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BNT162b2
2.5 Clinical Overview
CONFIDENTIAL
Page 12.5 CLINICAL OVERVIE W
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2.5 Clinical Overview
CONFIDENTIAL
Page 2TABLE OF CONTENTS
LIST OF IN -TEXT TABL ES................................ ................................ ................................ ....4
LIST OF IN -TEXT FIGU RES................................ ................................ ................................ .11
ABBREVIAT IONS................................ ................................ ................................ ................. 13
2.5. CLINI CAL OVERVI EW................................ ................................ ................................ ..15
2.5.1. Product Development Rationale ................................ ................................ ...........16
2.5.1.1. Therapeutic Context ................................ ................................ ................. 16
2.5.1.1.1. Disease or Condition ................................ .............................. 16
2.5.1.1.2. Clinical Features and Epidemiology of COVID -19............... 16
2.5.1.2. Vaccine Clinical Development Program ................................ ................. 17
2.5.1.2.1. Rationale for Development ................................ .................... 17
2.5.1.2.2. Vaccine Product I nformation ................................ ................. 19
2.5.1.2.3. Vaccine Development Program ................................ ..............20
2.5.1.2.4. Proposed Indication ................................ ................................ 25
2.5.1.2.5. Rationale for Candidate and Dose Selection .......................... 25
2.5.1.3. Regulatory Status................................ ................................ ..................... 25
2.5.1.4. Ethical Considerations ................................ ................................ .............26
2.5.2. Overview of Biopharmaceutics ................................ ................................ ............26
2.5.2.1. Formulation Development ................................ ................................ .......26
2.5.2.2. Biopharmaceutical Studies................................ ................................ ......27
2.5.2.3.Bioanalytical and Analy tical Methods Used in Human Studies ..............27
2.5.3. Overview of Clinical Pharmacology ................................ ................................ ....27
2.5.4. Overview of Efficacy (Including Immunogenicity )................................ .............27
2.5.4.1. Efficacy Endpoints and Anal ysis Methods ................................ ..............28
2.5.4.1.1. Efficacy Endpoints in Study C4591001 ................................ .28
2.5.4.1.2. Efficacy Analysis Methods in Study C4591001 .................... 30
2.5.4.2. Immunogenicit y Endpoints and Analy sis Methods ................................ .32
2.5.4.2.1. I mmunogenicity Endpoints in Study BNT162 -01................. 32
2.5.4.2.2. I mmunogenicity Endpoints in Study C4591001 .................... 33
2.5.4.2.3. I mmunogenicity Analysis Methods ................................ .......33
2.5.4.3. Efficacy Results................................ ................................ ....................... 35
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Page 32.5.4.3.1. Interim Anal ysis of Efficacy in Study C4591001 .................. 35
2.5.4.3.2. Final Anal ysis of Efficacy in Study C4591001 ...................... 44
2.5.4.3.3. Updated Anal ysis of Efficacy in Study C4591001 ................ 78
2.5.4.4. Immunogenicit y Results................................ ................................ ........114
2.5.4.4.1. Phase 1 I mmunogenicity in Study BNT162 -01................... 114
2.5.4.4.2. Phase 1 I mmunogenicity in Study C4591001 ...................... 122
2.5.4.4.3. Phase 2 I mmunogenicity in Study C4591001 ...................... 126
2.5.4.4.4. I mmunogenicity Conclusions ................................ ...............139
2.5.5. Overview of Safety................................ ................................ ............................. 140
2.5.5.1. Safet y Endpoints and Anal ysis Methods ................................ ...............140
2.5.5.1.1. Safet y Endpoints in Study BNT162-01................................ 140
2.5.5.1.2. Safet y Endpoints in Study C4591001 ................................ ..141
2.5.5.1.3. Safet y Analysis Methods ................................ ...................... 144
2.5.5.2. Safet y Results –Phase 1 Safet y in Study BNT162 -01.......................... 145
2.5.5.2.1. Safet y Populations – Phase 1................................ ...............146
2.5.5.2.2. Reactogenicit y –Phase 1................................ ...................... 147
2.5.5.2.3. Adverse Events –Phase 1................................ .................... 147
2.5.5.3. Safet y Results –Phase 1 Safet y in Study C4591001 ............................. 148
2.5.5.3.1. Safet y Populations – Phase 1................................ ...............148
2.5.5.3.2. Reactogenicit y –Phase 1................................ ...................... 149
2.5.5.3.3. Adverse Events –Phase 1................................ .................... 150
2.5.5.4. Safet y Results –Phase 2 Safet y in Study C4591001 ............................. 151
2.5.5.4.1. Safet y Populations – Phase 2................................ ...............151
2.5.5.4.2. Reactogenicit y –Phase 2................................ ...................... 152
2.5.5.4.3. Adverse Events –Phase 2................................ .................... 153
2.5.5.5. Safet y Results -Phase 2/3 Safet y in Study C4591001 .......................... 154
2.5.5.5.1. Safet y Populations – Phase 2/3 ................................ ............154
2.5.5.5.2. Reactogenicit y –Phase 2/3 ................................ .................. 168
2.5.5.5.3. Adverse Events –Phase 2/3 ................................ ................. 177
2.5.5.5.4. Deaths –Phase 2/3 ................................ ............................... 272
2.5.5.5.5. Serious Adverse Events –Phase 2/3 ................................ ....274
2.5.5.5.6. Adverse Events L eading to Withdrawal – Phase 2/3 ...........295
2.5.5.5.7. Other Significant Adverse Events –Phase 2/3 ..................... 303
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Page 42.5.5.6. Clinical L aboratory Evaluations ................................ ............................ 319
2.5.5.6.1. Clinical L aboratory Evaluations in Study BNT162 -01........319
2.5.5.6.2. Clinical L aboratory Evaluations in Study C4591001 ..........320
2.5.5.7. Other Safet y Assessments ................................ ................................ ......320
2.5.5.7.1. Severe COVID -19 Illness................................ ..................... 320
2.5.5.7.2. Pregnancies ................................ ................................ ...........320
2.5.5.7.3. Adverse Drug Reactions................................ ....................... 321
2.5.5.8. Safet y in Special Groups and Situations ................................ ................ 322
2.5.5.8.1. Geriatric Use ................................ ................................ ........322
2.5.5.8.2. Pediatric Use ................................ ................................ ........322
2.5.5.8.3. Use During Pregnancy and Lactation................................ ...322
2.5.5.8.4. Use in Immunocompromised Individuals ............................ 323
2.5.5.8.5. Other Safet y Considerations ................................ ................. 323
2.5.5.9. Post -Authorization Safety Summary ................................ ..................... 323
2.5.5.10. Safet y Conclusions ................................ ................................ ..............324
2.5.6. Benefits and Risks Conclusions ................................ ................................ .........325
2.5.6.1. Benefits ................................ ................................ ................................ ..325
2.5.6.2. Risks ................................ ................................ ................................ ......327
2.5.6.3. Benefit -Risk Conclusions ................................ ................................ ......329
2.5.7. References ................................ ................................ ................................ ..........331
LIST OF IN -TEXT TABL ES
Table1. Efficacy Populations –Interim Analy sis 1................................ ...............36
Table2. D emographic Characteristics –Subjects Without Evidence of
Infection Prior to 7 Day s After Dose 2 –Evaluable Efficacy
Population (7 Day s) –Interim Anal ysis 1................................ ................ 37
Table3. Vaccine Efficacy –First COVID -19 Occurrence From 7 Day s After
Dose 2 –Subjects Without Evidence of Infection Prior to 7 Day s
After Dose 2 – Evaluable Efficacy Population (7 Day s) –Interim
Analysis 1................................ ................................ ................................ .40
Table4. Vaccine Efficacy –First COVID -19 Occurrence From 7 Day s After
Dose 2, b y Subgroup – Subjects Without Evidence of Infection
Prior to 7 Day s After Dose 2 – Evaluable Efficacy Population (7
Days) –Interim Anal ysis 1................................ ................................ .......41
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Page 5Table5. Severe COVID -19 Occurrence After Dose 1 –Dose 1 All -Available
Efficacy Population – Interim Anal ysis 1................................ ................. 43
Table6. Efficacy Populations ................................ ................................ ................. 45
Table7. Demographic Characteristics –Subjects Without Evidence of
Infection Prior to 7 Day s After Dose 2 –Evaluable Efficacy (7
Days) Population ................................ ................................ ...................... 47
Table8. Vaccine Efficacy –First COVID -19 Occurrence From 7 Day s After
Dose 2 –Subjects Without Evidence of Infection Prior to 7 Day s
After Dose 2 –Evaluable Efficacy (7 Days) Population .......................... 49
Table9. Vaccine Efficacy –First COVID -19 Occurrence From 7 Day s After
Dose 2 –Subjects Without Evidence of Infection Prior to 7 Day s
After Dose 2 – Dose 2 All -Available Efficacy Population ....................... 50
Table10. Vaccine Efficacy –First COVID -19 Occurrence From 7 Day s After
Dose 2 – Subjects With or Without Evidence of Infection Prior to 7
Days After Dose 2 – Evaluable Efficacy (7 Days) Population ................. 51
Table11. Vaccine Efficacy –First COVID -19 Occurrence From 7 Day s After
Dose 2 – Subjects With or Without Evidence of Infection Prior to 7
Days After Dose 2 – Dose 2 All -Available Efficacy Population .............52
Table12. Vaccine Efficacy –First COVID -19 Occurrence After Dose 1 –
Dose 1 All -Available Efficacy Population ................................ ...............53
Table13. Vaccine Efficacy –First COVID -19 Occurrence From 7 Day s After
Dose 2, b y Subgroup –Subjects Without Evidence of Infection
Prior to 7 Day s After Dose 2 – Evaluable Efficacy (7 Day s)
Population ................................ ................................ ................................ .56
Table14. Vaccine Efficacy –First COVID -19 Occurrence F rom 7 Day s After
Dose 2, b y Subgroup –Subjects With or Without Evidence of
Infection Prior to 7 Day s After Dose 2 –Evaluable Efficacy (7
Days) Population ................................ ................................ ...................... 58
Table15. Vaccine Efficacy –First COVID -19 Occurrence From 7 Day s After
Dose 2, b y Requested Subgroup – Subjects Without Evidence of
Infection Prior to 7 Day s After Dose 2 –Evaluable Efficacy (7
Days) Population ................................ ................................ ...................... 60
Table16. Vaccine Efficacy –First COVID -19 Occurrence From 7 Day s After
Dose 2, b y Risk Status – Subjects Without Evidence of Infection
Prior to 7 Day s After Dose 2 – Evaluable Efficacy (7 Day s)
Population ................................ ................................ ................................ .62
Table17. Vaccine Efficacy –First COVID -19 Occurrence From 7 Day s After
Dose 2, b y Comorbidity Status –Subjects Without Evidence of
Infection Prior to 7 Day s After Dose 2 –Evaluable Efficacy (7
Days) Population ................................ ................................ ...................... 64
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Page 6Table18. Vaccine Efficacy –First COVID -19 Occurrence From 14 Days
After Dose 2 – Subjects Without Evidence of I nfection Prior to 14
Days After Dose 2 – Evaluable Efficacy (14 Days) Population ...............66
Table19. Vaccine Efficacy –First COVID -19 Occurrence From 14 Days
After Dose 2 – Subjects With or Without Evidence of Infection
Prior to 14 Day s After Dose 2 – Evaluable Effi cacy (14 Days)
Population ................................ ................................ ................................ .67
Table20. Vaccine Efficacy – First Severe COVID- 19 Occurrence From 7
Days After Dose 2 – Subjects Without Evidence of Infection Prior
to 7 Days After Dose 2 –Evaluable Efficacy (7 Days) Population ..........68
Table21. Vaccine Efficacy – First Severe COVID -19 Occurrence From 7
Days After Dose 2 – Subjects With or Without Evidence of
Infection Prior to 7 Day s After Dose 2 –Evaluable Efficacy (7
Days) Population ................................ ................................ ...................... 70
Table22. Vaccine Efficacy – First Severe COVID- 19 Occurrence After Dose
1 –Dose 1 All -Available Efficacy Population ................................ .........71
Table23. Vaccine Efficacy – First Severe COVID-19 Occurrence Based on
CDC-Definition After Dose 1 –Dose 1 All -Available Efficacy
Population ................................ ................................ ................................ .72
Table24. Vaccine Efficacy – First Severe COVID- 19 Occurrence From 14
Days After Dose 2 – Subjects Without Evidence of Infection Prior
to 14 Day s After Dose 2 –Evaluable Efficacy (14 Days) Population ......73
Table25. Vaccine Efficacy – First Severe COVID- 19 Occurrence From 14
Days After Dose 2 – Subjects With or Without Evidence of
Infection Prior to 14 Days After Dose 2 –Evaluable Efficacy (14
Days) Population ................................ ................................ ...................... 74
Table26. Vaccine Efficacy –First COVID -19 Occurr ence Based on CDC -
