Phase 1/2) ...............................................................133 
10.10.1. SoA – Substudy B (Phase 1/2) ..............................................................133 
10.10.2. Introduction ...........................................................................................136 
10.10.2.1. Substudy Rationale ..............................................................136 
10.10.2.2. Background ..........................................................................136 
10.10.2.3. Benefit/Risk Assessment .....................................................137 
10.10.3. Objectives, Endpoints, and Estimands (Substudy B)............................138 
10.10.4. Substudy B Design ................................................................................141 
10.10.4.1. Overall Design .....................................................................141 
10.10.4.2. Scientific Rationale for Study Design .................................143 
10.10.4.3. Justification for Dose ...........................................................143 
10.10.4.4. End of Study Definition .......................................................143 
10.10.5. Substudy B Population ..........................................................................144 
10.10.5.1. Substudy B Inclusion Criteria ..............................................144 
10.10.5.2. Substudy B Exclusion Criteria .............................................145 
10.10.6. Substudy B Intervention and Concomitant Therapy .............................146 
10.10.6.1. Study Intervention(s) Administered .....................................146 
10.10.6.2. Measures to Minimize Bias: Randomization and 
Blinding ...........................................................................................148 
10.10.6.3. Study Intervention Compliance ...........................................149 
10.10.6.4. Dose Modification ...............................................................149 
10.10.6.5. Continued Access to Study Intervention After the End 
of the Study ......................................................................................149 
10.10.6.6. Treatment of Overdose ........................................................149 
10.10.6.7. Concomitant Therapy...........................................................149 
10.10.7. Discontinuation of Substudy B Intervention and Participant 
Discontinuation/Withdrawal ...........................................................................149 
10.10.8. Substudy B Assessments and Procedures .............................................149 

PF-07252220 [Influenza modRNA Vaccine] 
Protocol C4781001 
Final Protocol Amendment 5, 03 July 2022 
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10.10.8.1. Clinical Safety Laboratory Assessments ............................. 150 
10.10.8.2. Efficacy and/or Immunogenicity Assessments .................... 150 
10.10.8.3. Safety Assessments .............................................................. 150 
10.10.8.4. Adverse Events, Serious Adverse Events, and Other 
Safety Reporting .............................................................................. 150 
10.10.8.5. ECGs .................................................................................... 150 
10.10.8.6. Stopping Rules..................................................................... 150 
10.10.8.7. Immunogenicity Assessments .............................................. 151 
10.10.8.8. Substudy B Procedures ........................................................ 152 
10.10.9. Substudy B Statistical Considerations ................................................... 163 
10.10.9.1. Statistical Hypotheses .......................................................... 163 
10.10.9.2. Analysis Sets ........................................................................ 164 
10.10.9.3. Statistical Analyses .............................................................. 164 
10.10.9.4. Interim Analyses .................................................................. 169 
10.10.9.5. Sample Size Determination .................................................. 169 
10.11. Appendix 11: Criteria for Allowing Inclusion of Participants With 
Chronic Stable HIV, HCV, or HBV Infection ......................................................... 170 
10.12. Appendix 12: Genetics ...................................................................................... 171 
10.13. Appendix 13: Protocol Amendment History ..................................................... 172 
10.14. Appendix 14: Abbreviations .............................................................................. 180 
11. REFERENCES ................................................................................................................. 183 
 
 
LIST OF TABLES 
Table 1. 
Local Reaction Grading Scale ..................................................................49 
Table 2. 
Systemic Event Grading Scale ..................................................................50 
Table 3. 
Scale for Fever ..........................................................................................51 
Table 4. 
Probability of Observing at Least 1 AE by Assumed True Event 
Rates With Different Sample Sizes ..........................................................66 
Table 5. 
Initial Strain and Dose Level Combinations to Be Used in the bIRV 
During Substudy A ..................................................................................104 
Table 6. 
Substudy B Study Intervention Schedule ................................................147 

PF-07252220 [Influenza modRNA Vaccine] 
Protocol C4781001 
Final Protocol Amendment 5, 03 July 2022 
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Brief Title: 
A Study to Evaluate the Safety, Tolerability, and Immunogenicity of a Modified RNA 
Vaccine Against Influenza. 
Rationale 
Influenza is a major cause of morbidity and mortality worldwide, occurring in annual 
seasonal epidemics and occasionally in global pandemics. Due to the ongoing variability in 
circulating influenza viruses, recommendations for the viruses to be targeted by each 
influenza season’s vaccines reflect the global influenza virus surveillance that continues 
throughout the year in both hemispheres. This means that the schedule for vaccine 
production, release, and administration is highly compressed. 
In recent years, the use of mRNA as the basis for potential vaccine candidates has shown 
increasing promise. Various approaches to optimize the response to mRNA vaccines have 
been used. This includes modRNA in which some nucleosides are replaced by naturally 
occurring modified nucleosides, such as pseudouridine, which decreases innate immune 
activation and increases translation. Two lipid nanoparticle-encapsulated modRNA vaccines 
encoding the SARS-CoV-2 spike protein have been developed in response to the public 
health emergency presented by the COVID-19 pandemic: BNT162b2 (Pfizer/BioNTech) and 
mRNA-1273 (Moderna), with both vaccines demonstrating high effectiveness with no 
significant safety concerns during Phase 3 development. Since its first marketing 
authorization in December 2020, BNT162b2 has been administered to hundreds of millions 
of individuals worldwide. 
Postauthorization safety surveillance in the US has confirmed the safety profile seen in 
clinical trials, and has also identified adverse reactions of anaphylaxis and an increased risk 
of myocarditis and pericarditis. 
The experience with modRNA-based COVID-19 vaccines supports use of the modRNA 
platform for potential rapid development of vaccines encoding the seasonally adapted H1, 
H3, and 2 B HAs for the prevention of influenza. Potential advantages of this platform 
include accelerated manufacturing, thereby allowing a later decision as to the HA strains to 
include in the seasonal vaccine, and potentially higher efficacy relative to currently licensed 
influenza vaccines. 
This is a Phase 1/2 randomized study to evaluate the safety, tolerability, and immunogenicity 
of a modRNA vaccine against influenza in healthy individuals. This study will be conducted 
across 2 substudies – Substudy A and Substudy B. Substudy A will describe the safety and 
immunogenicity of mIRV A or B at 4 dose levels, bIRV encoding both A and B strains in 
4 dose-level combinations shown in Section 1.2.1, and qIRV encoding 2 A strains and 2 B 
strains at a dose level ofCCI 
. 

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Additionally, Substudy A will describe: 
• The immune response elicited by licensed QIV following prior receipt of a modRNA 
vaccine, to assess potential priming of the immune response, and 
• The immune response elicited by mIRV A or B following prior receipt of licensed QIV, 
to assess if the immune response following QIV may be enhanced. 
Substudy B will describe the safety and immunogenicity of the following vaccination 
schedules: 
In participants 65 to 85 years of age: 
• 2 Doses of qIRV encoding 2 A strains and 2 B strains at a dose level of CCI 
, 
administered 21 days apart. 
• 2 Doses of licensed QIV, administered 21 days apart (as a control group). 
• A dose of licensed QIV following by a dose of bIRV encoding 2 A strains at a dose level 
of either CCI 
, administered 21 days apart. 
• A dose of licensed QIV administered concurrently in the opposite arm with bIRV 
encoding 2 A strains at a dose level of either CCI 
. 
• A dose of bIRV encoding 2 A strains at a dose level of CCI 
 administered 
concurrently in the opposite arm with bIRV encoding 2 B strains at a dose level of CCI 
. 
• A dose of qIRV encoding 2 A strains and 2 B strains at the following dose level 
combinations: 
CC 
 
 
• A dose of licensed QIV (as a control group). 
In participants 18 to 64 years of age: 
• A dose of qIRV encoding 2 A strains and 2 B strains at a dose level of CCI 
. 
• A dose of qIRV encoding 2 A strains and 2 B strains at a dose level of CCI 
. 
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Objectives, Endpoints, and Estimands 
For the purposes of the following estimands: 
• Seroconversion is defined as an HAI titer <1:10 prior to vaccination and ≥1:40 at the time point of interest, or an HAI titer of 
≥1:10 prior to vaccination with a 4-fold rise at the time point of interest. 
Substudy A (Phase 1) 
 
Objectives 
Estimands 
Endpoints 
Primary Safety: 
Primary Safety: 
Primary Safety: 
To describe the safety and tolerability of 
mIRV, bIRV, and qIRV in adults 65 to 85 
years of age 
In participants receiving at least 1 dose of study intervention, the 
percentage of participants reporting: 
• 
Local reactions for up to 7 days following Vaccinations 1 and 2 
• 
Systemic events for up to 7 days following Vaccinations 1 and 2 
• 
AEs 4 weeks after Vaccinations 1 and 2 
• 
SAEs from the first vaccination to 6 months after the last 
vaccination 
The percentage of participants with: 
• 
Abnormal hematology and chemistry laboratory values 2 days 
and 1 week after Vaccination 1 
• 
Grading shifts in hematology and chemistry laboratory 
assessments between baseline and 2 days and 1 week after 
Vaccination 1 
The percentage of participants with: 
• 
New ECG abnormalities 2 days and 1 week after Vaccination 1 
• 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 
Hematology and chemistry laboratory parameters detailed 
in Section 10.2 
ECG abnormalities consistent with probable or possible 
myocarditis or pericarditis as defined in Section 8.2.7 

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Objectives 
Estimands 
Endpoints 
Secondary: 
Secondary: 
Secondary: 
To describe the immune responses elicited 
by mIRV, bIRV, and qIRV in adults 
65 to 85 years of age 
In participants complying with the key protocol criteria (evaluable 
participants) at 1, 4, and 8 weeks after receipt of Vaccination 1: 
• HAI GMTs at 1, 4, and 8 weeks after receipt of Vaccination 1 
• HAI GMFR from before Vaccination 1 to 1, 4, and 8 weeks after 
receipt of Vaccination 1 
• The proportion of participants achieving HAI seroconversion for 
each strain at 1, 4, and 8 weeks after receipt of Vaccination 1 
• The proportion of participants with HAI titers ≥1:40 for each 
strain before Vaccination 1 and at 1, 4, and 8 weeks after receipt 
of Vaccination 1 
HAI titers for each strain targeted by the study vaccine 
In participants having received qIRV or licensed QIV at Visit 1, 
complying with the key protocol criteria (evaluable participants) at 
1, 4, and 8 weeks after receipt of Vaccination 1: 
• The proportion of participants achieving HAI seroconversion for 
all strains at 1, 4, and 8 weeks after receipt of Vaccination 1 
• The proportion of participants with HAI titers ≥1:40 for all 
strains before vaccination to 1, 4, and 8 weeks after receipt of 
Vaccination 1 
• GMR of HAI titers for each strain in qIRV recipients compared 
to comparator recipients 4 weeks after Vaccination 1 
• The difference in percentage of participants achieving 
seroconversion for each strain at 4 weeks after Vaccination 1 in 
qIRV recipients compared to comparator recipients 
HAI titers for each strain targeted by the study vaccine 
Tertiary/Exploratory: 
Tertiary/Exploratory: 
Tertiary/Exploratory: 
CCI 
 

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Objectives  
CCI 
Estimands 
Endpoints 

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Objectives 
CC 
Estimands 
Endpoints 
CCI 

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Substudy B (Phase 1/2) 
 
Objectives 
Estimands 
Endpoints 
Primary Safety: 
Primary Safety: 
Primary Safety: 
To describe the safety and tolerability of 
modRNA influenza vaccines when 
administered in differing vaccination 
schedules in adults 18 to 64 and 65 to 
85 years of age 
In participants receiving at least 1 dose of study intervention, the 
percentage of participants reporting: 
• 
Local reactions for up to 7 days following each vaccination 
• 
Systemic events for up to 7 days following each vaccination 
• 
AEs from the first vaccination to 4 weeks after the last 
vaccination 
• 
SAEs from the first vaccination to 6 months after the last 
vaccination 
The percentage of participants with: 
• 
Abnormal troponin I laboratory values 2 days after the last 
vaccination 
The percentage of participants with: 
• 
New ECG abnormalities 2 days after the last 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 
Troponin I laboratory parameters detailed in Section 10.2 
ECG abnormalities consistent with probable or possible 
myocarditis or pericarditis as defined in Section 8.2.7 
Secondary: 
Secondary: 
Secondary: 
To describe the immune responses elicited 
by modRNA influenza vaccines when 
administered in differing vaccination 
schedules in adults 65 to 85 years of age 
In participants complying with the key protocol criteria (evaluable 
participants) at Day 21 (if applicable) and 1, 4, and 8 weeks after 
receipt of the last vaccination: 
• HAI GMTs before Vaccination 1, prior to Vaccination 2 
(Day 21, if applicable), and at 1, 4, and 8 weeks after receipt of 
the last vaccination 
• HAI GMFR from before Vaccination 1 to prior to Vaccination 2 
(Day 21, if applicable) and to 1, 4, and 8 weeks after receipt of 
the last vaccination 
• The proportion of participants achieving HAI seroconversion for 
each strain prior to Vaccination 2 (Day 21, if applicable) and at 
1, 4, and 8 weeks after receipt of the last vaccination 
• The proportion of participants with HAI titers ≥1:40 for each 
strain before Vaccinations 1 and 2 (Day 21, if applicable) and at 
1, 4, and 8 weeks after receipt of the last vaccination 
HAI titers for each strain targeted by the study vaccine 
In participants having received at least 1 dose of a quadrivalent 
vaccine, complying with the key protocol criteria (evaluable 
participants), at Day 21 (if applicable) and at 1, 4, and 8 weeks after 
receipt of the last vaccination: 
HAI titers for each strain targeted by the study vaccine 

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Objectives 
Estimands 
Endpoints 
• The proportion of participants achieving HAI seroconversion for 
all strains prior to Vaccination 2 (Day 21, if applicable) and at 1, 
4, and 8 weeks after receipt of the last vaccination 
• The proportion of participants with HAI titers ≥1:40 for all 
strains before Vaccinations 1 and 2 (Day 21, if applicable) and 
1, 4, and 8 weeks after receipt of the last vaccination 
To describe the immune responses elicited 
by qIRV in adults 18 to 64 years of age 
In participants complying with the key protocol criteria (evaluable 
participants) at 1, 4, and 8 weeks after receipt of vaccination: 
• HAI GMTs before vaccination and at 1, 4, and 8 weeks after 
receipt of vaccination 
• HAI GMFR from before vaccination to 1, 4, and 8 weeks after 
receipt of vaccination 
• The proportion of participants achieving HAI seroconversion for 
each strain at 1, 4, and 8 weeks after receipt of vaccination 
• The proportion of participants with HAI titers ≥1:40 for each 
strain before vaccination and at 1, 4, and 8 weeks after receipt of 
vaccination 
• The proportion of participants achieving HAI seroconversion for 
all strains at 1, 4, and 8 weeks after receipt of vaccination 
• The proportion of participants with HAI titers ≥1:40 for all 
strains before vaccination and 1, 4, and 8 weeks after receipt of 
vaccination 
HAI titers for each strain targeted by the study vaccine 
Tertiary/Exploratory: 
Tertiary/Exploratory: 
Tertiary/Exploratory: 
CCI 
 

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CCI 
Endpoints 
Estimands 
Objectives 

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Overall Design 
This is a Phase 1/2 randomized study to evaluate the safety, tolerability, and immunogenicity 
of a modRNA vaccine against influenza in healthy individuals. This study will be conducted 
across 2 substudies – Substudy A and Substudy B. 
Substudy A (Phase 1) 
This is a Phase 1 randomized, observer-blinded (sponsor-unblinded) substudy to evaluate the 
safety, tolerability, and immunogenicity of qIRV in healthy individuals 65 to 85 years of age. 
Participants will be randomized to receive at Vaccination 1 (Visit 1): 
• mIRV at a dose level ofCCI 
 encoding A strain, or QIV, 
• mIRV at a dose level ofCCI 
, encoding B strain, or QIV, 
• bIRV in the dose level combinations shown in the table in Section 1.2, encoding both A 
and B strains, or QIV, or 
• qIRV encoding 2 A strains and 2 B strains at a dose level ofCCI 
, or QIV. 
During initial enrollment, each group (vaccine formulation/dose level, or control) will 
comprise 15 participants 65 to 85 years of age. 
Safety data accumulated at least 1 week following Vaccination 1 with mIRV, bIRV, and 
qIRV will be reviewed and, if deemed acceptable, a further 360 participants can be enrolled 
and randomized 1:1 to receive either qIRV or QIV. 
However, based upon preliminary immunogenicity data, the sponsor decided not to expand 
enrollment into Substudy A. Therefore, approximately 255 participants were enrolled in 
Substudy A. 
The sponsor’s IRC judged that the safety profile observed from groups during initial 
enrollment supports the development of the planned Substudy B. 
Participants from the initial enrollment period will be unblinded at Visit 5 (8 weeks after 
Vaccination 1) and licensed QIV will be administered at Visit 5 to participants not having 
previously received licensed QIV. Additionally, at Visit 5A, participants who previously 
received licensed QIV at Visit 1 will receive either: 
 
• mIRV at a dose level of CCI encoding A strain (up to 30 participants who previously 
received licensed QIV at Visit 1), or 
 
• mIRV at a dose level of CCI encoding B strain (up to 30 participants who previously 
received licensed QIV at Visit 1). 

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CCI 
Vaccinations administered at either Visit 5 or Visit 5A will be considered Vaccination 2 for 
these participants. 
It is anticipated that the following strains will be used in each IRV, but the final strain 
selection will be detailed in the IP manual: 
• mIRV: CCI 
 
• bIRV: CCI 
 in dose level combinations 
shown in Section 1.2 
• qIRV: 
 
Substudy B (Phase 1/2) 
This is a randomized, single-blinded (sponsor-unblinded) substudy to evaluate the safety and 
immunogenicity of the vaccination schedules detailed below. The design of Substudy B is 
summarized in Section 1.2.2. 
Participants 65 to 85 years of age will be randomized to one of the following vaccination 
schedules, and will be blinded to which 1-visit or 2-visit vaccination schedules they will 
receive: 
2-Visit Schedules 
• 2 Doses of qIRV encoding 2 A strains and 2 B strains at a dose level of CCI 
 
, administered 21 days apart. 
• 2 Doses of licensed QIV, administered 21 days apart (as a control group). 
• A dose of licensed QIV followed by a dose of bIRV encoding 2 A strains at a dose 
level of either CCI 
, administered 21 days apart. 
1- Visit Schedules 
• A dose of licensed QIV administered concurrently in the opposite arm with bIRV 
encoding 2 A strains at a dose level of either CCI 
. 
•  A dose of bIRV encoding 2 A strains at a dose level of CCI 
 administered 
concurrently in the opposite arm with bIRV encoding 2 B strains at a dose level of 
CCI 
. 
• A dose of qIRV encoding 2 A strains and 2 B strains at the following dose level 
combinations: 
CC 
CCI 

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CCI 
CCI 
 
CC 
 
• A dose of licensed QIV (as a control group). 
Substudy B enrollment of participants 65 to 85 years of age will be separated into an initial 
and expanded enrollment. Depending on the availability of study intervention and 
operational prioritization, groups of participants 65 to 85 years of age in Substudy B may not 
all be randomized concurrently; however, a minimum of 2 groups will be open for 
randomization at any one time. Participants 18 to 64 years of age will only be included in the 
study during expanded enrollment – 240 participants 18 to 64 years of age will be 
randomized 1:1 to receive either a single dose of CCI  qIRV (encoding 2 A strains and 2 B 
strains at a dose level of 
) or a single dose of CCI  qIRV (encoding 2 A 
strains and 2 B strains at a dose level of CCI 
). 
It is anticipated that the following strains will be used in the bIRV, but the final strain 
selection will be detailed in the IP manual: 
. It is anticipated that the following strains will be used in the 
qIRV, but the final strain selection will be detailed in the IP manual: CCI 
The strains 
used in qIRV may vary depending on the time of enrollment relative to the annual influenza 
season. 
Number of Participants 
Up to approximately 255 participants will be enrolled in Substudy A. Up to approximately 
1725 participants will be enrolled in Substudy B (165 participants during initial enrollment, 
and up to a maximum of 13 groups of 120 participants each being included in the 
expanded-enrollment stage). The duration of participation for each participant enrolled in 
either substudy will be up to approximately 8 months. 
Data Monitoring Committee or Other Independent Oversight Committee 
This study 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. 
Statistical Methods 
The following summarizes the statistical methods for both Substudies A and B. 
Since the study is descriptive in nature, the planned sample size for the study was not based 
on any statistical hypothesis testing. 
The primary safety objective for the study will be evaluated by descriptive summary statistics 
for local reactions, systemic events, and AEs/SAEs for each vaccine group. 
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The secondary immunogenicity objectives will be evaluated descriptively by GMT, GMFR, 
proportion of participants achieving seroconversion measured by HAI, proportion of 
participants with HAI titers ≥1:40, and the associated 95% CIs, for each strain at the various 
time points, by vaccine group. Additionally, the GMR of HAI antibody titers from selected 
modRNA vaccine recipients compared to the comparator group (eg, licensed QIV recipients), 
and the percentage difference in the proportion of participants achieving seroconversion for each 
strain at 4 weeks after vaccination, will be described by vaccine group. 

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1.2. Schema 
1.2.1. Substudy A (Phase 1) Schema 
 
Vaccination 1 (Initial Enrollment) 
IRV Groups 
Comparator 
Intervention 
Strain(s) 
Dose Level(s) 
mIRV 
A 
CCI 
 
(N=15/dose level) 
Licensed QIV 
(N=15) 
mIRV 
B 
CCI 
 
(N=15/dose level) 
Licensed QIV 
(N=15) 
bIRV 
A and B 
Dose combinations as shown in table belowa 
(N=15/dose combination) 
Licensed QIV 
(N=15) 
qIRV 
2 x A 
2 x B 
CCI encoding HA of each strain 
(N=15) 
Licensed QIV 
(N=15) 
 
Vaccination 2 (Initial Enrollment) 
mIRV A (CCI ; N~30) or 
mIRV B (CCI ; N~30) 
Licensed QIV 
(N~195) 

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A 
CCI  
CCI  
CCI 
 
a. 
Initial Strain and Dose Level Combinations to Be Used in the bIRV During Substudy A 
 
B 
CCI  
CCI 
X 
X 
X 
X 

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1.2.2. Substudy B (Phase 1/2) Schema 
Initial Enrollment (Participants 65 to 85 Years of Age) 
(N = 15 per group) 
 
 
Expanded Enrollment 
(N = 120 per group) 
Vaccination 1 
Vaccination 2 
Vaccination 1 
Vaccination 2 
Right Deltoid 
qIRV CCI 
2 x A, 2 x B CCI 
 
 
Licensed QIV 
 
 
Licensed QIV 
 
Licensed QIV 
bIRV CCI 
2 x A CCI 
bIRV CCI 
2 x A CCI 
Left Deltoid 
 
 
 
 
 
 
 
 
 
 
Licensed QIV 
Licensed QIV 
Right Deltoid 
qIRV 
CCI  
2 x A, 2 x B 
CCI 
 
bIRV CCI 
2 x A CCI 
 
bIRV CCI 
2 x A CCI 
 
Licensed QIV 
Left Deltoid 
 
a 
 
 
 
Participants 
18 to 64 years 
of age 
Right Deltoid 
qIRV CCI  
2 x A, 2 x B 
CCI 
qIRV CCI 
2 x A, 2 x B 
CCI    
Licensed QIVb 
Left Deltoid 
 
 
 
 
 
 
 
Placebo 
qIRV CCI 
2 x A, 2 x B CCI 
Licensed QIV 
bIRV CCI 
2 x B CCI 
qIRV CCI 
2 x A CCI 
2 x B CCI 
qIRV CCI 
2 x A CCI 
2 x B CCI 
 
 
 
bIRV CCI 
2 x A 
 
Participants 
65 to 85 years 
of age 
Other vaccine group(s) as selected by 
the sponsor’s IRC from initial 
enrollment for expanded enrollment. 
Expanded-enrollment groups may also 
be included that comprise only the first 
dose from 2-visit–schedule initial 
enrollment groups. 
a. 
Safety and immunogenicity data accumulated at least 1 week following the last vaccination in each group will be reviewed and, if the data are deemed 
acceptable, an additional 120 participants will be enrolled in that group (expanded enrollment). 
b. At the discretion of the sponsor’s IRC, a control group of 120 participants may be enrolled during expanded enrollment who will receive a dose of licensed 
QIV followed by placebo, administered 21 days apart. 
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1.3. Schedule of Activities 
The SoA table provides an overview of the protocol visits and procedures. Refer to 
Section 10.9.8 for detailed information on each procedure and assessment required for 
compliance with the protocol regarding Substudy A, and to Section 10.10.8 for Substudy B. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA 
table, in order to conduct evaluations or assessments required to protect the well-being of the 
participant. 
See Section 10.9.1 for the Substudy A SoA. 
See Section 10.10.1 for the Substudy B SoA. 
2. INTRODUCTION 
2.1. Study Rationale 
This is a Phase 1/2 randomized study to evaluate the safety, tolerability, and immunogenicity 
of a modRNA vaccine against influenza in healthy individuals. This study will be conducted 
across 2 substudies – Substudy A and Substudy B. Substudy A will describe the safety and 
immunogenicity of mIRV A or B at 4 dose levels, bIRV encoding both A and B strains in the 
dose-level combinations shown in Table 5, and qIRV encoding 2 A strains and 2 B strains at 
a dose level of CCI 
. Additionally, Substudy A will describe: 
• The immune response elicited by licensed QIV following prior receipt of a modRNA 
vaccine, to assess potential priming of the immune response, and 
• The immune response elicited by mIRV A or B following prior receipt of licensed QIV, 
to assess if the immune response following QIV may be enhanced. 
Safety and immunogenicity data reported to date from Substudy A are detailed in the IB. 
In summary, following review of the safety data from Substudy A up to 1 week following 
Vaccination 1 in all groups, no safety concerns have been identified. Specifically, 1-week 
follow-up reactogenicity data of 194 participants who received mIRV, bIRV, or qIRV in 
Substudy A showed most events to be mild to moderate in severity, with the most common 
events being pain at the injection site, fatigue, and headache. 
Immunogenicity data up to 1 week following Vaccination 1 in Substudy A showed: 
• The proportion of participants achieving seroconversion following administration of 
mIRV encoding A or B strain increased in a dose-dependent manner. 
• The proportion of participants achieving seroconversion 1 week following administration 
of mIRV at a dose level of CCI  encoding A strain was 71.4% compared to 53.7% of 
participants having received licensed QIV. 

