A PHASE 1/2/3, PLACEBO-CONTROLLED, RANDOMIZED ... - …

1 PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines) Protocol C4591001 Page 1 A PHASE 1/2/3, PLACEBO-CONTROLLED, RANDOMIZED , OBSERVER-BLIND, DOSE-FINDING STUDY TO EVALUATE THE SAFETY, TOLERABILITY, IMMUNOGENICITY, AND EFFICACY OF SARS-COV-2 RNA VACCINE CANDIDATES AGAINST COVID-19 IN HEALTHY INDIVIDUALS Study Sponsor: BioNTech Study Conducted By: Pfizer Study Intervention Number: PF-07302048 Study Intervention Name: RNA-Based COVID-19 Vaccines US IND Number: 19736 EudraCT Number: 2020-002641-42 Protocol Number: C4591001 PHASE : 1/2/3 Short Title: A PHASE 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, and Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Individuals PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines) Protocol C4591001 Page 2 TABLE OF CONTENTS LIST OF TABLES.

2 8 1. PROTOCOL SUMMARY ..9 Synopsis ..9 Schema ..17 Schedule of Activities ..18 PHASE 1 ..18 PHASE 2/3 ..23 2. INTRODUCTION ..26 Study Rationale ..26 Background ..26 Clinical Overview ..27 Benefit/Risk Assessment ..27 Risk Assessment ..29 Benefit Assessment ..31 Overall Benefit/Risk Conclusion ..31 3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ..31 For PHASE 1 ..31 For PHASE 2/3 ..33 4. STUDY Overall Design ..36 PHASE 1 ..36 PHASE 2/3 ..37 Scientific Rationale for Study Design ..39 Justification for Dose ..39 End of Study Definition ..40 5. STUDY POPULATION ..40 Inclusion Criteria.

3 40 Exclusion Criteria ..41 PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines) Protocol C4591001 Page 3 Lifestyle Considerations ..44 Contraception ..44 Screen Failures ..44 Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention Administration ..44 6. STUDY INTERVENTION ..45 Study Intervention(s) Administered ..46 Manufacturing Process ..46 Administration ..46 Preparation/Handling/Storage/Accountabil ity ..47 Preparation and Dispensing ..48 Measures to Minimize Bias: Randomization and Allocation to Study Intervention ..48 Blinding of Site Personnel.

4 48 Blinding of the Sponsor ..49 Breaking the Blind ..50 Study Intervention Compliance ..50 Concomitant Therapy ..50 Prohibited During the Study ..50 Permitted During the Study ..51 Dose Modification ..51 Intervention After the End of the Study ..52 7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL ..52 Discontinuation of Study Intervention ..52 Participant Discontinuation/Withdrawal From the Study ..53 Withdrawal of Consent ..53 Lost to Follow-up ..54 8. STUDY ASSESSMENTS AND PROCEDURES ..54 Efficacy and/or Immunogenicity Assessments ..55 Biological Samples.

5 58 Safety Assessments ..58 Clinical Safety Laboratory Assessments ( PHASE 1 Participants Only) ..59 PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines) Protocol C4591001 Page 4 Electronic Diary ..59 Grading Scales ..60 Local Reactions ..60 Systemic Events ..61 Fever ..62 Antipyretic Medication ..62 PHASE 1 Stopping Rules ..62 Surveillance of Events That Could Represent Enhanced COVID-19 and PHASE 2/3 Stopping Rule ..64 Randomization and Vaccination After a Stopping Rule Is Met ..64 Pregnancy Testing ..65 Adverse Events and Serious Adverse Events ..65 Time Period and Frequency for Collecting AE and SAE Information.

6 65 Reporting SAEs to Pfizer Safety ..66 Recording Nonserious AEs and SAEs on the CRF ..66 Method of Detecting AEs and SAEs ..66 Follow-up of AEs and SAEs ..66 Regulatory Reporting Requirements for SAEs ..67 Exposure During Pregnancy or Breastfeeding, and Occupational Exposure ..67 Exposure During Pregnancy ..67 Exposure During Breastfeeding ..69 Occupational Exposure ..69 Cardiovascular and Death Events ..70 Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs or Adverse Events of Special Interest ..70 Lack of Efficacy ..70 Medical Device Deficiencies.

7 70 Medication Errors ..70 Treatment of Overdose ..71 Pharmacokinetics ..72 Pharmacodynamics ..72 PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines) Protocol C4591001 Page 5 Genetics ..72 Biomarkers ..72 Immunogenicity Assessments ..72 Health Economics ..72 Study Procedures ..72 PHASE 1 ..72 Screening: (0 to 28 Days Before Visit 1) ..72 Visit 1 Vaccination 1: (Day 1) ..74 Visit 2 Next-Day Follow-up Visit (Vaccination 1): (1 to 3 Days After Visit 1) ..76 Visit 3 1-Week Follow-up Visit (Vaccination 1): (6 to 8 Days After Visit 1) ..78 Visit 4 Vaccination 2: (19 to 23 Days After Visit 1).

8 79 Visit 5 1-Week Follow-up Visit (Vaccination 2): (6 to 8 Days After Visit 4) ..81 Visit 6 2-Week Follow-up Visit (Vaccination 2): (12 to 16 Days After Visit 4) ..82 Visit 7 1-Month Follow-up Visit: (28 to 35 Days After Visit 4) ..83 Visit 8 6-Month Follow-up Visit: (175 to 189 Days After Visit 4) ..84 Visit 9 12-Month Follow-up Visit: (350 to 378 Days After Visit 4) ..84 Visit 10 24-Month Follow-up Visit: (714 to 742 Days After Visit 4) ..85 PHASE 2/3 ..85 Visit 1 Vaccination 1: (Day 1) ..85 Visit 2 Vaccination 2: (19 to 23 Days After Visit 1) ..88 Visit 3 1-Month Follow-up Visit (After Vaccination 2): (28 to 35 Days After Visit 2).

9 90 Visit 4 6-Month Follow-up Visit: (175 to 189 Days After Visit 2) ..91 Visit 5 12-Month Follow-up Visit: (350 to 378 Days After Visit 2) ..91 Visit 6 24-Month Follow-up Visit: (714 to 742 Days After Visit 2) ..92 PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines) Protocol C4591001 Page 6 Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction ..92 COVID-19 Surveillance (All Participants) ..93 Potential COVID-19 Illness Visit: (Optimally Within 3 Days After Potential COVID-19 Illness Onset) ..95 Potential COVID-19 Convalescent Visit: (28 to 35 Days After Potential COVID-19 Illness Visit).

10 96 Communication and Use of Technology ..96 SARS-CoV-2 NAAT Results From Visits 1 and 2 and Potential COVID-19 Illness Visits ..97 9. STATISTICAL CONSIDERATIONS ..98 Estimands and Statistical Hypotheses ..98 Estimands ..98 Statistical Hypotheses ..99 Statistical Hypothesis Evaluation for Efficacy ..99 Statistical Hypothesis Evaluation for Immunogenicity ..99 Sample Size Determination ..99 Analysis Sets ..101 Statistical Analyses ..102 Immunogenicity Analyses ..102 Efficacy Analyses ..107 Safety Analyses ..109 Other Analyses ..110 Interim Analyses ..111 Analysis Data Monitoring Committee or Other Independent Oversight Committee.