Defined S ymptoms From 7 Day s After Dose 2 – Subjects Without
Evidence of Infection Prior to 7 Day s After Dose 2 –Evaluable
Efficacy (7 Days) Population ................................ ................................ ....75
Table27. Vaccine Efficacy –First COVID -19 Occurrence Based on CDC-
Defined S ymptoms From 7 Day s After Dose 2 – Subjects With or
Without Evidence of I nfection Prior to 7 Day s After Dose 2 –
Evaluable Efficacy (7 Days) Population ................................ ................... 76
Table28. Efficacy Populations –Blinded Placebo -Controlled Follow -up
Period................................ ................................ ................................ ........79
Table29. Demographic Characteristics –Blinded Placebo -Controlled Follow-
up Period – Subjects Without Evidence of Infection Prior to 7 Day s
After Dose 2 – Evaluable Efficacy (7 Days) Population .......................... 81
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Page 7Table30. Vaccine Efficacy –First COVID -19 Occurrence From 7 Day s After
Dose 2 –Blinded Plac ebo-Controlled Follow- up Period –Subjects
Without Evidence of I nfection Prior to 7 Day s After Dose 2 –
Evaluable Efficacy (7 Days) Population ................................ ................... 83
Table31. Vaccine Efficacy –First COVID -19 Occurrence From 7 Day s After
Dose 2 –Blinded Placebo-Controlled Follow- up Period –Subjects
With or Without Evidence of Infection Prior to 7 Day s After Dose 2
–Evaluable Efficacy (7 Days) Populati on................................ ................ 84
Table32. Vaccine Efficacy –First COVID -19 Occurrence After Dose 1 –
Blinded Placebo -Controlled Follow- up Period – Dose 1 All-
Available Efficacy Population ................................ ................................ ..86
Table33. Vaccine Efficacy –First COVID -19 Occurrence From 7 Day s After
Dose 2, b y Subgroup – Blinded Placebo -Controlled Follow -up
Period –Subjects Without Evidence of Infection Prior to 7 Day s
After Dose 2 – Evaluable Efficacy (7 Days) Population .......................... 90
Table34. Vaccine Efficacy –First COVID -19 Occurrence From 7 Day s After
Dose 2, b y Subgroup –Blinded Placebo -Controlled Follow -up
Period – Subjects With or Without Evidence of Infection Prior to 7
Days After Dose 2 – Evaluable Eff icacy (7 Days) Population ................. 93
Table35. Vaccine Efficacy –First COVID -19 Occurrence After Dose 1, by
Subgroup –Blinded Placebo -Controlled Follow -up Period –Dose 1
All-Available Efficacy Population ................................ ........................... 97
Table36. Vaccine Efficacy –First COVID -19 Occurrence From 7 Day s After
Dose 2, b y Risk Status – Blinded Placebo -Controlled Follow-up
Period –Subjects Without Evidence of Infection Prior to 7 Day s
After Dose 2 – Evaluable Efficacy (7 Days) Population ........................ 100
Table37. Vaccine Efficacy –First COVID -19 Occurrence From 7 Day s After
Dose 2, b y Risk Status – Blinded Placebo -Controlled Follow-up
Period – Subjects With or Without Evidence of Infection Pri or to 7
Days After Dose 2 – Evaluable Efficacy (7 Days) Population ............... 102
Table38. Vaccine Efficacy –First COVID -19 Occurrence From 7 Day s After
Dose 2, b y Comorbidity Status –Blinded Placebo -Controlled
Follow-up Period – Subjects Without Evidence of I nfection Prior to
7 Days After Dose 2 – Evaluable Efficacy (7 Days) Population ............104
Table39. Vaccine Efficacy –First COVID -19 Occurrence From 7 Day s After
Dose 2, b y Comorbidity Status –Blinded Placebo -Controlled
Follow-up Period – Subjects With or Without Evidence o f Infection
Prior to 7 Day s After Dose 2 – Evaluable Efficacy (7 Day s)
Population ................................ ................................ ............................... 106
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Page 8Table40. Vaccine Efficacy –First Severe COVID-19 Occurrence From 7
Days After Dose 2 – Blinded Placebo -Controlled Follow -up Period
–Subjects Without Evidence of Infection Prior to 7 Day s After
Dose 2 –Evaluable Efficacy (7 Days) Population ................................ .108
Table41. Vaccine Efficacy – First Severe COVID-19 Occurrence Based on
CDC-Definition From 7 Day s After Dose 2 – Blinded Placebo -
Controlled Follow- up Period – Subjects Without Eviden ce of
Infection Prior to 7 Day s After Dose 2 –Evaluable Efficacy (7
Days) Population ................................ ................................ .................... 109
Table42. Vaccine Efficacy –First Severe COVID-19 Occurrence From 7
Days After Dose 2 – Blinded Placebo -Controlled Follow -up Period
– Subjects With or Without Evidence of Infection Prior to 7 Day s
After Dose 2 – Evaluable Efficacy (7 Days) Population ........................ 110
Table43. Vaccine Efficacy – First Severe COVID-19 Occurrence Based on
CDC-Definition From 7 Day s After Dose 2 – Blinded Placebo -
Controlled Follow- up Period –Subjects With or Without Evidence
of Infection Prior to 7 Day s After Dose 2 –Evaluable Efficacy (7
Days) Population ................................ ................................ .................... 111
Table44. Vaccine Efficacy – First Severe COVID- 19 Occurrence After Dose
1 –Blinded Placebo -Controlled Follow- up Period –Dose 1 All -
Available Efficacy Population ................................ ................................ 112
Table45. Immunogenicit y Populations – Phase 2................................ .................. 128
Table46. Demographic Characteristics –Phase 2 – Dose 2 Evaluable
Immunogenicity Population ................................ ................................ ....129
Table47. Summary of Geometric Mean Titers/Concentrations – Phase 2 –
Dose 2 Evaluable Immunogenicity Population................................ ......133
Table48. Summary of Geometric Mean Fold Rises From Before Vaccination
to Each Subsequent Time Point – Phase 2 – Dose 2 Evaluable
Immunogenicit y Population ................................ ................................ ....134
Table49. Summary of Geometric Mean Titers/Concentrations by Baseline
SARS-CoV-2 Status – Phase 2 –Dose 2 Evaluable I mmunogenicity
Population ................................ ................................ ............................... 136
Table50. Summary of Geometric Mean Fold Rises From Before Vaccination
to EachSubsequent Time Point by Baseline SARS -CoV-2 Status –
Phase 2 – Dose 2 Evaluable I mmunogenicity Population ...................... 138
Table51. Safety Population –Phase 2/3 Subjects ≥16 Years of Age .................... 154
Table52. Follow-up Time After Dose 2 – Phase 2/3 Subjects ≥16 Years of
Age –Safety Population ................................ ................................ .........156
Table53. Follow-up Time After Dose 1 of BNT162b2 – Phase 2/3 Subjects
≥16 Years of Age (Subjects Who Original ly Received Placebo) –
Safety Population ................................ ................................ .................... 157
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Page 9Table54. Disposition of All Randomized Subjects – Phase 2/3 Subjects ≥16
Years of Age ................................ ................................ ........................... 159
Table55. Demographic Characteristics – Phase 2/3 Subjects ≥16 Years of
Age –Safety Population ................................ ................................ .........162
Table56. Demographic Characteristics –Subjects With at Least 6 Months of
Follow-up Time After Dose 2 – Phase 2/3 Subjects ≥16 Years of
Age (Subjects Who Originally Received BNT162b2) –Safety
Population ................................ ................................ ............................... 164
Table57. Demographic Characteristics –Subjects Who Originall y Received
Placebo and Then Received BNT162b2 After Unblinding – Phase
2/3 Subjects ≥16 Years of Age – Safety Population ............................... 166
Table58. Number (%) of Subjects Reporting at Least 1 Adverse Event From
Dose 1 to 1 Month After Dose 2 – Blinded Placebo- Controlled
Follow-up Period – Phase 2/3 Subjects ≥16 Years of Age – Safety
Population ................................ ................................ ............................... 179
Table59. Number (%) of Subjects Reporting at Least 1 Adverse Event From
Dose 1 to 1 Month After Dose 2, b y System Organ Class and
Preferred Term –Blinded Placebo -Controlled Follow -up Period –
Phase 2/3 Subjects ≥16 Years of Age – Safety Population .................... 182
Table60. Incidence Rates of at Least 1 Adverse Event From Dose 1 to
Unblinding Date –Phase 2/3 Subjects ≥16 Years of Age – Safety
Population ................................ ................................ ............................... 215
Table61. Incidence Rates of at Least 1 Adverse Event From Unblinding Date
to Data Cutoff Date (13MAR2021) – Open-Label Follow -up Period
–Subjects Who Originally Received BNT162b2 –Phase 2/3
Subjects ≥16 Years of Age – Safety Population ................................ .....222
Table62. Number (%) of Subjects Reporting at Least 1 Adverse Event From
Dose 1 to 6 Months After Dose 2 –Subjects With at Least 6
Months of Follow- up Time After Dose 2 – Phase 2/3 Subjects ≥16
Yearsof Age (Subjects Who Originally Received BNT162b2) –
Safety Population ................................ ................................ .................... 225
Table63. Number (%) of Subjects Reporting at Least 1 Ad verse Event From
Dose 1 to 6 Months After Dose 2, b y Time Period – Subjects With
at Least 6 Months of Follow- up Time After Dose 2 – Phase 2/3
Subjects ≥16 Years of Age (Subjects Who Originally Received
BNT162b2) –Safety Population ................................ ............................ 226
Table64. Number (%) of Subjects Reporting at Least 1 Adverse Event From
Dose 1 to 6 Months After Dose 2, b y System Organ Class and
Preferred Term – Subjects With at Least 6 Months of Follow -up
Time After Dose 2 –Phase 2/3 Subjects ≥16 Years of Age
(Subjects Who Originally Received BNT162b2) –Safety
Population ................................ ................................ ............................... 227
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Page 10Table65. Incidence Rates of at Least 1 Adverse Event From Dose 3 to Data
Cutoff Date (13MAR2021) –Open-Label Follow -up Period –
Subjects Who Originally Received Placebo and Then Received
BNT162b2 After Unblinding –Phase 2/3 Subjects ≥16 Years of
Age –Safety Population ................................ ................................ .........251
Table66. Incidence Rates of at Least 1 Adverse Event From Dose 3 to Data
Cutoff Date (13MAR2021), by System Organ Class and Preferred
Term –Open-Label Follow -up Period – Subjects Who Originally
Received Placebo and Then Received BNT162b2 After Unblinding
– Phase 2/3 Subjects ≥16 Years of Age – Safety Population ................. 255
Table67. Incidence Rates of Deaths From Dose 1 to Unblinding Date –
Blinded Placebo -Controlled Follow- up Period – Phase 2/3 Subjects
≥16 Years of Age –Safety Population ................................ ................... 272
Table68. Number (%) of Subjects Reporting at Least 1 Serious Adverse
Event From Dose 1 to 1 Month After Dose 2, b y System Organ
Class and Preferred Term –Blinded Placebo -Controlled Follow -up
Period – Phase 2/3 Subjects ≥16 Years of Age – Safety Population ......275
Table69. Number (%) of Subjects Reporting at Least 1 Serious Adverse
Event From Dose 1 to 6 Months After Dose 2, b y System Organ
Class and Preferred Term –Subjects With at L east 6 Months of
Follow-up Time After Dose 2 – Phase 2/3 Subjects ≥16 Years of
Age (Subjects Who Originally Received BNT162b2) –Safety
Population ................................ ................................ ............................... 285
Table70. Incidence Rates of at Least 1 Serious Adverse Event From Dose 3
to Data Cutoff Date (13MAR2021), by System Organ Class and
Preferred Term –Open-Label Follow -up Period –Subjects Who
Originally Received Placebo and Then Received BNT162b2 After
Unblinding – Phase 2/3 Subjects ≥16 Years of Age – Safety
Population ................................ ................................ ............................... 291
Table71. Number (%) of Subjects Withdrawn Because of Adverse Events
From Dose 1 to 1 Month Af ter Dose 2, by System Organ Class and
Preferred Term –Blinded Placebo -Controlled Follow -up Period –
Phase 2/3 Subjects ≥16 Years of Age – Safety Population .................... 296
Table72. Incidence Rates of Subjects Withdrawn Because of Adverse Events
From Dose 3 to Data Cutoff Date (13MAR2021), by System Organ
Class and Preferred Term –Open-Label Follow -up Period –
Subjects Who Originally Received P lacebo and Then Received
BNT162b2 After Unblinding –Phase 2/3 Subjects ≥16 Years of
Age –Safety Population ................................ ................................ .........301
Table73. Selected S tandard MedDRA Queries From Dose 1 to Unblinding
Date –Blinded Placebo -Controlled Follow- up Period –Phase 2/3
Subjects ≥16 Years of Age – Safety Population ................................ .....306
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Page 11Table74. Incidence Rates of at Least 1 Adverse Event Category of Special
Interest From Dose 1 to Unblinding Date, b y Adverse Event
Category and Preferred Term –Blinded Placebo -Controlled
Follow-up Period – Phase 2/3 Subjects ≥16 Years of Age – Safety
Population ................................ ................................ ............................... 312
LIST OF IN -TEXT FIGU RES
Figure 1. Cumulative Incidence Curves for the First COVID- 19 Occurrence
After Dose 1 – Dose 1 All -Available Efficacy Population –Final
Analysis................................ ................................ ................................ ....54
Figure2. Cumulative I ncidence Curves for the First COVID- 19 Occurrence
After Dose 1 – Blinded Placebo -Controlled Follow -up Period –
Dose 1 All -Available Efficacy Population – Updated Anal ysis............... 87
Figure 3. Durability of BNT162b2 Induced CD4+ and CD8+ T Cell
Responses Against Full -Length S Protein ................................ ..............116
Figure4. S- Specific CD4+ T Cell Cy tokine Production in Response to
BNT162b2 – 18to55Years of Age ................................ ....................... 118
Figure5. S- Specific CD4+ T Cell Cy tokine Production in Response to
BNT162b2 – 56to85Years of Age ................................ ....................... 118
Figure6. Persistence of S -Specific CD4+ T Cell Cy tokine Production in