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• The proportion of participants achieving seroconversion 1 week following administration 
of mIRV at a dose level of CCI  encoding B strain was 42.9% compared to 23.8% of 
participants having received licensed QIV. 
• Potential interference in the immune response elicited against B strain was observed 
when mIRVs encoding A and B strains were combined and administered as bIRV, eg, the 
proportion of participants achieving seroconversion 1 week following administration of 
bIRV at a dose level of CCI  encoding A strain and CCI  encoding B strain was 6.7% 
for B strain compared to 25.0% of participants having received mIRV at a dose level of 
CCI encoding B strain. 
•  The difference in the proportion of participants achieving seroconversion against 
CCI 
 1 week following 
Vaccination 1 was 29.8%, 27.4%, -8.2%, and 0.0%, respectively, when comparing 
participants who received qIRV to those who received licensed QIV. 
These data support exploration of alternative vaccination schedules incorporating IRV, which 
are included in Substudy B. 
Substudy B will describe the safety and immunogenicity of the following vaccination 
schedules: 
In participants 65 to 85 years of age: 
• 2 Doses of qIRV encoding 2 A strains and 2 B strains at a dose level of CCI 
, 
administered 21 days apart. 
• 2 Doses of licensed QIV, administered 21 days apart (as a control group). 
• A dose of licensed QIV followed by a dose of bIRV encoding 2 A strains at a dose level 
of either CCI 
, administered 21 days apart. 
• A dose of licensed QIV administered concurrently in the opposite arm with bIRV 
encoding 2 A strains at a dose level of either CCI 
. 
• A dose of bIRV encoding 2 A strains at a dose level of CCI 
 administered 
concurrently in the opposite arm with bIRV encoding 2 B strains at a dose level of CCI 
. 
• A dose of qIRV encoding 2 A strains and 2 B strains at the following dose level 
combinations: 
CC 
 
 
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• A dose of licensed QIV (as a control group). 
In participants 18 to 64 years of age: 
• A dose of qIRV encoding 2 A strains and 2 B strains at a dose level of CCI 
. 
• A dose of qIRV encoding 2 A strains and 2 B strains at a dose level of CCI 
 
2.2. Background 
2.2.1. Influenza 
Influenza is a major cause of morbidity and mortality worldwide, occurring in annual 
seasonal epidemics and occasionally in global pandemics.1 Symptomatic influenza infection 
causes a febrile illness with respiratory and systemic symptoms,2 although it may often be 
asymptomatic.3 The risk of complications and hospitalization from influenza are higher in 
people ≥65 years of age, young children, and people with certain underlying medical 
conditions. In the US, an average of >200,000 hospitalizations per year are related to 
influenza,4 while the annual global number of deaths is estimated to range from almost 
300,000 to over 600,000.5 
Influenza viruses are part of the Orthomyxoviridae family and are divided into 3 genera or 
types (A, B, and C) based upon antigenic differences in the nucleoprotein and the matrix 
protein. Influenza A viruses are further classified into subtypes based upon the membrane 
glycoproteins, HA and NA.6 The RNA genome is segmented, which allows genetic 
reassortment among viruses of the same type.6 This genetic instability can result in the 
phenomenon known as antigenic shift, involving a major change in 1 or both of the HAs and 
NAs, which, if efficiently transmissible, can result in a pandemic. More common are 
multiple point mutations in the genome, leading to more minor changes in the HA and NA, 
known as antigenic drift.4 This genetic instability is what necessitates vaccines that are 
tailored annually.4 
2.2.2. Influenza Vaccination 
The first influenza vaccines were licensed in the 1940s,7 and now a number of different types 
of vaccine exist: inactivated, recombinant, and LAIV.8 The viruses that form the basis for 
inactivated vaccines are replicated in either embryonated hens’ eggs or mammalian cell 
lines,9 and some are combined with an adjuvant, such as MF59, to improve the immune 
response, particularly important in older individuals.8 Multivalent vaccines are produced for 
routine seasonal immunization, targeting 3 or 4 influenza viruses.8 Trivalent vaccines target 
2 A subtypes and 1 B virus, although in recent years these have been replaced by 
quadrivalent vaccines which target an additional B virus (to cover 2 antigenically distinct 
lineages).10 Standard inactivated vaccines generally contain 15 µg of each HA for adult 
intramuscular injection, although the high-dose inactivated vaccine contains 60 µg of each 
HA.11 

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Due to the ongoing variability in circulating influenza viruses, recommendations for the 
viruses to be targeted by each influenza season’s vaccines reflect the global influenza virus 
surveillance that continues throughout the year in both hemispheres.11 This means that the 
schedule for vaccine production, release, and administration is highly compressed. 
2.2.2.1. Assessing Influenza Vaccine Immunogenicity 
Dependent upon the components included in each influenza vaccine, vaccination is intended 
to induce antibodies against HA and NA.12 Strain-specific immunogenicity can be measured 
by the HAI and microneutralization assays, although antibody titers measured by the HAI are 
most commonly used to assess vaccine responses.11 In general, an HAI titer between 1:32 
and 1:40 is considered protective at a group level.11 This is reflected in regulatory guidance, 
where, for example: 
Seroconversion is defined as a prevaccination HAI titer <1:10 and a postvaccination HAI 
titer ≥1:40 or a prevaccination HAI titer ≥1:10 and a minimum 4-fold rise in postvaccination 
HAI antibody titer.11 
A reasonable statistical correlate for an efficacy of 50%-70% against clinical symptoms 
of influenza is defined as an HAI titer of 1:40.13 
Regulatory guidance allows for authorization of a new seasonal influenza vaccine on the 
basis of immunogenicity and/or efficacy data.13,14 
2.2.3. Nucleoside-Modified mRNA Vaccines 
In recent years, the use of mRNA as the basis for potential vaccine candidates has shown 
increasing promise.15 Various approaches to optimize the response to mRNA vaccines have 
been used. This includes modRNA, in which some nucleosides are replaced by naturally 
occurring modified nucleosides, such as pseudouridine, that decrease innate immune 
activation and increase translation.15 
Two lipid nanoparticle-encapsulated modRNA vaccines encoding the SARS-CoV-2 spike 
protein have been developed in response to the public health emergency presented by the 
COVID-19 pandemic: BNT162b2 (Pfizer/BioNTech)16 and mRNA-1273 (Moderna).17 
ModRNA vaccine candidate dose levels up to 100 µg18 and 250 µg17 were studied in the 
candidate selection/dose-finding stage of development for the 2 vaccines, respectively. 
Phase 3 development in participants >12 years of age was conducted with 2 doses of 
BNT162b2 30 µg16 and 2 doses of mRNA-1273 100 µg,19 with both vaccines demonstrated 
to be highly effective with no identified significant safety concerns.16,19 Since its first 
marketing authorization in December 2020, BNT162b2 has been administered to hundreds of 
millions of individuals worldwide.20,21 Postauthorization safety surveillance in the US has 
confirmed the safety profile seen in clinical trials, and has also identified adverse reactions of 
anaphylaxis and an increased risk of myocarditis and pericarditis.22 

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2.2.4. Potential for mRNA Influenza Vaccines 
The experience with modRNA-based COVID-19 vaccines supports use of the modRNA 
platform for potential rapid development of vaccines encoding the seasonally adapted H1, 
H3, and 2 B HAs for the prevention of influenza. 
The modRNA platform would present a number of potential advantages. Manufacturing 
could be accelerated as no reassortant step is required to produce manufacturing strains. 
This allows the decision on HA sequence to be made later than with current vaccines, and no 
egg adaptation is required, reducing the probability of vaccine being mismatched with 
circulating strains. The induction of not only anti-HA antibodies but also potential CD4+ 
and CD8+ T-cell responses (as seen with BNT162b2)23 could improve upon the efficacy 
observed with existing influenza vaccines. 
Similar advantages would also be highly relevant to a pandemic influenza vaccine in the 
event that one is required. 
2.3. Benefit/Risk Assessment 
modRNA vaccines expressing the SARS-CoV-2 spike protein have been shown to be safe, 
adequately tolerated, and efficacious in the prevention of COVID-19 when administered as 
2 doses at a 21- to 28-day interval.16,19 These vaccines have been authorized in many 
countries around the world, and following receipt of the first temporary authorization 
approximately 774,478,440 doses of BNT162b2 have been shipped worldwide 
(from 01 December 2020 through 18 June 2021).21 
This supports use of the modRNA platform for potentially rapid development of vaccines 
encoding the seasonally adapted H1, H3, and 2 B HAs for the prevention of influenza. 
2.3.1. Risk Assessment 
 
Identified/Potential Risk of 
Clinical Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Study Intervention: mIRV, bIRV, qIRV 
Local and systemic reactions to 
the vaccine may occur (injection 
site redness, injection site 
swelling, and injection site pain; 
fever, fatigue, headache, chills, 
muscle pain, and joint pain) 
following vaccination. 
These are common adverse 
reactions seen with other 
vaccines,24 as well as the 
COVID-19 vaccine BNT162b2, 
which is also based on 
modRNA. The most common 
events reported in a large-scale 
efficacy study with BNT162b2 
(C4591001) were mild to 
moderate pain at the injection 
site, fatigue, and headache.16 
1-Week follow-up 
reactogenicity data of 194 
participants who received 
mIRV, bIRV, or qIRV in 
Substudy A showed most events 
to be mild to moderate in 
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. 
All study participants will be observed 
for at least 30 minutes after vaccination. 

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Identified/Potential Risk of 
Clinical Significance 
 
 
 
 
The safety profile of a novel 
vaccine is not yet fully 
characterized. 
Summary of Data/Rationale 
for Risk 
severity, with the most common 
events being pain at the 
injection site, fatigue, and 
headache. 
Although qIRV/bIRV/mIRV are 
novel vaccines, they are based 
on the same platform 
(modRNA) as the COVID-19 
vaccine BNT162b2, which has 
been shown to have a positive 
benefit/risk profile. 
Mitigation Strategy 
 
 
 
 
 
AE and SAE reports will be collected 
from the signing of the ICD to 4 weeks 
and 6 months, respectively, after the 
vaccination. 
All participants will be observed for at 
least 30 minutes after vaccination. 
Administration of bIRV or qIRV 
This is supported by an 
Participants receiving CCI 
will 
at a total dose of CCI . 
 
 
 
 
 
 
 
 
 
Unknown safety profile of 
mIRV A/B administered within 
at least 8 weeks after QIV. 
 
 
 
 
Unknown safety profile of bIRV 
administered concurrently with 
QIV. 
 
 
 
 
Cases of anaphylaxis, 
myocarditis, and pericarditis 
have been reported after 
authorization in recipients of 
BNT162b2.21 
acceptable tolerability profile 
for a single dose up to CCI  and 
opportunity to increase the 
immune response. 
 
 
 
 
 
 
 
Administration of mIRV A/B 
following QIV will allow an 
assessment of whether the 
immune response elicited by 
QIV may be augmented by a 
modRNA influenza vaccine. 
 
Concurrent administration of 
bIRV with licensed QIV will 
allow an assessment of whether 
the immune response elicited by 
QIV may be augmented by a 
modRNA influenza vaccine. 
 
Anaphylaxis: The estimated rate 
is 5.0 per million doses 
administered.25 
 
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 several days after 
vaccination. These are 
generally mild cases, and 
individuals tend to recover 
be vaccinated in a stepwise manner, to 
ensure that initial tolerability is 
acceptable prior to dosing of the whole 
group (see Section 10.10.4.1). 
AE and SAE reports will be collected 
from the signing of the ICD to 4 weeks 
and 6 months, respectively, after 
vaccination. 
 
All participants will be observed for at 
least 30 minutes after vaccination. 
AE and SAE reports will be collected 
from the signing of the ICD to 4 weeks 
and 6 months, respectively, after the 
mIRV A/B vaccination. 
 
All participants will be observed for at 
least 30 minutes after vaccination. 
AE and SAE reports will be collected 
from the signing of the ICD to 4 weeks 
and 6 months, respectively, after the 
bIRV A/A vaccination. 
 
All participants will be observed for at 
least 30 minutes after vaccination. 
Based on the immunogenicity results at 
the Phase 3 interim analysis, participants 
who were randomized to receive qIRV 
may be offered a licensed QIV. 
Specific reference to these risks is made 
within the ICD, with instruction to 
contact a healthcare professional if a 
case is suspected. 
For anaphylaxis, there is an on-site 
30-minute observation period after 
vaccination. 
Routine ECG and biochemistry 
monitoring in first week after 
vaccination. Instructions for handling 
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Identified/Potential Risk of 
Clinical Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
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. 
pericarditis are found in 
Section 10.9.8.8.11. 
Study Intervention: QIV 
Local and systemic reactions to 
the vaccine may occur. 
The QIV to be used in this study 
is unknown at the time of 
protocol authorship. However, 
the most common local 
reactions and systemic events 
observed following vaccination 
with seasonal influenza vaccines 
are pain at the injection site, 
injection site erythema and 
induration, fever, malaise, 
myalgia, headache, and 
fatigue.26 
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 conduct 
per protocol. 
All study participants will be observed 
for at least 30 minutes after vaccination. 
Unknown safety profile of QIV 
when administered as 2-dose 
series. 
Administration of 2 doses of 
QIV will act as a control group 
in Substudy B and allow 
assessment of whether the 
immune response elicited by 
other vaccination groups in 
Substudy B is superior. 
AE and SAE reports will be collected 
from the signing of the ICD to 4 weeks 
and 6 months, respectively, after the last 
vaccination. 
All participants will be observed for at 
least 30 minutes after vaccination. 
Study Procedures 
Participants will be required to 
attend healthcare facilities during 
the global SARS-CoV-2 
pandemic. 
Without appropriate social 
distancing and PPE, there is a 
potential for increased exposure 
to SARS-CoV-2. 
Pfizer will work with sites to ensure 
appropriate COVID-19 prevention 
strategies. 
Monitoring for cases of COVID-19 
developing during the study, which will 
be reported as AEs. 
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 are detailed in Section 10.9.2.3 for participants enrolled in 
Substudy A and in Section 10.10.2.3 for participants enrolled in Substudy B. 
2.3.3. Overall Benefit/Risk Conclusion 
Considering the measures taken to minimize risks to participants participating in the study, 
the potential risks identified in association with mIRV, bIRV, and qIRV are justified by the 
anticipated benefits that may be afforded to healthy participants. 

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More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of qIRV, mIRV, and bIRV may be found in the IB, which is the SRSD for this 
study. The SRSD for the comparator agent (QIV) is the US package insert. 
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS 
See Section 10.9.3 for the objectives, estimands, and endpoints for Substudy A. 
See Section 10.10.3 for the objectives, estimands, and endpoints for Substudy B. 
4. STUDY DESIGN 
4.1. Overall Design 
This is a Phase 1/2 randomized study to evaluate the safety, tolerability, and immunogenicity 
of a modRNA vaccine against influenza in healthy individuals. This study will be conducted 
across 2 substudies – Substudy A and Substudy B. 
See Section 10.9.4 for details of the study design for Substudy A. 
See Section 10.10.4 for details of the study design for Substudy B. 
4.2. Scientific Rationale for Study Design 
See Section 2.2.4 and Section 2.1. 
4.2.1. Diversity of Study Population 
This study can fulfill its objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds. Use of a 
prescreener for study recruitment purposes will include collection of information that reflects 
the enrollment of a diverse participant population including, where permitted under local 
regulations, age, sex, race, and ethnicity. The following eligibility criteria are designed to 
select participants for whom participation in the study is considered appropriate. All relevant 
medical and nonmedical conditions should be taken into consideration when deciding 
whether a particular participant is suitable for this protocol. Prospective approval of protocol 
deviations to recruitment and enrollment criteria, also known as protocol waivers or 
exemptions, is not permitted. 
4.2.2. Choice of Contraception/Barrier Requirements 
Human reproductive safety data are not available for the modRNA influenza vaccines used in 
this study, but there is no suspicion of human teratogenicity based on the intended 
pharmacology of the compound. The use of a highly effective method of contraception is 
required for sexual intercourse involving a WOCBP (see Appendix 4). 
4.3. Justification for Dose 
Based on the extensive experience with the modRNA-based BNT162b2 COVID-19 vaccine 
at a dose level of CCI  Substudy A did not employ dose escalation. All dose levels to be 
studied for a particular candidate can be enrolled concurrently, up to a dose level of CCI . 

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Based on preliminary data from Substudy A, Substudy B will study increased doses of 
influenza modRNA vaccine: either 1 or 2 doses ofCCI , 1 dose of CCI , or 1 dose of CCI . 
This is supported by an acceptable tolerability profile for a single dose up to CCI  and 
opportunity to increase the immune response. Participants in the first group receiving CCI  
will be vaccinated in a stepwise manner, to ensure that initial tolerability is 
acceptable prior to dosing of the whole group (see Section 10.10.4.1). 
4.4. End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study. 
A participant is considered to have completed the study if he/she has completed all periods of 
the study, including the last visit. 
5. STUDY POPULATION 
This study can fulfill its objectives only if appropriate participants are enrolled. The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate. All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. Inclusion Criteria 
See Section 10.9.5.1 for Substudy A inclusion criteria. 
See Section 10.10.5.1 for Substudy B inclusion criteria. 
5.2. Exclusion Criteria 
See Section 10.9.5.2 for Substudy A exclusion criteria. 
See Section 10.10.5.2 for Substudy B exclusion criteria. 
5.3. Lifestyle Considerations 
5.3.1. Contraception 
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods 
(see Appendix 4, Section 10.4.4) and will confirm that the participant has been instructed in 
its consistent and correct use. At time points indicated in the SoA, the investigator or 
designee will inform the participant of the need to use 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 

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have changed since the last visit. In addition, the investigator or designee will instruct the 
participant to call immediately if the selected contraception method is discontinued or if 
pregnancy is known or suspected in the participant or partner. 
5.4. Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants to 
meet the CONSORT publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. 
5.5. 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 eligible. Participants meeting these criteria at 
Vaccination 1 will be considered screen failures if enrollment has closed once the 
condition(s) has/have resolved. 
1. Current febrile illness (body temperature ≥100.4°F [≥38°C]) or other acute illness within 
48 hours before study intervention administration. 
2. Receipt of any nonstudy vaccine within 28 days, before study intervention 
administration. 
3. Anticipated receipt of any nonstudy vaccine within 28 days, after study intervention 
administration. 
4. Receipt of short-term (<14 days) systemic corticosteroids. Study intervention 
administration should be delayed until systemic corticosteroid use has been discontinued 
for at least 28 days. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin or 
eyes) corticosteroids are permitted. 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol. 

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6.1. Study Intervention(s) Administered 
6.1.1. Administration 
Standard vaccination practices must be observed and vaccine must not be injected into blood 
vessels. Appropriate medication and other supportive measures for management of an acute 
hypersensitivity reaction should be available in accordance with local guidelines for standard 
immunization practices. 
Administration of study interventions should be performed by an appropriately qualified, 
GCP-trained, and vaccine experienced member of the study staff (eg, physician, nurse, 
physician’s assistant, nurse practitioner, pharmacist, or medical assistant) as allowed by 
local, state, and institutional guidance. 
Study intervention administration details will be recorded on the CRF. 
See Section 10.9.6.1 for study intervention administration details for Substudy A. 
See Section 10.10.6.1 for study intervention administration details for Substudy B. 
6.1.2. Medical Devices 
The comparator vaccine detailed in Section 10.9.6.1 and Section 10.10.6.1 may be provided 
as a PFS and, in which case, should be considered a medical device. 
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 8.3.9) and appropriately managed by the sponsor. 
6.2. Preparation, Handling, Storage, and Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study interventions received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study interventions 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated recording) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff. At a minimum, daily minimum and 
maximum temperatures for all site storage locations must be documented and available 
upon request. Data for nonworking days must indicate the minimum and maximum 
temperatures since previously documented for all site storage locations upon return to 
business. 

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3. Any excursions from the study intervention label storage conditions should be reported to 
Pfizer upon discovery along with any actions taken. The site should actively pursue 
options for returning the study intervention to the storage conditions described in the 
labeling, as soon as possible. Once an excursion is identified, the study intervention must 
be quarantined and not used until Pfizer provides permission to use the study 
intervention. Specific details regarding the definition of an excursion and information the 
site should report for each excursion will be provided to the site in the IP manual. 
4. Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the label. 
5. Study interventions should be stored in their original containers. 
6. See the IP manual for storage conditions of the study intervention once prepared. 
7. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records), such as the IPAL or 
sponsor-approved equivalent. All study interventions will be accounted for using a study 
intervention accountability form/record. 
8. Further guidance and information for the final disposition of unused study interventions 
are provided in the IP manual. All destruction must be adequately documented. If 
destruction is authorized to take place at the investigator site, the investigator must ensure 
that the materials are destroyed in compliance with applicable environmental regulations, 
institutional policy, and any special instructions provided by Pfizer. 
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IP manual. 
6.2.1. Preparation and Dispensing 
See the IP manual for instructions on how to prepare the study intervention for 
administration. Study intervention should be prepared and dispensed by an appropriately 
qualified and experienced member of the study staff (eg, physician, nurse, physician’s 
assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as allowed by 
local, state, and institutional guidance. A second staff member will verify the preparation 
and dispensing. 
See Section 10.9.6.1.4 for further details regarding study intervention preparation and 
dispensing for Substudy A. 
See Section 10.10.6.1.4 for further details regarding study intervention preparation and 
dispensing for Substudy B. 

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6.3. Measures to Minimize Bias: Randomization and Blinding 
6.3.1. Allocation to Study Intervention 
Allocation (randomization) of participants to vaccine groups will proceed through the use of 
an IRT system (IWR). The site personnel (study coordinator or specified designee) will be 
required to enter or select information including but not limited to the user’s ID and 
password, the protocol number, and the participant number. The site personnel will then be 
provided with a 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 
depending on the role/permission the user is granted and must be stored in the site’s blinded 
or unblinded files as appropriate. 
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system. 
See Section 10.9.6.2.1 for further details regarding allocation of study intervention in 
Substudy A. 
See Section 10.10.6.2.1 for further details regarding allocation of study intervention in 
Substudy B. 
6.3.2. Blinding Arrangements 
Substudy A blinding arrangements for site personnel and the sponsor are detailed in 
Section 10.9.6.2.2 and Section 10.9.6.2.3. 
Substudy B blinding arrangements for site personnel and the sponsor are detailed in 
Section 10.10.6.2.2 and Section 10.10.6.2.3. 
6.4. Study Intervention Compliance 
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention. 
6.5. Dose Modification 
Not applicable. 
6.6. Continued Access to Study Intervention After the End of the Study 
No intervention will be provided to study participants at the end of their study participation. 

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6.7. Treatment of Overdose 
For this study, any dose of study intervention greater than 1 dose of study intervention within 
a 24-hour time period will be considered an overdose. 
Pfizer does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator should: 
1. Contact the medical monitor within 24 hours. 
2. Closely monitor the participant for any AEs/SAEs. 
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF. 
4. Overdose is reportable to Pfizer Safety only when associated with an SAE. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant. 
6.8. Concomitant Therapy 
The following concomitant medications and vaccinations will be recorded in the CRF: 
• Prior receipt of any COVID-19 vaccine. 
• For Substudy A, licensed influenza vaccine, if received during the prior influenza season. 
• For Substudy B, any licensed influenza vaccine received in the prior 12 months. 
• Any vaccinations received from 28 days prior to study enrollment until the last visit 
(Visit 6 for Substudy A and Visit 207 for Substudy B). 
• Prohibited medications listed in Section 6.8.1 will be recorded and include start and stop 
dates, name of the medication, dose, unit, route, and frequency. 
• All current medications at baseline will be recorded and include start date, name of the 
medication, dose, unit, route, and frequency. 
6.8.1. Prohibited During the Study 
Receipt of the following vaccines and medications during the time periods listed below may 
exclude a participant from the per-protocol analysis from that point onward and may require 
vaccinations to be discontinued in that participant; however, it is anticipated that the 
participant would not be withdrawn from the study (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 each study vaccination. 
• Receipt of any mRNA-platform SARS-CoV-2 vaccine within 60 days before and 60 days 
after study vaccination that contains modRNA for Substudy A, and within 28 days before 
and 28 days after any study vaccination that contains modRNA for Substudy B. 
• For Substudy A, receipt of any other (nonstudy) seasonal influenza vaccine at any time 
during study participation is prohibited. 
• For Substudy B, receipt of any other (nonstudy) seasonal influenza vaccine from 
enrollment to Visit 207 (8-week follow-up visit) is prohibited. 
• 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 last study intervention. 
• Receipt of blood/plasma products or immunoglobulins within 60 days before enrollment 
through conclusion of the study is prohibited. 
• Prophylactic antipyretics and other pain medication to prevent symptoms associated with 
study intervention administration are not permitted. However, if a participant is taking a 
medication for another condition, even if it may have antipyretic or pain-relieving 
properties, it should not be withheld prior to study vaccination. 
6.8.2. Permitted During the Study 
• Medication other than that described as prohibited in Section 6.8.1 required for treatment 
of preexisting conditions or acute illness is permitted. 
• Inhaled, topical, or localized injections of corticosteroids (eg, intra-articular or intrabursal 
administration) are permitted. 
• Hormonal contraceptives that meet the requirements of this study are allowed to be used 
in participants who are WOCBP (see Appendix 4). 

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7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. Reasons for permanent discontinuation of study intervention include the 
following: AEs, participant request, investigator request, pregnancy, and protocol deviation 
(including no longer meeting all the inclusion criteria, or meeting 1 or more exclusion 
criteria). 
Note that discontinuation of study intervention does not represent withdrawal from the study. 
If study intervention is permanently discontinued, the participant will remain in the study to 
be evaluated for safety and immunogenicity. See the SoA for data to be collected at the time 
of discontinuation of study intervention and follow-up for any further evaluations that need 
to be completed. Participants who remain in the study for evaluation of safety will be 
contacted by telephone 6 months after their last study vaccination to record AEs as described 
in Section 8.3. 
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information. 
7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study include the following: 
• Refused further study procedures; 
• Lost to follow-up; 
• Death; 
• Study terminated by sponsor; 
• AEs; 
• Participant request; 
• Investigator request; 
• Protocol deviation. 

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If a participant does not return for a scheduled visit, every effort should be made to contact 
the participant. All attempts to contact the participant and information received during 
contact attempts must be documented in the participant’s source document. In any 
circumstance, every effort should be made to document participant outcome, if possible. 
The investigator or his or her designee should capture the reason for withdrawal in the CRF 
for all participants. 
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly. 
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent. 
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible. The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of study intervention or also from study procedures 
and/or posttreatment study follow-up, and entered on the appropriate CRF page. In the event 
that vital status (whether the participant is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed 
in accordance with local law. 
7.3. Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to attend a required study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible. Counsel the participant on the importance of maintaining the assigned visit 
schedule, and ascertain whether the participant wishes to and/or should continue in the 
study; 

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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, he/she will be considered to have 
withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES 
See Section 10.9.8 for assessments and procedures specific to Substudy A, and 
Section 10.10.8 for assessments and procedures specific to Substudy B. 
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures. 
The date of birth will be collected to critically evaluate the immune response and safety 
profile by age. 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Clinical safety laboratory assessments will be collected in this study (see Section 10.2). 

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Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner. 
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study. 
8.1. Efficacy and/or Immunogenicity Assessments 
Blood samples will be obtained for immunogenicity testing at the visits specified in the study 
SoA (see Section 10.9.1 for the Substudy A SoA, and Section 10.10.1 for the Substudy B 
SoA). 
Note that all immunogenicity analyses will be based upon samples analyzed at the central 
laboratory. 
8.1.1. Biological Samples 
Blood samples will be used only for scientific research. Each sample will be labeled with a 
code so that the laboratory personnel testing the samples will not know the participant’s 
identity. Samples that remain after performing assays outlined in the protocol may be stored 
by Pfizer. Unless a time limitation is required by local regulations or ethical requirements, 
the samples will be stored for up to 15 years after the end of the study and then destroyed. 
If allowed by the ICD, stored samples may be used for additional testing to better understand 
the immune responses to the vaccine(s) under study in this protocol, to inform the 
development of other products, and/or for vaccine-related assay work supporting vaccine 
programs. No testing of the participant’s genetic material will be performed, with the 
exception of those participants who have provided specific consent to genetic testing of the 
blood samples for PBMC isolation. 
The participant may request that his or her samples, if still identifiable, be destroyed at any 
time; however, any data already collected from those samples will still be used for this 
research. The biological samples may be shared with other researchers as long as 
confidentiality is maintained and no testing of the participant’s genetic material is performed, 
with the exception of those participants who have provided specific consent to genetic testing 
of the blood samples for PBMC isolation. 
8.2. Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues. 

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A clinical assessment, including medical history, will be performed on all participants at their 
first visit to establish a baseline. Significant medical history and observations from any 
physical examination, if performed, will be documented in the CRF. 
AEs and SAEs are collected, recorded, and reported as defined in Section 8.3. 
Acute reactions within the first 30 minutes after administration of the study intervention will 
be assessed and documented in the AE CRF. 
The safety parameters also include reactogenicity e-diary reports of local reactions and 
systemic events (including fever) and use of antipyretic medication that occur in the 7 days 
after administration of the study intervention. These prospectively self-collected occurrences 
of local reactions and systemic events are graded as described in Section 8.2.3.1. 
8.2.1. Physical Examinations 
A physical examination will be performed at the screening visit and, if clinically indicated, 
prior to the participant’s first vaccination (Visits 1 and 201 for Substudies A and B, 
respectively). Physical examination findings collected during the study will be considered 
source data and will not be required to be reported, unless otherwise noted. Any untoward 
physical examination findings that are identified during the active collection period and meet 
the definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.3.1 to Section 8.3.3. 
8.2.2. Vital Signs 
The participant’s body temperature will be measured prior to each vaccination. Additionally, 
weight, height (at screening), pulse rate, and seated blood pressure will be measured prior to 
the participants first vaccination. 
8.2.3. Electronic Diary 
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. 