Response to BNT162b2 ................................ ................................ ..........120
Figure7. Geometric Mean Titers and 95% CI s: SARS-CoV-2 Neutralization
Assay –NT50 –Phase 1, 2 Doses, 21 Day s Apart –BNT162b2 (30
µg)/Placebo – Evaluable Immunogenicit y Population ........................... 124
Figure8. Geometric Mean Concentrations and 95% CIs: S1- Binding IgG
Level Assay –Phase 1, 2 Doses, 21 Day s Apart – BNT162b2 (30
µg)/Placebo – Evaluable Immunogenicit y Population ........................... 125
Figure9. Geometric Mean Titers: SARS -CoV-2 Neutralization Assay –
NT50 –Evaluable Immunogenicity Population – Phase 2..................... 131
Figure10. Geometric Mean Concentrations: SARS -CoV-2 S1-Binding IgG
Level Assay – Evaluable Immunogenicit y Population – Phase 2..........132
Figure 11. Participants Reporting Local Reactions, b y Maximum Severity,
Within 7 Days After Each Dose, by Age Group – Reactogenicit y
Subset for Phase 2/3 Analy sis –SafetyPopulation Age Group: 16 -
55 Years................................ ................................ ................................ ..171
Figure 12. Participants Reporting Local Reactions, b y Maximum Severity,
Within 7 Days After Each Dose, by Age Group – Reactogenicit y
Subset for Phase 2/3 Analy sis –SafetyPopulation Age Group: >55
Years................................ ................................ ................................ .......172
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Page 12Figure 13. Participants Reporting Sy stemic Events, by Maximum Severity ,
Within 7 Days After Each Dose, by Age Group – Reactogenicit y
Subset for Phase 2/3 Analy sis –SafetyPopulation Age Group: 16 -
55 Years................................ ................................ ................................ ..175
Figure 14. Participants Reporting Sy stemic Events, by Maximum Severity ,
Within 7 Days After Each Dose, by Age Group – Reactogenicit y
Subset for Phase 2/3 Analy sis –SafetyPopulation Age Group: >55
Years................................ ................................ ................................ .......176
Figure 15. Study C4591001 Phase 2/3 Safety Analyses: Time Periods and
Analysis Groups ................................ ................................ ...................... 178
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Page 13ABBREVIATIONS
Abbreviation Definition
ACE-2 angiotensin -converting enzyme 2
ADR adverse reaction
AE adverse event
AESI adverse event of special interest
BMI body mass index
C4591001 Efficacy Final
Analysis Interim CSRStudy C4591001 interim clinical study report including prespecified final analysis
of efficacy and available immunogenicity and safety data up to data cutoff date of
14 November 2020
C4591001 6 -Month
Update Interim CSRStudy C4591001 interim clinical stud y report including updated efficacy,
immunogenicity, and safety up to 6 months after Dose 2 up to data cutoff date of
13 March 2021
CBER (US FDA) Center for Biologics Evaluation and Research
CDC (US) Centers for Disease Control and Prevention
CDS Core Data Sheet
CFR case fatality rate
CHMP Committee for Human Products for Medicinal Use
CMC chemistry, manufacturing, and controls
CoV Coronavirus
COVID-19 Coronavirus Disease 2019
CTA Clinical Trial Application
DART developmental and reproductive toxicity
DMC (US Study C4591001 ) Data Monitoring Committee
ELISPOT enzyme-linked immuno-spot
EMA European Medicines Agency
EU European Union
EUA Emergency Use Application
FACS fluorescence -activated cell sorting
FDA (US) Food and Drug Administration
FIH first-in-human
GCP Good Clinical Practice
GLP Good Laboratory Practice
GMP Good Manufacturing Practice
GMFR geometric mean -fold rise
GMT/GMC geometric mean titer/concentration
HIV human immunodeficiency virus
ICH International Council on Harmonisation
ICU intensive care unit
ID intradermal(ly)
IFN interferon -gamma
IL-2 interleukin -2
IL-4 interleukin -4
IM intramuscular(ly)
IND Investigational New Drug application
iPSP initial Pediatric Study Plan
IRC (US Study C4591001 ) Internal Revie w Committee
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Page 14Abbreviation Definition
IRR illness rate ratio
LLN lower limit of normal
LNP lipid nanoparticle
LPX lipoplex
MedDRA Medical Dictionary for Regulatory Activities
MERS Middle East respiratory syndrome
modRNA nucleoside- modified messenger RNA
mRNA messenger RNA
NAAT nucleic acid amplification testing
NHP non-human primate
NI Non-inferiority
P2 S SARS-CoV-2 full-length, P2 mutant, “heads up,” prefusion spike glycoprotein
PDCO Paediatric Committee
PCR polymerase chain reaction
PIP Paediatric Investigational Plan
PSP Pediatric Study Plan
PT Preferred Term
RBD receptor binding domain
RNA-LNP RNA lipid nanoparticle
saRNA self-amplifying messenger RNA
SRC (German Study BNT162-01) Safety Review Committee
ssRNA single-stranded RNA
SAE serious adverse event
SARS severe acute respiratory syndrome
SARS-CoV-2 SARS Coronavirus -2; virus causing the disease COVID -19
S glycoprotein, S spike glycoprotein
SmPC Summary of Product Characteristics
SMQ Standard MedDRA query
SOC System Organ Class
Th1/Th2 helper T cell type 1/type 2
UK United Kingdom
uRNA non-modified uridine containing mRNA
US United States
USP United States Pharmacopeia
VAE(R)D vaccine-associated enhanced ( respiratory )disease
VE vaccine efficacy
WHO World Health Organization
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Page 152.5. CLINICAL OVERVIEW
This Clinical Overview (CO) describes the clinical data fora prophylactic, RNA -based
SARS-CoV-2 vaccine developed b y BioNTech and Pfizer. Evidence is presented in this CO
for the efficacy , immunogenicity , and safety and tolerability of the vaccine compared with
placebo administered to healthy participants ≥12 years of age.
The pivotal data are derived from a singleregistration alstudy, Phase 1/2/3 Study C4591001,
conducted under a United States (US) Investigational New Drug ( IND) Application .
Supporting data are presented from the first -in-human (FIH) dose -findingstudy, Phase 1/2
Study BNT162-01 ,conducted in German yunder a Clinical Trial A pplication (CTA).The
clinical experience reflected in this CO represents approximately 44,000 study participants
≥16 years of age ,including individuals with stable infections and common comorbidities that
represent real -world population characteristics.
The proposed indication and dosing administration for BNT162b2(30 µg)are:
Proposed i ndication : Activeimmunization to prevent COVID-19disease caused by
SARS-CoV-2 virus,in individuals ≥16yearsof age
Dosing administration :single 0.3-mLintramuscular (IM) dose followed by a
second 0.3-mLdose 3 weekslater
Efficacy analyses areevent-drivenin Study C4591001 Phase2/3 participants ≥12 y ears of
age. Prespecified analyses wereconducted on 94 confirmed COVID-19 cases (interim
analysis data cutoff date: 04November 2020)and170confirmed cases (final anal ysis data
cutoff date : 14November 2020)reported in participants without evidence of past
SARS-CoV-2 infection before or during the vaccin ation regimen. Updatedanalyses of
1165confirmed cases in blinded placebo-controlled follow -up from Dose 1 to adata cutoff
date of 13 March 2021 evaluated duration of protection.
Immunogenicit yanalyses of adults (18 to 85 years of age )in Study C4591001 include data
up to 1month after Dose 2inPhase 2,andup to 6 months after Dose 2 inPhase1.
Safetydataare collected cumulatively in Study C4591001 . Someparticipants ≥16 y ears of age
have been unblinded to treatment assignment, therefore safet y data are presented separatel y
for blinded placebo -controlled and open-label periods. Key safety data in the CO include:
Blinded placebo -controlled period:Dose 1 to1 month after Dose 2 and tounblinding date:
Phase 1 participants randomized to BNT162b2 30 µg ( to ~6 months after Dose 2)
Phase 2/3 participants ≥16 years of age including HIV+ subset(to ~5 months after Dose 2)
O
pen-labelobservational period:from unblinding data todata cutoff date :
Phase 2/3 participants ≥16 years of age originall y randomized to BNT162b2
Phase 2/3 participants ≥16 years of age originall y randomized to placebo whothen
receivedBNT162b2 after being unblinded
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Page 16Cumulative follow-up from Dose 1 to6 months after Dose 2 :Phase 2/3 participants
originally randomized to BNT162b2 (inclusive of blinded data and open-labeldata),
comprised of at least 3000 in each adult age group (16 to 55 y ears of age, >55 y ears of age)
Supportive analy sesfrom Study BNT162-01 are presented for immunogenicity data
including T cell responses, and safety dataincludingreactogenicity and adverse events
(AEs), for adult participants in the Phase 1 portion of the study .
2.5.1. Product Development Rationale
2.5.1.1.Therapeutic Context
2.5.1.1.1. Disease or Condition
COVID-19 is caused by SARS-CoV-2, a zoonotic virus that first emerged as a human
pathogen in China and has rapidly spread around the world by human to human transmission.
In December 2019, a pneumonia outbreak of unknown cause occurred in Wuhan, China.
InJanuary 2020, it became clear that a novel Coronavirus (2019- nCoV) was the underl ying
cause. In earl y January 2020, the genetic sequence of the 2019 -nCoV became available to the
World Health Organization (WHO) and public (MN908947.3), and the virus was ca tegorized
in the Betacoronavirus subfamily . By sequence analy sis, the phy logenetic tree revealed a
closer relationship to severe acute respiratory syndrome (SARS) virus isolates than to other
coronavirus es thatinfect humans, including the Middle East resp iratory syndrome (MERS)
coronavirus.1,2
SARS-CoV-2 infections and the resulting disease COVID -19 have spread globall y,and on
11March 2020 the WHO characterized the COVID -19 outbreak as a pandemic . As of
April2021, there have been > 145million globall y confirmed COVID -19 cases and
>3million deaths, with 192 countries/regions affected ;among these, the US leads with the
highest number of reported cases at>31million confirmed cases and >5 70,000 deaths.3
At the time of this submission , theongoing pandemic remainsa significant challenge to
public health and economic stability worldwide , for which for a licensed prophylactic
vaccineis a necessary and critical mitigation .
2.5.1.1.2. Clinical Features and Epidemiology of COVID-19
COVID-19 presentation is generall y with cough and fever, with chest radiograph y showing
ground-glass opacities or patch y shadowing.4However, man y patients present without fever
or radiographic changes, and infections may be asymptomatic which isrelevant to controlling
transmission. For sy mptomatic patients, disease progression may lead to acute respiratory
distress sy ndrome requiring ventilation , subsequent multi -organ failure , and death.4
Common sy mptoms in hospitalized patients (in order of highest to lowest frequency ) include
fever, dry cough, shortness of brea th,fatigue,myalgias, nausea/vomiting or diarrhea,
headache, weakness, and rhinorrhea .4Anosmia (loss of smell) or ageusia (loss of taste) may
be the sole presenting s ymptomin approximately 3%of individuals who have COVID-19.4
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Page 17The USCenters for Disease Control and Prevention (CDC) defined COVID-19 symptomsas
including 1or more of the following :5
Fever
New or increased cough
New or increased shortness of breath
Chills
New or increased muscle pain
New loss of taste or smell
Sore throat
Diarrhea
Vomiting
Fatigue
Headache
Nasal congestion or runny nose
Nausea
All ages may present with the disease, but notabl y, case fatality rates (CFR) are elevated in
persons >60 years of age.6Comorbiditi es are also associated with increased CFR, including
cardiovascular disease, diabetes, hypertension, and chronic respiratory disease.7Healthcare
workers are over -represented among COVID -19 patients due to occupational exposure to
infected patients.7
2.5.1.2. Vaccine Clinical Development Program
2.5.1.2.1. Rationale for Development
2.5.1.2.1.1. Current Therapies
Clinical management of COVID-19includes a variety of therapies, which are primarily
recommended for usein a hospitalized or clinical trial setting,such as:8
Severe disease or critical care hospital setting
dexamethasone (corticosteroid)
tocilizumab (targeted immunotherap y agent)
remdesivir (antiviral agent)
baricitinib ( JAK inhibitor) in combination with remdesivir
Ambulatory caresetting
casirivimab andimdevimab (monoclonal antibodies)
bamlanivimab (monoclonal antibody )
Clinical trial setting
convalescent plasma
famatodine (H2 blocker)
ivermectin (anti-parasitic).
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Page 18Currently available therapies have different benefit-risk considerations depending on the
stage of illness and disease manifestations.4,8While care for individuals who have
COVID-19 has improved with clinical experience, there remains an urgent and unmet need
for a licensed prophylactic vaccine during the ongoing pandemic.
2.5.1.2.1.2. BNT162b2 Development
Pfizer and BioNTech develop ed aninvestigational vaccinethat targets SARS-CoV-2,
intendedtopreventCOVID-19, for which BioNTech initiate da FIH study in April 2020 in
Germany (BNT162 -01) and Pfizer initiate da Phase 1/2/3 study (C4591001) shortly
afterwards in the USwhich expanded to include global sites upon initiation of the Phase 2/3
part of the stud y. Additional information on Study BNT162- 01 is provided in
Section 2.5.1.2.3.2.1 , and onStudy C4591001 is provided in Section 2.5.1.2.3.2.2 .
The vaccine is based on SARS -CoV-2 spike glycoprotein (S)antigens encoded in RNA
formulated in lipid nanoparticles (LNPs) and is referred to as BNT162b2 (BioNTech code
numberBNT162, Pfizer code number PF -07302048) .Thestructural elements of the vector
backbones of BNT162 vaccines are optimized for prolonged and strong translation of the
antigen-encoding RNA. The potency of RNA vaccines is further optimized by encapsulation
of the RNA into LNPs, which protect the RNA fr om degradation by RNAses and enable
transfection of host cells after IM delivery .
Development of RNA -based vaccines encoding viral antigens provides significant
advantages over more traditional vaccine approaches :
RNA-basedvaccines do not carry risks associated with infection.
RNA-basedvaccines can mimic antigen expression during natural infection by directing
expression of apathogen antigen with high precision and flexibility of antigen design.
RNA occurs naturall y in the body, is metabolized and eliminated b y the body ’s natural
mechanisms, does not integrate into the genome, and istransiently expressed .