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The investigator or designee must obtain stop dates from the participant for any ongoing 
local reactions, systemic events, or use of antipyretic medication on the last day that the 
reactogenicity e-diary was completed. The stop dates should be documented in the source 
documents and the information entered in the CRF. 
8.2.3.1. 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.24 
8.2.3.2. 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 B, local reactions will be assessed at the injection site on 
the right arm only. 
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. 
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 and, if it is determined to be 
related to the administration of the study intervention, further vaccinations will be 
discontinued in that participant. 
 
Table 1. 
Local Reaction Grading Scale 
 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
Life-Threatening 
(Grade 4) 
Pain at the 
injection site 
Does not interfere 
with activity 
Interferes with activity Prevents daily 
activity 
Emergency room visit 
or hospitalization for 
severe pain 
Redness 
>2.0 cm to 5.0 cm 
(5 to 10 measuring 
device units) 
>5.0 cm to 10.0 cm 
(11 to 20 measuring 
device units) 
>10 cm 
(≥21 measuring 
device units) 
Necrosis or exfoliative 
dermatitis 

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Table 1. 
Local Reaction Grading Scale 
 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
Life-Threatening 
(Grade 4) 
Swelling 
>2.0 cm to 5.0 cm 
(5 to 10 measuring 
device units) 
>5.0 cm to 10.0 cm 
(11 to 20 measuring 
device units) 
>10 cm 
(≥21 measuring 
device units) 
Necrosis 
 
 
8.2.3.3. Systemic Events 
During the reactogenicity e-diary reporting period, participants will be asked to assess 
vomiting, diarrhea, headache, fatigue, chills, new or worsened muscle pain, and new or 
worsened joint pain and to record the symptoms in the reactogenicity e-diary. The symptoms 
will be assessed by the participant as absent, mild, moderate, or severe according to the 
grading scale in Table 2. 
If a Grade 3 systemic event is reported in the reactogenicity e-diary, a telephone contact 
should occur to ascertain further details and determine whether a site visit is clinically 
indicated. Only an investigator or medically qualified person is able to classify a 
participant’s systemic event as Grade 4. If a participant experiences a confirmed Grade 4 
systemic event, the investigator must immediately notify the sponsor and, if it is determined 
to be related to the administration of the study intervention, further vaccinations will be 
discontinued in that participant. 
 
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 

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Table 2. 
Systemic Event Grading Scale 
 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life- 
Threatening 
(Grade 4) 
New or worsened 
joint pain 
Does not interfere 
with activity 
Some interference 
with activity 
Prevents daily routine 
activity 
Emergency room visit 
or hospitalization for 
severe new or worsened 
joint pain 
Abbreviation: IV = intravenous. 
 
 
8.2.3.4. 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. 
If a fever of ≥39.0°C (≥102.1°F) is reported in the reactogenicity e-diary, a telephone contact 
should occur to ascertain further details and determine whether a site visit is clinically 
indicated. Only an investigator or medically qualified person is able to confirm a 
participant’s fever as >40.0°C (>104.0°F). If a participant experiences a confirmed fever 
>40.0°C (>104.0°F), the investigator must immediately notify the sponsor and, if it is 
determined to be related to the administration of the study intervention, further vaccinations 
will be discontinued in that participant. 
 
Table 3. 
Scale for Fever 
 
≥38.0-38.4°C (100.4-101.1°F) 
>38.4-38.9°C (101.2-102.0°F) 
>38.9-40.0°C (102.1-104.0°F) 
>40.0°C (>104.0°F) 
 
 
8.2.3.5. 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). 

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8.2.4. Clinical Safety Laboratory Assessments 
Clinical safety laboratory assessments will be collected in both Substudies A and B. 
See Section 10.2. 
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA. Unscheduled clinical laboratory 
measurements may be obtained at any time during the study to assess any perceived safety 
issues. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. Refer to 
the laboratory normal ranges (provided separately) for grading scales for abnormalities. 
Clinically significant abnormal laboratory findings are those that are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for the 
participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified. 
See Section 10.6 for suggested actions and follow-up assessments in the event of potential 
DILI. 
8.2.5. Pregnancy Testing 
Following screening, pregnancy tests may be urine or serum tests, but must have a sensitivity 
of at least 25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in 
the SoA, immediately before the administration of each vaccine dose. A negative pregnancy 
test result will be required prior to the participant’s receiving the study intervention. 
Pregnancy tests may also be repeated if requested by IRBs/ECs or if required by local 
regulations. In the case of a positive confirmed pregnancy, the participant will not be 
administered the study intervention dose and will be withdrawn from the study. 
8.2.6. Stopping Rules 
The following stopping rules are in place for both Substudies A and B; see also 
Section 10.9.8.6 and Section 10.10.8.6, respectively. 
8.2.7. ECGs and Echocardiograms 
ECGs will be collected at the times specified in Section 10.9.1 for Substudy A and 
Section 10.10.1 for Substudy B. 

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All scheduled 12-lead ECGs should be performed after the participant has rested quietly for 
at least 10 minutes in a supine position. The ECGs should be obtained prior to blood 
collection, measurement of blood pressure, and measurement of pulse rate. ECGs will be 
performed in triplicate. 
ECG data will be submitted to a central laboratory for measurement. The final ECG report 
from the central laboratory should be maintained in the participant’s source documentation 
and be the final interpretation of the ECG recording. Any clinically significant changes from 
the baseline/Day 1 ECG may potentially be AEs (Appendix 5) and should be evaluated 
further, as clinically warranted. 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that lead placement be in 
the same position each time in order to achieve precise ECG recordings. 
ECG values of potential clinical concern are listed in Appendix 5. 
ECG abnormalities consistent with probable or possible myocarditis or pericarditis are those 
judged as such by a cardiologist, 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 
Echocardiograms may be performed as detailed in Section 10.9.8.8.11 and 
Section 10.10.8.8.11. 
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The definitions of an AE and an SAE can be found in Appendix 3. 
The definitions of device-related safety events (ADEs and SADEs) can be found in 
Section 10.7. Device deficiencies are covered in Section 8.3.9. 
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc.). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 

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During the active collection period as described in Section 8.3.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner. 
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion. 
8.3.1. Time Period and Frequency for Collecting AE and SAE Information 
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant 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 4 (4-week follow-up visit), and from Visit 5 to Visit 5B (4-week post–Vaccination 2 
follow-up visit) for Substudy A. Additionally, for Substudy A, any AEs occurring up to 
48 hours after the blood draws at Visits 4 and 5B must be recorded on the CRF. 
• Visit 206 (4-week follow-up visit) for Substudy B. Additionally, for Substudy B, any 
AEs occurring up to 48 hours after the blood draws at Visits 206 and 207 must be 
recorded on the CRF. 
SAEs will be collected from the time the participant provides informed consent to 
approximately 6 months after the participant’s last study vaccination (Visit 6 for Substudy A 
and Visit 208 for Substudy B). 
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator. 
For participants who are screen failures, the active collection period ends when screen failure 
status is determined. 
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn. 
If a participant permanently discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the Vaccine SAE Reporting Form. 
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any 
SAE, including a death, at any time after a participant has completed the study, and he/she 
considers the event to be reasonably related to the study intervention, the investigator must 
promptly report the SAE to Pfizer using the Vaccine SAE Reporting Form. 

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8.3.1.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the Vaccine SAE Reporting Form immediately 
upon awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available. 
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF 
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF. 
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant. 
8.3.2. Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. Follow-Up of AEs and SAEs 
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3). 
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3. 
8.3.4. Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. 

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The sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements. 
8.3.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure 
Environmental exposure occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. 
An environmental exposure may include exposure during pregnancy, exposure during 
breastfeeding, and occupational exposure. 
Any such exposure to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness. 
8.3.5.1. Exposure During Pregnancy 
An EDP occurs if: 
• A female participant is found to be pregnant while receiving or after discontinuing study 
intervention. 
• A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception. 
• A female is found to be pregnant while being exposed or having been exposed to study 
intervention due to environmental exposure. Below are examples of environmental EDP: 
• A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by inhalation or skin contact. 
• A male family member or healthcare provider who has been exposed to the study 
intervention by inhalation or skin contact then exposes his female partner prior to or 
around the time of conception. 
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

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• If EDP occurs in a participant or a participant’s partner, the investigator must report this 
information to Pfizer Safety on the Vaccine SAE Reporting Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until 28 days after the 
last dose of study intervention. 
• 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; 
• Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs 
when the investigator assesses the infant death as related or possibly related to exposure 
to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner. 

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8.3.5.2. Exposure During Breastfeeding 
An exposure during breastfeeding occurs if: 
• A female participant is found to be breastfeeding while receiving or after discontinuing 
study intervention. 
• A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental exposure 
during breastfeeding is a female family member or healthcare provider who reports that 
she is breastfeeding after having been exposed to the study intervention by inhalation or 
skin contact. 
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the Vaccine SAE Reporting Form. When exposure 
during breastfeeding occurs in the setting of environmental exposure, the exposure 
information does not pertain to the participant enrolled in the study, so the information is not 
recorded on a CRF. However, a copy of the completed Vaccine SAE Reporting Form is 
maintained in the investigator site file. 
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use. However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding. 
8.3.5.3. Occupational Exposure 
The investigator must report any instance of occupational exposure to Pfizer Safety within 
24 hours of the investigator’s awareness using the Vaccine SAE Reporting Form, regardless 
of whether there is an associated SAE. Since the information about the occupational 
exposure does not pertain to a participant enrolled in the study, the information is not 
recorded on a CRF; however, a copy of the completed Vaccine SAE Reporting Form must be 
maintained in the investigator site file. 
8.3.6. Cardiovascular and Death Events 
Not applicable. 
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
Not applicable. 
8.3.8. Adverse Events of Special Interest 
For all study phases, the following events are considered AESIs: 
• A confirmed diagnosis of influenza; 

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• A confirmed diagnosis of myocarditis or pericarditis. See Section 10.9.8.8.11 and 
Section 10.10.8.8.11 for additional procedures for monitoring of potential myocarditis or 
pericarditis in Substudies A and B, respectively. 
AESIs are examined as part of routine safety data review procedures throughout the clinical 
trial and as part of signal detection processes. 
All AESIs must be reported as an AE or SAE following the procedures described in 
Sections 8.3.1 through Section 8.3.4. An AESI is to be recorded as an AE or SAE on the 
CRF. In addition, an AESI that is also an SAE must be reported using the Vaccine SAE 
Reporting Form. 
8.3.8.1. 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. 
8.3.9. Medical Device Deficiencies 
Medical devices being provided for use in this study as the study intervention may be 
supplied in PFS. 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 10.7. 
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 Section 8.3.1 through Section 8.3.4 and 
Appendix 3 of the protocol. 
8.3.9.1. 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 10.7. 

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8.3.9.2. 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. 
8.3.9.3. Prompt Reporting of Device Deficiencies to the Sponsor 
When a device deficiency occurs: 
1. The unblinded site staff notifies the sponsor by a contact method as detailed in the IP 
manual 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 non-serious) 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 
investigator, the investigator must immediately notify Pfizer Safety of the SAE 
(see Section 8.3.1.1). 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 8.3.1.1 and 
Section 8.3.1.2. 
The sponsor will be the contact for the receipt of device deficiency information. 
8.3.9.4. 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. 
8.3.10. Medication Errors 
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength. 
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors. 

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

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8.5. Genetics 
Some of the blood samples collected for PBMC isolation may be used for DNA and/or RNA 
isolation. The DNA and/or RNA samples from the PBMC isolation may be used for 
sequencing of participants’ antibody and/or BCR heavy- and light-chain genes, TCR genes, 
and/or mRNAs, for understanding the B-cell, T-cell, and antibody repertoires. 
See Section 10.12 for information regarding genetic research. Details on processes for 
collection and shipment of these samples will be provided separately. 
8.6. Biomarkers 
Biomarkers are not evaluated in this study. 
8.7. Immunogenicity Assessments 
Immunogenicity assessments are described in Section 8.1. 
8.8. Health Economics 
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study. 
9. STATISTICAL CONSIDERATIONS 
Methodology for summary and statistical analyses of the data collected in this study is 
described here and further detailed in an 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 10.9.9 and Section 10.10.9 for Substudy A and Substudy B statistical 
hypotheses, respectively. 
9.1.1. Estimands 
Refer to Section 10.9.3 and Section 10.10.3 for estimands relating to Substudy A and 
Substudy B, respectively. 
9.1.2. Multiplicity Adjustment 
Please see Section 10.9.9.1.2 and Section 10.10.9.1.2 for Substudy A and Substudy B, 
respectively. 

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9.2. Analysis Sets 
For purposes of analysis for the study, the following analysis sets are defined: 
 
Population 
Description 
Enrolled 
All participants who sign the ICD. 
Randomly assigned to 
study intervention 
All participants who are assigned a randomization number in 
the IWR system. 
Vaccination 1 evaluable 
For Substudy A only. All participants who are eligible, 
receive the study intervention (Vaccination 1) to which they 
were randomized, have blood drawn for assay testing within 
specified time frames after Vaccination 1, have at least 1 valid 
and determinate assay result at the 4-week post–Vaccination 1 
visit, and have no major protocol violations before 
Vaccination 2. 
Vaccination 2 evaluable 
All participants who are eligible; receive the first study 
intervention(s) (Vaccination 1) (1 vaccination, or 2 different 
vaccinations administrated in the left and right arms) to which 
they were randomized, and the second study vaccination 
(Vaccination 2) if they received only 1 vaccination before; 
have blood drawn for assay testing within specified time 
frames after Vaccination 2 and have at least 1 valid and 
determinate assay result at the 4-week post–Vaccination 2 
visit, or have blood drawn for assay testing within specified 
time frames after Vaccination 1 (for participants with 2 
vaccinations administrated) and have at least 1 valid and 
determinate assay result at the 4-week post–Vaccination 1 
visit; and have no major protocol violations. 
Vaccination 1 mITT 
For Substudy A only. All randomized participants who 
receive the study intervention (Vaccination 1) and have at 
least 1 valid and determinate assay result after Vaccination 1 
but before Vaccination 2. 
Vaccination 2 mITT 
All randomized participants who receive the study 
intervention(s) (Vaccination 1 and Vaccination 2; or 
Vaccination 1 only [2 vaccinations administrated in the left 
and right arms]) and have at least 1 valid and determinate 
assay result after Vaccination 2, or have at least 1 valid and 
determinate assay result after Vaccination 1 (for participants 
with 2 vaccinations administrated). 
Safety 
All participants who receive the study intervention. 

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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 general considerations of statistical analyses. 
Refer to appendices for description of the statistical analyses for primary, secondary, and/or 
exploratory endpoints. Statistical analyses for Substudy A and Substudy B are detailed in 
Section 10.9.9 and Section 10.10.9, respectively. 
9.3.1. General Considerations 
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. Completely 
missing reactogenicity e-diary data will not be imputed; missing AE dates will be handled 
according to the Pfizer safety rules. 
For all the immunogenicity endpoints, the analysis will be based on the evaluable 
immunogenicity population. Antibody titers below the LLOQ or denoted as BLQ will be set 
to 0.5 × LLOQ for GMT analysis. No other missing assay data will be imputed in the 
analyses. All immunogenicity analyses will be performed after the imputation of the 
antibody concentrations or antibody titers that are below the LLOQ. 
An additional analysis may be performed based on the mITT populations if there is a large 
enough difference in sample size between the mITT population and the evaluable 
immunogenicity population. Participants will be summarized according to the vaccine group 
to which they were randomized. Missing serology data will not be imputed. 
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 between-group difference for binary 
endpoints will be calculated using the Miettinen and Nurminen method. 
9.3.1.2. Analyses for Continuous Data 
Unless otherwise stated, descriptive statistics for continuous variables are n, mean, median, 
standard deviation, minimum, and maximum. 

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9.3.1.2.1. Geometric Means 
The geometric means will be calculated as the mean of the assay results after making the 
logarithm transformation and then exponentiating the mean to express results on the original 
scale. Two-sided 95% CIs will be obtained by taking log transforms of assay results, 
calculating the 95% CI with reference to Student’s t-distribution, and then exponentiating the 
confidence limits. 
9.3.1.2.2. Geometric Mean Fold Rises 
GMFRs are defined as ratios of the results after vaccination to the results before vaccination. 
GMFRs are limited to participants with nonmissing values at both time points. 
GMFRs will be calculated as the mean of the difference of logarithmically transformed assay 
results (later time point minus earlier time point) and exponentiating the mean. The 
associated 2-sided 95% CIs will be obtained by constructing CIs using Student’s 
t-distribution for the mean difference on the logarithm scale and exponentiating the 
confidence limits. 
9.3.1.2.3. Geometric Mean Ratios 
The GMR will be calculated as the mean of the difference of logarithmically transformed 
assay results and exponentiating the mean. Two-sided CIs will be obtained by calculating 
CIs using Student’s t-distribution for the mean difference of the logarithmically transformed 
assay results and exponentiating the confidence limits. 
9.3.1.2.4. Reverse Cumulative Distribution Curves 
Empirical RCDCs will plot proportions of participants with values equal to or exceeding a 
specified assay value versus the indicated assay value, for all observed assay values. Data 
points will be joined by a step function with the line first going down and then to the right to 
the next assay value. 
9.3.2. Safety Analyses 
All safety analyses will be performed on the safety population. 
9.4. Interim Analyses 
Details for interim analyses will be provided in the appendix - Section 10.9.9.4 and 
Section 10.10.9.4 for Substudy A and Substudy B, respectively. 
9.5. Sample Size Determination 
The study sample size for the study is not based on any statistical hypothesis testing. 
Fifteen participants will be enrolled in each group (vaccine formulation/dose level or control) 
for Vaccination 1 in Substudy A, and also into each group for Vaccination 1 in Substudy B. 
There are 17 such groups planned to be enrolled in Substudy A; therefore, up to 
approximately 255 participants in total are planned to be enrolled in Substudy A. 

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During initial enrollment, there are 11 groups for Vaccination 1 in Substudy B, with 
approximately 15 participants planned to be enrolled per group. Additionally, following IRC 
review of safety and immunogenicity at least 1 week following the last vaccination in each 
group from initial enrollment, a further 120 participants may be enrolled in selected groups, 
including 2 groups of participants 18 to 64 years of age (expanded enrollment). Therefore, 
up to approximately 1725 participants are planned to be enrolled in Substudy B. 
For safety outcomes in the study, Table 4 shows the probability of observing at least 1 AE for 
a given true event rate of a particular AE, at various sample sizes. 
 
Table 4. 
Probability of Observing at Least 1 AE by Assumed True Event Rates 
With Different Sample Sizes 
 
Assumed True Event Rate of an AE 
Sample 
Size (N) 
0.01% 
0.32% 
0.50% 
1.0% 
2.0% 
5% 
10% 
15 
0.00 
0.05 
0.07 
0.14 
0.26 
0.54 
0.79 
30 
0.00 
0.09 
0.14 
0.26 
0.45 
0.79 
0.96 
45 
0.00 
0.13 
0.2 
0.36 
0.6 
0.9 
0.99 
60 
0.01 
0.17 
0.26 
0.45 
0.7 
0.95 
>0.99 
90 
0.01 
0.25 
0.36 
0.6 
0.84 
0.99 
>0.99 
120 
0.01 
0.32 
0.45 
0.7 
0.91 
>0.99 
>0.99 
135 
0.01 
0.35 
0.49 
0.74 
0.93 
>0.99 
>0.99 
150 
0.01 
0.38 
0.53 
0.78 
0.95 
>0.99 
>0.99 
195 
0.02 
0.46 
0.62 
0.86 
0.98 
>0.99 
>0.99 
270 
0.03 
0.58 
0.74 
0.93 
>0.99 
>0.99 
>0.99 
275 
0.03 
0.59 
0.75 
0.94 
>0.99 
>0.99 
>0.99 
410 
0.04 
0.73 
0.87 
0.98 
>0.99 
>0.99 
>0.99 
420 
0.04 
0.74 
0.88 
0.99 
>0.99 
>0.99 
>0.99 
445 
0.04 
0.76 
0.89 
0.99 
>0.99 
>0.99 
>0.99 
540 
0.05 
0.82 
0.93 
>0.99 
>0.99 
>0.99 
>0.99 
695 
0.07 
0.89 
0.97 
>0.99 
>0.99 
>0.99 
>0.99 
815 
0.08 
0.93 
0.98 
>0.99 
>0.99 
>0.99 
>0.99 
945 
0.09 
0.95 
0.99 
>0.99 
>0.99 
>0.99 
>0.99 
1080 
0.10 
0.97 
>0.99 
>0.99 
>0.99 
>0.99 
>0.99 
1215 
0.11 
0.98 
>0.99 
>0.99 
>0.99 
>0.99 
>0.99 
1350 
0.13 
0.99 
>0.99 
>0.99 
>0.99 
>0.99 
>0.99 
1485 
0.14 
0.99 
>0.99 
>0.99 
>0.99 
>0.99 
>0.99 

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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines; 
• Applicable ICH GCP guidelines; 
• Applicable laws and regulations, including applicable privacy laws. 
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents (eg, 
advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC by 
the investigator, and reviewed and approved by the IRB/EC before the study is initiated. 
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC; 
• Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures; 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies (if applicable), European Medical Device Regulation 
2017/745 for clinical device research (if applicable), and all other applicable local 
regulations. 
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 his/her 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 study 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 his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities. 
The investigator further must ensure that each study participant is fully informed about his or 
her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data. 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD. 
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study. 

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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 his or her actual identity and medical record ID. In case of 
data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws. 
10.1.5. Committees Structure 
10.1.5.1. Data Monitoring Committee 
This study 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. 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, 
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. 
• For Substudy A, review of safety data accumulated at least 1 week following vaccination 
with mIRV, bIRV, and qIRV at Visit 1. 

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• For Substudy B, review of safety and immunogenicity data accumulated at least 1 week 
following the last vaccination in each group. 
10.1.6. Dissemination of Clinical Study Data 
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted. 
www.clinicaltrials.gov 
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law. 
EudraCT 
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements. 
www.pfizer.com 
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are 
posted to www.clinicaltrials.gov. 
Documents within marketing authorization packages/submissions 
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website. Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data. Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015. 

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Data sharing 
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class. Pfizer will make data from these trials available 
24 months after study completion. Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted. 
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes. 
10.1.7. Data Quality Assurance 
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document. 
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password-protected or secured in a locked room to 
prevent access by unauthorized third parties. 
QTLs are predefined parameters that are monitored during the study. Important deviations 
from the QTLs and any remedial actions taken will be summarized in the clinical study 
report. 
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. This 
verification may also occur after study completion. It is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process. 
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, virtual, or on-site monitoring), are provided in the data management plan and 
monitoring plan maintained and utilized by the sponsor or designee. 
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 

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Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained. 
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems. 
The investigator(s) will notify the sponsor or its agents immediately of any regulatory retain 
notification in relation to the study. Furthermore, the investigator will cooperate with the 
sponsor or its agents to prepare the investigator site for the inspection and will allow the 
sponsor or its agent, whenever feasible, to be present during the inspection. The investigator 
site and investigator will promptly resolve any discrepancies that are identified between the 
study data and the participant's medical records. The investigator will promptly provide 
copies of the inspection findings to the sponsor or its agent. Before response submission to 
the regulatory authorities, the investigator will provide the sponsor or its agents with an 
opportunity to review and comment on responses to any such findings. 
10.1.8. Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site. 
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available. 
Definition of what constitutes source data and its origin can be found in the study monitoring 
plan, which is maintained by the sponsor. 
Description of the use of the computerized system is documented in the study monitoring 
plan, which is maintained by the sponsor. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements. 

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10.1.9. Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date. 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants. 
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/EC 
or local health authorities, the sponsor's procedures, or the ICH GCP guidelines; 
• Inadequate recruitment of participants by the investigator; 
• Discontinuation of further study intervention development. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights. 
10.1.10. Publication Policy 
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications, 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission. This allows the sponsor to protect proprietary information and to 
provide comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer 

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intervention-related information necessary for the appropriate scientific presentation or 
understanding of the study results. 
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors. 
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites. In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by mutual 
agreement. 
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply. 
10.1.11. Sponsor’s Qualified Medical Personnel 
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study 
documentation/study portal or other electronic system. 
To facilitate access to appropriately qualified medical personnel for study-related medical 
questions or problems, participants are provided with an ECC at the time of informed 
consent. The ECC contains, at a minimum, (a) protocol and study intervention identifiers, 
(b) participant’s study identification number, (c) site emergency phone number active 
24 hours/day, 7 days per week, and (d) Pfizer Call Center number. 
The ECC is intended to augment, not replace, the established communication pathways 
between the investigator, site staff, and study team. The ECC is to be used by healthcare 
professionals not involved in the research study only, as a means of reaching the investigator 
or site staff related to the care of a participant. The Pfizer Call Center number should only be 
used when the investigator and site staff cannot be reached. The Pfizer Call Center number is 
not intended for use by the participant directly; if a participant calls that number directly, he 
or she will be directed back to the investigator site. 

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10.2. Appendix 2: Clinical Laboratory Tests 
The following safety laboratory tests will be performed at times defined in Section 10.9.1 for 
Substudy A and Section 10.10.1 for Substudy B. Additional laboratory results may be 
reported on these samples as a result of the method of analysis or the type of analyzer used 
by the clinical laboratory, or as derived from calculated values. These additional tests would 
not require additional collection of blood. 
 
Substudy A 
Hematology 
Chemistry 
Hemoglobin 
BUN and creatinine 
Hematocrit 
AST, ALT 
RBC count 
Total bilirubin 
MCV 
Alkaline phosphatase 
MCH 
Cardiac troponin I 
MCHC 
C-reactive protein 
Platelet count 
WBC count 
Total neutrophils (Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
Substudy B 
Hematology 
Chemistry 
N/A 
Cardiac troponin I 
Please refer to the laboratory normal ranges (provided separately) for grading scales for 
abnormalities. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues. Investigators must document their review of each 
laboratory safety report. 

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

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

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

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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 
exposure during pregnancy or 
breastfeeding. 
Note: Instances of EDP or EDB 
not associated with an AE or SAE 
are not captured in the CRF. 
All instances of EDP are 
reported (whether or not there is 
an associated SAE).* 
All instances of EDB are 
reported (whether or not there is 
an associated SAE). ** 
Environmental or occupational 
exposure to the product under 
study to a non-participant (not 
involving EDP or EDB). 
None. Exposure to a study non- 
participant is not collected on the 
CRF. 
The exposure (whether or not 
there is an associated AE or 
SAE) must be reported.*** 
* 
EDP (with or without an associated AE or SAE): any pregnancy information is reported to Pfizer Safety 
using the Vaccine SAE Reporting Form and EDP Supplemental Form; if the EDP is associated with an 
SAE, then the SAE is reported to Pfizer Safety using the Vaccine SAE Reporting Form. 
** EDB is reported to Pfizer Safety using the Vaccine SAE Reporting Form, which would also include 
details of any SAE that might be associated with the EDB. 
*** Environmental or occupational exposure: AEs or SAEs associated with occupational exposure are 
reported to Pfizer Safety using the Vaccine SAE Reporting Form. 
 
• When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event. 

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• 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. 

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

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Follow-Up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations, as medically indicated or as requested by the 
sponsor, to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers. 
• If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings, including histopathology. 
• New or updated information will be recorded in the originally submitted documents. 
• The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information. 
 