RNA-based vaccines are manufactured by a cell-free in vitro transcription process, which
allows eas y and rapid production and the prospect of produc ing high numbers of vaccine
doses within a shorter time period than could be traditionally achieved with conventional
vaccine approaches. This capability is pivotal to enable the most effective response in
outbreak scenarios and makes RNA-based vaccines an attractive platform to achieve a
timely and effective response to emerging infectious disease threats.
BioNTech is a pioneer in the field of RNA technology . The core innovation is based on
invivodelivery of a pharmacologically optimized, antigen -encoding RNA to induce robust
neutralizing antibodies and a concomitant T cell response to achieve protective immunization
with minimal vaccine doses.9,10,11
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Page 192.5.1.2.2. Vaccine Product Information
BioNTech has developed multiple RNA-LNPplatforms, including nucleoside- modified RNA
(modRNA) which has blunted innate immune sensor activating capacit y and thus augmented
antigen expression. Each modRNA candidate encodeseithera P2 mutant S (P2S) or the
trimerized receptor binding domain (RBD) of S. Each candidate is given a V number to
indicate the specific version of the optimized insert genomic sequence. BNT162 vaccine
candidates tested in German Study BNT162 -01 and pivotal Study C4591001 are:
BNT162b 1 (RBP020.3) modRNA encoding RBD (V5)
BNT162b2 (RBP020.2) modRNA encoding P2 S (V9)
Vaccine candidates based on ot her RNA platformsthat were tested in Study BNT162 -01 but
were not tested in pivotal StudyC4591001 arenot discussed further herein.
2.5.1.2.2.1. Characterization of the Vaccine Product
Coronavirus Spike Glycoprotein as Vaccine Target
Coronaviruses are a family of (+)ssRNA enveloped viruses that encode four structural
proteins. Among these four structural proteins, S is the key target antigen for vaccine
development. The vaccine candidates used forclinical testing featured the following vaccine
antigens:
Secreted, trimerized variant RBD of SARS -CoV-2 S (V5)12
Membrane -anchored, full -length S with 2 point mutations within central helix domain (V9).
Mutation of these 2 amino acids to proline locks S in an antigenicall y preferred prefusion
conformation.13,14
Lipid Nanoparticle Formulation
Vaccine candidates are encapsulated into LNPs, which enable transfection of the RNA into
host cells after IM injection. The same LNP formulation is used for all vaccine candidates.
The LNPs are composed of four different lipids in a defined ratio. During mixing o f the RNA
and the dissolved lipids, the lipids form the nanoparticles encapsulating the RNA. After
injection, the L NPs are taken up by the cells, and the RNA is released into the cy tosol. In the
cytosol, the RNA is translated into the encoded viral protein. The encoded antigen induces an
adaptive immune response. The antigen may be incorporated into cellular membranes (P2 S)
or secreted into the extracellular environment (RBD) and induces an adaptive immune
response. As S is the antigen that recognizes the host cell receptor and enables infection of
the host cells, it is a key target of virus neutralizing antibodies. Further, as RNA-expressed S
is being degraded intracellularly , the resulting peptides can be presented at the cell surface,
triggering a specif ic T cell-mediated immune response with activity against the virus.
Additional details on the product formulation are provided in Section 2.5.2.1.
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Page 202.5.1.2.3. Vaccine Development Program
2.5.1.2.3.1. Nonclinical Stud ies
Key nonclinical evaluation sof BNT162b2 included pharmacology (mouse immunogenicit y
studies,non-human primate [ NHP]immunogenicity and challenge studies) and toxicity
(twoGood Laboratory Practice [ GLP] rat repeat- dose toxicity studies)invitro and in vivo.
Adevelopmental and reproductive toxicity (DART)study was completed in rats.
Nonclinical studies in mice and NHP demonstrate that BNT162b2 elicits a rapid antibody
response with measurable SARS -CoV-2 neutralizing titers after a single dose and substantial
increases in titers after a second dose that exceed titers in sera from SARS -CoV-2/
COVID-19-recovered individuals. A Th1 -dominant T cell response was evident in both mice
and NHPs. S -specific CD8+ T cell responses were also detectable in BNT162b2- immunized
animals. The strongly Th1-biased CD4+ T cell response and interferon -γ (IFNγ)+ CD8+
Tcell response after immunization with BNT162b2 is a pattern favored for vaccine safet y
and efficacy and provi ded added reassurance for clinical safet y.15In A SARS-CoV-2 rhesus
challenge model, BNT162b2 provided complete protection from the presence of detectable
viral RNA in the lungs compared to the saline control with no clinical, radiological ,or
histopatholog ical evidence of vaccine -elicited disease enhancement.16
Administration of BNT162b2 by IM injection to male and female Wistar Han rats once every
week, for a total of 3 weekly cycles of dosing, was tolerated without evidence of s ystemic
toxicityin GLP-compliant repeat -dose toxicity studies.
In a DART study, 0.06 mL of a vaccine formulation containing the same quantity of
nucleoside -modified mRNA (30 µg) and other ingredients included in a single human dose of
BNT162b2 was administered to female rats by the IMroute on four occasions: 21 and
14days prior to mating, and on gestation day s 9 and 20. No vaccine -related adverse effects
on female fertility , fetal development ,or postnatal development were reported in the study .
In summary , the nonclinical packag e summarized above supports BNT162b2 administered
twice by IM injection at a dose of 30 µg RNA.Additional details of nonclinical studies are
provided in Module 2.4.
2.5.1.2.3.2. Clinical Stud ies
2.5.1.2.3.2.1. Phase 1/2 Study BNT162 -01
Study BNT162-01 is the ongoing, FIH, Phase 1 dose level- finding study , in which health y
younger adults (18 to 55 y ears of age )and older adults (56to 85 years of age )all receive
active vaccine. This study is evaluating the safet y and immunogenicit y of several different
candidate vaccines at various dose levels. The available Phase 1 safet y and immunogenicit y
data for younger and older adults are reported in this submission.
Multiple vaccine candidates are being evaluated in this study . For each vaccine candidate,
participants received escalating dose levels (N=12 per dose level) with progression to
subsequent dose levels based on recommendation from a Sponsor Safet y Review Committee
(SRC).
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Page 21The study design is detailed in the Module5.3.5.1 BNT162- 01 Protoc ol.
Study Eligibility Criteria
The BNT162- 01 study population includes male and female adult participants deemed
healthy and without COVID -19 symptoms or evidence of SARS- CoV-2 infection within
30days prior to entering the study . Inclusion criteria allowe d for preexisting stable disease
defined as disease not requiring significant change in therap y or hospitalization for
worsening disease during the 6 weeks prior to enrollment. I ndividuals with medical
conditions considered to possibly confound evaluation of vaccine safet y or immunogenicit y
were excluded.
Phase 1
In Study BNT162 -01, vaccine candidates from the modRNA platform, administered IM in
the upper arm in a two-dose regimen separated by approximately 21 days,were:
BNT162b1 (dose levels: 1, 3, 10, 20, 30, 50, 60 µg)
BNT162b2 (doselevels: 1, 3, 10, 20, 30 , 50, 60 µg)
For each vaccine candidate, participants received escalating dose levels ( N=12 per dose
level) with progression to subsequent dose levels based on recommendation from a Sponsor
Safety Review Committee (SRC). Note: theSRC recommended that a second dose of
BNT162b1 at 60 µgnot be administered due to reactogenicit y after the first dose. Note that at
the time of BNT162 -01 Interim CSR preparation, data for BNT162b2 dose levels of 50µ g
and 60 µg were not available.
Dosing with other candidates on different platforms, BNT162a1 (uRNA) and BNT162c2
(saRNA), isnot discussed as it is not relevant to progression with modRNA candidates.
Safety and immunogenicity data(including T cell immune response data) from the Phase 1
part of Study BNT162- 01 are summarized in this submission in support of the larger dataset
from the Phase 1/2/3 registration Study C4591001.
2.5.1.2.3.2.2. Phase 1/2/3 Study C4591001
Study C4591001 is the ongoing, randomized, placebo-controlled, Phase 1/2/3 registration
study. It was started as a Phase 1/2 study in adults in the US, was then amended to expand
the study to a global Phase 2/3 study planning to enroll enoughparticipants to accrue
sufficient COVID -19 cases to conduct a timel y efficacy assessment; amended to include
older adolescents 16 to 17 years of age, then later amended to include younger adolescents
12to 15years of age.
The study design is detailed in Module 5.3.5.1 C4591001 Protocol.
Study Eli gibility Criteria
In Phase 1, two age groups were studied separately, younger participants (18 to 55 y ears of
age) and older participants (65 to 85 years of age). The study population includes male and
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Page 22female participants deemed health y as determined by me dical history , physical examination
(ifrequired), and clinical judgment of the investigator to be eligible for inclusion in the
study. Exclusions included screened individuals with high risk of exposure to SARS -CoV-2
infection due to exposure in the workp lace and/or medical conditions that represent risk
factors, clinically important prior illness or laboratory abnormalities, serological evidence of
prior SARS -CoV-2 infection or current SARS -CoV-2 infection as measured by polymerase
chain reaction (PCR).
In Phase 2/3, participants were enrolled with stratification of younger adults (18 to 55years
of age) and older adults (>55 years of age) to achieve approximately 40% enrollment in the
older adult group. Additional adolescents were added later b y a protocol amendment: older
adolescents 16 to 17 years of age are included in the y ounger adult stratum (ie, 16 to 55 y ears
of age), and younger adolescents 12 to15years of age were analyzedas a separate age
stratum. Eligibility in Phase 2/3 included higher ri sk for acquiring COVID -19 in the
investigator’s judgment, due to medical conditions or exposure, such as:
Chronic condition (eg, hy pertension; diabetes; asthma; pulmonary , liver, or kidney disease)
Autoimmune disease requiring therapeutic intervention (or history of)
Chronic HIV, HCV, or HBV infection that is stable and controlled
Vaping or smoking (or history of smoking within the prior y ear)
Resident in a long- term facility
Occupation with high risk of SARS -CoV-2 exposure (eg, healthcare, emergency response)
Phase 1
ThePhase 1 part of the study , randomized p articipants 4:1 to receive active vaccine or
placebo. The vaccines candidates, administered IM in the upper arm in a two-dose regimen
separated b y approximately 21 days, were:
BNT162b1 (dose levels: 10, 20, 30, 100 µg)
BNT162b2 (dose levels: 10, 20, 30 µg)
Phase 1 of Study C4591001 was conducted in the US . For each of the two vaccine candidates
evaluated, younger participants received escalating dose levels (N=15 per dose level, 4:1
randomization ratio between vaccine and placebo) with progression to subsequent dose levels
and the older age group (N=15 per dose level, 4:1 randomization ratio between vaccine and
placebo) based on recommendation from an Internal Review Committee (IRC ). Note: the
IRC recommended that a second dose of BNT162b1 at 100 µgnot be administered and
discontinued due to reactogenicity after the first dose in the y ounger age group. Participants
in this group of younger adults instead received a second dose of BNT162 b1 at the 10 µg
dose level approximately 3 months after Dose 1, and the 100 µg dose level was discontinued
(ie, not administered to older adults receiving BNT162b1).
The Sponsor/agent study team was not blinded in this part of the study . Participants who
enrolled in Phase 1 are followed for cases of COVID -19 but do not contribute to the efficacy
assessment. Safet y follow-up will continue for at least 2 y ears and/or end of study . Based
upon review of safet y and immunogenicit y from the Phase 1 part of the study , the final
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Page 23candidate and dose level was selected as BNT162b2 at 30 µg given twice 21 day s apart.
Details are provided in Section2.5.1.2.5.
Booster E valuation
Phase 1 participants who were randomized to either BNT162b1 or BNT162b2 at dose levels
of 10,20, or 30 µg are being offered booster vaccination with BNT162b2 at 30 µg,
approximately 6to 12 months after their second dose of BNT162b1 or BNT162b2. This
provides an earl y assessment of the safet y and immunogenicit y associated with a third
vaccine dose. Data from Phase 1 participants who receive a booster are not included in this
submission and will be reported at a later time.
Phase 2
Phase 2/3 of Study C4591001 commenced with the selected vaccine candidate and dose level
administered to participants who were randomized 1:1 to receive vaccine or placebo.
Phase 2 was conducted in the US. The Phase 2 portion of the study evaluated reactogenicit y
and immunogenic ity for 360 participants 18 to 85 y ears of age enrolled into the study when
the Phase 2/3 part commenced, balancing younger (≤55 years of age) and older (>55 years of
age) strata within each group. Phase 2 participants in this blinded part of the study also
contribute to the overall efficacy and safet y assessments in the Phase 3 portion of the study .
Phase 3
Phase 3 (which is ongoing) included planned interim analy ses of the first primary efficacy
endpoint, ongoing efficacy and safet y evaluations including reactogenicity assessment in a
subset of participants, and exploratory vaccine immunogenicit y evaluation in a subset of
participants. Phase 3 is being conducted at sites in the US, Brazil, Argentina, Turkey , South
Africa, and German y. Participants were str atified by age group as previously described. The
final efficacy analysis was conducted when at least the prespecified total number of
164efficacy events accrued. Safet y and long -term persistence of efficacy follow-up will
continue for at least 2 y ears and/or end of study . Safety and efficacy anal yses included the
360participants who were anal yzed for Phase 2.
Booster and Variant Strain Evaluation
For further evaluation of booster effects and protection against emerging SARS -CoV-2
variants of concern , a subset of existing Phase 3 participants 18 to 55 y ears of age will be
randomized 1:1 to receive either receive a third dose of BNT162b2 or a third dose of
prototype based upon the South African variant, BNT162b2 SA, approximately 5 to 7 months
after theirsecond dose of BNT162b2 . An additional subset of existing Phase 3 participants
18 to 55 y ears of age will be enrolled to receive a third and fourth dose of BNT162b2 SA. A
new cohort will be recruited who are COVID -19 vaccine- naïve (ie, have not received
BNT162b2) and have not experienced COVID-19 to receive BNT162b2 SAas a two-dose
series 21 day s apart.Data from Phase 3 participants who receive a booster and/or
BNT162b2 SAare not included in this submission and will be reported at a later time .
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Page 24Unblinding Considerations
Unblinding to randomized treatment assignment has begun for participants ≥16 years of age
inthe study, with respect to the participants, Sponsor, andsite personnel . This is subsequent
to authorizations/approvals granted in the US and other regions starting in December 2020
(refer to Section 2.5.1.3).
Individual s 16 years of age or older have been unblinded at such time that they become
locally eligible and wishto know their treatment assignment to confirm prior vaccination
with BNT162b2 (if randomized to this group), or to receive BNT162b2 (if randomized to
placebo). Unblinded recipients originally randomized to BNT162b2 c ontinue to be followed
in an open -label(ie, observational ) manner. Unblinded recipients originall y randomized to
placebo areoffered BNT162b2 vaccination and thereafter followed in an open-labelmanner.
Participants randomized to placebo who became eligible for vaccination with BNT162b2
(oranother COVID -19 vaccine) had the opportunity to receive BNT162b2 in a phased
manner as part of the study (no later than at the approximate time participants in Phase 2/3
reach Visit 4). The investigator ensured t he participant met at least one of the
recommendation criteria. Any participant who originall y received placebo and subsequentl y
received BNT162b2 was moved to a new visit schedule to receive both doses of BNT162b2
at each of two additional vaccination vis its (Visits 101 and 102).
Sponsor and site personnel who are responsible for the ongoing conduct of the study remain
blinded to the data from participants whose treatment assignment hasnot beendisclosed in
the ongoing study(ie, not unblinded) , with rega rd to individual participants’ randomization.
Safety evaluation for these participants by the study team remains blinded until a decision is
made to unblind the entire study . Aseparate (from study conduct) unblinded submissions
team is responsible for reg ulatory submissions.
All participants continue to be expected toremainin study follow-upfor a maximum of
approximately 2 years after Dose 2 of randomized study intervention .
2.5.1.2.3.2.3. Planned Studies
The following studies (or additional anal yses fromongoing studies)are planned in 2021:
Pediatric studies in children <12 years of age: C4591007
Maternal immunization during pregnancy : C4591015
Immunocompromised adults, children <18 y ears of age: BNT162-01, C4591024
Lot consistency : C4591017
Lyophilized product bridging: C4591020
Process 1 and Process 2 comparison: C4591001
Booster vaccination(s) with BNT162b2: C4591001
SARS-CoV-2 variant strain change (BNT162b2 SA): C4591001
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Page 252.5.1.2.4. Proposed Indication
The proposed indication for BNT162b2 (30 µg) is:
Active immunization to prevent COVID-19 disease caused b y SARS-CoV-2 virus,in
individuals ≥16 years of age .
Supplemental applications are planned forpediatric population s,maternal immunization , use
in immunocompromised individuals, and booster doseand/or strain changes, pending
conclusion of the appropriate studies/anal ysesand Agency feedback.
2.5.1.2.5. Rationale for Candidate and Dose Selection
BioNTech has evaluated multiple RNA -LNP platforms, including nucleoside -modified RNA
(modRNA) which has blunted i nnate immune sensor activating capacit y and thus augmented
antigen expression. Two modRNA candidates were evaluated in the Phase 1 portions of
Studies BNT162- 01 and C4591001. The final candidate and dose level (BNT162b2 at 30 μg)
was selected following rev iew of immunogenicity and safet y data from the Phase 1 part of
Study C4591001 and available nonclinical data.
The final vaccine candidate selection for clinical development in Phase 2/3 was based on:
NHP challenge data; BNT162b2 led to earlier virus cleara nce, no evidence of virus in lung
Favorable reactogenicity for BNT162b2 in both y ounger and older Phase 1 participants
Robust immunogenicity in both y ounger and older Phase 1 participants at 30 μg dose level.
BNT162b2 at 30 µg proceeded into the Phase 2/3 portion of Study C4591001 because this
dose and construct provided the optimum combination of a favorable reactogenicity profile
and a robust immune response, likely to afford protection against COVID- 19 in younger and
older age groups.
2.5.1.3.Regulatory Status
BNT162b2 has received temporary authorizations for emergency supply in 28countries and
conditional marketing authorizations in 39countries globall y. The name of the product
supplied under emergency/temporary use authorization for all applicable regions is Pfizer -
BioNTech COVID -19 Vaccine. The name of the product supplied under conditional
marketing authorization for all applicable regions is COMI RNATY [COVID -19 mRNA
Vaccine (nucleoside modified)].
United States
In the US, the vaccine is in clinical development under an Investigative New Drug (IND)
application, BB-IND 19,736. Fast Track Designation was granted on 07 July 2020 for
individuals ≥18 years of age. An EUA application was filed to the US Food and Drug
Administration (FDA ) on 20 November 2020 and the product was authorized for emergency
use in the US on 11 December 2020 for individuals ≥ 16 years of age (EUA 27034) .
Anamendment to the EUA was submitted 09 April 2021 to support emergency use in
participants 12 to 15 y ears of age.
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Page 26The agreed Pediatric Study Plan (PSP) was submitted to the FDA on 02 April 2021 and was
agreed by the FDA on 23 April 2021.
European Union
Arolling Marketing Authorization Application (MAA) was initiated on 05 October 2020
with nonclinical data, followed by Module 3 documents submitted on 05 November 2020,
and completed with submission of clinical modules on 07December 2020. Conditional
marketing approval was granted b y the European Medicines Agency (EMA)on
21December 2020for individuals ≥ 16 years of age .A Type II Variation to support use
individuals ≥12 years of age is planned to be submitted to EMA in second quarter 2021.
A Paediatric Investigational Plan (PI P) was submitted to the Paediatric Committee (PDCO)
on 21 September 2020 . An agreed PI P decision was received 27 November 2020. A PIP
modification request was submitted to PDCO on 24 March 2021 and was agreed by PDCO
on 21April 2021.
Rest of World
Marketing Authorization Applications wereinitiated beginning in October 2020 and have
been approved in manycountries global lyincluding Switzerland, Japan, Australia ,New
Zealandand Brazil. Requests for temporary authorization for emergency supply have been
filedand approved in many countries globally under emergency or temporary use
authorization procedures or special imp ort procedures beginning in November 2020
(including the UK and Canada) . The World Hea lth Organization (WHO) issued a positive
opinion on the Emergency Use L istingof COMIRNATY on 31 D ecember 2021.
2.5.1.4.Ethical Considerations
All studies in the clinical development program were conducted in compliance with the
ethical principles originating in or derived from the Declaration of Helsinki and in
compliance with all International Councilon Harmonisation (ICH) Good Clinical Practice
(GCP) Guidelines. They were designed, performed, and anal yzed in accordance with all
applicable regulations, laws, and guidelines in effect at the time they were conducted from
the US FDA , EUDirective 2001/20/EC ,and local regulatory agencies in countries where the
study was conducted. T he study design reflect srecommendations from local review
boards/committees , andother local regulatory authorities.
The pivotal Phase 1/2/3 Study C4591001 was conducted at sites in the US, Brazil, Argentina,
Turkey, South Africa, and German y; the majorit y of participants were enrolled at sites in the
US(refer to Section 2.5.5.5.1). The supporting Phase 1/2 Study BNT162-01 was conducted
at sites in German y.
2.5.2.Overview of Biopharmaceutics
2.5.2.1.Formulation Development
TheBNT162b2 vaccine is provided in a multi-dose vial that contains a frozen concentrated
solution that is preservative -freeand must be thawed and diluted prior to administration. The
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Page 27BNT162b2 concentrate must be diluted in its original vial using0.9% Sodium Chloride
Injection, USP, resulting in an off -white suspension . The 0.9% Sodium Chloride Injection,
USP is not packaged with the vaccine and must be sourced separatel y.
The vaccine is a dministered IMas a series of two 30 -µgdoses of the diluted vaccine solution
(0.3 mL each) according to the following schedule: asingle 0.3- mL dose followed by a
second0.3-mL dose 21 day slater.
Details of formulation development and storage conditions are provided in Module 3.
Manufacturing Process
The scale of BNT162b2 manufacturing has been increased to support future supply . The
safety and immunogenicity of prophylactic BNT162b2 in Study C4591001 participants
vaccinated with material generated using the existing manufacturing process (Process 1) and
with material from lots generated using the manufacturing process supporting increased
supply (Process 2) is planned to be evaluated (asnoted in in Section 2.5.1.2.3.2.3 ).
2.5.2.2.Biopharmaceutical Studies
Bioavailability and bioequivalence assessments are not relevant to vaccine antigenicity and
have not been measured.
The major pharmacod ynamic effect of a vaccine, unlike a drug, is to elicit an immune
response to the antigens includedin the vaccine. Vaccine induced activation of antigen -
presenting cells takes place at the site of injection (ie, muscle) which is rapidly followed b y
antigen-presenting cell migration via l ymphatic vessels towards the draining l ymph node
where vaccine antigens activate specific B and T cells. T here is no specific vaccine antigen
blood level required to elicit the immune res ponse.
2.5.2.3. Bioanalytical and Analytical Methods Used in Human Studies
Information on assay sused toassessSARS-CoV-2infection and immune response isin
Module 2.7.1. Only validated (PCRand neutralization immunoassay ) or qualified (Luminex
immunoassay ) methodswere used.
2.5.3.Overview of Clinical Pharmacology
Pharmacokinetic studies are not usuall y required forvaccines. Measurement of the plasma
concentration of the vaccine over time is not feasible .
2.5.4. Overview of Efficacy (Including Immunogenicity)
Efficacy was evaluated in Phase 2/ 3 of pivotal study C4591001; the methods for evaluation
of efficacy are provided in Section 2.5.4.1and results are in Section 2.5.4.3.
Immunogenicit ywas evaluated in Phase 1 of Study BNT162 -01 and in allphases of Study
C4591001. The methods for evaluation of immunogenicity are provided in Section 2.5.4.2,
and results are provided in Section 2.5.4.4. Phase 3 immunogenicit y analyses areplanned to
be completed at a later time andare not included in this submission.
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Page 28Details of efficacy and immunogenicit y analysis methods in Study C4591001 are provided in
the Module 5.3.5.1 C4591001 Protocol and SAP, and forStudy BNT162- 01 are provided in
the Module 5.3.5.1 BNT162-01 Protocoland SAP.
2.5.4.1. Efficacy Endpoints and Analysis Methods
Methods and validation of the PCR test for efficacy anal yses are provided in Module2.7.1.
Details of efficacy evaluations are provided in Module 2.7.3 andsummarized below.
Statistical analy sis methods are summarized in Section 2.5.4.1.2.
2.5.4.1.1. EfficacyEndpoints in Study C4591001
Efficacy was assessed based on confirmed cases of COVID -19, where the case onset date
was the date that s ymptoms were first experienced by the participant and the cases met
evaluable criteria as summarized below .
2.5.4.1.1.1. Primary Efficacy Endpoints
Study C4591001 is the pivotal (and only ) efficacy study. The primary efficacy endpoints in
the Phase 3 part of the study were:
First primary endpoint : COVID-19 incidence per 1000 person- years of follow -up in
participants withoutserological or virological evidence of past SARS -CoV-2 infection
before and during the vaccination regimen – cases confirmed ≥7 day s after Dose 2
Second primary endpoint : COVID-19 incidence per 1000 person -years of follow -up in
participants with orwithoutevidence of SARS-CoV-2 infection before and during the
vaccination regimen –cases confirmed ≥7days after Dose 2.
2.5.4.1.1.2. Secondary Efficacy Endpoints
Study C4591001 has secondary endpoints based on different approaches to COVID- 19 case
evaluation criteria as follows:
COVID-19 confirmed at least 14 days after Dose 2 :COVID-19 incidence per
1000person-years of follow -up in participants either (1) withoutor (2) with or without
serological or virological evidence of past SARS -CoV-2 infection before and during the
vaccination regimen –cases confirmed ≥14days after Dos e 2
Severe COVID -19: incidence per 1000 person- years of follow -up in participants either
(1)withoutor (2) with or withoutevidence of past SARS -CoV-2 infection before and
during the vaccination regimen – cases confirmed either (1) ≥7 days after Dose 2 or
(2)≥14days after Dose 2
CDC-defined COVID -19: incidence per 1000 person- years of follow -up in participants
either (1) without or (2) withorwithoutevidence of SARS -CoV-2 infection before and
during the vaccination regimen – cases confirmed either (1) ≥7 days after Dose 2 or
(2)≥14days after Dose 2.
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Page 292.5.4.1.1.3. COVID-19 Case Determination
Participants who developed an y potential COVID -19 symptoms listed in the protocol were to
contact the site immediately and if confirmed to participate in an in- person or telehe alth visit
as soon as possible (optimally within 3 day s of symptom onset, and at the latest 4 day s after
symptom resolution). At the visit (or prior to the visit, if a participant utilized a self -swab as
permitted per protocol), investigators were to colle ct clinical information and results from
local standard- of-care tests sufficient to confirm a COVID -19 diagnosis.
Investigators were to obtain a nasal swab (mid -turbinate) for testing at a central laboratory
using a validated reverse transcription –polymerase chain reaction (RT- PCR) test (Cepheid;
EUA200047/A001) to detect SARS -CoV-2. If the evaluation was conducted by telehealth,
the participant was to self- collect a nasal swab and ship for assessment at the central
laboratory . Alocal nucleic acid amplification test ( NAAT) result was onl y acceptable if it
met protocol -specified criteria and if a central laboratory result was not available , in which
case a local NAAT result could be used if obtained using one of the following assays:
Cepheid Xpert Xp ress SARS- CoV-2
Roche cobas SARS -CoV-2 real-time RT-PCR test (EUA200009/A001)
Abbott Molecular/RealTime SARS -CoV-2 assay (EUA200023/A001).