10.3.4. Reporting of SAEs 
 
SAE Reporting to Pfizer Safety via Vaccine SAE Reporting Form 
• Facsimile transmission of the Vaccine SAE Reporting Form is the preferred method 
to transmit this information to Pfizer Safety. 
• In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the Vaccine SAE Reporting Form sent by overnight mail 
or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the Vaccine SAE Reporting Form pages within the designated 
reporting time frames. 

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10.4. Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. Male Participant Reproductive Inclusion Criteria 
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s): 
• Refrain from donating sperm. 
PLUS either: 
• Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent. 
OR 
• Must agree to use contraception/barrier as detailed below: 
• Agree to use a male condom when having sexual intercourse with a woman of 
childbearing potential who is not currently pregnant. 
• In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods below in Section 10.4.4). 
10.4.2. Female Participant Reproductive Inclusion Criteria 
For Substudy A and participants 65 to 85 years of age at the time of enrollment in Substudy 
B, a female participant is eligible to participate if she is not pregnant or breastfeeding, and is 
not a WOCBP (see definitions below in Section 10.4.3). 
For Substudy B participants 18 to 64 years of age at the time of enrollment, the criteria below 
are part of inclusion criterion 1 (Age and Sex; Section 10.10.5.1) 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 

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• 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. 
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 an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study. 
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. 

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• A female on HRT and whose menopausal status is in doubt will be required to use 
one of the nonestrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
10.4.4. Contraception Methods 
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials. 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation. 
2. Intrauterine device. 
3. Intrauterine hormone-releasing system. 
4. Bilateral tubal occlusion (eg, bilateral tubal ligation). 
5. Vasectomized partner: 
• A vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used. The spermatogenesis cycle is approximately 
90 days. 
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
• Oral; 
• Intravaginal; 
• Transdermal. 
7. Progestogen-only hormone contraception associated with inhibition of ovulation: 
• Oral; 
• Injectable. 
8. Sexual abstinence: 
• Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 

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in relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 
9. Progestogen-only oral hormonal contraception where inhibition of ovulation is not the 
primary mode of action. 
10. Male or female condom with or without spermicide. 
11. Cervical cap, diaphragm, or sponge with spermicide. 
12. A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods). 

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10.5. Appendix 5: 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 msec. 
• New prolongation of QTcF to >480 msec (absolute) or by ≥60 msec 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 seconds’ 
duration. 
• Frequent PVCs, triplets, or short intervals (<30 sec) of consecutive ventricular 
complexes. 
ECG Findings That May Qualify as SAEs 
• QTcF prolongation >500 msec. 
• New ST-T changes suggestive of myocardial ischemia. 
• New-onset left bundle branch block (QRS >120 msec). 
• New-onset right bundle branch block (QRS >120 msec). 
• Symptomatic bradycardia. 
• Asystole: 
• In awake, symptom-free patients in sinus rhythm, with documented periods of 
asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node; 
• In awake, symptom-free patients with atrial fibrillation and bradycardia with 
1 or more pauses of at least 5 seconds or longer; 
• Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm. 
• Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute). 

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• Ventricular rhythms of >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 seconds’ 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 enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team and are not to be 
considered as all inclusive of what is to be reported as an AE or SAE. 

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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 Substudy B. However, 
should an investigator deem it necessary to assess LFTs because a participant presents with 
clinical signs/symptoms, such LFT results should be managed and followed as described 
below. 
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations 
(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be 
elevated within the same laboratory sample). In rare instances, by the time TBili elevations 
are detected, AST/ALT values might have decreased. This occurrence is still regarded as a 
potential DILI. Therefore, abnormal elevations in either AST OR ALT in addition to TBili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded. 
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values: 
• Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value >2 × ULN 
with no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or not 
available. 
• For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline: 
• Preexisting AST or ALT baseline values above the normal range: AST or ALT values 
>2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is smaller). 
• Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller). 

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

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10.7. Appendix 7: 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). 
10.7.1. 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. 
 
10.7.2. 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 adverse device effect 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 is a serious adverse device effect that by its nature, incidence, severity, or 
outcome has not been identified in the current version of the risk analysis 
management file. 
 
10.7.3. 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. 
 
10.7.4. 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 investigator 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 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). 

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• For device deficiencies, it is very important that the unblinded site staff describes 
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 product information in his/her assessment. 
• For each device deficiency, the investigator must document in the medical notes 
that he/she has reviewed the device deficiency and has provided an assessment of 
causality. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the sponsor. 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 

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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 Appendix 3. 
 
10.7.5. Reporting of SAEs 
Reporting of an SAE to Pfizer Safety must be performed according to the processes 
described in Appendix 3 (Section 10.3.4). 
10.7.6. 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, a 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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10.8. Appendix 8: Alternative Measures During Public Emergencies 
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of 
the COVID-19 pandemic globally and will become effective for other public emergencies 
only upon written notification from Pfizer. 
Use of these alternative study measures are expected to cease upon the return of business as 
usual (including the lifting of any quarantines and travel bans/advisories). 
10.8.1. Telehealth Visits 
In the event that in-clinic study visits cannot be conducted, every effort should be made to 
follow up on the safety of study participants at scheduled visits per the SoA or unscheduled 
visits. Telehealth visits may be used to continue to assess participant safety and collect data 
points. Telehealth includes the exchange of healthcare information and services via 
telecommunication technologies (eg, audio, video, video-conferencing software) remotely, 
allowing the participant and the investigator to communicate on aspects of clinical care, 
including medical advice, reminders, education, and safety monitoring. The following 
assessments must be performed during a telehealth visit: 
• Review and record any AEs and SAEs since the last contact. Refer to Section 8.3. 
• Record nonstudy vaccinations as described in Section 6.8. 
• Record details of any of the prohibited medications specified in Section 6.8.1 received by 
the participant if required for his or her clinical care. 
• Review and record contraceptive method and results of pregnancy testing. Confirm that 
the participant is adhering to the contraception method(s) required in the protocol. Refer 
to Appendix 4. 
Study participants must be reminded to promptly notify site staff about any change in their 
health status. 

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10.9. Appendix 9: Substudy A (Phase 1) 
10.9.1. SoA – Substudy A (Phase 1) 
 
Visit Number 
Screening 
1 
2 
3 
4 
5 
5A 
5B 
6 
Visit Description 
Screening Vaccination Day 3 
Follow- 
up 
Visit 
1- 
Week 
Follow- 
up 
Visit 
4- 
Week 
Follow- 
up 
Visit 
8- 
Week 
Follow- 
up 
Visit 
Vaccination 
2 
4-Week Post– 
Vaccination 2 
Follow-up Visit 
6-Month 
Telephone 
Contact 
Visit Window (Days) 
0 to 28 
Days 
Before 
Visit 1 
Day 1 
2-4 
Days 
After 
Visit 1 
6 to 8 
Days 
After 
Visit 1 
26 to 
30 
Days 
After 
Visit 1 
52 to 
60 
Days 
After 
Visit 1 
52 to 97 Days 
After Visit 1a 
26 to 45 
Days 
After 
Vaccination at 
Visit 5 or 5Ab 
175 to 189 
Days After 
Last Study 
Vaccination 
Obtain informed consent 
X 
X 
X 
X 
Assign participant number 
X 
Obtain demography and medical history data 
X 
Obtain details of medications currently taken 
X 
Perform physical examination 
X 
Perform clinical assessment 
X 
Measure vital signs (including body 
temperature) 
X 
X 
X 
Measure body temperature 
X 
X 
Collect blood sample for hematology and 
chemistry laboratory tests 
~20 mL 
~20 mL 
~20 mL ~20 mL 
Perform 12-lead triplicate ECG 
X 
X 
X 
X 
Collect prior COVID-19 vaccine information 
X 
Collect prior licensed influenza vaccine 
information from the last season 
X 
Collect nonstudy vaccine information 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Confirm eligibility 
X 
X 
X 
Collect prohibited medication use 
X 
X 
X 
X 
X 
X 
Review hematology, chemistry, and ECG 
results 
X 
X 
X 
X 

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Visit Number 
Screening 
1 
2 
3 
4 
5 
5A 
5B 
6 
Visit Description 
Screening Vaccination Day 3 
Follow- 
up 
Visit 
1- 
Week 
Follow- 
up 
Visit 
4- 
Week 
Follow- 
up 
Visit 
8- 
Week 
Follow- 
up 
Visit 
Vaccination 
2 
4-Week Post– 
Vaccination 2 
Follow-up Visit 
6-Month 
Telephone 
Contact 
Visit Window (Days) 
0 to 28 
Days 
Before 
Visit 1 
Day 1 
2-4 
Days 
After 
Visit 1 
6 to 8 
Days 
After 
Visit 1 
26 to 
30 
Days 
After 
Visit 1 
52 to 
60 
Days 
After 
Visit 1 
52 to 97 Days 
After Visit 1a 
26 to 45 
Days 
After 
Vaccination at 
Visit 5 or 5Ab 
175 to 189 
Days After 
Last Study 
Vaccination 
Confirm use of contraceptives (if appropriate) 
X 
X 
X 
X 
X 
X 
X 
Obtain randomization number and study 
intervention allocation 
X 
Collect blood sample for immunogenicity 
assessment 
~50 mL 
~50 mL ~50 mL ~50 mL 
~50 mLc 
~50 mL 
Collect blood sample for cell-mediated 
immunogenicity assessmentd 
~50 mL 
~50 mL ~50 mL 
Administer blinded study intervention 
X 
Unblind participant’s vaccine assignment 
X 
Administer licensed influenza vaccinee 
X 
Administer open-label mIRV A or B, as 
appropriatef 
X 
Assess acute reactions for at least 30 minutes 
after study intervention administration 
X 
X 
X 
Explain to the participant e-diary completion 
requirements and assist the participant with 
downloading the app or issue provisioned 
device if required 
X 
X 
X 
Provide thermometer and measuring device 
X 
X 
X 
Review reactogenicity e-diary data (daily 
review is optimal during the active diary 
period) 

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Visit Number 
Screening 
1 
2 
3 
4 
5 
5A 
5B 
6 
Visit Description 
Screening Vaccination Day 3 
Follow- 
up 
Visit 
1- 
Week 
Follow- 
up 
Visit 
4- 
Week 
Follow- 
up 
Visit 
8- 
Week 
Follow- 
up 
Visit 
Vaccination 
2 
4-Week Post– 
Vaccination 2 
Follow-up Visit 
6-Month 
Telephone 
Contact 
Visit Window (Days) 
0 to 28 
Days 
Before 
Visit 1 
Day 1 
2-4 
Days 
After 
Visit 1 
6 to 8 
Days 
After 
Visit 1 
26 to 
30 
Days 
After 
Visit 1 
52 to 
60 
Days 
After 
Visit 1 
52 to 97 Days 
After Visit 1a 
26 to 45 
Days 
After 
Vaccination at 
Visit 5 or 5Ab 
175 to 189 
Days After 
Last Study 
Vaccination 
Review ongoing reactogenicity e-diary 
symptoms and obtain stop dates 
X 
X 
X 
Collect AEs and SAEs as appropriate 
X 
X 
X 
X 
Xg 
X 
X 
X 
X 
Collect e-diary or assist the participant with 
deleting application 
Xh 
X 
X 
Abbreviations: COVID-19 = coronavirus disease 2019; ECG = electrocardiography; SoA = schedule of activities. 
a. 
Visit 5A procedures for participants who received QIV at Visit 1 only. Visit 5 and 5A procedures may be conducted at the same visit, depending on the 
timing of these visits relative to implementation of protocol amendment 2. 
b. Visit 5B to be conducted 26 to 45 days after either Visit 5 or Visit 5A, depending on at which visit Vaccination 2 was performed. 
c. 
Blood draw at Visit 5A to be conducted prior to vaccination only if Visit 5 and 5A procedures are being conducted as separate visits. 
d. Additional 50 mL for cell-mediated immunogenicity assessments as detailed in Section 10.9.4.1. 
e. 
Individual participants will be unblinded and licensed influenza vaccine administered at Visit 5 to participants not having previously received seasonal 
QIV. 
f. 
Either mIRV A or mIRV B to be administered to participants having received QIV at Visit 1. 
g. Any AEs occurring up to 48 hours after the blood draw must be recorded (see Section 8.3). 
h. If Visit 3 is conducted after Day 7. 

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10.9.2. Introduction 
10.9.2.1. Substudy Rationale 
Substudy A is a Phase 1 randomized, observer-blinded (sponsor-unblinded) substudy to 
evaluate the safety and immunogenicity of: 
• Various dose levels of mIRV and bIRV encoding A and/or B strain(s) in participants 65 
to 85 years of age, and 
• qIRV encoding 2 A strains and 2 B strains at a dose level of CCI 
. See 
Section 10.9.4 for more details regarding the design. 
10.9.2.2. Background 
See Section 2.2. 
10.9.2.3. Benefit/Risk Assessment 
In addition to those risks detailed in Section 2.3, the following additional risks are noted for 
Substudy A: 
• Unknown safety profile of mIRV A/B administered approximately 8 weeks after QIV – 
this risk is justified in order to describe whether the immune response elicited by QIV 
may be augmented by a modRNA influenza vaccine. However, in order to mitigate this 
risk, AE and SAE reports will be collected from the signing of the ICD to 4 weeks after 
the vaccination, and all participants will be observed for at least 30 minutes after mIRV 
A/B vaccination. 
Benefits to individual participants enrolled in Substudy A may be: 
• Receipt of a potentially efficacious influenza vaccine at no cost to the participant, and 
provision of the immunogenicity results following administration. 
• Receipt of a licensed seasonal influenza vaccine at no cost to the participant. 
• Contributing to research to help others. 
Please see Section 2.3.3 for details of the SRSDs relating to study intervention used in 
Substudy A. 
 
 
 
 
 
 
 
 
 
 
 
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10.9.3. Objectives, Endpoints, and Estimands (Substudy A) 
For the purposes of the study estimands: 
• Seroconversion is defined as an HAI titer <1:10 prior to vaccination and ≥1:40 at the time point of interest, or an HAI titer of 
≥1:10 prior to vaccination with a 4-fold rise at the time point of interest. 
 
Objectives 
Estimands 
Endpoints 
Primary Safety: 
Primary Safety: 
Primary Safety: 
To describe the safety and 
tolerability of mIRV, bIRV, 
and qIRV in adults 65 to 
85 years of age 
In participants receiving at least 1 dose of study intervention, the 
percentage of participants reporting: 
• Local reactions for up to 7 days following Vaccinations 1 and 2 
• Systemic events for up to 7 days following Vaccinations 1 and 2 
• AEs 4 weeks after Vaccinations 1 and 2 
• 
SAEs from the first vaccination to 6 months after the last 
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 
The percentage of participants with: 
• Abnormal hematology and chemistry laboratory values 2 days and 
1 week after Vaccination 1 
• Grading shifts in hematology and chemistry laboratory 
assessments between baseline and 2 days and 1 week after 
Vaccination 1 
• Hematology and chemistry laboratory parameters detailed in 
Section 10.2 
The percentage of participants with: 
• New ECG abnormalities 2 days and 1 week after Vaccination 1 
ECG abnormalities consistent with probable or possible myocarditis 
or pericarditis as defined in Section 8.2.7 
Secondary: 
Secondary: 
Secondary: 
To describe the immune 
responses elicited by mIRV, 
bIRV, and qIRV in adults 65 to 
85 years of age 
In participants complying with the key protocol criteria (evaluable 
participants) at 1, 4, and 
8 weeks after receipt of Vaccination 1: 
• HAI GMTs at 1, 4, and 
8 weeks after receipt of Vaccination 1 
• HAI GMFR from before Vaccination 1 to 1, 4, and 8 weeks after 
receipt of Vaccination 1 
• The proportion of participants achieving HAI seroconversion for 
each strain at 1, 4, and 8 weeks after receipt of Vaccination 1 
HAI titers for each strain targeted by the study vaccine 

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Objectives 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tertiary/Exploratory: 
CCI 
Estimands 
• The proportion of participants with HAI titers ≥1:40 for each 
strain before Vaccination 1 and at 1, 4, and 8 weeks after receipt 
of Vaccination 1 
In participants having received qIRV or licensed QIV at Visit 1, 
complying with the key protocol criteria (evaluable participants) at 1, 
4, and 8 weeks after receipt of Vaccination 1: 
• The proportion of participants achieving HAI seroconversion for 
all strains at 1, 4, and 8 weeks after receipt of Vaccination 1 
• The proportion of participants with HAI titers ≥1:40 for all strains 
before vaccination to 1, 4, and 8 weeks after receipt of 
Vaccination 1 
• GMR of HAI titers for each strain in qIRV recipients compared to 
comparator recipients 4 weeks after Vaccination 1 
• The difference in percentage of participants achieving 
seroconversion for each strain at 4 weeks after Vaccination 1 in 
qIRV recipients compared to comparator recipients 
Tertiary/Exploratory: 
Endpoints 
 
 
 
 
HAI titers for each strain targeted by the study vaccine 
 
 
 
 
 
 
 
 
 
 
 
 
Tertiary/Exploratory: 

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Objectives 
 
CC 
Estimands 
Endpoints 
CCI 

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Objectives  
CCI 
Estimands 
Endpoints 

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10.9.4. Substudy A Design 
10.9.4.1. Overall Design 
This is a randomized, observer-blinded (sponsor-unblinded) substudy to evaluate the safety 
and immunogenicity of mIRV and bIRV encoding both A and B strains in the dose-level 
combinations shown in Table 5, and qIRV, in participants 65 to 85 years of age. 
Participants will be randomized to receive at Vaccination 1 (Visit 1): 
• mIRV at a dose level of CCI 
 encoding A strain, or QIV, 
• mIRV at a dose level of CCI 
, encoding B strain, or QIV, 
• bIRV in the dose level combinations shown in Table 5 below, encoding both A and B 
strains, or QIV, or 
• qIRV encoding 2 A strains and 2 B strains at a dose level of CCI 
, or QIV. 
 
Table 5. 
Initial Strain and Dose Level Combinations to Be Used in the bIRV During 
Substudy A 
 
 
 
QIV will act as a control. During initial enrollment, each group (vaccine formulation/dose 
level, or control) will comprise 15 participants. 
Safety data accumulated at least 1 week following Vaccination 1 with mIRV, bIRV, and 
qIRV will be reviewed and, if deemed acceptable, a further 360 participants can be enrolled 
(expanded enrollment) and randomized 1:1 to receive either qIRV or QIV. However, based 
upon preliminary immunogenicity data, the sponsor decided not to expand enrollment in 
Substudy A. Therefore, approximately 255 participants were enrolled in Substudy A. 
The sponsor’s IRC judged that the safety profile observed from groups during initial 
enrollment supports the development of the planned Substudy B. 
All participants will be asked to complete a reactogenicity e-diary for 7 days following 
Vaccination 1. Blood samples of approximately 50 mL will be collected for immunogenicity 
assessments prior to vaccination on Day 1 and at 1, 4, and 8 weeks after Vaccination 1. 
The total duration of the study for each participant will be up to approximately 8 months. 
B Strain 
CCI  
CCI 
CCI  
CCI  
CCI 
X 
X 
X 
X 
A Strain 

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CCI 
All participants will be asked to provide an additional blood sample of approximately 20 mL 
at time points specified in Section 10.9.1 for assessment of hematology and chemistry 
laboratory tests. 
All participants enrolled prior to expanded enrollment will be asked to provide an additional 
blood sample of 50 mL at time points specified in Section 10.9.1 for assessment of 
cell-mediated immunogenicity. 
It is anticipated that the following strains will be used in each IRV, but the final strain 
selection will be detailed in the IP manual: 
• mIRV:CCI 
 
• bIRV: CCI 
 in dose level combinations 
shown in Section 1.2 
• qIRV: 
 
Dependent upon safety and/or immunogenicity data generated during this phase, it is possible 
that additional bIRV groups may be initiated to study further dose level and strain 
combinations. 
Participants from the initial enrollment period will be unblinded at Visit 5 (8 weeks after 
Vaccination 1) and licensed QIV will be administered at Visit 5 to participants not having 
previously received licensed QIV. Additionally, at Visit 5A, participants who previously 
received QIV at Visit 1 will receive either: 
 
• mIRV at a dose level of CCI encoding A strain (up to 30 participants who previously 
received licensed QIV at Visit 1), or 
 
• mIRV at a dose level of CCI encoding B strain (up to 30 participants who previously 
received licensed QIV at Visit 1). 
Vaccinations administered at either Visit 5 or Visit 5A will be considered Vaccination 2 for 
these participants. 
Following implementation of protocol amendment 2, all participants will be asked to 
complete a reactogenicity e-diary for 7 days following Vaccination 2. Blood samples of 
approximately 50 mL will be collected for immunogenicity assessments prior to Vaccination 
2 and 4 weeks afterwards. 
10.9.4.2. Scientific Rationale for Study Design 
See Section 2.1. 

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10.9.4.3. Justification for Dose 
See Section 4.3. 
10.9.4.4. End of Study Definition 
See Section 4.4. 
10.9.5. Substudy A Population 
10.9.5.1. Substudy A Inclusion Criteria 
Participants are eligible to be included in Substudy A only if all of the following criteria 
apply: 
 
Substudy 
A 
Age and Sex: 
1. Male or female participants 65 to 85 years of age at Visit 1 (Day 1). 
• 
Refer to Appendix 4 for reproductive criteria for male 
(Section 10.4.1) and female (Section 10.4.2) participants. 
X 
Type of Participant and Disease Characteristics: 
2. 
Participants who are willing and able to comply with all scheduled visits, vaccination plan, 
laboratory tests, lifestyle considerations, and other study procedures. 
X 
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: With the exception of heart disease, which is exclusionary (see exclusion criterion 18), 
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 10.11. 
X 
4. 
Male participant who is able to father children and willing to use an acceptable method of 
contraception as outlined in this protocol for at least 28 days after the last dose of study 
intervention; or female participant not of childbearing potential; or male participant not able 
to father children. 
Note: Female participants of nonchildbearing potential must meet the criteria described in the 
WOCBP section (Section 10.4.3). 
X 
Informed Consent: 
5. 
Capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the ICD and in this protocol. 
X 

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10.9.5.2. Substudy A Exclusion Criteria 
Participants are excluded from Substudy A if any of the following criteria apply: 
 
Substudy 
A 
Medical Conditions: 
1. 
Other medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for the 
study. 
X 
2. 
History of severe adverse reaction associated with a vaccine and/or severe allergic reaction 
(eg, anaphylaxis) to any component of the study intervention(s). 
X 
3. 
Immunocompromised individuals with known or suspected immunodeficiency, as determined 
by history and/or laboratory/physical examination. 
X 
4. 
Bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion 
of the investigator, contraindicate intramuscular injection. 
X 
5. 
Women who are pregnant or breastfeeding. 
X 
6. 
Allergy to egg proteins (egg or egg products) or chicken proteins. 
X 
Prior/Concomitant Therapy: 
7. 
Any participant who has had significant exposure (someone who was within 6 feet of an 
infected person for a cumulative total of 15 minutes or more over a 24-hour period) to 
someone with laboratory-confirmed SARS-CoV-2 infection, COVID-19, or influenza in the 
past 14 days known prior to Visit 1. 
X 
8. 
Any participant who has a SARS-CoV-2 RT-PCR or antigen test in the past 10 days prior to 
Visit 1 that has not been confirmed as negative. 
X 
9. 
Individuals who receive treatment with radiotherapy or immunosuppressive therapy, 
including cytotoxic agents or systemic corticosteroids (if systemic corticosteroids are 
administered for ≥14 days at a dose of ≥20 mg/day of prednisone or equivalent), eg, for 
cancer or an autoimmune disease, or planned receipt throughout the study. 
Inhaled/nebulized, intra-articular, intrabursal, or topical (skin or eyes) corticosteroids are 
permitted. 
X 
10. Receipt of blood/plasma products, immunoglobulin, or monoclonal antibodies, from 60 days 
before study intervention administration, or planned receipt throughout the study. 
X 
11. Vaccination with any influenza vaccine within 6 months (175 days) before study intervention 
administration. 
X 
12. Any participant who has received or plans to receive a modRNA-platform SARS-CoV-2 
vaccine within 60 days of Visit 1. 
X 
Prior/Concurrent Clinical Study Experience: 
13. Participation in other studies involving study intervention within 28 days prior to study entry 
and/or during study participation. 
X 

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Substudy 
A 
Other Exclusions: 
14. Any screening hematology and/or blood chemistry laboratory value that meets the definition 
of a ≥ Grade 1 abnormality, or an abnormal C-reactive protein or troponin I value. 
Note: With the exception of bilirubin, participants with any stable Grade 1 abnormalities 
(according to the toxicity grading scale) may be considered eligible at the discretion of the 
investigator. (Note: A “stable” Grade 1 laboratory abnormality is defined as a report of 
Grade 1 on an initial blood sample that remains ≤ Grade 1 upon repeat testing on a second 
sample from the same participant.) Please refer to the laboratory normal ranges (provided 
separately) for grading scales for abnormalities. 
X 
15. Screening 12-lead ECG that is consistent with probable or possible myocarditis or 
pericarditis, or demonstrates clinically relevant abnormalities that may affect participant 
safety or interpretation of study results (eg, QTcF interval >450 msec, complete left bundle 
branch block, signs of an acute or indeterminate-age myocardial infarction, ST-T interval 
changes suggestive of myocardial ischemia, second- or third-degree AV block, or serious 
bradyarrhythmias or tachyarrhythmias). 
X 
16. Investigator site staff or Pfizer employees directly involved in the conduct of the study, site 
staff otherwise supervised by the investigator, and their respective family members. 
X 
17. Participation in strenuous or endurance exercise through Visit 3. 
X 
18. Prior history of heart disease. 
X 
 
10.9.6. Substudy A Intervention and Concomitant Therapy 
10.9.6.1. Study Intervention(s) Administered 
Study interventions for Substudy A will include: 
 
Intervention 
Name 
mIRV 
qIRV 
QIV 
QIV 
Type 
Vaccine 
Vaccine 
Vaccine 
Vaccine 
Dose 
Formulation 
modRNA 
modRNA 
Unit Dose 
Strength(s) 
CCI 
.3 mL 
CCI 
CCI 
0.7 mL 
0.7 mL 
.3 mL 
Dosage Level(s) 
CCI 
 
Route of 
Administration 
Intramuscular 
injection 
Intramuscular 
injection 
Intramuscular 
injection 
Intramuscular 
injection 
Use 
Experimental 
Experimental 
Experimental 
Standard of care (to 
be offered to Phase 1 
participants as 
detailed in 
Section 10.9.4.1) 
IMP or NIMP 
IMP 
IMP 
IMP 
NIMP 
Sourcing 
Provided centrally 
by the sponsor 
Provided centrally 
by the sponsor 
Provided centrally by 
the sponsor 
Provided centrally by 
the sponsor 

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Intervention 
Name 
mIRV 
qIRV 
QIV 
QIV 
Packaging and 
Study intervention 
Study intervention 
Study intervention 
Study intervention 
Labeling 
will be provided in a will be provided in a will be provided either will be provided 
glass vial as open- 
glass vial as open- 
as a PFS or in a glass 
either as PFS or in a 
label supply. Each 
label supply. Each 
vial as open-label 
glass vial as open- 
vial will be labeled 
vial will be labeled 
supply. Each 
label supply. Each 
as required per 
as required per 
PFS/vial will be 
PFS/vial will be 
country requirement 
country requirement 
labeled as required per labeled as required 
country requirement 
per country 
requirement 
 
mIRVs will be mixed at the site to generate bIRV in the dose-level combinations as shown in 
Table 5. 
10.9.6.1.1. Administration 
See Section 6.1.1. 
During Substudy A, participants will receive 1 dose of study intervention as randomized at 
Visit 1 and either Visit 5 or 5A in accordance with the SoA (Section 10.9.1). Study 
intervention should be administered intramuscularly into the deltoid muscle, preferably of the 
nondominant arm. 
Study intervention at Visit 1 will be administered only by an unblinded administrator. Study 
intervention at Visits 5 and 5A will be administered in an open-label manner. 
10.9.6.1.2. Medical Devices 
See Section 6.1.2. 
10.9.6.1.3. Preparation, Handling, Storage, and Accountability 
See Section 6.2. 
10.9.6.1.4. Preparation and Dispensing 
See Section 6.2.1. 
During Substudy A, study intervention will be prepared by qualified unblinded site personnel 
according to the IP manual or package insert and the study intervention administered in such 
a way to ensure the participants remain blinded. 