Evidence of prior SARS-CoV-2infection were determined b y virological testing via NAAT
on mid-turbinate swab andserological testing for SARS -CoV-2 N-bindingantibodies.
Case Definitions
COVID-19 cases(defined per FDA guidance)17were based on SARS -CoV-2 positive test
result per central laboratory or local testing facility (using an acceptable test per protocol and
if no central laboratory result was available) and presence of atleast 1of the following :
Fever
New or increased cough
New or increased shortness of breath
Chills
New or increased muscle pain
New loss of taste or smell
Sore throat
Diarrhea
Vomiting
CDC criteria- defined COVID -19 cases could include the following additional symptoms:
Fatigue
Headache
Nasal congestion or runny nose
Nausea
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Page 30Severe COVID -19cases(defined per FDA guidance)17included presence of at least 1 of the
following :
Clinical signs at rest indicative of severe s ystemic illness :
Respiratory rate≥30 breaths per minute
Heart rate≥125 beats per minute
SpO2≤93% on room air at sea level or PaO2/FiO2 <300mm Hg
Respiratory failure:
needing high -flow oxygen
noninvasive ventilation
mechanical ventilation
ECMO
Evidence of shock :
Systolic blood pressure <90 mm Hg
Diastolic blood pressure <60 mm Hg
Requiring vasopressors
Significant acute renal, hepatic, or neurologic d ysfunction
Admission to an intensive care unit (ICU)
Death
Efficacy analysis for severe COVID -19 cases was also conducted using the CDC definition
of severe COVID -19 (hospitalization, admission to the ICU, intubation or mechanical
ventilation, or death ).18
2.5.4.1.2. EfficacyAnalysis Methods in Study C4591001
The statistical anal yses of efficacydata presented in this CO are from Study C4591001 and
werebased on the evaluable efficacy andall-available popu lations.
2.5.4.1.2.1. Sample Size Determination
ForPhase 1: thestudy sample size was not based on any statistical hy pothesis testing.
Efficacy was not evaluated in Phase 1.
For Phase 2/3 : the sample size assumeda true VE of 60% after the seconddose of study
intervention, for which a total of approximately 164 first confirmed COVID -19 illness cases
would provide approximately 90% power. This w ould be achieved with 17,600 evaluable
participants per group (or 21,999 vaccine recipients randomized i n a 1:1 ratio with placebo )
for a total sample size of 43,998 . This assume da 1.3% illness rate per year in the placebo
group, accrual of 164 primaryendpoint cases within 6 months, and 20% of the participants
being non -evaluable or having serological evid ence of prior infection with SARS -CoV-2
(potentially making them immune to further infection ).
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Page 312.5.4.1.2.2. EfficacyAnalysis Methods
The statistical anal yses of efficacydatafrom Study C4591001 were based on the evaluable
efficacypopulations and all -available efficacypopulations (described in Module 2.7.3).
Interim Analysis
During Phase 2/3, interim analy ses were pre -specified in the protocol to be conducted after
accrual of at least 62, 92, and 120 evaluable COVID- 19 cases, where overwhelming efficacy
could be declared if the primary endpoint was met with a posterior probability that the true
VE is >30% (ie, Pr[VE >30%| data] >99.5% at an interim anal ysis or >98.6% at the final
analysis). The success threshold for each interim analy sis was calibrated to protec t overall
type I error at 2.5%. Futility was also assessed, and the study could be stopped for lack of
benefit if the predicted probability of demonstrating vaccine efficacy at the final anal ysis was
<5% at an y of the first 2 planned interim anal yses. Efficacy and futility boundaries were
applied in a nonbinding way . The calculation of posterior probability and the credible
interval were adjusted for surveillance time. For subgroup anal yses of the primary efficacy
endpoint, a 2 -sided 95% confidence interval (CI) was calculated.
VE is defined as 100%×(1–IRR), where illness rate ratio (IRR) is calculated as the ratio of
first confirmed COVID -19 illness rate in the vaccine group to the corresponding illness rate in
the placebo group. VE is demonstrated if t here is convincing evidence (ie, posterior probability
greater than 99.5% at an interim analy sis or greater than 98.6% at the final anal ysis) that the
true VE of BNT162b2 is >30% using a beta- binomial model, where VE represents efficacy for
prophylactic BN T162b2 against confirmed COVID -19 in participants without evidence of past
SARS-CoV-2 infection before and during the vaccination regimen . Participants with positive
or unknown NAAT results at any illness visit prior to 7 day s after Dose 2 were not include d in
the evaluation for VE. Cases were counted from 7 day s after Dose 2.
Interim anal ysis was performed for the first primary efficacy endpoint onl y. Other efficacy
data analyzed for the interim analy sis were summarized with descriptive summary statistics,
including COVID -19 case counts in the BNT162b2 and placebo groups on the basis of:
evidence of prior SARS -CoV-2 infection at baseline per NAAT or N -antigen binding assay
demographic subgroup (ie, age, sex, race, ethnicity ,country)
COVID-19 cases meeting protocol criteria as severe after the first and second doses.
Overwhelming efficacy success criteria on the first primary efficacy endpoint were met at the
first planned interim analy sisof 94 accrued COVID -19 cases as of04 November 2020, after
whichadditionalformal interim anal yses werenot conducted.
Final Analysis
Thefinal analysis of primary and secondary efficacy endpoints was pre -specified in the
protocol to be conducted after accrual of the final number of COVID -19 cases (at least
164cases).Subgroup analy ses of VE based on baseline SARS -CoV-2 status and demographics
were performed for the primary endpoints and secondary endpoint of severe COVID-19 cases.
Additional post hoc analyses of subgroups defined by comorbidity risk assessment were
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Page 32performed. Secondary efficacy was analy zedin the same manner as primary efficacy
(Section 2.5.4.1.2.2 ), using the case definitions for severe COVID -19and CDC criteria for
COVID-19 (Section2.5.4.1.1.2 ).
Final anal ysisof efficacy was based on 170 COVID -19 cases accrued in the evaluable efficacy
population of participants without evidence of past SARS-CoV-2 infection before and during
the vaccination regimen as of 14 November 2020. The prespecified final analy ses of efficacy
included primary and secondary endpoints in the evaluable and all -available efficacy
populations. No additional formal h ypothesis testing for anal yses of clinically confirmed
COVID-19 casesis planned.
Updated Analysis
Following the protocol specified interim analy sis of efficacy and final analy sis of efficacy ,
updateddescriptive efficacy analyses were conducted for the two primary efficacy endpoints,
including subgroup analyses,and for the secondary efficacy endpoint of severe disease , using
statistical methods described in the study statistical analy sis plan.
The point estimate of V Eand associated 2 -sided 95% CI derived using the Clopper -Pearson
method adjusted for s urveillance timewere provided as descriptive summary . Updated
analyses in the EUA amendment include COVID- 19 cases accrued inblinded follow -up to the
data cutoff date (13 March 2021).
2.5.4.2.Immunogenicity Endpoints and Analysis Methods
Assay methods and qualification /validation reports for immunoassay sare provided in
Module2.7.1.Details of i mmunogenicit y analyses are provided in Module 2.7.3 and
summarized below. Statistical anal ysis methods are provided in Section 2.5.4.2.3.
2.5.4.2.1. Immunogenicity Endpoints in Study BNT162- 01
In Study BNT162 -01, immunogenicit y was evaluated in Phase 1 using a SARS -CoV-2 serum
neutralization assay to determine neutralizing titers and the fold rise in SARS -CoV-2 serum
neutralizing titers. Only validated neutralization assay s were used. Immunogenicity was assessed
at Day 1 (before Dose 1) and at 7 days after Dose 1 (Day 8); and at Day 22 (before Dose 2) and
at 7 daysafter Dose 2 (Day 29), 21daysafter Dose 2 (Day 43), 28days(approximately 1 month)
after Dose 2 (Day 50), and 63days (9 weeks or approximately 2months) after Dose 2(Day 85).
T cells isolated from peripheral blood mononuclear cells (PBMCs) obtained from whole blood
samples o f vaccinated Phase 1 participants were evaluated by enzyme-linked immuno -spot
(ELISPOT) and intracellular cy tokine staining visualized with fluorescence- activated cell
sorting (FACS). Blood samples were collected prior to Dose 1and on Day 29 (7 day s after
Dose 2). In a subsetof study participants who receiv ed10, 20, and 30 µg BNT162b2, blood
samples were also collected on Day 85 (63 days, or approximately 2 months ,after Dose 2) and
Day184 (162days,or approximately 6 months, after Dose 2) andanalyzed.Assessments
included cy tokines associated with Th1 responses such as IFN and IL-2 and those associated
with Th2 responses such as IL -4, to analy ze the induction of balanced versus Th1 -dominant or
Th2-dominant immune responses .
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Page 332.5.4.2.2. Immunogenicity Endpoints in Study C4591001
In Study C4591001, immunogenicity was evaluated in Phase 1 and Phase 2 using a
SARS-CoV-2 serum neutralization assay to determine titers and a SARS -CoV-2 RBD-or
S1-binding IgG direct Luminex immunoassay to determine antibod y binding levels. Only
validated neutralization andqualified Luminex assays were used.
In Phase 1, immunogenicity was assessed at Day 1 (before Dose 1) and 7 day s after Dose 1;
and at Day 21 (before Dose 2) and 7 day s, 14days, 1month, and 6monthsafter Dose 2.
Datawere summarized for each dose level and age group.
In Phase 2, immunogenicity was assessed at Day 1 (before Dose 1) and 1 month after Dose 2.
Data were summarized byage group and by evidence of prior SARS -CoV-2 infection at
baseline per NAAT (PCR) or N- binding IgG assay. Data from the 6 -month post Dose 2 time
point were not available at the time of the submission data cutoff date (13 March 2021) .
In Phase 2/3, exploratory immunogenicit y assessments are planned at time points up to
24months, to be reported at a later time.
2.5.4.2.3. Immunogenicity Analysis Methods
2.5.4.2.3.1. Immunogenicity Analysis Methods in Study BNT162 -01
The statistical anal yses of immunogenicit y datafrom Study BNT162-01 werebased on the
immunogenicit y set(described in Module 2.7.3).
Immunogenicit y data from the SARS -CoV-2 neutralization assay were analyzedfor Study
BNT162-01 participants similarly to data in Study C4591001 (refer to Section 2.5.4.2.3.2 ).
T cells were isolated from CD4- and CD8- depleted PBMCs obtained from whole blood
samples of vaccinated Phase 1 participants. PBMCs were tested for antigen induced cy tokine
production, evalu ated by ELISPOT and intracellular cy tokine staining with FACS anal ysis.
ELISPOT
Sample controls included anti -CD3 antibody -mediated stimulation (positive), medium
(negative), and an optional mix of viral antigens for T cell response benchmarking:
CEF:HLA classI restricted peptides originating from cytomegalovirus (CMV), Epstein -
Barr Virus (EBV) ,and influenza virus, which are expected to stimulate IFNproduction
from CD8+Tcells in the majority of donors.
CEFT:HLA class II restricted peptides originat ing from CMV, EBV, influenza virus,
and tetanus toxin, which are expected to stimulate IFNproduction from CD 4+Tcells in
the majority of donors.
The ELISPOT assay was used to measure the frequency of cytokine-secreting cells in
samples of peripheral blo od mononuclear cells (PBMCs) obtained from whole blood samples
of vaccinated participants. Briefly, PBMCs enriched for CD4+ or CD8+effector cells were
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Page 34placed in ELISPOT plates pre-coated with antibodies specific for IFNγ and incubated
overnight ( ≥18 hours) with peptides originating from the vaccine antigens (ie, from RBD or
full-length S protein). IFNsecreted b y CD4+ or CD8+ cells in response to stimulation by
the peptides was bound to the plate by the coating antibody .After incubation, the plates were
developed b y addition of alkaline phosphatase conjugated secondary anti-IFNγ antibody
followed b y enzyme substrate; each spot corresponds to the IFN secreted by a single cell.
Developed plates wereread by an AID ELISPOTReader.
Intracellular C ytokine S taining withFACS Analysis
Intracellular cy tokine staining is a flow cy tometry-based assay to detect production and
accumulation of cy tokines intracellularl y upon cell stimulation. Antigen s timulation was
performed using sy nthetic peptides covering the encoded antigens (eg,15-mer overlapping
peptides covering the whole length of the vaccine antigen with 11 amino acid overlap). These
peptide pools represent the vaccine -encoded SARS -CoV-2 RBD, and SARS-CoV-2 S1
subpool 1 an d subpool 2 pepmix es as well as a combination of subpool 1 and subpool 2.
Briefly, vaccine antigen -stimulated PBMCs were treated with protein transport inhibitors to
retain intracellular cy tokines and labelled on the extracellular surface with fluor -conjugated
antibodies for CD4, CD8, and CD3. PBMCs were fixed and permeabilized for intracellular
cytokine staining of cy tokines with fluor -conjugated antibodies, and samples were anal yzed
using FACS on a fl ow cytometer to visualize the proportions of vaccine antigen -specific Th1
and Th2 CD4+ T cells and cy totoxic CD8+ T cells producing each cy tokine.
Comparisons between pre -and post-vaccination samples for each subject were used as a
surrogate for inductio n or expansion of cellular immune responses, and to characterize the
balance of generated Th1 and Th2 responses upon vaccination. F or benchmarking, PBMCs
from recovered COVID -19 patients were used.
2.5.4.2.3.2. Immunogenicity Analysis Methods in Study C4591001
The statistical anal yses of immunogenicit y datafrom Study C4591001 were based on the
evaluable immunogenicity population s and all-available immunogenicit y populations
(described in Module 2.7.3).