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10.9.6.2. Measures to Minimize Bias: Randomization and Blinding 
10.9.6.2.1. Allocation to Study Intervention 
See Section 6.3.1. 
Allocation of study intervention at Visit 1 in Substudy A will be conducted via IRT. Study 
intervention allocation at Visits 5 and 5A will be conducted in an open-label manner outside 
of the IRT based on what each participant received as study intervention at Visit 1 as detailed 
in Section 10.9.4. 
10.9.6.2.2. Blinding of Site Personnel 
Substudy A is observer-blinded, such that study staff receiving, storing, dispensing, 
preparing, and administering the study interventions will be unblinded. All other study and 
site personnel, including the investigator, investigator staff, and participants, will be blinded 
until participants are unblinded at Visit 5. In particular, the individuals who evaluate 
participant safety will be blinded. Because there are differences in physical appearance of 
the study interventions, these will be administered in a manner that prevents the study 
participants from identifying the study intervention group based on its appearance. 
The PI will assign the responsibility of the unblinded dispensers/administrators to persons 
who will not participate in the evaluation of any study participant. To ensure adequate 
coverage, at least 2 unblinded dispensers/administrators will be assigned per site. Members 
of the study site staff or clinic pharmacy should fulfill these roles. Contact between the 
unblinded dispensers and study participants should be kept to a minimum. The investigator, 
study coordinator, and any site staff other than the unblinded dispensers/administrators must 
not be allowed to know the study intervention assigned to any study participant and must not 
be allowed to see the study intervention container contents. In the event of a Quality 
Assurance audit, the auditor(s) will be allowed access to unblinded study intervention records 
at the site(s) to verify that randomization/dispensing has been done accurately. 
The study will be unblinded by site staff on an ongoing basis as participants complete Visit 5 
to determine if licensed QIV or mIRV may be administered (Section 10.9.8.8.6). 
10.9.6.2.3. Blinding of the Sponsor 
To facilitate rapid review of data in real time, sponsor staff will be unblinded to study 
intervention allocation for the participants throughout Substudy A. 
10.9.6.2.4. Breaking the Blind 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s study 
intervention assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the sponsor prior to 
unblinding a participant’s vaccine assignment unless this could delay further management of 
the participant. If a participant’s vaccine assignment is unblinded, the sponsor must be 

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notified within 24 hours after breaking the blind. The date and reason that the blind was 
broken must be recorded in the source documentation and CRF. 
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system. 
10.9.6.3. Study Intervention Compliance 
See Section 6.4. 
10.9.6.4. Dose Modification 
Not applicable. 
10.9.6.5. Continued Access to Study Intervention After the End of the Study 
See Section 6.6. 
10.9.6.6. Treatment of Overdose 
See Section 6.7. 
10.9.6.7. Concomitant Therapy 
See Section 6.8. 
10.9.7. Discontinuation of Substudy A Intervention and Participant 
Discontinuation/Withdrawal 
See Section 7. 
10.9.8. Substudy A Assessments and Procedures 
The minimal blood sampling volume for all individual participants in this study is 
approximately 530 mL prior to expanded enrollment and 280 mL for participants enrolled 
thereafter. For participants enrolled during expanded enrollment, additional optional whole 
blood samples of approximately 50 mL at Visits 1, 3, and 4 will be obtained from 
participants for isolation of PBMCs as detailed in Section 10.9.4.1. 
For all participants, other additional blood samples may be taken for safety assessments at 
times specified by Pfizer, provided the total volume taken during the study does not exceed 
550 mL during any period of 60 consecutive days. 
10.9.8.1. Clinical Safety Laboratory Assessments 
Please see Section 8.2.4. Additionally, see Section 10.2 for the list of clinical safety 
laboratory tests to be performed and the SoA for the timing and frequency. 

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10.9.8.2. Efficacy and/or Immunogenicity Assessments 
Samples will be collected at time points as specified in Section 10.9, and the following assay 
run on samples at each of these time points: 
• HAI 
PBMC samples will be used to describe T-cell responses. Some of the sample may be used 
for sequencing of participants’ antibody and/or BCR heavy- and light-chain genes, TCR 
genes, and/or mRNAs for understanding the B-cell, T-cell, and antibody repertoires. 
10.9.8.2.1. Biological Samples 
See Section 8.1.1. 
10.9.8.3. Safety Assessments 
See Section 8.2. 
10.9.8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting 
See Section 8.3. 
10.9.8.5. ECGs 
See Section 8.2.7. 
10.9.8.6. Stopping Rules 
The following stopping rules are in place for Substudy A participants, based on review of 
AE, ECG, and laboratory data. These data will be monitored on an ongoing basis by the 
investigator (or medically qualified designee) and sponsor in order to promptly identify and 
flag any event that potentially contributes to a stopping rule. 
The sponsor study team will be unblinded, so will be able to assess whether or not a stopping 
rule has been met on the basis of a participant’s individual study intervention allocation. 
In the event that sponsor personnel confirm that a stopping rule is met, the following actions 
will commence: 
• The IRC will review all appropriate data. 
• The stopping rule will PAUSE randomization and study intervention administration for 
all vaccine candidates at all dose levels. 
• 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. 

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A stopping rule is met if any of the following rules occur within 4 weeks after administration 
of mIRV, bIRV, or qIRV at Vaccination 1. The mIRV, bIRV, and qIRV groups will be 
evaluated for contribution to stopping rules collectively; vaccine candidate dose levels will 
contribute to stopping rules together. 
Stopping Rule Criteria: 
1. If any participant vaccinated with any IRV (at any dose level) develops: 
• 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. 
• An abnormal troponin I value that is confirmed abnormal on repeat testing, assessed 
as related to study intervention by the investigator. 
2. If ≥1 participant vaccinated with any IRV (at any dose level) develops confirmed 
myocarditis or pericarditis. 
3. If any participant vaccinated with any IRV (at any dose level) dies. 
4. ≥1 participant vaccinated with any IRV experiences a Grade 4 unsolicited AE, or SAE of 
any severity, assessed as related by the investigator. 
5. ≥2 participants vaccinated with any IRV (at any dose level) develop the same or similar 
Grade 3 or higher unsolicited AE (including laboratory abnormalities, except lymphocyte 
count and C-reactive protein), other than myocarditis/pericarditis, assessed as related to 
study intervention by the investigator. Note that the local reactions, systemic events, and 
fever specified in Section 8.2.3, reported within 7 days from the day of administration of 
the study intervention, irrespective whether they are recorded in the e-diary or as AEs, are 
excluded from this stopping rule. 
10.9.8.7. Immunogenicity Assessments 
See Section 10.9.8.2. 

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10.9.8.8. Substudy A Procedures 
10.9.8.8.1. Screening (0 to 28 Days Before Visit 1) 
Before enrollment and before any study-related procedures are performed, voluntary, written, 
study-specific informed consent will be obtained from the participant. Each signature on the 
ICD must be personally dated by the signatory. The investigator or his or her designee will 
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The 
source data must reflect that the informed consent was obtained before participation in the 
study. 
It is anticipated that the procedures below will be conducted in a stepwise manner. 
• Assign a single participant number using the IRT system. 
• Obtain the participant’s demography (including date of birth, sex, race, and ethnicity). 
The full date of birth will be collected to critically evaluate the immune response and 
safety profile by age. 
• Obtain any medical history of clinical significance. 
• Obtain details of any medications currently taken. 
• Perform 12-lead triplicate ECG. 
• Perform physical examination, including vital signs (weight, height, body temperature, 
pulse rate, and seated blood pressure), evaluating any clinically significant abnormalities 
within the following body systems: general appearance; skin; head, eyes, ears, nose, and 
throat; heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph 
nodes. 
• Collect a blood sample of approximately 20 mL as detailed in the laboratory manual for 
hematology and chemistry laboratory tests as described in Section 10.2. 
• Discuss contraceptive use as described in Section 10.4. 
• Record nonstudy vaccinations as described in Section 6.8. 
• Record prior receipt of any COVID-19 vaccine as described in Section 6.8. 
• Record licensed influenza vaccine information, if received during the prior influenza 
season, as described in Section 6.8. 
• Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met. 
• Record AEs as described in Section 8.3. 

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• Remind the participant to use appropriate contraceptives throughout the study, if 
applicable. 
• The investigator or an authorized designee completes the CRF. 
10.9.8.8.2. Visit 1 – Vaccination (Day 1) 
It is anticipated that the procedures below will be conducted in a stepwise manner. 
• Discuss contraceptive use as described in Section 10.4. 
• Record nonstudy vaccinations as described in Section 6.8. 
• Review screening laboratory results (hematology and chemistry) and ECG results. 
• Perform 12-lead triplicate ECG. 
• Perform a clinical assessment. If the clinical assessment indicates that a physical 
examination is necessary to comprehensively evaluate the participant, perform a physical 
examination and record any findings in the source documents and, if clinically 
significant, record on the medical history CRF. 
• Measure vital signs, including body temperature, pulse rate, and seated blood pressure. 
• Collect a blood sample of approximately 20 mL as detailed in the laboratory manual for 
hematology and chemistry laboratory tests as described in Section 10.2. 
• Ensure that the participant continues to meet all of the inclusion criteria and none of the 
exclusion criteria. 
• 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. 
• If the participant has consented to provide a blood sample for description of 
cell-mediated immune response, collect a blood sample (approximately 50 mL) for 
PBMC isolation. 
• Unblinded site staff member(s) will dispense/administer 1 dose of study intervention into 
the deltoid muscle of the preferably nondominant arm. Please refer to the IP manual for 
further instruction on this process. 

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• Blinded site staff must observe the participant for at least 30 minutes after study 
intervention administration for any acute reactions. Record any acute reactions 
(including time of onset) in the participant’s source documents and on the AE page of the 
CRF, and on an SAE form as applicable. 
• Issue a measuring device to measure local reactions at the injection site and a 
thermometer for recording daily temperatures and provide instructions on their use. 
• Explain the e-diary 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 to Day 7, with Day 1 being 
the day of vaccination. 
• Ask the participant to contact the site staff or investigator immediately if he or she 
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 is 
the day of vaccination) to determine if an unscheduled reactogenicity visit is required: 
• Fever ≥39.0°C (≥102.1°F). 
• Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units). 
• Severe pain at the injection site. 
• Any severe systemic event. 
• Record AEs as described in Section 8.3. 
• 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 if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.9.8.8.11). 
• Schedule an appointment for the participant to return for the next study visit. 
• Remind the participant to bring the e-diary to the next visit. 
• Complete the source documents. 
• The investigator or an authorized designee completes the CRFs and an unblinded 
dispenser/administrator updates the study intervention accountability records. 
• The investigator or appropriately qualified designee reviews the reactogenicity e-diary 
data online following vaccination to evaluate participant compliance and as part of the 
ongoing safety review. Daily review is optimal during the active diary period. 

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10.9.8.8.3. Visit 2 – Day 3 Follow-up Visit (After Vaccination) – 2 to 4 Days After Visit 1 
• Record AEs as described in Section 8.3. 
• Record nonstudy vaccinations as described in Section 6.8. 
• Record prohibited medication use as described in Section 6.8.1. 
• Discuss contraceptive use as described in Section 10.4. 
• Review laboratory results (hematology and chemistry) and ECG results. Any abnormal 
troponin I level must result in further assessments as outlined in Section 10.9.8.8.11. 
• Perform 12-lead triplicate ECG. Any new ECG abnormality (compared to baseline) 
consistent with probable or possible myocarditis or pericarditis (as listed in Section 8.2.7) 
must result in further assessments as outlined in Section 10.9.8.8.11. 
• Measure vital signs, including body temperature, pulse rate, and seated blood pressure. 
• Collect a blood sample of approximately 20 mL as detailed in the laboratory manual for 
hematology and chemistry tests. 
• Ask the participant to contact the site staff or investigator immediately if he or she 
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 is 
the day of vaccination) to determine if an unscheduled reactogenicity visit is required: 
• Fever ≥39.0°C (≥102.1°F). 
• Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units). 
• Severe pain at the injection site. 
• Any severe systemic event. 
• Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs. 
• Ask the participant to contact the site staff or investigator if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.9.8.8.11). 
• Schedule an appointment for the participant to return for the next study visit. 
• Complete the source documents. 
• The investigator or an authorized designee completes the CRFs. 

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10.9.8.8.4. Visit 3 – 1-Week Follow-up Visit (After Vaccination) – 6 to 8 Days After 
Visit 1 
• Record AEs as described in Section 8.3. 
• Record nonstudy vaccinations as described in Section 6.8. 
• Record prohibited medication use as described in Section 6.8.1. 
• Discuss contraceptive use as described in Section 10.4. 
• Review laboratory results (hematology and chemistry) and ECG results. Any abnormal 
troponin I level must result in further assessments as outlined in Section 10.9.8.8.11. 
• Perform 12-lead triplicate ECG. Any new ECG abnormality (compared to baseline) 
consistent with probable or possible myocarditis or pericarditis (as listed in 
Section 8.2.7) must result in further assessments as outlined in Section 10.9.8.8.11. 
• Collect a blood sample of approximately 20 mL as detailed in the laboratory manual for 
hematology and chemistry tests. 
• Collect a blood sample of approximately 50 mL for immunogenicity testing. 
• If the participant has consented to provide a blood sample for description of 
cell-mediated immune response, collect a blood sample (approximately 50 mL) for 
PBMC isolation. 
• Review the participant’s reactogenicity e-diary data. If the e-diary collection period is 
complete: 
• 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. 
• Collect the participant’s e-diary or assist the participant with removing the study 
application from his or her own personal device (if the visit is conducted after 
Day 7). 
• Ask the participant to contact the site staff or investigator immediately if he or she 
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 is 
the day of vaccination) to determine if an unscheduled reactogenicity visit is required: 
• Fever ≥39.0°C (≥102.1°F). 
• Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units). 

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• Severe pain at the injection site. 
• Any severe systemic event. 
• Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs. 
• Ask the participant to contact the site staff or investigator if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.9.8.8.11). 
• Schedule an appointment for the participant to return for the next study visit. 
• Complete the source documents. 
• The investigator or an authorized designee completes the CRFs. 
10.9.8.8.5. Visit 4 – 4-Week Follow-up Visit (After Vaccination) – 26 to 30 Days After 
Visit 1 
• Record AEs as described in Section 8.3. 
• Record nonstudy vaccinations as described in Section 6.8. 
• Record prohibited medication use as described in Section 6.8.1. 
• Discuss contraceptive use as described in Section 10.4. 
• Review laboratory results (hematology and chemistry) and ECG results. Any abnormal 
troponin I level must result in further assessments as outlined in Section 10.9.8.8.11. 
• Collect a blood sample of approximately 50 mL for immunogenicity testing. 
• If the participant has consented to provide a blood sample for description of 
cell-mediated immune response, collect a blood sample (approximately 50 mL) for 
PBMC isolation. 
• 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 his or her own personal device. 
• Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3. 

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10.9.8.8.6. Visit 5 – 8-Week Follow-up Visit (After Vaccination) – 52 to 60 Days After 
Visit 1 
Before any study-related procedures are performed relating to protocol amendment 2, 
voluntary, written, informed consent (via an ICD addendum) will be obtained from the 
participant. Each signature on the ICD addendum must be personally dated by the signatory. 
The investigator or his or her designee will also sign the ICD addendum. A copy of the 
signed and dated ICD addendum must be given to the participant. 
If the participant does not consent to administration of Vaccination 2, his or her next visit 
should be Visit 6. 
For participants who received QIV at Visit 1, Visit 5 and 5A procedures may be conducted at 
the same visit, depending on the timing of these visits relative to implementation of protocol 
amendment 2, and the availability of mIRV A/B on site. 
• Record AEs as described in Section 8.3. 
• Record nonstudy vaccinations as described in Section 6.8. 
• Record prohibited medication use as described in Section 6.8.1. 
• Collect a blood sample of approximately 50 mL for immunogenicity testing. 
• Unblind the participant’s study intervention assignment. If the participant has not 
previously received licensed QIV at Visit 1: 
• Discuss contraceptive use as described in Section 10.4. 
• Measure the participant’s body temperature. 
• Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5. 
• Administer licensed influenza vaccine to the participant per local guidelines if 
available or when it becomes available for the season, and record this vaccination in 
the CRF. This vaccination will be considered Vaccination 2 for these participants. 
• Site staff must observe the participant for at least 30 minutes after study intervention 
administration for any acute reactions. Record any acute reactions (including time of 
onset) in the participant’s source documents and on the AE page of the CRF, and on 
an SAE form as applicable. 

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• For participants who receive QIV at Visit 5 after implementation of protocol amendment 
2: 
• If required, 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 
to Day 7, with Day 1 being the day of vaccination. 
• Ensure the participant has a measuring device to measure local reactions at the 
injection site and a thermometer for recording daily temperatures. 
• Ensure the participant remains comfortable with his or her chosen e-diary platform, 
confirm instructions on e-diary completion, and ask the participant to complete the 
reactogenicity e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination. 
• Ask the participant to contact the site staff or investigator immediately if he or she 
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 
is the day of vaccination) to determine if an unscheduled reactogenicity visit is 
required: 
• Fever ≥39.0°C (≥102.1°F). 
• Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units). 
• Severe pain at the injection site. 
• Any severe systemic event. 
• Record AEs as described in Section 8.3. 
• 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 if the participant 
experiences acute chest pain, shortness of breath, or palpitations (see 
Section 10.9.8.8.11). 
• 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. 

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• The investigator or appropriately qualified designee reviews the reactogenicity 
e-diary data online following vaccination to evaluate participant compliance and as 
part of the ongoing safety review. Daily review is optimal during the active diary 
period. 
• Complete the source documents. 
• The investigator or an authorized designee completes the CRFs. 
10.9.8.8.7. Visit 5A – Vaccination 2 – 52 to 97 Days After Visit 1 
Visit 5A procedures should only be conducted for participants who received QIV at Visit 1, 
and therefore did not receive QIV at Visit 5. 
Before any study-related procedures are performed relating to protocol amendment 2, 
voluntary, written, informed consent (via an ICD addendum) will be obtained from the 
participant. Each signature on the ICD addendum must be personally dated by the signatory. 
The investigator or his or her designee will also sign the ICD addendum. A copy of the 
signed and dated ICD addendum must be given to the participant. If the participant does not 
consent to administration of Vaccination 2, his or her next visit should be Visit 6. 
• Based on the participant’s unblinded vaccination assignment obtained at Visit 5, confirm 
the participant received QIV at Visit 1. 
• Record nonstudy vaccinations as described in Section 6.8. 
• Record prohibited medication use as described in Section 6.8.1. 
• Discuss contraceptive use as described in Section 10.4. 
• Measure the participant’s body temperature. 
• Ensure that the participant continues to meet all of the inclusion criteria and none of the 
exclusion criteria. 
• Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5. 
• If Visit 5 and 5A procedures are being conducted as separate visits, collect a blood 
sample of approximately 50 mL for immunogenicity testing. 
• Site staff member(s) will dispense/administer either of the following into the deltoid 
muscle of the preferably nondominant arm: 
 
• mIRV at a dose level of CCI 
• mIRV at a dose level of CCI 
encoding A strain, or 
encoding B strain 

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• 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. 
• If required, 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 to Day 7, with 
Day 1 being the day of vaccination. 
• Ensure the participant has a measuring device to measure local reactions at the injection 
site and a thermometer for recording daily temperatures. 
• Ensure the participant remains comfortable with his or her chosen e-diary platform, 
confirm instructions on e-diary completion, and ask the participant to complete the 
reactogenicity e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination. 
• Ask the participant to contact the site staff or investigator immediately if he or she 
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 is 
the day of vaccination) to determine if an unscheduled reactogenicity visit is required: 
• Fever ≥39.0°C (≥102.1°F). 
• Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units). 
• Severe pain at the injection site. 
• Any severe systemic event. 
• Record AEs as described in Section 8.3. 
• 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 if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.9.8.8.11). 
• Schedule an appointment for the participant to return for the next study visit. 
• Remind the participant to bring the e-diary to the next visit. 
• Complete the source documents. 
• The investigator or an authorized designee completes the CRFs. 

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• The investigator or appropriately qualified designee reviews the reactogenicity 
e-diary data online following vaccination to evaluate participant compliance and as part 
of the ongoing safety review. Daily review is optimal during the active diary period. 
10.9.8.8.8. Visit 5B – 4-Week Post–Vaccination 2 Follow-up Visit – 26 to 45 Days After 
Visit 5 or 5A 
Before any study-related procedures are performed relating to protocol amendment 2, 
voluntary, written, informed consent (via an ICD addendum) will be obtained from the 
participant. Each signature on the ICD addendum must be personally dated by the signatory. 
The investigator or his or her designee will also sign the ICD addendum. A copy of the 
signed and dated ICD addendum must be given to the participant. If the participant does not 
consent to administration of Vaccination 2, his or her next visit should be Visit 6. 
If the participant does not consent to this visit, his or her next visit should be Visit 6. 
• Record AEs as described in Section 8.3. 
• Record nonstudy vaccinations as described in Section 6.8. 
• Record prohibited medication use as described in Section 6.8.1. 
• 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 his or her own personal device. 
• Collect a blood sample of approximately 50 mL for immunogenicity testing. 
• Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs. 
• Complete the source documents. 
• The investigator or an authorized designee completes the CRFs. 
• Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3. 
10.9.8.8.9. Visit 6 – 6-Month Follow-up Telephone Contact – 175 to 189 Days After Last 
Study Vaccination 
• Contact the participant by telephone. 
• Record AEs as described in Section 8.3. 

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• Record nonstudy vaccinations as described in Section 6.8. 
• Complete the source documents. 
• The investigator or an authorized designee completes the CRFs. 
10.9.8.8.10. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction 
If a Grade 3 local reaction (Section 8.2.3.2), systemic event (Section 8.2.3.3), or fever 
(Section 8.2.3.4) is reported in the reactogenicity e-diary, a telephone contact should occur to 
ascertain further details and determine whether a site visit is clinically indicated. If a 
suspected Grade 4 local reaction (Section 8.2.3.2), systemic event (Section 8.2.3.3), or fever 
(Section 8.2.3.4) 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 8.2.3.2. 

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• Assess systemic events (if present) in accordance with the grades provided in 
Section 8.2.3.3. 
• 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. 
10.9.8.8.11. Additional Procedures for Monitoring of Potential Myocarditis or 
Pericarditis 
Any study participant who reports acute chest pain, shortness of breath, palpitations, or any 
other symptom(s) that might be indicative of myocarditis or pericarditis within 4 weeks after 
study vaccination (Vaccination 1 or 2) must be specifically evaluated by a cardiologist for 
possible myocarditis or pericarditis. The same applies for any participant in whom a new 
ECG abnormality (compared to baseline) consistent with probable or possible myocarditis or 
pericarditis (as listed in Section 8.2.7) or abnormal troponin I level is observed at Visit 2 or 3. 
In addition to a clinical evaluation, the following should be performed: 
• ECG and 
• Measurement of the troponin level 
For any participant in whom a new ECG abnormality (compared to baseline) consistent with 
probable or possible myocarditis or pericarditis (as listed in Section 8.2.7) or abnormal 
troponin I level is observed at Visit 2 or 3, this should be achieved by repeating the 
assessments with the central vendor(s). 
If myocarditis or pericarditis is suspected based upon the initial evaluation, the following 
should also be performed: 
• Cardiac echocardiogram and/or 
• Cardiac magnetic resonance study 
Details of the symptoms reported, and results of the investigations performed, will be 
recorded in the CRF. 
10.9.9. Substudy A Statistical Considerations 
See Section 9 for general statistical considerations and phase specifics below. 
10.9.9.1. Statistical Hypotheses 
There are no statistical hypotheses in Substudy A. 

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10.9.9.1.1. Estimands 
The estimands corresponding to the primary, secondary, and exploratory objectives are 
described in the table in Section 10.9.3. 
10.9.9.1.2. Multiplicity Adjustment 
There is no multiplicity adjustment for Phase 1 of the study as all analyses are descriptive in 
nature. 
10.9.9.2. Analysis Sets 
See Section 9.2 for defined analysis sets. 
10.9.9.3. Statistical Analyses 
The SAP will be developed and finalized for this phase 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. 
10.9.9.3.1. General Considerations 
See Section 9 for general considerations of statistical analyses. 
Note that, if a clear HAI result is not obtainable for any strain, neutralizing titers will replace 
HAI titers as the main immunogenicity endpoint for that strain. 

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10.9.9.3.2. Primary Endpoint(s)/Estimand(s) Analysis 
 
Endpoint 
Statistical Analysis Methods 
Safety 
• Point estimates and the associated exact 2-sided 95% CIs will be 
calculated using the Clopper-Pearson method for the proportion of 
participants reporting each event (local reactions, systemic events, 
and AEs) for each vaccine group after Vaccinations 1 and 2. 
• Point estimates and the associated exact 2-sided 95% CIs will be 
calculated using the Clopper-Pearson method for the proportion of 
participants reporting each event (SAEs) for each vaccine group 
after the last vaccination. 
• Point estimates and the associated exact 2-sided 95% CIs will be 
calculated using the Clopper-Pearson method for the proportion of 
participants reporting each event (abnormal hematology and 
chemistry laboratory) for each study vaccine at 2 days and 1 week 
after Vaccination 1. 
• Point estimates and the associated exact 2-sided 95% CIs will be 
calculated using the Clopper-Pearson method for the proportion of 
participants reporting grading shifts in hematology and chemistry 
laboratory assessment between baseline and 2 days, and 1 week, 
after Vaccination 1. 
• Point estimates and the associated exact 2-sided 95% CIs will be 
calculated using the Clopper-Pearson method for the proportion of 
participants with new ECG abnormalities at 2 days and 1 week after 
Vaccination 1. 

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10.9.9.3.3. Secondary Endpoint(s)/Estimand(s) Analysis 
 
Endpoint 
Statistical Analysis Methods 
Secondary 
immunogenicity 
• HAI GMTs and associated 2-sided 95% CIs will be provided for 
each strain, by vaccine group, at 1, 4, and 8 weeks after receipt of 
Vaccination 1. 
• HAI GMFRs from before Vaccination 1 to 1, 4, and 8 weeks after 
receipt of Vaccination 1, and associated 2-sided 95% CIs, will be 
provided for each strain, by vaccine group. 
• The proportion of participants achieving HAI seroconversion at 1, 4, 
and 8 weeks after receipt of Vaccination 1, and the proportion of 
participants with HAI titers ≥1:40 before Vaccination 1 and at 1, 4, 
and 8 weeks after receipt of Vaccination 1, and associated 2-sided 
Clopper-Pearson 95% CIs will be provided for each strain. 
• The proportion of participants achieving HAI seroconversion for all 
strains (targeted by the study vaccine) at 1, 4, and 8 weeks after 
receipt of Vaccination 1, and the proportion of participants with HAI 
titers ≥1:40 for all strains (targeted by the study vaccine) before 
Vaccination 1 and at 1, 4, and 8 weeks after receipt of Vaccination 
1, and associated 2-sided Clopper-Pearson 95% CIs will be provided 
for participants who received qIRV or licensed QIV at Visit 1. 
• GMRs of HAI titers for each strain in qIRV recipients compared to 
QIV comparator recipients 4 weeks after Vaccination 1 and 
associated 2-sided 95% CIs will be provided. 
• The difference in percentage of participants achieving 
seroconversion for each strain at 4 weeks after Vaccination 1 in 
qIRV recipients compared to QIV comparator recipients, and 
associated 2-sided 95% CIs, will be provided. The 2-sided 95% CIs 
for the difference in percentages of participants achieving 
seroconversion between vaccine groups will be calculated using the 
Miettinen and Nurminen method. 

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10.9.9.3.4. Tertiary/Exploratory Endpoint(s) 
Endpoint 
Statistical Analysis Methods 
Tertiary/ 
exploratory 
CC 
CCI 

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10.9.9.3.5. Other Analyses 
The data collected for study participants who report any symptom(s) that might be indicative 
of myocarditis or pericarditis (ECG, troponin level, cardiac echocardiogram, and/or cardiac 
magnetic resonance study) within 4 weeks after a study vaccination (Vaccination 1 or 2) will 
be summarized and listed by vaccine group. 
Endpoint 
Statistical Analysis Methods 
CC 
CCI 

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10.9.9.4. Interim Analyses 
No formal interim analysis will be conducted for this study phase. As the study is open-label 
to the sponsor, the sponsor will conduct unblinded reviews of the data during the course of 
the study for the purpose of safety assessment, dose selection, and/or supporting clinical 
development. 
10.9.9.5. Sample Size Determination 
See Section 9.5. 

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10.10. Appendix 10: Substudy B (Phase 1/2) 
10.10.1. SoA – Substudy B (Phase 1/2) 
 
Visit Number 
Screening 
201 
202 
203 
204 
205 
206 
207 
208 
Visit Description 
Screening 
Vaccination 
1 
1-Week 
Post– 
Vaccination 1 
Visita 
Vaccination 
2b 
Day 3 
Follow- 
up Visit 
1-Week 
Follow- 
up Visit 
4-Week 
Follow- 
up Visit 
8-Week 
Follow- 
up Visit 
6-Month 
Telephone 
Contact 
Visit Window (Days) 
0 to 28 Days 
Before 
Visit 201 
Day 1 
6 to 8 
Days 
19 to 23 
Days After 
Visit 201 
2 to 4 
Days 
6 to 8 
Days 
26 to 30 
Days 
52 to 60 
Days 
175 to 189 
Days 
Visits 204 through 208 to be conducted within 
the number of days indicated relative to the 
participant’s last study vaccination 
Obtain informed consent 
X 
Assign participant number 
X 
Obtain demography and medical history data 
X 
Obtain details of medications currently taken 
X 
Perform physical examinationc 
X 
X 
Perform clinical assessment 
X 
Measure vital signs (including body 
temperature) 
X 
X 
X 
Measure body temperature 
X 
Perform 12-lead triplicate ECG 
X 
X 
X 
Collect blood sample for troponin I laboratory 
testing 
~2.5 mL 
~2.5 mL 
~2.5 mL 
Collect prior COVID-19 vaccine information 
X 
Collect details of any licensed influenza 
vaccine received in the prior 12 months 
X 
Collect nonstudy vaccine information 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Confirm eligibility 
X 
X 
X 
Collect prohibited medication use 
X 
X 
X 
X 
X 
X 
Review troponin I and ECG results 
X 
X 
X 
X 
Perform urine pregnancy test on WOCBP 
X 
X 
Confirm use of contraceptives (if appropriate) 
X 
X 
X 
X 
X 
X 
X 

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Visit Number 
Screening 
201 
202 
203 
204 
205 
206 
207 
208 
Visit Description 
Screening 
Vaccination 
1 
1-Week 
Post– 
Vaccination 1 
Visita 
Vaccination 
2b 
Day 3 
Follow- 
up Visit 
1-Week 
Follow- 
up Visit 
4-Week 
Follow- 
up Visit 
8-Week 
Follow- 
up Visit 
6-Month 
Telephone 
Contact 
Visit Window (Days) 
0 to 28 Days 
Before 
Visit 201 
Day 1 
6 to 8 
Days 
19 to 23 
Days After 
Visit 201 
2 to 4 
Days 
6 to 8 
Days 
26 to 30 
Days 
52 to 60 
Days 
175 to 189 
Days 
Visits 204 through 208 to be conducted within 
the number of days indicated relative to the 
participant’s last study vaccination 
Obtain randomization number and study 
intervention allocation 
X 
Collect blood sample for immunogenicity 
assessment 
~50 mL 
~50 mL 
~50 mL ~50 mL ~50 mL 
Collect blood sample for cell-mediated 
immunogenicity assessmentd 
~50 mL 
~ 50 mL 
~50 mL ~50 mL 
Administer study intervention 
X 
X 
Assess acute reactions for at least 30 minutes 
after study intervention administration 
X 
X 
Explain to the participant e-diary completion 
requirements and assist the participant with 
downloading the app or issue provisioned 
device if required 
X 
Provide thermometer and measuring device 
X 
Review reactogenicity e-diary data (daily 
review is optimal during the active diary 
period) 
Review ongoing reactogenicity e-diary 
symptoms and obtain stop dates 
X 
X 
X 
X 

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Visit Number 
Screening 
201 
202 
203 
204 
205 
206 
207 
208 
Visit Description 
Screening 
Vaccination 
1 
1-Week 
Post– 
Vaccination 1 
Visita 
Vaccination 
2b 
Day 3 
Follow- 
up Visit 
1-Week 
Follow- 
up Visit 
4-Week 
Follow- 
up Visit 
8-Week 
Follow- 
up Visit 
6-Month 
Telephone 
Contact 
Visit Window (Days) 
0 to 28 Days 
Before 
Visit 201 
Day 1 
6 to 8 
Days 
19 to 23 
Days After 
Visit 201 
2 to 4 
Days 
6 to 8 
Days 
26 to 30 
Days 
52 to 60 
Days 
175 to 189 
Days 
Visits 204 through 208 to be conducted within 
the number of days indicated relative to the 
participant’s last study vaccination 
Collect AEs and SAEs as appropriate 
X 
X 
X 
X 
X 
X 
Xe 
Xe 
X 
Collect e-diary or assist the participant with 
deleting application 
Xf 
X 
Abbreviations: COVID-19 = coronavirus disease 2019; ECG = electrocardiography. 
a. 
Visit 202 is to be conducted during initial enrollment for participants assigned to a 2-visit vaccination schedule only. 
b. Vaccination 2 (Visit 203) is only conducted for participants randomized to receive a 2-visit vaccination schedule. 
c. 
Physical examination at Visit 201 will be conducted if clinically indicated. 
d. Additional 50 mL for cell-mediated immunogenicity assessments as detailed in Section 10.10.4. 
e. 
Any AEs occurring up to 48 hours after the blood draw must be recorded (see Section 8.3). 
f. 
If Visit 205 is conducted after Day 7. 

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10.10.2. Introduction 
10.10.2.1. Substudy Rationale 
Substudy B is a Phase 1/2 randomized, single-blind (sponsor-unblinded) substudy to evaluate 
the safety and immunogenicity of the following vaccination schedules: 
In participants 65 to 85 years of age: 
• 2 Doses of qIRV encoding 2 A strains and 2 B strains at a dose level of CCI 
, 
administered 21 days apart. 
• 2 Doses of licensed QIV, administered 21 days apart (as a control group). 
• A dose of licensed QIV followed by a dose of bIRV encoding 2 A strains at a dose level 
of either CCI 
, administered 21 days apart. 
• A dose of licensed QIV administered concurrently in the opposite arm with bIRV 
encoding 2 A strains at a dose level of either CCI 
. 
• A dose of bIRV encoding 2 A strains at a dose level of CCI 
 administered 
concurrently in the opposite arm with bIRV encoding 2 B strains at a dose level of CCI 
. 
• A dose of qIRV encoding 2 A strains and 2 B strains at the following dose level 
combinations: 
CC 
 
 
• A dose of licensed QIV (as a control group). 
In participants 18 to 64 years of age: 
• A dose of qIRV encoding 2 A strains and 2 B strains at a dose level of CCI 
. 
• A dose of qIRV encoding 2 A strains and 2 B strains at a dose level of CCI 
. 
10.10.2.2. Background 
See Section 2.2. 
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10.10.2.3. Benefit/Risk Assessment 
Benefits to individual participants enrolled in Substudy B may be: 
• Contributing to research to help others. 
Please see Section 2.3.3 for details of the SRSDs relating to the study intervention used in 
Substudy B. 

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10.10.3. Objectives, Endpoints, and Estimands (Substudy B) 
For the purposes of the study estimands: 
• Seroconversion is defined as an HAI titer <1:10 prior to vaccination and ≥1:40 at the time point of interest, or an HAI titer of 
≥1:10 prior to vaccination with a 4-fold rise at the time point of interest. 
 
Objectives 
Estimands 
Endpoints 
Primary Safety: 
Primary Safety: 
Primary Safety: 
To describe the safety and tolerability of 
modRNA influenza vaccines when 
administered in differing vaccination 
schedules in adults 18 to 64 and 65 to 
85 years of age 
In participants receiving at least 1 dose of study intervention, the 
percentage of participants reporting: 
• Local reactions for up to 7 days following each vaccination 
• Systemic events for up to 7 days following each vaccination 
• 
AEs from the first vaccination to 4 weeks after the last 
vaccination 
• 
SAEs from the first vaccination to 6 months after the last 
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 
The percentage of participants with: 
• 
Abnormal troponin I laboratory values 2 days after the last 
vaccination 
Troponin I laboratory parameters detailed in Section 10.2 
The percentage of participants with: 
• New ECG abnormalities 2 days after the last vaccination 
ECG abnormalities consistent with probable or possible 
myocarditis or pericarditis as defined in Section 8.2.7 
Secondary: 
Secondary: 
Secondary: 
To describe the immune responses elicited 
by modRNA influenza vaccines when 
administered in differing vaccination 
schedules in adults 65 to 85 years of age 
In participants complying with the key protocol criteria (evaluable 
participants) at Day 21 (if applicable) and 1, 4, and 8 weeks after 
receipt of the last vaccination: 
• HAI GMTs before Vaccination 1, prior to Vaccination 2 
(Day 21, if applicable), and at 1, 4, and 8 weeks after receipt of 
the last vaccination 
• HAI GMFR from before Vaccination 1 to prior to Vaccination 2 
(Day 21, if applicable) and to 1, 4, and 8 weeks after receipt of 
the last vaccination 
• The proportion of participants achieving HAI seroconversion for 
each strain prior to Vaccination 2 (Day 21, if applicable) and at 
1, 4, and 8 weeks after receipt of the last vaccination 
HAI titers for each strain targeted by the study vaccine 

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Objectives 
Estimands 
Endpoints 
• The proportion of participants with HAI titers ≥1:40 for each 
strain before Vaccinations 1 and 2 (Day 21, if applicable) and at 
1, 4, and 8 weeks after receipt of the last vaccination 
In participants having received at least 1 dose of a quadrivalent 
vaccine, complying with the key protocol criteria (evaluable 
participants), at Day 21 (if applicable) and at 1, 4, and 8 weeks after 
receipt of the last vaccination: 
• The proportion of participants achieving HAI seroconversion for 
all strains prior to Vaccination 2 (Day 21, if applicable) and at 1, 
4, and 8 weeks after receipt of the last vaccination 
• The proportion of participants with HAI titers ≥1:40 for all 
strains before Vaccinations 1 and 2 (Day 21, if applicable) and 
1, 4, and 8 weeks after receipt of the last vaccination 
HAI titers for each strain targeted by the study vaccine 
To describe the immune responses elicited 
by qIRV in adults 18 to 64 years of age 
In participants complying with the key protocol criteria (evaluable 
participants) at 1, 4, and 8 weeks after receipt of vaccination: 
• HAI GMTs before vaccination and at 1, 4, and 8 weeks after 
receipt of vaccination 
• HAI GMFR from before vaccination to 1, 4, and 8 weeks after 
receipt of vaccination 
• The proportion of participants achieving HAI seroconversion for 
each strain at 1, 4, and 8 weeks after receipt of vaccination 
• The proportion of participants with HAI titers ≥1:40 for each 
strain before vaccination and at 1, 4, and 8 weeks after receipt of 
vaccination 
• The proportion of participants achieving HAI seroconversion for 
all strains at 1, 4, and 8 weeks after receipt of vaccination 
• The proportion of participants with HAI titers ≥1:40 for all 
strains before vaccination and 1, 4, and 8 weeks after receipt of 
vaccination 
HAI titers for each strain targeted by the study vaccine 

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Objectives 
Estimands 
Endpoints 
 
 
CCI 
Tertiary/Exploratory: 
Tertiary/Exploratory: 
Tertiary/Exploratory: 

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CCI 
10.10.4. Substudy B Design 
10.10.4.1. Overall Design 
This is a randomized, single-blinded (sponsor-unblinded) substudy to evaluate the safety and 
immunogenicity of the vaccination schedules detailed below. The design of Substudy B is 
summarized in Section 1.2.2. 
Participants 65 to 85 years of age will be randomized to one of the following vaccination 
schedules at Visit 201 (Vaccination 1) and will be blinded to which 1-visit or 2-visit 
vaccination schedules they will receive: 
2-Visit Schedules 
• 2 Doses of qIRV encoding 2 A strains and 2 B strains at a dose level of CCI 
, 
administered 21 days apart. 
• 2 Doses of licensed QIV, administered 21 days apart (as a control group). 
• A dose of licensed QIV following by a dose of bIRV encoding 2 A strains at a dose level 
of either CCI 
, administered 21 days apart. 
1-Visit Schedules 
• A dose of licensed QIV administered concurrently in the opposite arm with bIRV 
encoding 2 A strains at a dose level of either CCI 
. 
• A dose of bIRV encoding 2 A strains at a dose level of CCI 
 administered 
concurrently in the opposite arm with bIRV encoding 2 B strains at a dose level of CCI 
 
• A dose of qIRV encoding 2 A strains and 2 B strains at the following dose level 
combinations: 
CC 
 
 
• A dose of licensed QIV (as a control group). 
It is anticipated that the following strains will be used in the bIRV, but the final strain 
selection will be detailed in the IP manual: 
It is anticipated that the following strains will be used in the 
qIRV, but the final strain selection will be detailed in the IP manual: CCI 
CCI 

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The strains used in qIRV may vary depending on the time of enrollment relative to the annual 
influenza season. 
Substudy B enrollment of participants 65 to 85 years of age will be separated into an initial 
and expanded enrollment. Depending on the availability of study intervention and 
operational prioritization, groups of participants 65 to 85 years of age in Substudy B may not 
all be randomized concurrently; however, a minimum of 2 groups will be open for 
randomization at any one time. Participants 18 to 64 years of age will only be included in the 
study during expanded enrollment: 240 participants 18 to 64 years of age will be randomized 
1:1 to receive either a single dose of CCI  qIRV (encoding 2 A strains and 2 B strains at a 
dose level of CCI 
) or a single dose of CCI  qIRV (encoding 2 A strains and 2 B 
strains at a dose level of CCI 
). 
During initial enrollment (participants 65 to 85 years of age): 
• Each group (vaccine formulation/dose level, or control) will comprise 15 participants. 
Hence, Substudy B initial enrollment will comprise approximately 90 participants. 
 
• Enrollment will be controlled for the first group in which the total dose of modRNA 
vaccine administered at a single vaccination is CCI , and also for the first group in which 
the total dose is CCI  as follows: 
• No more than 5 participants can be vaccinated on the first day. 
• Vaccination of the remaining participants will commence no sooner than 24 hours 
after the fifth participant received his or her vaccination. 
• Safety and immunogenicity data accumulated at least 1 week following the last 
vaccination in each group will be reviewed by the sponsor’s IRC and, if deemed 
acceptable, an additional 120 participants 65 to 85 years of age will be enrolled in that 
group (expanded enrollment). 
• If a group is not selected for enrollment expansion or, based on review of 
immunogenicity data at the 4-week time point, at the sponsor’s discretion, subsequent 
collection of blood samples from participants in that group may be halted and/or not 
analyzed. 
As detailed above, Substudy B expanded enrollment will comprise group(s) of 
120 participants following the vaccination schedule(s) as selected by the sponsor’s IRC from 
initial enrollment. Additionally, 
• 240 participants 18 to 64 years of age will be randomized 1:1 to receive either a single 
dose of CCI  qIRV (encoding 2 A strains and 2 B strains at a dose level of CCI 
 
) or a single dose of CCI 
level of CCI 
). 
qIRV (encoding 2 A strains and 2 B strains at a dose 

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• Expanded-enrollment groups may also be included that comprise only the first dose from 
2-visit–schedule initial enrollment groups, eg, 1 dose of qIRV at a dose level of CCI  
. 
• At the discretion of the sponsor’s IRC, a control group of 120 participants may be 
enrolled during expanded enrollment who will receive a dose of licensed QIV followed 
by placebo, administered 21 days apart. 
Therefore, Substudy B expanded enrollment will consist of approximately 120 to 1725 
participants, depending on the number of groups selected to progress to expanded enrollment. 
Stopping rules will apply throughout initial and expanded enrollment as detailed in 
Section 10.10.8.6. 
All participants will be asked to complete a reactogenicity e-diary for 7 days following each 
vaccination. Blood samples of approximately 50 mL will be collected for immunogenicity 
assessments prior to Vaccination 1, prior to Vaccination 2 (if applicable), and at 1, 4, and 
8 weeks after the participant’s last vaccination. 
The total duration of the study for each participant will be up to approximately 8 months. 
All participants will be asked to provide an additional blood sample of approximately 2.5 mL 
at time points specified in Section 10.10.1 for assessment of troponin I. 
All participants enrolled prior to expanded enrollment will be asked to provide an additional 
blood sample of 50 mL at time points specified in Section 10.10.1 for assessment of 
cell-mediated immunogenicity. 
During expanded enrollment, all or a subset of participants will be asked to provide an 
additional optional blood sample of 50 mL at time points specified in Section 10.10.1 for 
assessment of cell-mediated immunogenicity. The number of participants asked to provide 
these samples will be determined by Pfizer, contingent on operational considerations. 
10.10.4.2. Scientific Rationale for Study Design 
See Section 2.1. 
10.10.4.3. Justification for Dose 
See Section 4.3. 
10.10.4.4. End of Study Definition 
See Section 4.4. 

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10.10.5. Substudy B Population 
10.10.5.1. Substudy B Inclusion Criteria 
Participants are eligible to be included in Substudy B only if all of the following criteria 
apply: 
 
Substudy B 
Age and Sex: 
1. During enrollment of Groups 1 to 12 (Table 6): male or female participants 65 to 85 years 
of age at Visit 201 (Day 1) or, 
During enrollment of Groups 13 and 14 (Table 6): male or female participants 18 to 
64 years of age at Visit 201 (Day 1). 
• 
Refer to Appendix 4 for reproductive criteria for male 
(Section 10.4.1) and female (Section 10.4.2) participants. 
X 
Type of Participant and Disease Characteristics: 
2. 
Participants who are willing and able to comply with all scheduled visits, vaccination 
plan, laboratory tests, lifestyle considerations, and other study procedures. 
X 
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: With the exception of heart disease, which is exclusionary (see exclusion criterion 
16), 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 10.11. 
X 
4. 
For participants 65 to 85 years of age at the time of enrollment, receipt of licensed 
influenza vaccination for the 2021-2022 northern hemisphere season >4 months 
(120 days) before study intervention administration. 
X 
Informed Consent: 
5. 
Capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the ICD and in this protocol. 
X 

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10.10.5.2. Substudy B Exclusion Criteria 
Participants are excluded from Substudy B if any of the following criteria apply: 
 
Substudy B 
Medical Conditions: 
1. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the 
risk of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study. 
X 
2. 
History of severe adverse reaction associated with a vaccine and/or severe 
allergic reaction (eg, anaphylaxis) to any component of the study intervention(s). 
X 
3. 
Immunocompromised individuals with known or suspected immunodeficiency, 
as determined by history and/or laboratory/physical examination. 
X 
4. 
Bleeding diathesis or condition associated with prolonged bleeding that would, 
in the opinion of the investigator, contraindicate intramuscular injection. 
X 
5. 
Women who are pregnant or breastfeeding. 
X 
6. 
Allergy to egg proteins (egg or egg products) or chicken proteins. 
X 
Prior/Concomitant Therapy: 
7.  Any participant who has had significant exposure (someone who was within 
6 feet of an infected person for a cumulative total of 15 minutes or more over a 
24-hour period) to someone with laboratory-confirmed SARS-CoV-2 infection, 
COVID-19, or influenza in the past 14 days known prior to Visit 201. 
X 
8. 
Any participant who has a SARS-CoV-2 RT-PCR or antigen test in the past 
10 days prior to Visit 201 that has not been confirmed as negative. 
X 
9. 
Individuals who receive treatment with radiotherapy or immunosuppressive 
therapy, including cytotoxic agents or systemic corticosteroids (if systemic 
corticosteroids are administered for ≥14 days at a dose of ≥20 mg/day of 
prednisone or equivalent), eg, for cancer or an autoimmune disease, or planned 
receipt throughout the study. Inhaled/nebulized, intra-articular, intrabursal, or 
topical (skin or eyes) corticosteroids are permitted. 
X 
10. Receipt of blood/plasma products, immunoglobulin, or monoclonal antibodies, 
from 60 days before study intervention administration, or planned receipt 
throughout the study. 
X 
11. Any participant who has received or plans to receive a modRNA-platform 
SARS-CoV-2 vaccine within 28 days of Visit 201. 
X 
12. Any participant who has received licensed influenza vaccination for the 
2022-2023 northern hemisphere influenza season. 
X 
Prior/Concurrent Clinical Study Experience: 
13. Participation in other studies involving study intervention within 28 days prior to 
study entry and/or during study participation. 
X 

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Substudy B 
Other Exclusions: 
14. Investigator site staff or Pfizer employees directly involved in the conduct of the 
study, site staff otherwise supervised by the investigator, and their respective 
family members. 
X 
15. Participation in strenuous or endurance exercise through Visit 205. 
X 
16. Prior history of heart disease. 
X 
17. Any abnormal screening troponin I laboratory value. 
X 
18. Screening 12-lead ECG that, as judged by the investigator, is consistent with 
probable or possible myocarditis or pericarditis, or demonstrates clinically 
relevant abnormalities that may affect participant safety or interpretation of study 
results. Participants with a screening 12-lead ECG that shows an average QTcF 
interval >450 msec, complete left bundle branch block, signs of an acute or 
indeterminate-age myocardial infarction, ST-T interval changes suggestive of 
myocardial ischemia, second- or third-degree AV block, or serious 
bradyarrhythmias or tachyarrhythmias should be excluded from study 
participation. 
X 
 
10.10.6. Substudy B Intervention and Concomitant Therapy 
10.10.6.1. Study Intervention(s) Administered 
Study interventions for Substudy B will include: 
 
Intervention 
Name 
mIRV 
qIRV 
QIV 
Normal Saline 
Placebo 
Type 
Vaccine 
Vaccine 
Vaccine 
Placebo 
Dose 
Formulation 
modRNA 
modRNA 
Normal saline (0.9% 
sodium chloride 
solution for injection) 
Unit Dose 
Strength(s) 
CCI 
0.3 mL 
CCI 
CCI 
0.7 mL 
0.3 mL 
Dosage Level(s) 
CCI 
N/A 
Route of 
Administration 
Intramuscular 
injection 
Intramuscular 
injection 
Intramuscular 
injection 
Intramuscular 
injection 
Use 
Experimental 
Experimental 
Experimental 
Placebo for expanded 
enrollment 
IMP or NIMP 
IMP 
IMP 
IMP 
IMP 
Sourcing 
Provided centrally 
by the sponsor 
Provided centrally 
by the sponsor 
Provided centrally by 
the sponsor 
Provided centrally by 
the sponsor 

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Intervention 
Name 
mIRV 
qIRV 
QIV 
Normal Saline 
Placebo 
Packaging and 
Study intervention 
Study intervention 
Study intervention 
Study intervention 
Labeling 
will be provided in a will be provided in a will be provided either will be provided in a 
glass vial as open- 
glass vial as open- 
as a PFS or in a glass 
glass or plastic vial as 
label supply. Each 
label supply. Each 
vial as open-label 
open-label supply. 
vial will be labeled 
vial will be labeled 
supply. Each PFS/vial Each vial will be 
as required per 
as required per 
will be labeled as 
labeled as required 
country requirement 
country requirement 
required per country 
per country 
requirement 
requirement 
 
 
mIRVs encoding HA for each A and B strain will be mixed at the site to generate either 
bIRV at a dose level of either CCI 
, or qIRV at dose level combinations 
other than CCI 
. Please see the IP manual for further details. 
10.10.6.1.1. Administration 
See Section 6.1.1. 
During Substudy B, participants will receive study intervention as randomized at Visit 201 
and, if applicable, at Visit 203 in accordance with the SoA (Section 10.10.1). 
Study intervention should be administered intramuscularly as detailed in Table 6. 
 
Table 6. 
Substudy B Study Intervention Schedule 
 
Participant 
Age 
Vaccine 
Group 
1 
Study Intervention - Vaccination 1 
Study Intervention - Vaccination 2 
Right Deltoida 
qIRV CCI 
2 x A, 2 x B 
CCI 
 
Licensed QIV 
Left Deltoid 
Right Deltoida 
qIRV CCI 
2 x A, 2 x B 
Left Deltoid 
2 
3 
Licensed QIV 
4 
5 
bIRV CCI 
2 x A CCI 
bIRV CCI 
2 x A CCI 
 
Licensed QIV 
65 to 
85 years of 
age 
6 
7 
Licensed QIV 
bIRV CCI 
2 x A CCI 
bIRV CCI 
2 x A CCI 
qIRV CCI 
2 x A, 2 x B 
Licensed QIV 
 
Licensed QIV 
8 
9 
Licensed QIV 
bIRV CCI 
2 x B CCI 
qIRV CCI 
2 x A CCI 
2 x B CCI 
bIRV CCI 
2 x A 
10 
CCI 
CCI 
CCI 

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Table 6. 
Substudy B Study Intervention Schedule 
 
a. 
Local reactions will be assessed at the injection site on the right deltoid (see Section 8.2.3.2). 
 
Study intervention in Substudy B will be administered in a single-blinded manner. 
10.10.6.1.2. Medical Devices 
See Section 6.1.2. 
10.10.6.1.3. Preparation, Handling, Storage, and Accountability 
See Section 6.2. 
10.10.6.1.4. Preparation and Dispensing 
See Section 6.2.1. 
During Substudy B, study intervention will be prepared by qualified site personnel according 
to the IP manual or package insert and the study intervention administered in such a way to 
ensure that the participants remain blinded. 
10.10.6.2. Measures to Minimize Bias: Randomization and Blinding 
10.10.6.2.1. Allocation to Study Intervention 
See Section 6.3.1. 
Allocation of study intervention at Visit 201 in Substudy B will be conducted via IRT. 
qIRV 
2 x A 
2 x B CCI 
Licensed QIV 
qIRV CCI 
2 x A, 2 x B 
qIRV 
2 x A, 2 x B 
CCI 
14 
Left Deltoid 
Right Deltoida 
Left Deltoid 
CCI 
Placebo 
Study Intervention - Vaccination 2 
13 
 
18 to 
64 years of 
age 
12 
11 
Right Deltoida 
Study Intervention - Vaccination 1 
Vaccine 
Group 
Participant 
Age 
CCI 
CCI 
CCI 

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10.10.6.2.2. Blinding of Site Personnel 
Substudy B is single-blinded, such that all site personnel, including the investigator, 
investigator staff, and study staff receiving, storing, dispensing, preparing, and administering 
the study interventions will be unblinded. Study participants, however, will remain blinded 
to which 1- or 2-visit vaccination schedule they receive (see Section 10.10.4.1). 
10.10.6.2.3. Blinding of the Sponsor 
To facilitate rapid review of data in real time, sponsor staff will be unblinded to study 
intervention allocation for the participants throughout Substudy B. 
10.10.6.2.4. Breaking the Blind 
Not applicable. 
10.10.6.3. Study Intervention Compliance 
See Section 6.4. 
10.10.6.4. Dose Modification 
Not applicable. 
10.10.6.5. Continued Access to Study Intervention After the End of the Study 
See Section 6.6. 
10.10.6.6. Treatment of Overdose 
See Section 6.7. 
10.10.6.7. Concomitant Therapy 
See Section 6.8. 
10.10.7. Discontinuation of Substudy B Intervention and Participant 
Discontinuation/Withdrawal 
See Section 7. 
10.10.8. Substudy B Assessments and Procedures 
The minimal blood sampling volume for all individual participants in this study is 
approximately 457.5 mL prior to expanded enrollment and 257.5 mL for participants enrolled 
thereafter. For participants enrolled during expanded enrollment, additional optional whole 
blood samples of approximately 50 mL at Visits 201, 202, 205, and 206 will be obtained 
from participants for isolation of PBMCs as detailed in Section 10.10.4.1. 
For all participants, other additional blood samples may be taken for safety assessments at 
times specified by Pfizer, provided the total volume taken during the study does not exceed 
550 mL during any period of 60 consecutive days. 