Data were reported for SARS-CoV-2 serum neutralizing titers and SAR S-CoV-2 S1-binding
and RBD-binding IgG concentrations , including :
geometric mean titers/concentrations (GMTs/GMCs)
geometric mean -fold rise (GMFR)
For immunogenicity results of SARS -CoV-2 serum neutralizing titers and S 1-or RBD-
binding IgG concentrations, GMTs or GMCs were computed with associated 95% CIs. The
GMTs and GMCs were calculated as the mean of assay results after logarithm transformation
and then exponentiating the mean to express results on the original scale. Two -sided 95% CIs
were obtained b y taking log -transforms of titers, calculating the 95% CI with reference to
Student’s t -distribution, and then exponentiating the confidence limits .
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Page 35GMFRs werelimited to participants with non -missing values prior to first dose and the post-
dosetime point. The GMFR was calculated b y exponentiating the mean of the difference of
logarithm transformed assay results: (later time point )– (earlier time point). Two -sided CIs
were obtained b y calculating CIs using Student’s t -distribution for the mean difference of the
logarithm transformed assay results and exponentiating the confidence limits.
Exact 95% CI sfor binary endpoints were computed using F distribution (Clopper -Pearson).
2.5.4.2.3.3. Human Convalescent Sera Panel for Serology Comparisons
To facilitate interpretation of immunogenicit y data generated in StudiesBNT162-01 and
C4591001, a human convalescent serum (HCS) panel was obtained from Sanguine Biosciences
(Sherman Oaks, CA), MT Group (Van Nu ys, CA), and Pfizer Occupational Health and
Wellness ( Pearl River, NY).19,20The 38 sera in the panel were collected from SARS-CoV-2
infected or COVID -19 diagnosed individuals 18 to 83 years of age ≥14 days after PCR -
confirmed diagnosis at a time when they were asymptomatic . The serum donors had
predominantly had symptomatic infections (35 /38) including 1 who had been hospitalized.
2.5.4.3.EfficacyResults
Details of e fficacy analysis results from the first planned (and successful) interim anal ysis
and the planned final analy sis of efficacy are provided in Module 5.3.5.1 C4591001 Efficacy
Final Anal ysis Interim CSRSection 10 and Section 11 .Updatedefficacy results are provided
in Module 5.3.5.1 C4591001 6- Month UpdateInterim CSRSection 10 and Section 11 .
Allefficacy data are also presented in Module 2.7.3 andsummarized below.
2.5.4.3.1. Interim Analysis of Efficacy in Study C4591001
A prespecified interim analy sis of efficacy was conducted after accrual of 94 COVID -19
cases. Efficacy data for the Phase 3 portion of Study C4591001 were anal yzed for all
enrolled participants who met the protocol- specified criteria for efficacy evaluation, with an
interim analy sis cutoff date of 04 November 2020. Data are summarized for the efficacy
populations. Additional analy ses were conducted by subgroups (age, sex, race , ethnicity,
country, and baseline SARS -CoV-2 status).
COVID-19 case evaluation is discussed in Section 2.5.4.1. For the first primary efficacy
endpoint, VEfor BNT162b2 against confirmed COVID- 19 was evaluated in participants
without evidence of pastSARS-CoV-2 infection before and during the vaccination regimen .
Participants with positive or unknown NAAT results at any illness visit prior to 7 day s after
Dose 2 were not included in VE evaluation. Cases were counted from 7 days after Dose 2.
Efficacy population characteristics in the interim anal ysis are presented in
Section 2.5.4.3.1.1 , and results of the interim analy sis are presented in Section 2.5.4.3.1.2
(first prima ry endpoint) and Section 2.5.4.3.1.3 (additional descriptive results).
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Page 362.5.4.3.1.1. Efficacy Populations – Interim Analysis
The proportions of participants includ ed in the interimanalysis efficacy populations was
similar in the BNT162b2 and placebo groups ( Table1). Most particip ants who were excluded
from the evaluable efficacy population had not received all vaccinations as randomized or
did not receive Dose 2 within the predefined window (ie, 19 to 42 days after Dose 1). There
were 302participants (1.4%) in the BNT162b2 group and 52 participants (0.2%) in the
placebo group excluded for having important protocol deviations on or prior to 7 days after
Dose2.
Table1.Efficacy Populations – Interim Analysis 1
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
na(%)Placebo
na(%)Total
na(%)
Randomizedb21653 (100.0) 21672 (100.0) 43325 (100.0)
Dose 1 all -available efficacy population 21617 (99.8) 21633 (99.8) 43250 (99.8)
Subjects without evidence of infection before Dose 1 17237 (79.6) 17221 (79.5) 34458 (79.5)
Subjects excluded from Dose 1 all -available efficacy population 36 (0.2) 39 (0.2) 75 (0.2)
Reason for exclusionc
Did not receive at least 1 vaccination 35 (0.2) 39 (0.2) 74 (0.2)
Did not provide informed consent 1 (0.0) 0 1 (0.0)
Dose 2 all -available efficacy population 18868 (87.1) 18877 (87.1) 37745 (87.1)
Subjects without evidence of infection prior to 7 days after
Dose 216463 (76.0) 16426 (75.8) 32889 (75.9)
Subjects excluded from Dose 2 all -available efficacy population 2785 (12.9) 2795 (12.9) 5580 (12.9)
Reason for exclusionc
Did not complete 2 vaccination doses 2784 (12.9) 2795 (12.9) 5579 (12.9)
Did not provide informed consent 1 (0.0) 0 1 (0.0)
Evaluable efficacy population (7 Days) 18380 (84.9) 18618 (85.9) 36998 (85.4)
Subjects without evidence of infection prior to 7 days after
Dose 216061 (74.2) 16218 (74.8) 32279 (74.5)
Subjects excluded from evaluable efficacy population (7 Days) 3273 (15.1) 3054 (14.1) 6327 (14.6)
Reason for exclusionc
Randomized but did not meet all eligibility criteria 15 (0.1) 16 (0.1) 31 (0.1)
Did not provide informed consent 1 (0.0) 0 1 (0.0)
Did not receive all vaccination(s) as randomized or did not
receive Dose 2
within the predefined window (19 -42 days after Dose 1)3038 (14.0) 3035 (14.0) 6073 (14.0)
Had other important protocol deviations on or prior to 7 days
after Dose 2302 (1.4) 52 (0.2) 354 (0.8)
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Page 37Table1.Efficacy Populations – Interim Analysis 1
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
na(%)Placebo
na(%)Total
na(%)
Note: Data from subjects who are not confirmed 7 days post dose 2 cases are included in the analysis to comprehensively
show all data reported and/or contribute to the total surveillance time calculation but may be subject to change with
additional follow -up.
a.n = Number of subjects with the specified characteristic.
b.These values are the denominators for the percentage calculations.
c.Subjects may have been excluded for more than 1 reason.
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Demographics of participants in the interim analy sis evaluable efficacy population for
participants without evidence of infection before and during the vaccination regimen were
similar in theBNT162b2 and placebo groups (Table2). This anal ysispopulation had
generallysimilar demographics compared to the safet y population (refer to Section 2.5.5.5.1 ).
Demographic characteristics for the interim anal ysis Dose 2 all -available efficacy population
were similar to the evaluable efficacy population.
Table2.Demographic Characteristics – Subjects Without Evi dence of Infection
Prior to 7 Days After Dose 2 – Evaluable Efficacy Population (7 Days) –
Interim Analysis 1
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=16061)
nb(%)Placebo
(Na=16218)
nb(%)Total
(Na=32279)
nb(%)
Sex
Male 8197 (51.0) 8144 (50.2) 16341 (50.6)
Female 7864 (49.0) 8074 (49.8) 15938 (49.4)
Race
White 13502 (84.1) 13692 (84.4) 27194 (84.2)
Black or African American 1298 (8.1) 1303 (8.0) 2601 (8.1)
American Indian or Alaska native 88 (0.5) 82 (0.5) 170 (0.5)
Asian 712 (4.4) 716 (4.4) 1428 (4.4)
Native Hawaiian or other Pacific Islander 40 (0.2) 26 (0.2) 66 (0.2)
Multiracial 341 (2.1) 297 (1.8) 638 (2.0)
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Page 38Table2.Demographic Characteristics – Subjects Without Evi dence of Infection
Prior to 7 Days After Dose 2 – Evaluable Efficacy Population (7 Days) –
Interim Analysis 1
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=16061)
nb(%)Placebo
(Na=16218)
nb(%)Total
(Na=32279)
nb(%)
Not reported 80 (0.5) 102 (0.6) 182 (0.6)
Ethnicity
Hispanic/Latino 4415 (27.5) 4383 (27.0) 8798 (27.3)
Non-Hispanic/non -Latino 11553 (71.9) 11736 (72.4) 23289 (72.1)
Not reported 93 (0.6) 99 (0.6) 192 (0.6)
Country
Argentina 2445 (15.2) 2415 (14.9) 4860 (15.1)
Brazil 889 (5.5) 889 (5.5) 1778 (5.5)
South Africa 215 (1.3) 218 (1.3) 433 (1.3)
USA 12512 (77.9) 12696 (78.3) 25208 (78.1)
Age group
16-55 Years 9093 (56.6) 9172 (56.6) 18265 (56.6)
>55 Years 6968 (43.4) 7046 (43.4) 14014 (43.4)
Age at vaccination (years)
Mean (SD) 50.9 (15.58) 50.7 (15.68) 50.8 (15.63)
Median 52.0 52.0 52.0
Min, max (16, 89) (16, 91) (16, 91)
Note: Data from subjects who are not confirmed 7 days post dose 2 cases are included in the analysis to comprehensively
show all data reported and/or contribute to the total surveillance time calculation but may be subject to change with
additional follow -up.
a.N = number of subjects in the specified group, or the total sample. This value is the denominator for the percentage
calculations.
b.n = Number of subjects with the specified characteristic.
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Page 392.5.4.3.1.2. Primary Efficacy – Interim Analysis
Among participants included in the evaluable efficacy population, 32,279 participants overall
(16,061 in the BNT162b2 group and 16,218 in the placebo groups) did not have evidence of
prior infection with SARS- CoV-2 through 7 day s after Dose 2 (Table2).
As of the ti me of the interim analy sis, there were 4 confirmed COVID-19 cases in the
BNT162b2 group and 90 confirmed COVID -19 cases in the placebo group (Table3).
Allevaluable cases were confirmed b y tests conducted at the central laboratory.
VE for BNT162b2 against confirmed COVID -19 cases was evaluated in participants without
evidence of pastSARS-CoV-2 infection before and during the vaccination regimen with
cases counted from 7 days after Dose 2.
VE of BNT162b2 was 95.5% with a >99.99% posterior probabilit y for the true VE being
>30% conditioning on available data, to overwhelmingly meet the prespec ified interim
analysis success criterion (>99.5%).
The 95% credible interval for the vaccine efficacy was 88.8% to 98.4%, indicating that given
these observed data there was a 95% probability that the true VE lies in this interval. Also,
note that the posterior probability that true VE >86.0% is 99.5% and VE >88.8% is 97.5%.
VE of BNT162b2 for the same primary efficacy endpoint based on the all- available efficacy
population was 95.7%, with 4 cases in the BNT162b2 group and 93 cases in the placebo group .
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Page 40Table3.Vaccine Efficacy – First COVID -19 Occurrence From 7 Days After Dose 2
–Subjects Without Evidence of Infection Prior to 7 Days After Dose 2 –
Evaluable Efficacy Population (7 Days) – Interim Analysis 1
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=16061)Placebo
(Na=16218)
Efficacy Endpoint n1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE
(%)(95%
CIe)Pr (VE >30% |
data)f
First COVID -19 occurrence from
7 days after Dose 241.722 (15899) 901.732 (16010) 95.5(88.8,
98.4)>0.9999
Abbreviations: N -binding = SARS -CoV-2 nucleoprotein-binding; NAAT = nucleic acid amplification test; SARS-CoV -2 =
severe acute respiratory syndrome coronavirus 2; VE = vaccine efficacy.
Note: Subjects who had no serological or virological evidence (prior to 7 days after receipt of the last dose) of past SARS -
CoV-2 infection (ie, N -binding antibody [serum] negative at Visit 1 and SARS-CoV -2 not detected by NAAT [nasal swab]
at Visits 1 and 2), and had negative NAAT at any unscheduled visit p rior to 7 days after Dose 2 were included in the
analysis.
Note: Data from subjects who are not confirmed 7 days post dose 2 cases are included in the analysis to comprehensively
show all data reported and/or contribute to the total surveillance time calcu lation but may be subject to change with
additional follow -up.
a.N = number of subjects in the specified group.
b.n1 = Number of subjects meeting the endpoint definition.
c.Total surveillance time in 1000 person -years for the given endpoint across all subjects within each group at risk for
the endpoint. Time period for COVID -19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
d.n2 = Number of subjects at risk for the endpoint.
e.Credible interval for VE was calculated using a beta -binomial model with prior beta (0.700102, 1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details.
f.Posterior probability (Pr) was calculated using a beta -binomial model w ith prior beta (0.700102, 1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details. This probability must be at least
99.5% at the interim analysis in order to conclude that the vaccine is efficacious.
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Efficacy in Subgroups –Interim Analysis
VE in participants without prior evidence of SARS -CoV-2 infection was further evaluated b y
subgroups based on age, sex, race, ethnicity, and country . VE was >90% in all subgroups
(Table4).
Results for the Dose 2 all -available population were similar, withno clinically meaningful
differences in VE on the basis of subgroup.