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10.10.8.1. Clinical Safety Laboratory Assessments 
Please see Section 8.2.4. Additionally, see Section 10.2 for the list of clinical safety 
laboratory tests to be performed and the SoA for the timing and frequency. 
10.10.8.2. Efficacy and/or Immunogenicity Assessments 
Samples will be collected at time points as specified in Section 10.10.1, and the following 
assay will be run on samples at each of these time points: 
• HAI 
PBMC samples will be used to describe T-cell responses. Some of the samples may be used 
for sequencing of participants’ antibody and/or BCR heavy- and light-chain genes, TCR 
genes, and/or mRNAs for understanding the B-cell, T-cell, and antibody repertoires. 
10.10.8.2.1. Biological Samples 
See Section 8.1.1. 
10.10.8.3. Safety Assessments 
See Section 8.2. 
Note, for Substudy B, local reactions will be assessed at the injection site on the right arm 
only (see Section 8.2.3.2). 
10.10.8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting 
See Section 8.3. 
10.10.8.5. ECGs 
See Section 8.2.7. 
10.10.8.6. Stopping Rules 
The following stopping rules are in place for Substudy B participants, based on review of 
AE, ECG, and laboratory data. These data will be monitored on an ongoing basis by the 
investigator (or medically qualified designee) and sponsor in order to promptly identify and 
flag any event that potentially contributes to a stopping rule. 
The sponsor study team will be unblinded, so they will be able to assess whether or not a 
stopping rule has been met on the basis of a participant’s individual study intervention 
allocation. 
In the event that sponsor personnel confirm that a stopping rule is met, the following actions 
will commence: 
• The IRC will review all appropriate data. 

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• The stopping rule will PAUSE randomization and study intervention administration for 
all vaccine candidates at the affected and, if applicable, higher total dose level CCI 
 
, eg, if a stopping rule is met in a group receiving study intervention at a total dose 
of CCI , this will pause randomization and study intervention administration in all 
groups receiving study intervention at a total dose level of CCI 
. 
• 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 rules occur within 4 weeks after administration 
of any IRV at Vaccination 1 or 2. Each IRV dose level will be evaluated for contribution to 
stopping rules independently. 
Stopping Rule Criteria: 
1. If any participant vaccinated with any IRV develops: 
• 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 
• An abnormal troponin I value that is confirmed abnormal on repeat testing, assessed 
as related to study intervention by the investigator. 
2. If ≥1 participant vaccinated with any IRV develops confirmed myocarditis or pericarditis. 
3. If any participant vaccinated with any IRV dies. 
4. If ≥1 participant vaccinated with any IRV experiences a Grade 4 unsolicited AE, or SAE 
of any severity, assessed as related by the investigator. 
5. If ≥2 participants vaccinated with any IRV at the same dose level develop the same or 
similar Grade 3 or higher unsolicited AE, other than myocarditis/pericarditis, assessed as 
related to study intervention by the investigator. Note that the local reactions, systemic 
events, and fever specified in Section 8.2.3, reported within 7 days from the day of 
administration of the study intervention, irrespective of whether they are recorded in the 
e-diary or as AEs, are excluded from this stopping rule. 
10.10.8.7. Immunogenicity Assessments 
See Section 10.10.8.2. 

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10.10.8.8. Substudy B Procedures 
10.10.8.8.1. Screening (0 to 28 Days Before Visit 201) 
Before enrollment and before any study-related procedures are performed, voluntary, written, 
study-specific informed consent will be obtained from the participant. Each signature on the 
ICD must be personally dated by the signatory. The investigator or his or her designee will 
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The 
source data must reflect that the informed consent was obtained before participation in the 
study. 
It is anticipated that the procedures below will be conducted in a stepwise manner. 
• Assign a single participant number using the IRT system. 
• Obtain the participant’s demography (including date of birth, sex, race, and ethnicity). 
The full date of birth will be collected to critically evaluate the immune response and 
safety profile by age. 
• Obtain any medical history of clinical significance. 
• Obtain details of any medications currently taken. 
• Perform 12-lead triplicate ECG. 
• Perform physical examination, including vital signs (weight, height, body temperature, 
pulse rate, and seated blood pressure), evaluating any clinically significant abnormalities 
within the following body systems: general appearance; skin; head, eyes, ears, nose, and 
throat; heart; lungs; abdomen; musculoskeletal; extremities; neurological; and lymph 
nodes. 
• Collect a blood sample of approximately 2.5 mL as detailed in the laboratory manual for 
troponin I laboratory testing as described in Section 10.2. 
• Perform urine pregnancy test on WOCBP as described in Section 8.2.5. 
• Discuss contraceptive use as described in Section 10.4. 
• Record nonstudy vaccinations as described in Section 6.8. 
• Record prior receipt of any COVID-19 vaccine as described in Section 6.8. 
• Record details of any licensed influenza vaccine received in the prior 12 months, as 
described in Section 6.8. 
• Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met. 

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• Record AEs as described in Section 8.3. 
• Remind the participant to use appropriate contraceptives throughout the study, if 
applicable. 
• The investigator or an authorized designee completes the CRF. 
10.10.8.8.2. Visit 201 – Vaccination 1 (Day 1) 
It is anticipated that the procedures below will be conducted in a stepwise manner; ensure 
that procedures listed prior to administration of the vaccine are conducted prior to 
vaccination. 
• Discuss contraceptive use as described in Section 10.4. 
• Record nonstudy vaccinations as described in Section 6.8. 
• Review screening laboratory troponin I and ECG results. 
• 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. 
• Perform 12-lead triplicate ECG. 
• Collect a blood sample of approximately 2.5 mL as detailed in the laboratory manual for 
troponin I laboratory testing as described in Section 10.2. 
• Measure vital signs, including body temperature, pulse rate, and seated blood pressure. 
• Perform urine pregnancy test on WOCBP as described in Section 8.2.5. 
• Ensure that the participant continues to meet all of the inclusion criteria and none of the 
exclusion criteria. 
• 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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• If the participant has consented to provide a blood sample for description of 
cell-mediated immune response, collect a blood sample (approximately 50 mL) for 
PBMC isolation. 
• Site staff member(s) will dispense/administer study intervention, depending on the 
allocated study intervention/vaccine schedule, as detailed in Table 6. Please refer to the 
IP manual for further instruction on this process. 
• Site staff must observe the participant for at least 30 minutes after study intervention 
administration for any acute reactions. Record any acute reactions (including time of 
onset) in the participant’s source documents and on the AE page of the CRF, and on an 
SAE form as applicable. 
• Issue a measuring device to measure local reactions at the injection site and a 
thermometer for recording daily temperatures and provide instructions on their use. 
• Explain the e-diary 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 to Day 7, with Day 1 being 
the day of vaccination. 
• Ask the participant to contact the site staff or investigator immediately if he or she 
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 is 
the day of vaccination) to determine if an unscheduled reactogenicity visit is required: 
• Fever ≥39.0°C (≥102.1°F). 
• Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units). 
• Severe pain at the injection site. 
• Any severe systemic event. 
• Record AEs as described in Section 8.3. 
• 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 if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.10.8.8.11). 
• 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. 

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• Complete the source documents. 
• Complete the CRFs and study intervention accountability records. 
• The investigator or appropriately qualified designee reviews the reactogenicity e-diary 
data online following vaccination to evaluate participant compliance and as part of the 
ongoing safety review. Daily review is optimal during the active diary period. 
10.10.8.8.3. Visit 202 – 1-Week Post–Vaccination 1 Visit – 6 to 8 Days After 
Vaccination 1 
Visit 202 is to be conducted during initial enrollment for participants assigned to 2-visit 
vaccination schedules only. 
• Record AEs as described in Section 8.3. 
• Record nonstudy vaccinations as described in Section 6.8. 
• Record prohibited medication use as described in Section 6.8.1. 
• Discuss contraceptive use as described in Section 10.4. 
• Review troponin I laboratory and ECG results. Any abnormal troponin I level must 
result in further assessments as outlined in Section 10.10.8.8.11. 
• Collect a blood sample (approximately 50 mL) for PBMC isolation. 
• Review the participant’s reactogenicity e-diary data. If the e-diary collection period is 
complete, 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. 
• Ask the participant to contact the site staff or investigator immediately if he or she 
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 is 
the day of vaccination) to determine if an unscheduled reactogenicity visit is required: 
• Fever ≥39.0°C (≥102.1°F). 
• Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units). 
• Severe pain at the injection site. 
• Any severe systemic event. 
• Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs. 

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• Ask the participant to contact the site staff or investigator if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.10.8.8.11). 
• Schedule an appointment for the participant to return for the next study visit. 
• Complete the source documents. 
• The investigator or an authorized designee completes the CRFs. 
10.10.8.8.4. Visit 203 – Vaccination 2 – 19 to 23 Days After Visit 201 
Vaccination 2 (Visit 203) should only be conducted for participants randomized to 2-visit 
vaccination schedules. 
It is anticipated that the procedures below will be conducted in a stepwise manner; ensure 
that procedures listed prior to administration of the vaccine are conducted prior to 
vaccination. 
• Review the participant’s reactogenicity e-diary data. Collect stop dates of any 
reactogenicity e-diary events ongoing on the last day that the reactogenicity e-diary was 
completed and record stop dates in the CRF if required. 
• Review troponin I and ECG results. 
• Discuss contraceptive use as described in Section 10.4. 
• Record nonstudy vaccinations as described in Section 6.8. 
• Record prohibited medication use as described in Section 6.8.1. 
• Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met. If not, the participant may not receive further study intervention but will remain 
in the study to be evaluated for safety and immunogenicity (see Section 7.1). 
• Measure the participant’s body temperature. 
• Ensure that the participant meets none of the temporary delay criteria as described in 
Section 5.5. 
• Collect a blood sample (approximately 50 mL), before administration of study 
intervention, for immunogenicity assessment. 
• Site staff member(s) will dispense/administer study intervention, depending on the 
allocated study intervention/vaccine schedule, as detailed in Table 6. Please refer to the 
IP manual for further instruction on this process. 

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• Site staff must observe the participant for at least 30 minutes after study intervention 
administration for any acute reactions. Record any acute reactions (including time of 
onset) in the participant’s source documents and on the AE page of the CRF, and on an 
SAE form as applicable. 
• Ensure the participant has a measuring device to measure local reactions at the injection 
site and a thermometer for recording daily temperatures. 
• Ensure the participant remains comfortable with the chosen e-diary platform, confirm 
instructions on e-diary completion, and ask the participant to complete the reactogenicity 
e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination. 
• Ask the participant to contact the site staff or investigator immediately if he or she 
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 is 
the day of vaccination) to determine if an unscheduled reactogenicity visit is required: 
• Fever ≥39.0°C (≥102.1°F). 
• Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units). 
• Severe pain at the injection site. 
• Any severe systemic event. 
• Record AEs as described in Section 8.3. 
• 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 if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.10.8.8.11). 
• 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. 
• Complete the CRFs and 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. 

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10.10.8.8.5. Visit 204 – Day 3 Follow-up Visit (After Vaccination 1 or 2) – 2 to 4 Days 
After Last Study Vaccination 
Visit 204 is to be conducted within 2 to 4 days after Visit 201 or 203, depending on if the 
participant is assigned to a 1- or 2-visit vaccination schedule. 
• Record AEs as described in Section 8.3. 
• Record nonstudy vaccinations as described in Section 6.8. 
• Record prohibited medication use as described in Section 6.8.1. 
• Discuss contraceptive use as described in Section 10.4. 
• Perform 12-lead triplicate ECG. Any new ECG abnormality (compared to baseline) 
consistent with probable or possible myocarditis or pericarditis (as listed in Section 8.2.7) 
must result in further assessments as outlined in Section 10.10.8.8.11. 
• Measure vital signs, including body temperature, pulse rate, and seated blood pressure. 
• Collect a blood sample of approximately 2.5 mL as detailed in the laboratory manual for 
troponin I laboratory testing as described in Section 10.2. 
• Ask the participant to contact the site staff or investigator immediately if he or she 
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 is 
the day of vaccination) to determine if an unscheduled reactogenicity visit is required: 
• Fever ≥39.0°C (≥102.1°F). 
• Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units). 
• Severe pain at the injection site. 
• Any severe systemic event. 
• Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs. 
• Ask the participant to contact the site staff or investigator if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.10.8.8.11). 
• Schedule an appointment for the participant to return for the next study visit. 
• Complete the source documents. 
• The investigator or an authorized designee completes the CRFs. 

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10.10.8.8.6. Visit 205 – 1-Week Follow-up Visit (After Vaccination 1 or 2) – 6 to 8 Days 
After Last Study Vaccination 
Visit 205 is to be conducted within 6 to 8 days after Visit 201 or 203, depending on if the 
participant is assigned to a 1- or 2-visit vaccination schedule. 
• Record AEs as described in Section 8.3. 
• Record nonstudy vaccinations as described in Section 6.8. 
• Record prohibited medication use as described in Section 6.8.1. 
• Discuss contraceptive use as described in Section 10.4. 
• Review troponin I laboratory and ECG results. Any abnormal troponin I level must 
result in further assessments as outlined in Section 10.10.8.8.11. 
• Collect a blood sample of approximately 50 mL for immunogenicity testing. 
• If the participant has consented to provide a blood sample for description of 
cell-mediated immune response, collect a blood sample (approximately 50 mL) for 
PBMC isolation. 
• Review the participant’s reactogenicity e-diary data. If the e-diary collection period is 
complete: 
• 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. 
• Collect the participant’s e-diary or assist the participant with removing the study 
application from his or her own personal device (if the visit is conducted after Day 7). 
• Ask the participant to contact the site staff or investigator immediately if he or she 
experiences any of the following from Day 1 to Day 7 after vaccination (where Day 1 is 
the day of vaccination) to determine if an unscheduled reactogenicity visit is required: 
• Fever ≥39.0°C (≥102.1°F). 
• Redness or swelling at the injection site measuring greater than 10 cm 
(>20 measuring device units). 
• Severe pain at the injection site. 
• Any severe systemic event. 
• Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs. 

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• Ask the participant to contact the site staff or investigator if the participant experiences 
acute chest pain, shortness of breath, or palpitations (see Section 10.10.8.8.11). 
• Schedule an appointment for the participant to return for the next study visit. 
• Complete the source documents. 
• The investigator or an authorized designee completes the CRFs. 
10.10.8.8.7. Visit 206 – 4-Week Follow-up Visit (After Vaccination 1 or 2) – 26 to 
30 Days After Last Study Vaccination 
Visit 206 is to be conducted within 26 to 30 days after Visit 201 or 203, depending on if the 
participant is assigned to a 1- or 2-visit vaccination schedule. 
• Record AEs as described in Section 8.3. 
• Record nonstudy vaccinations as described in Section 6.8. 
• Record prohibited medication use as described in Section 6.8.1. 
• Discuss contraceptive use as described in Section 10.4. 
• Collect a blood sample of approximately 50 mL for immunogenicity testing, unless 
advised otherwise by the sponsor based on the vaccine group to which the participant is 
assigned. 
• If the participant has consented to provide a blood sample for description of 
cell-mediated immune response, collect a blood sample (approximately 50 mL) for 
PBMC isolation, unless advised otherwise by the sponsor based on the vaccine group to 
which the participant is assigned. 
• 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 his or her own personal device. 
• Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3. 
• Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs. 
• Complete the source documents. 

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• The investigator or an authorized designee completes the CRFs. 
10.10.8.8.8. Visit 207 – 8-Week Follow-up Visit (After Vaccination 1 or 2) – 52 to 
60 Days After Last Study Vaccination 
Visit 207 is to be conducted within 52 to 60 days after Visit 201 or 203, depending on if the 
participant is assigned to a 1- or 2-visit vaccination schedule. 
• Record AEs as described in Section 8.3. 
• Record nonstudy vaccinations as described in Section 6.8. 
• Record prohibited medication use as described in Section 6.8.1. 
• Collect a blood sample of approximately 50 mL for immunogenicity testing, unless 
advised otherwise by the sponsor based on the vaccine group to which the participant is 
assigned. 
• Record any AEs that occur within the 48 hours after the blood draw as described in 
Section 8.3. 
• Ask the participant to contact the site staff or investigator if a medically attended event 
(eg, doctor’s visit, emergency room visit) or hospitalization occurs. 
• Complete the source documents. 
• The investigator or an authorized designee completes the CRFs. 
10.10.8.8.9. Visit 208 – 6-Month Follow-up Telephone Contact – 175 to 189 Days After 
Last Study Vaccination 
Visit 208 is to be conducted within 175 to 189 days after Visit 201 or 203, depending on if the 
participant is assigned to a 1- or 2-visit vaccination schedule. 
• Contact the participant by telephone. 
• Record AEs as described in Section 8.3. 
• Record nonstudy vaccinations as described in Section 6.8. 
• Complete the source documents. 
• The investigator or an authorized designee completes the CRFs. 

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10.10.8.8.10. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction 
If a Grade 3 local reaction (Section 8.2.3.2), systemic event (Section 8.2.3.3), or fever 
(Section 8.2.3.4) is reported in the reactogenicity e-diary, a telephone contact should occur to 
ascertain further details and determine whether a site visit is clinically indicated. If a 
suspected Grade 4 local reaction (Section 8.2.3.2), systemic event (Section 8.2.3.3), or fever 
(Section 8.2.3.4) 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 8.2.3.2. 
• Assess systemic events (if present) in accordance with the grades provided in 
Section 8.2.3.3. 
• Assess other findings associated with the reaction and record this on the AE page of the 
CRF if appropriate. 

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• The investigator or an authorized designee will complete the unscheduled visit 
assessment page of the CRF. 
10.10.8.8.11. Additional Procedures for Monitoring of Potential Myocarditis or 
Pericarditis 
Any study participant who reports acute chest pain, shortness of breath, palpitations, or any 
other symptom(s) that might be indicative of myocarditis or pericarditis within 4 weeks after 
study vaccination (Vaccination 1 or 2) must be specifically evaluated by a cardiologist for 
possible myocarditis or pericarditis. The same applies for any participant in whom a new 
ECG abnormality (compared to baseline) consistent with probable or possible myocarditis or 
pericarditis (as listed in Section 8.2.7) or abnormal troponin I level is observed at Visit 202 or 
204. 
In addition to a clinical evaluation, the following should be performed: 
• ECG and 
• Measurement of the troponin level 
For any participant in whom a new ECG abnormality (compared to baseline) consistent with 
probable or possible myocarditis or pericarditis (as listed in Section 8.2.7) or abnormal 
troponin I level is observed at Visit 202 or 204, this should be achieved by repeating the 
assessments with the central vendor(s). 
If myocarditis or pericarditis is suspected based upon the initial evaluation, the following 
should also be performed: 
• Cardiac echocardiogram and/or 
• Cardiac magnetic resonance study 
Details of the symptoms reported, and results of the investigations performed, will be 
recorded in the CRF. 
10.10.9. Substudy B Statistical Considerations 
See Section 9 for general statistical considerations and phase specifics below. 
10.10.9.1. Statistical Hypotheses 
There are no statistical hypotheses in Substudy B. 
10.10.9.1.1. Estimands 
The estimands corresponding to the primary, secondary, and exploratory objectives are 
described in the table in Section 10.10.3. 

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10.10.9.1.2. Multiplicity Adjustment 
There is no multiplicity adjustment for Substudy B as all analyses are descriptive in nature. 
10.10.9.2. Analysis Sets 
See Section 9.2 for defined analysis sets. 
10.10.9.3. Statistical Analyses 
The SAP will be developed and finalized for this phase 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. 
10.10.9.3.1. General Considerations 
See Section 9 for general considerations of statistical analyses. 
Note that, if a clear HAI result is not obtainable for any strain, neutralizing titers will replace 
HAI titers as the main immunogenicity endpoint for that strain. 

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10.10.9.3.2. Primary Endpoint(s)/Estimand(s) Analysis 
 
Endpoint 
Statistical Analysis Methods 
Safety 
(adults 65 to 
85 years of age) 
• Point estimates and the associated exact 2-sided 95% CIs will be 
calculated using the Clopper-Pearson method for the proportion of 
participants reporting each event (local reactions and systemic 
events) for each vaccine group for up to 7 days following each 
vaccination. 
• Point estimates and the associated exact 2-sided 95% CIs will be 
calculated using the Clopper-Pearson method for the proportion of 
participants reporting each AE from the first vaccination to 4 weeks 
after the last vaccination, by vaccination group. 
• Point estimates and the associated exact 2-sided 95% CIs will be 
calculated using the Clopper-Pearson method for the proportion of 
participants reporting each SAE from the first vaccination to 
6 months after the last vaccination, by vaccination group. 
• Point estimates and the associated exact 2-sided 95% CIs will be 
calculated using the Clopper-Pearson method for the proportion of 
participants reporting abnormal troponin I levels for each study 
vaccine at 2 days after the last vaccination. 
• Point estimates and the associated exact 2-sided 95% CIs will be 
calculated using the Clopper-Pearson method for the proportion of 
participants with new ECG abnormalities at 2 days after the last 
vaccination. 

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Endpoint 
Statistical Analysis Methods 
Safety 
(adults 18 to 
64 years of age) 
• Point estimates and the associated exact 2-sided 95% CIs will be 
calculated using the Clopper-Pearson method for the proportion of 
participants reporting each event (local reactions and systemic 
events) for up to 7 days after vaccination. 
• Point estimates and the associated exact 2-sided 95% CIs will be 
calculated using the Clopper-Pearson method for the proportion of 
participants reporting each AE from the first vaccination to 4 weeks 
after vaccination. 
• Point estimates and the associated exact 2-sided 95% CIs will be 
calculated using the Clopper-Pearson method for the proportion of 
participants reporting each SAE from the first vaccination to 
6 months after vaccination. 
• Point estimates and the associated exact 2-sided 95% CIs will be 
calculated using the Clopper-Pearson method for the proportion of 
participants reporting abnormal troponin I levels at 2 days after 
vaccination. 
• Point estimates and the associated exact 2-sided 95% CIs will be 
calculated using the Clopper-Pearson method for the proportion of 
participants with new ECG abnormalities at 2 days after vaccination. 

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10.10.9.3.3. Secondary Endpoint(s)/Estimand(s) Analysis 
 
Endpoint 
Statistical Analysis Methods 
Secondary 
immunogenicity 
(adults 65 to 
85 years of age) 
• HAI GMTs and associated 2-sided 95% CIs will be provided for 
each strain, by vaccine group, before Vaccination 1 and prior to 
Vaccination 2 (Day 21, if applicable) and at 1, 4, and 8 weeks after 
receipt of the last vaccination. 
• HAI GMFRs from before Vaccination 1 to Vaccination 2 (Day 21, 
if applicable) and to 1, 4, and 8 weeks after receipt of the last 
vaccination, and associated 2-sided 95% CIs, will be provided for 
each strain, by vaccine group. 
• The proportion of participants achieving HAI seroconversion prior 
to Vaccination 2 (Day 21, if applicable) and at 1, 4, and 8 weeks 
after receipt of the last vaccination, and the proportion of 
participants with HAI titers ≥1:40 before Vaccination 1 and at 1, 4, 
and 8 weeks after receipt of the last vaccination, and associated 
2-sided Clopper-Pearson 95% CIs will be provided for each strain. 
• The proportion of participants achieving HAI seroconversion for all 
strains (targeted by the study vaccine) prior to Vaccination 2 
(Day 21, if applicable) and at 1, 4, and 8 weeks after receipt of the 
last vaccination, and the proportion of participants with HAI titers 
≥1:40 for all strains (targeted by the study vaccine) before 
Vaccinations 1 and 2 (Day 21, if applicable) and at 1, 4, and 8 weeks 
after receipt of the last vaccination, and associated 2-sided 
Clopper-Pearson 95% CIs will be provided. 
Secondary 
immunogenicity 
(adults 18 to 
64 years of age) 
• HAI GMTs and associated 2-sided 95% CIs will be provided for 
each strain before vaccination and at 1, 4, and 8 weeks after receipt 
of vaccination. 
• HAI GMFRs from before vaccination to 1, 4, and 8 weeks after 
receipt of vaccination, and associated 2-sided 95% CIs, will be 
provided for each strain. 
• The proportion of participants achieving HAI seroconversion at 1, 4, 
and 8 weeks after receipt of vaccination, and the proportion of 
participants with HAI titers ≥1:40 before vaccination and at 1, 4, and 
8 weeks after receipt of the vaccination, and associated 2-sided 
Clopper-Pearson 95% CIs, will be provided for each strain. 
• The proportion of participants achieving HAI seroconversion for all 
strains (targeted by the study vaccine) at 1, 4, and 8 weeks after 
receipt of vaccination, and the proportion of participants with HAI 
titers ≥1:40 for all strains (targeted by the study vaccine) before 
vaccination and at 1, 4, and 8 weeks after receipt of vaccination, and 
associated 2-sided Clopper-Pearson 95% CIs, will be provided. 

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10.10.9.3.4. Tertiary/Exploratory Endpoint(s) 
Endpoint 
Tertiary/ 
exploratory 
(adults 65 to 
85 years of age) 
Statistical Analysis Methods 
CC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tertiary/ 
exploratory 
(adults 18 to 
64 years of age) 
CC 
CCI 
CCI 

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10.10.9.3.5. Other Analyses 
The data collected for study participants who report any symptom(s) that might be indicative 
of myocarditis or pericarditis (ECG, troponin level, cardiac echocardiogram, and/or cardiac 
magnetic resonance study) within 4 weeks after a study vaccination (Vaccination 1 or 2) will 
be summarized and listed by vaccine group. 
10.10.9.4. Interim Analyses 
No formal interim analysis will be conducted for this study phase. As the study is open-label 
to the sponsor, the sponsor will conduct unblinded reviews of the data during the course of 
the study for the purpose of safety assessment, dose selection, and/or supporting clinical 
development. 
10.10.9.5. Sample Size Determination 
See Section 9.5. 
Endpoint 
Statistical Analysis Methods 
CC 
CCI 

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10.11. Appendix 11: 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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10.12. Appendix 12: Genetics 
Use/Analysis of DNA and/or RNA 
• Genetic variation may impact a participant’s response to study intervention as well as 
susceptibility to and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for PBMC isolation 
and may be used for DNA and/or RNA analysis. 
• The results of genetic analyses may be reported in a CSR or in a separate study summary, 
or may be used for internal decision-making without being included in a study report. 
• The sponsor will store the DNA and/or RNA samples in a secure storage space with 
adequate measures to protect confidentiality. 
• The samples will be retained as indicated: 
• Samples for specified genetic analysis (see Section 8.5) will be stored for up to 
15 years or other period as per local requirements. 
• Samples for genetic research will be labeled with a code. The key between the code and 
the participant’s personally identifying information (eg, name, address) will be held 
securely at the study site. 

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10.13. Appendix 13: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the table of contents (TOC). The protocol amendment summary of changes 
tables for past amendment(s) can be found below: 
Amendment 4 (08 February 2022) 
Overall Rationale for the Amendment: 
Addition of further groups to Substudy B to describe the safety and immunogenicity of the 
following vaccination schedules: 
• A dose of bIRV encoding 2 A strains at a dose level of CCI 
 administered 
concurrently in the opposite arm with bIRV encoding 2 B strains at a dose level of CCI  
. 
• A dose of qIRV encoding 2 A strains and 2 B strains at one of the following dose level 
combinations: 
CC 
 
 
• A dose of licensed QIV (as a control group). 
CCI 

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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Updated the number of 
participants. 
To reflect additional randomization groups added 
to Substudy B. 
1.2.2 Substudy B 
(Phase 1/2) Schema 
Updated the schema to include 
additional randomization 
groups. 
Additional groups added to the Substudy B 
design. 
2.1 Study Rationale 
Added a description of 
additional Substudy B 
randomization groups. 
Additional groups added to the Substudy B 
design. 
2.3.1 Risk Assessment 
Added qIRV and a reference to 
CCI  to the requirement for 
stepwise enrollment. 
Risk mitigation when dosing participants with 
CCI  modRNA. 
9.2 Analysis Sets 
Updated the definition of the 
safety population in line with 
the SAP. 
Correct an error. 
9.5 Sample Size 
Determination 
Updated text to reflect the new 
study sample size. 
Additional groups added to the Substudy B 
design. 
10.9.3 Objectives, 
Endpoints, and 
Estimands (Substudy A) 
Removed the 
microneutralization objective 
and estimands. Removed 
microneutralization as a 
replacement for HAI if clear 
HAI results are not obtainable. 
Applied corresponding updates 
to Substudy B and made 
updates in Sections 10.9.8.2, 
10.9.9.3.4, 10.10.3, 10.10.8.2, 
and 10.10.9.3.4. 
A validated microneutralization assay may not be 
available for the time of study reporting. 
Although such testing may be conducted in the 
future, these exploratory estimands have been 
removed from the protocol for clarity. Removal 
of microneutralization as a replacement for HAI 
is warranted based on experience to-date from 
HAI assays used in this study. 
10.10.2.1 Substudy 
Rationale 
Added a description of 
additional Substudy B 
randomization groups. 
Additional groups added to the Substudy B 
design. 
10.10.4.1 Overall Design Added a description of 
additional Substudy B 
randomization groups, and 
associated details, eg, 
nonconcurrent randomization. 
Additional groups added to the Substudy B 
design. 
10.10.6.1 Study 
Intervention(s) 
Administered 
Updated text to confirm that 
qIRV doses other than 7CCI 
will be generated on 
site by mixing of mIRVs. 
Additional qIRV groups added to the Substudy B 
design. 
10.10.6.1.1 
Administration 
Added Table 6 detailing the 
Substudy B study intervention 
schedule. 
Additional groups added to the Substudy B 
design – study intervention is to be administered 
in specific arms to ensure accurate assessment of 
local reactions. 
10.10.8.8.7 4-Week 
Follow-up Visit; and 
10.10.8.8.8 8-Week 
Follow-up Visit 
Clarified that blood sample 
collection may be halted at the 
discretion of the sponsor, 
consistent with 
Section 10.10.4.1. 
For consistency with existing wording in 
Section 10.10.4.1. 

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Amendment 3 (13 January 2022) 
Overall Rationale for the Amendment: 
Addition of Phase 1/2 Substudy B to describe the safety and immunogenicity of the 
following vaccination schedules: 
• 2 Doses of qIRV encoding 2 A strains and 2 B strains at a dose level of CCI 
, 
administered 21 days apart, 
• 2 Doses of licensed QIV, administered 21 days apart (as a control group), 
• A dose of licensed QIV followed by a dose of bIRV encoding 2 A strains at a dose level 
of either CCI 
, administered 21 days apart, and 
• A dose of licensed QIV administered concurrently in the opposite arm with bIRV 
encoding 2 A strains at a dose level of either CCI 
. 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.2.1 Substudy A 
(Phase 1) Schema 
Removed expanded enrollment 
from Substudy A. 
Based upon preliminary immunogenicity data, 
the sponsor decided not to expand enrollment into 
Substudy A. 
1.2.2 Substudy B 
(Phase 1/2) Schema 
Schema included to match the 
addition of Substudy B. 
Addition of Substudy B in protocol 
amendment 3. 
2.1 Study Rationale 
Rationale for Substudy B 
added. 
Addition of Substudy B in protocol 
amendment 3. 
2.3.1 Risk Assessment 
Added risks associated with 
vaccine groups in Substudy B. 
Addition of Substudy B in protocol 
amendment 3, which includes vaccine groups 
with a total dose of bIRV CCI , and groups 
with a previously undefined safety profile. 
4.1 Overall Design 
Detailed overall design moved 
to under Substudy A and B as 
appropriate. 
To document reorganization for clarity, and to 
reduce repetition. 
4.3 Justification for Dose Justification added for 2-dose 
vaccine groups and those 
containing a total dose of bIRV 
CCI . 
To support addition of Substudy B in protocol 
amendment 3, which includes vaccine groups 
with a total dose of bIRV CCI , and groups 
with a previously undefined safety profile. 
5.1 Inclusion Criteria, 
and 5.2. Exclusion 
Criteria 
Inclusion/exclusion criteria 
moved to under Substudy A and 
B as appropriate. 
To document reorganization for clarity. 
6.8 Concomitant 
Therapy 
Added details regarding prior 
influenza vaccine receipt for 
Substudy B, and other updates 
to accommodate Substudy B. 
Addition of Substudy B in protocol 
amendment 3. 
6.8.1 Prohibited During 
the Study 
Updated the criterion for receipt 
of mRNA-platform 
SARS-CoV-2 vaccine. 
To clarify that this criterion only applies to 
modRNA-containing study vaccinations, and that 
the window for Substudy B differs from that for 
Substudy A. 
8.2.1 Physical 
Examinations 
Made updates relative to 
Substudy B. 
Addition of Substudy B in protocol 
amendment 3. 

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Section # and Name 
Description of Change 
Brief Rationale 
8.2.2 Vital Signs 
Made updates relative to 
Substudy B. 
Addition of Substudy B in protocol 
amendment 3. 
8.2.3.2 Local Reactions 
Added a requirement for local 
reactions to be assessed from 
the right-arm injection site. 
Substudy B contains some groups in which 2 
vaccinations are administered at the same visit – 
stipulating the right arm allows for assessment of 
local reactions from the deltoid muscle in which 
bIRV is administered. 
8.2.4 Clinical Safety 
Laboratory Assessments 
Moved text from 
Section 10.9.8.1 to this section. 
Text is applicable to both Substudies A and B. 
8.2.6 ECGs and 
Echocardiograms 
Moved text from 
Section 10.9.8.5 to this section. 
Updated wording defining an 
ECG abnormality consistent 
with probable or possible 
myocarditis or pericarditis, for 
clarity. 
Text is applicable to both Substudies A and B. 
8.3.1 Time Period and 
Frequency for Collecting 
AE and SAE Information 
Added the time period for 
AE/SAE collection in 
Substudy B. 
Addition of Substudy B in protocol 
amendment 3. 
9.2 Analysis Sets 
Updated the analysis population 
definitions to accommodate the 
addition of Substudy B. 
Addition of Substudy B in protocol 
amendment 3. 
9.5 Sample Size 
Determination 
Updated the sample size 
calculation to accommodate the 
addition of Substudy B. 
Addition of Substudy B in protocol 
amendment 3. 
10.1.5.1 Data Monitoring 
Committee 
Added IRC responsibilities 
relating to Substudy B. 
Addition of Substudy B in protocol 
amendment 3. 
10.2 Appendix 2: 
Clinical Laboratory 
Tests 
Added troponin I measurements 
associated with Substudy B. 
Addition of Substudy B in protocol 
amendment 3. 
10.6 Appendix 6: Liver 
Safety: Suggested 
Actions and Follow-Up 
Assessments 
Template text inserted 
regarding not assessing LFTs in 
Substudy B. 
Addition of Substudy B in protocol 
amendment 3. 
10.9 Appendix 9: 
Substudy A (Phase 1) 
Updated terminology 
throughout to change Phase 1 to 
Substudy A. 
Addition of Substudy B in protocol 
amendment 3. 
10.9.3 OBJECTIVES, 
ENDPOINTS, AND 
ESTIMANDS 
(SUBSTUDY A) 
and 10.9.9.3.4 
Tertiary/Exploratory 
Endpoint(s) 
CCI 
Omitted in error from protocol amendment 2. 
10.9.4.1 Overall Design 
Removed expanded enrollment 
from Substudy A. 
Based upon preliminary immunogenicity data, 
the sponsor decided not to expand enrollment into 
Substudy A. 
10.10 Appendix 10: 
Substudy B (Phase 1/2) 
Added Substudy B. 
Based upon preliminary immunogenicity data, 
exploration of alternative vaccination schedules 
including IRV as warranted. 

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Amendment 2 (04 December 2021) 
Overall Rationale for the Amendment: 
Addition of an mIRV dose at approximately 8 weeks for participants having received QIV at 
Visit 1 and blood sample collection 28 days after 8-week mIRV/QIV dosing (Vaccination 2) 
to describe: 
• The immune response elicited by licensed QIV following prior receipt of a modRNA 
vaccine, to assess potential priming of the immune response, and 
• The immune response elicited by mIRV A or B following prior receipt of licensed QIV, 
to assess if the immune response following QIV may be enhanced. 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.2 Schema 
Addition of Vaccination 2 to 
reflect design changes per 
protocol amendment 2. 
To summarize design changes per protocol 
amendment 2. 
2.1 Study Rationale 
Provided rationale for addition 
of Vaccination 2 and blood 
draw following QIV dosing at 
Visit 5. 
To provide a scientific rationale for protocol 
amendment 2. 
2.2.3 Nucleoside- 
Modified mRNA 
Vaccines 
Update to the number of doses 
of BNT162b2 administered 
worldwide and postmarketing 
safety data. 
Updated data available at the time of the protocol 
amendment. 
2.3.1 Risk Assessment, 
and 10.9.2.3 
Benefit/Risk Assessment 
Addition of risk relating to 
vaccination of participants with 
mIRV within approximately 8 
weeks after QIV. 
Unknown safety profile of the vaccine 
combination. 
4.1 and 10.9.4.1 Overall 
Design 
Addition of an mIRV dose at 8 
weeks for participants having 
received QIV at Visit 1 and 
blood sample collection 28 days 
after 8-week qIRV/QIV dosing 
(Vaccination 2). 
To describe: (1) the immune response elicited by 
licensed QIV following prior receipt of a 
modRNA vaccine, to assess potential priming of 
the immune response, and (2) the immune 
response elicited by mIRV A or B following prior 
receipt of licensed QIV, to assess if the immune 
response following QIV may be enhanced. 
8.2.1 Physical 
Examinations 
Clarification that physical 
examinations may only be 
performed at Visit 1 if clinically 
indicated. 
Physical examination is conducted at screening, 
hence, not mandated at Visit 1. 
8.2.2 Vital Signs 
Detailing measurement of body 
temperature prior to 
Vaccination 2. 
To confirm that no febrile illness is present. 
8.2.3 Electronic Diary 
Detailing collection of local 
reactions and systemic events 
following Vaccination 2 via an 
e-diary. 
Required for collection of safety data to support 
the primary safety objective. 
8.3.1 Time Period and 
Frequency for Collecting 
AE and SAE Information 
Update to the AE collection 
period to incorporate 
Vaccination 2. 
Required for collection of safety data to support 
the primary safety objective. 

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Section # and Name 
Description of Change 
Brief Rationale 
9.2 Analysis Sets 
Addition of analysis sets 
following addition of 
Vaccination 2. 
Required to support analyses related to 
Vaccination 2. 
10.1.5.1 Data Monitoring 
Committee 
Clarification added that the IRC 
will be responsible for 
reviewing safety data only 
following Vaccination 1. 
To ensure clarity regarding the IRC’s role 
following addition of Vaccination 2. 
10.5 Appendix 5: ECG 
Findings of Potential 
Clinical Concern 
Addition of mandatory protocol 
template text previously 
incorporated via administrative 
letter. 
Mandatory protocol template text. 
10.6 Appendix 6: Liver 
Safety: Suggested 
Actions and Follow-Up 
Assessments 
Removal of the second 
paragraph stating that LFTs are 
not collected in this study. 
Paragraph retained in error during development 
of protocol amendment 1, and previously 
removed via administrative change letter. 
10.9.1 SoA – Phase 1, 
and 10.9.8.8 Phase 1 
Procedures 
Addition of Visits 5A and 5B to 
incorporate Vaccination 2 and 
the 4-week post–Vaccination 2 
follow-up visit. Additional 
procedures added to Visit 5 per 
the revised study design. 
To accommodate the revised study design and 
additional study objective relating to protocol 
amendment 2. 
10.9.3 OBJECTIVES, 
ENDPOINTS, AND 
ESTIMANDS, 
10.9.9.3.2 Primary 
Endpoint(s)/Estimand(s) 
Analysis, 10.9.9.3.3 
Secondary 
Endpoint(s)/Estimand(s) 
Analysis, and 10.9.9.3.4 
Tertiary/Exploratory 
Endpoint(s) 
Addition of a new exploratory 
objective relating to 
Vaccination 2 per the rationale 
for protocol amendment 2. 
Existing estimands revised to 
accommodate the revised study 
design. 
Analysis of data collected through additional 
procedures implemented as part of protocol 
amendment 2. 
10.9.6.1.1 
Administration 
Addition of administration 
details for Vaccination 2. 
Required following addition of Vaccination 2. 
10.9.6.2.1 Allocation to 
Study Intervention 
Detail added regarding 
allocation of mIRV at Visits 5 
and 5A. 
To confirm that study intervention allocation will 
be conducted in an open-label manner without the 
use of an IRT. 
10.9.6.2.2 Blinding of 
Site Personnel 
Clarifications added regarding 
unblinding of participants at 
Visit 5, and blinding of mIRV. 
Updates required with addition of Vaccination 2. 
10.9.8 STUDY 
ASSESSMENTS AND 
PROCEDURES 
Update to the total volume of 
blood drawn given the addition 
of blood draws at new visits – 
Visits 5A and 5B. 
To reflect the addition of further blood draws in 
the revised study design. 
10.9.8.5 ECGs 
Clarification added stipulating 
that ECGs will be read by a 
central vendor. 
Update previously incorporated via 
administrative letter. 
10.9.8.6 Stopping Rules 
Updated to confirm these rules 
only apply following 
Vaccination 1. 
Not applicable following Vaccination 2. 

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Amendment 1 (14 August 2021) 
Overall Rationale for the Amendment: 
Provide descriptive assessment of qIRV immunogenicity compared to licensed QIV at the 
earliest time point possible. 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Protocol Rationale and 
throughout 
Age of study population changed to 
65 to 85 years of age 
Age range focuses on target vaccine population. 
1.1 Protocol Rationale and 
throughout 
Removal of Phases 2 and 3 
Following regulatory feedback. 
1.1 Protocol Objectives, 
Endpoints, and Estimands 
and throughout 
Objectives, estimands, and 
endpoints updated 
Edits reflect the use of a licensed QIV as active 
comparator, the updated age of the study population, 
and the removal of Phases 2 and 3. 
1.1 Number of Participants 
Total number of participants 
reduced. Number of participants 
increased in Phase 1 
Number of participants reflects the updated study 
design. 
1.1 Data Monitoring 
Committee or Other 
Oversight Committee, and 
throughout 
Reference to DMC was removed 
Since no part of the study is blinded to the sponsor, and 
objectives are descriptive, an IRC can provide 
appropriate oversight without the need for a DMC. 
1.1 Statistical Methods 
Text updated to detail the analysis 
that will be performed 
Text updated to reflect the updated study design. 
1.2 Schema 
Schema updated to reflect design 
changes. 
Updates required to reflect the updated study design. 
2.3.1 Risk Assessment 
Addition of risk related to 
anaphylaxis, myocarditis, and 
pericarditis 
Data as reported after authorization in recipients of the 
COVID-19 vaccine BNT162b2, which is also based on 
modRNA. 
Section 4.1. Overall Design Text added to clarify which strains 
might be used in the event that the 
study continues beyond 2021-2022 
in the northern hemisphere. 
Clarification allows additional operational flexibility. 
Section 4.2.1 Diversity of 
Study Population 
Text updated 
Text updated to reflect latest sponsor standard 
wording. 
5.1 Inclusion Criteria and 
5.2 Exclusion Criteria 
Criteria removed for Phase 3 
Criteria updated for Phase 1 
Included exclusion criterion for 
Phase 1 
Criteria updated to reflect change in age of study 
population. 
Following regulatory feedback. 
6.8.1 Prohibited During the 
Study 
Addition of prohibited 
modRNA-platform SARS-CoV-2 
vaccine within 60 days before and 
60 days after vaccination 
Following regulatory feedback. 
8.2 Safety Assessments 
Addition of clinical safety 
laboratories and stopping rules for 
ECGs, echocardiogram, and a 
6-month visit for Phase 1 
Following regulatory feedback. 
8.3.8 Adverse Events of 
Special Interest 
AESIs added; confirmed diagnosis 
of myocarditis or pericarditis 
In light of cases reported after authorization in 
recipients of the COVID-19 vaccine BNT162b2, which 
is also based on modRNA. 
9 STATISTICAL 
CONSIDERATIONS 
Edits made throughout this section 
Edits made to reflect updated study population and 
study design. 
10.9 Appendix 9: Phase 1 
Text updated throughout section as 
appropriate to remove Phases 2, 
and reflect revised design of 
Phase 1 
Edits made to reflect updated study population, study 
design, study objectives, and monitoring for additional 
AESIs. 

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Section # and Name 
Description of Change 
Brief Rationale 
10.9.8.8.11 Additional 
Procedures for Monitoring 
of Potential Myocarditis or 
Pericarditis 
Text added to reflect additional 
monitoring that will be performed 
In light of cases reported after authorization in 
recipients of the COVID-19 vaccine BNT162b2, which 
is also based on modRNA. 
Section 10.9.8.1 Clinical 
Safety Laboratory 
Assessments 
Addition of clinical safety 
laboratories and stopping rules, 
addition of ECGs, echocardiogram 
for Phase 1 Updates made to visits 
Following regulatory feedback. 
Section 10.9.8.8.1 
Screening (0 to 28 Days 
Before Visit 1) 
Addition of screening visit for 
Phase 1 participants 
Following regulatory feedback. 
Section 10.9.8.8.3 Visit 2 – 
Day 3 Follow-up Visit 
(After Vaccination) – 2 to 4 
Days After Visit 1 
Additional visit at Day 3 for 
Phase 1 participants for safety 
monitoring 
Following regulatory feedback. 
Section 10.10 Appendix 9 
Phase 3 
Section removed. Phase 3 no 
longer taking place at this time 
Following regulatory feedback. 
Section 10.2 Appendix 2: 
Clinical Laboratory Tests 
Addition of clinical laboratory tests 
to be done for Phase 1 participants 
Following regulatory feedback. 
Throughout, as needed 
Minor editorial edits 
Minor edits made to correct any typographical or 
administrative errors. 

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10.14. Appendix 14: Abbreviations 
The following is a list of abbreviations that may be used in the protocol. 
 
Abbreviation 
Term 
Abs 
absolute 
ADE 
adverse device effect 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AV 
atrioventricular 
β-hCG 
beta-human chorionic gonadotropin 
BCR 
breakpoint cluster region 
bIRV 
bivalent influenza modRNA vaccine 
BLQ 
below the limit of quantitation 
BNT162b2 
Pfizer’s COVID-19 vaccine 
BUN 
blood urea nitrogen 
CBER 
Center for Biologics Evaluation and Research 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CRO 
contract research organization 
CSR 
clinical study report 
DILI 
drug-induced liver injury 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
EC 
ethics committee 
ECC 
emergency contact card 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDB 
exposure during breastfeeding 
e-diary 
electronic diary 
EDP 
exposure during pregnancy 
EMA 
European Medicines Agency 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 

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Abbreviation 
Term 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GMFR 
geometric mean fold rise 
GMR 
geometric mean ratio 
GMT 
geometric mean titer 
HA 
hemagglutinin 
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 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRT 
hormone replacement therapy 
IB 
investigator’s brochure 
ICD 
informed consent document 
ICH 
International Council for Harmonisation 
ID 
identification 
IMP 
investigational medicinal product 
IND 
investigational new drug 
INR 
international normalized ratio 
IP manual 
investigational product manual 
IPAL 
Investigational Product Accountability Log 
IRB 
institutional review board 
IRC 
internal review committee 
IRT 
interactive response technology 
IRV 
influenza modRNA vaccine 
IV 
intravenous(ly) 
IWR 
interactive Web-based response 
LAIV 
live attenuated influenza vaccine 
LFT 
liver function test 
LLOQ 
lower limit of quantitation 
LNP 
lipid nanoparticle 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
MCHC 
mean corpuscular hemoglobin concentration 
MedDRA 
Medical Dictionary for Regulatory Activities 
mIRV 
monovalent influenza modRNA vaccine 
mITT 
modified intent-to-treat 
modRNA 
nucleoside-modified messenger ribonucleic acid 

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Abbreviation 
Term 
MN 
microneutralization 
mRNA 
messenger ribonucleic acid 
NA 
neuraminidase 
N/A 
not applicable 
NIMP 
noninvestigational medicinal product 
PBMC 
peripheral blood mononuclear cell 
PFS 
prefilled syringe(s) 
PI 
principal investigator 
PT 
prothrombin time 
PVC 
premature ventricular contraction 
qIRV 
quadrivalent influenza modRNA vaccine 
QIV 
quadrivalent influenza vaccine 
QTcF 
QT interval corrected by the Fridericia formula 
QTL 
quality tolerance limit 
RBC 
red blood cell 
RCDC 
reverse cumulative distribution curve 
RNA 
ribonucleic acid 
RT-PCR 
reverse transcription–polymerase chain reaction 
SAE 
serious adverse event 
SADE 
serious adverse device effect 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SoA 
schedule of activities 
SOP 
standard operating procedure 
SRSD 
single reference safety document 
SUSAR 
suspected unexpected serious adverse reaction 
TBili 
total bilirubin 
TCR 
T-cell receptor 
TOC 
table of contents 
ULN 
upper limit of normal 
US 
United States 
USADE 
unanticipated serious adverse device effect 
WBC 
white blood cell 
WOCBP 
woman/women of childbearing potential 

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11. REFERENCES 
 
1 
Cunha BA. Influenza: historical aspects of epidemics and pandemics. Infect Dis Clin 
North Am 2004;18(1):141-55. 
2 
Monto AS, Gravenstein S, Elliott M, et al. Clinical signs and symptoms predicting 
influenza infection. Arch Intern Med 2000;160(21):3243-7. 
3 
Cowling BJ, Chan KH, Fang VJ, et al. Comparative epidemiology of pandemic and 
seasonal influenza A in households. N Engl J Med 2010;362(23):2175-84. 
4  Centers for Disease Control and Prevention. Epidemiology and prevention of 
vaccine-preventable diseases. Hamborsky J, Kroger A, Wolfe S, eds. 13th ed. 
Washington, DC: Public Health Foundation; 2015:187-208. 
5 
Iuliano AD, Roguski KM, Chang HH, et al. Estimates of global seasonal influenza- 
associated respiratory mortality: a modelling study. Lancet 2018;391(10127):1285-300. 
6 
Cox NJ, Subbarao K. Influenza. Lancet 1999;354(9186):1277-82. 
7 
Francis T Jr, Salk JE, Brace WM. The protective effect of vaccination against epidemic 
influenza B. JAMA 1946;131:275-8. 
8 
Grohskopf LA, Sokolow LZ, Olsen SJ, et al. Prevention and control of influenza with 
vaccines: recommendations of the Advisory Committee on Immunization Practices, 
United States, 2015-16 influenza season. MMWR Morb Mortal Wkly Rep 
2015;64(30):818-25. 
9 
Frey S, Vesikari T, Szymczakiewicz-Multanowska A, et al. Clinical efficacy of cell 
culture-derived and egg-derived inactivated subunit influenza vaccines in healthy adults. 
Clin Infect Dis 2010;51(9):997-1004. 
10 
Belshe RB. The need for quadrivalent vaccine against seasonal influenza. Vaccine 
2010;28(Suppl 4):D45-D53. 
11  Bresee JS, Fry AM, Sambhara S, et al. Inactivated influenza vaccines. In: Plotkin S, 
Orenstein WA, Offit PA, eds. Plotkin's vaccines. 7th ed. Philadelphia, PA: Elsevier; 
2018:456-88.e21. 
12 
Co MDT, Orphin L, Cruz J, et al. In vitro evidence that commercial influenza vaccines 
are not similar in their ability to activate human T cell responses. Vaccine 
2009;27(2):319-27. 

PF-07252220 [Influenza modRNA Vaccine] 
Protocol C4781001 
Final Protocol Amendment 5, 03 July 2022 
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Page 184 
 
 
 
13 
European Medicines Agency. Influenza vaccines - non-clinical and clinical module. 
Available from: https://www.ema.europa.eu/en/influenza-vaccines-non-clinical-clinical- 
module. Published: 21 Jul 2016. Accessed: 05 May 2021. 
14 
US Food and Drug Administration. Guidance for industry: clinical data needed to 
support the licensure of seasonal inactivated influenza vaccines. Available from: 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical- 
data-needed-support-licensure-seasonal-inactivated-influenza-vaccines. Published: May 
2007. Accessed 21 May 2021. 
15 
Pardi N, Hogan MJ, Porter FW, et al. mRNA vaccines - a new era in vaccinology. Nat 
Rev Drug Discov 2018;17(4):261-79. 
16 
Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA 
Covid-19 vaccine. N Engl J Med 2020;383(27):2603-15. 
17 
Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA vaccine against 
SARS-CoV-2 - preliminary report. N Engl J Med 2020;383(20):1920-31. 
18 
Mulligan MJ, Lyke KE, Kitchin N, et al. Phase I/II study of COVID-19 RNA vaccine 
BNT162b1 in adults. Nature 2020;586(7830): 589-93. 
19 
Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 
SARS-CoV-2 vaccine. N Engl J Med 2021;384(5):403-416. 
20 
Investigator’s Brochure, BNT162 (PF-07302048). 27 Oct 2021. 
21 
Investigator’s Brochure, influenza modRNA vaccine (PF-07252220). 11 Aug 2021. 
22 
Centers for Disease Control and Prevention. Safety of COVID-19 vaccines. 
Available from: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/safety-of- 
vaccines.html. Updated: 29 Dec 2021. Accessed: 10 Jan 2022. 
23 
Sahin U, Muik A, Vogler I, et al. BNT162b2 induces SARS-CoV-2-neutralising 
antibodies and T cells in humans. medRxiv. Available from: 
https://www.medrxiv.org/content/10.1101/2020.12.09.20245175v1. 
Accessed: 04 May 2021. 
24  US Food and Drug Administration. Guidance for industry: toxicity grading scale for 
healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials. 
Rockville, MD: Center for Biologics Evaluation and Research; September 2007. 
25 
Shimabukuru T. Advisory Committee on Immunization Practices (ACIP). COVID-19 
vaccine safety update [slide set]. 27 Jan 2021; Slide 30. 

PF-07252220 [Influenza modRNA Vaccine] 
Protocol C4781001 
Final Protocol Amendment 5, 03 July 2022 
PFIZER CONFIDENTIAL 
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26 
Centers for Disease Control and Prevention. Seasonal influenza vaccine safety: a 
summary for clinicians. Available from: 
https://www.cdc.gov/flu/professionals/vaccination/vaccine_safety.htm.  
Updated: 10 Dec 2021. Accessed: 10 Jan 2022. 

 
 
Document Approval Record 
 
 
C4781001 Clinical Protocol Amendment 5 Clean Copy, 03-Jul-2022 
 
A PHASE 1/2 RANDOMIZED STUDY TO EVALUATE THE SAFETY, 
TOLERABILITY, AND IMMUNOGENICITY OF A MODIFIED RNA VA 
CCINE AGAINST INFLUENZA IN HEALTHY INDIVIDUALS 
 
 
PPD 
 
PPD 
  
04-Jul-2022 00 09 57 
Final Approval 
 
04-Jul-2022 13 59 43 
Business Line Approver 
Document Name: 
Document Title: 
Signed By: 
Date(GMT) 
Signing Capacity