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Page 41Table4.Vaccine Efficacy – First COVID -19 Occurrence From 7 Days After Dose 2,
by Subgroup –Subjects Without Evidence of Infection Prior to 7 Days
After Dose 2 –Evaluable Efficacy Population (7 Days) – Interim Analysis 1
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=16061)Placebo
(Na=16218)
Efficacy Endpoint
Subgroupn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE (%) (95% CIe)
First COVID -19 occurrence from 7 days
after Dose 2
Overall 41.722 (15899) 901.732 (16010) 95.5 (88.1, 98.8)
Age group (years)
16 to 55 20.954 (8994) 670.959 (9040) 97.0 (88.7, 99.6)
>55 20.767 (6905) 230.773 (6970) 91.2 (64.6, 99.0)
Sex
Male 20.874 (8115) 380.865 (8029) 94.8 (79.8, 99.4)
Female 20.848 (7784) 520.867 (7981) 96.1 (85.1, 99.5)
Race
White 41.477 (13399) 851.491 (13530) 95.3 (87.4, 98.7)
Black or African American 00.124 (1263) 40.124 (1277) 100.0 (-51.8, 100.0)
All othersf00.121 (1237) 10.118 (1203) 100.0 (-3690.1, 100.0)
Ethnicity
Hispanic/Latino 10.464 (4389) 340.459 (4342) 97.1 (82.7, 99.9)
Non-Hispanic/non -Latino 31.247 (11418) 561.262 (11570) 94.6 (83.3, 98.9)
Country
Argentina 00.271 (2436) 280.266 (2402) 100.0 (86.2, 100.0)
Brazil 00.087 (878) 20.087 (879) 100.0 (-432.5, 100.0)
USA 41.360 (12384) 601.376 (12530) 93.3 (81.8, 98.2)
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Page 42Table4.Vaccine Efficacy – First COVID -19 Occurrence From 7 Days After Dose 2,
by Subgroup –Subjects Without Evidence of Infection Prior to 7 Days
After Dose 2 –Evaluable Efficacy Population (7 Days) – Interim Analysis 1
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=16061)Placebo
(Na=16218)
Efficacy Endpoint
Subgroupn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE (%) (95% CIe)
Abbreviations: N -binding = SARS -CoV-2 nucleoprotein-binding; NAAT = nucleic acid amplification test; SARS-CoV -2 =
severe acute respiratory syndrome coronavirus 2; VE = vaccine efficacy.
Note: Subjects who had no serological or virological evidence (prior to 7 days after receipt of the last dose) of past SARS -
CoV-2 infection (ie, N -binding antibody [serum] negative at Visit 1 and S ARS-CoV-2 not detected by NAAT [nasal swab]
at Visits 1 and 2), and had negative NAAT at any unscheduled visit prior to 7 days after Dose 2 were included in the
analysis.
Note: Data from subjects who are not confirmed 7 days post dose 2 cases are included in the analysis to comprehensively
show all data reported and/or contribute to the total surveillance time calculation but may be subject to change with
additional follow -up.
a.N = number of subjects in the specified group.
b.n1 = Number of subj ects meeting the endpoint definition.
c.Total surveillance time in 1000 person -years for the given endpoint across all subjects within each group at risk for
the endpoint. Time period for COVID -19 case accrual is from 7 days after Dose 2 to the end ofthe surveillance period.
d.n2 = Number of subjects at risk for the endpoint.
e.Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted to the surveillance
time.
f.American Indian or Alaska native, Asian, Native Hawaiian or other Pacific Islander, multiracial, not reported race
categories are presented as “All others”.
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2.5.4.3.1.3. Additional Descriptive Efficacy Results – Interim Analysis
2.5.4.3.1.3.1. Vaccine Efficacy by Baseline SARS- CoV-2 Status – Interim Analysis
COVID-19 cases evaluable for efficacy after Dose 2 were further evaluated by participant
SARS-CoV-2 status at baseline (ie, evidence of prior infection with SARS- CoV-2).
At the time of the interim anal ysis, there were 2 participants in the evaluable effic acy
population who had evaluable COVID -19 and were baseline positive for prior SARS -CoV-2
infection: 1 participant in the BNT162b2 group and 1 participant in the placebo group.
Results were similar for the Dose 2 all -available population (ie, 1 participan t with COVI D-19
in each group was baseline SARS- CoV-2 positive.
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Page 432.5.4.3.1.3.2. Efficacy for Severe COVID-19 Cases –Interim Analysis
Severe cases of COVID -19 were evaluated from after Dose 1 onwards, reported for the
Dose1 all -available efficacy population (see efficacy analysis populations in
Section 2.5.4.3.1.1 ).
As of the time of the interim analy sis of efficacy, a total of 7 severe cases of COVID -19 were
reported as occurring from Dose 1 onwards ( Table5). All of these severe cases were reported
in the placebo group. Of these, 5 of 7 severe cases were reported as occurri ng after Dose 1
and prior to Dose 2; the remaining 2 cases were reported ≥7 days after Dose 2.
Of these 7 severe cases reported in the placebo group, all were confirmed as being
SARS-CoV-2 negative at baseline.
Severe COVID -19 cases are also discussed in Section 2.5.5.7.1with regard to safet y and the
hypothetical risk of vaccine -associated enhanced disease (VAED) including vaccine-
associated enhanced respiratory disease (VAERD).
Table5.Severe COVID -19 Occurrence After Dose 1 – Dose 1 All -Available Efficacy
Population – Interim Analysis 1
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=21617)Placebo
(Na=21633)
Efficacy Endpoint nbnb
Severe COVID-19 occurrence after Dose 1 0 7
Note: Data from subjects who are not confirmed 7 days post dose 2 cases are included in the analysis to comprehensively
show all data reported and/or contribute to the total surveillance time calculation but may be subject to change with
additional follow -up.
a.N = number of subjects in the specified group.
b.n = Number of subjects meeting the endpoint definition.
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Page 442.5.4.3.1.4. Efficacy Conclusions –Interim Analysis
Interim Analysis of Efficacy Against Confirmed COVID -19
The first primary efficacy objective met success criteria at the first interim anal ysis
performed on an accrued 94 cases of COVID -19. BNT162b2 achieved VE of 95.5% with a
95% credible interval of 88.8% to 98.4% among participants without evidence of infect ion
before and during the vaccination regimen, and a >99.99% posterior probability for the true
VE being >30%, conditioning on available data.
InterimAnalysis of Efficacy in Subgroups
There was no clinicall y meaningful difference in VE for the first prima ry efficacy endpoint
by participant subgroup, as VE was >90% across age groups, for both male and female
participants, across race and ethnic groups, and on the basis of geographic location across
study countries.
Evaluation of efficacy among participants who had COVID- 19 based on prior SARS -CoV-2
infection status showed 2 participants with COVID -19 cases were SARS -CoV-2 positive at
baseline, 1 in each group.
InterimAnalysis of Efficacy Against Severe Disease
A total of 7 severe cases of COVID -19 were rep orted in the interim anal ysis of efficacy , with
5cases reported after Dose 1 and prior to Dose 2 and the remaining 2 cases reported ≥7 days
after Dose 2. All severe cases were reported in placebo recipients and none were reported in
BNT162b2 recipients. N one were baseline positive for SARS- CoV-2.
Overall Conclusions from Interim Analysis of Efficacy
The interim anal ysis efficacy results suggest BNT162b2 at 30 µg provided protection against
COVID-19 overall and across subgroups of participants who had no evidence of prior
infection with SARS -CoV-2, with severe cases observed exclusively in the placebo group.
2.5.4.3.2. Final Analysis of Efficacy in Study C4591001
Efficacy data for the Phase 3 portion of Study C4591001 were anal yzed for all enrolled
participants who m et the protocol -specified criteria for efficacy evaluation, in the
prespecified final anal ysis of primary and secondary endpoints after accrual of 170 confirmed
COVID-18 cases, with a final anal ysis cutoff date of 14 November 2020. Data were analy zed
for the efficacy populations.
COVID-19 case evaluation for primary and secondary efficacy endpoints is discussed in
Section 2.5.4.1 .Efficacy endpoints evaluated confirme d COVID -19 cases in participants
either without or with or without evidence of prior SARS -CoV-2 infection before and during
the vaccination regime n. Participants with positive or unknown NAAT results at any illness
visit prior to either 7 days after Dose 2 or 14 day s after Dose 2 (depending on the primary or
secondary endpoint definition) were not included in the evaluation for VE. Cases were
counted from either 7 days or 14 day s (depending on the endpoint definition) after Dose 2.
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Page 45Efficacy population characteristics in the final analy sis are presented in Section 2.5.4.3.2.1.1 ,
and results of the final analy sis are presented in Section 2.5.4.3.2.1.2 (primary endpoints) and
Section 2.5.4.3.2.1.3 (secondary endpoints).
2.5.4.3.2.1.1. Efficacy Populations –Final Analysis
The proportions of participants included in the final anal ysis efficacy populations was similar
in the BNT162b2 and placebo groups ( Table6). Most particip ants who were excluded from
the evaluable efficacy population had not received all vaccinations as randomized or did not
receive Dose 2 within the predefined window (ie, 19 to 42 days after Dose 1).
There were 311 participants (1.4%) in the BNT162b2 group and 60 participants (0.3%) in the
placebo group excluded for having important protocol deviations on or prior to 7 days after
Dose2. A post hoc evaluation was performed to assess the imbalance of these important
protocol deviations in the BNT162b2 and placebogroupsfor the final anal ysis of efficacy .
This showed that the majority ofexclusions from the evaluable efficacy (7days) population
in the BNT162b2 group were due to dosing/administration errors or administration of study
intervention that was deemed not suitable for use. This is detailed in the C4591001 Final
Analysis Interim CSRand in Module 2.7.3 .
Table6.Efficacy Populations
Vaccine Group (as
Randomized)
BNT162b2 (30
μg)
na(%)Placebo
na(%)Total
na(%)
Randomizedb21823 (100.0) 21828 (100.0) 43651 (100.0)
Dose 1 all -available efficacy population 21768 (99.7) 21783 (99.8) 43551 (99.8)
Subjects without evidence of infection before Dose 1 20314 (93.1) 20296 (93.0) 40610 (93.0)
Subjects excluded from Dose 1 all -available efficacy population 55 (0.3) 45 (0.2) 100 (0.2)
Reason for exclusionc
Did not receive at least 1 vaccination 54 (0.2) 45 (0.2) 99 (0.2)
Did not provide informed consent 1 (0.0) 0 1 (0.0)
Dose 2 all -available efficacy population 20566 (94.2) 20536 (94.1) 41102 (94.2)
Subjects without evidence of infection prior to 7 days after Dose 2 18701 (85.7) 18627 (85.3) 37328 (85.5)
Subjects without evidence of infection prior to 14 days after Dose 2 18678 (85.6) 18563 (85.0) 37241 (85.3)
Subjects excluded from Dose 2 all -available efficacy population 1257 (5.8) 1292 (5.9) 2549 (5.8)
Reason for exclusionc
Did not receive 2 vaccinations 1256 (5.8) 1292 (5.9) 2548 (5.8)
Did not provide informed consent 1 (0.0) 0 1 (0.0)
Evaluable efficacy (7 days) population 20033 (91.8) 20244 (92.7) 40277 (92.3)
Subjects without evidence of infection prior to 7 days after Dose 2 18242 (83.6) 18379 (84.2) 36621 (83.9)
Evaluable efficacy (14 days) population 20033 (91.8) 20243 (92.7) 40276 (92.3)
Subjects without evidence of infection prior to 14 days after Dose 2 18219 (83.5) 18315 (83.9) 36534 (83.7)
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Page 46Table6.Efficacy Populations
Vaccine Group (as
Randomized)
BNT162b2 (30
μg)
na(%)Placebo
na(%)Total
na(%)
Subjects excluded from evaluable efficacy (7 days) population 1790 (8.2) 1584 (7.3) 3374 (7.7)
Subjects excluded from evaluable efficacy (14 d ays) population 1790 (8.2) 1585 (7.3) 3375 (7.7)
Reason for exclusionc
Randomized but did not meet all eligibility criteria 36 (0.2) 26 (0.1) 62 (0.1)
Did not provide informed consent 1 (0.0) 0 1 (0.0)
Did not receive all vaccinations as randomized or did not receive
Dose 2
within the predefined window (19 -42 days after Dose 1)1550 (7.1) 1561 (7.2) 3111 (7.1)
Had other important protocol deviations on or prior to 7 days after
Dose 2311 (1.4) 60 (0.3) 371 (0.8)
Had other important protocol deviations on or prior to 14 days after
Dose 2311 (1.4) 61 (0.3) 372 (0.9)
Note: HIV -positive subjects are included in this summary but not included in the analyses of the overall study objectives.
a.n = Number of subjects with the specified characteristic.
b.These values are the denominators for the percentage calcul ations.
c.Subjects may have been excluded for more than 1 reason.
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Demographics of participants in the final anal ysis evaluable efficacy population for
participants without evidence of infection prior to 7 days after Dose2 were similar in the
BNT162b2 and placebo groups (Table7). This analy sispopulation had generall y similar
demographics compared to the safet y population (refer to Section 2.5.5.5.1 ).
Demographic characteristics for the final anal ysis Dose 2 all -available efficacy population
and the evaluable population without evidence of infection prior to 14 day s after Dose 2 were
similar to the Dose 2 evaluable efficacy (7 days) population.
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Page 47Table7.Demographi c Characteristics – Subjects Without Evidence of Infection
Prior to 7 Days After Dose 2 – Evaluable Efficacy (7 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=18242)
nb(%)Placebo
(Na=18379)
nb(%)Total
(Na=36621)
nb(%)
Sex
Male 9318 (51.1) 9225 (50.2) 18543 (50.6)
Female 8924 (48.9) 9154 (49.8) 18078 (49.4)
Race
White 15110 (82.8) 15301 (83.3) 30411 (83.0)
Black or African American 1617 (8.9) 1617 (8.8) 3234 (8.8)
American Indian or Alaska native 118 (0.6) 106 (0.6) 224 (0.6)
Asian 815 (4.5) 810 (4.4) 1625 (4.4)
Native Hawaiian or other Pacific Islander 48 (0.3) 29 (0.2) 77 (0.2)
Multiracial 448 (2.5) 402 (2.2) 850 (2.3)
Not reported 86 (0.5) 114 (0.6) 200 (0.5)
Ethnicity
Hispanic/Latino 4886 (26.8) 4857 (26.4) 9743 (26.6)
Non-Hispanic/non -Latino 13253 (72.7) 13412 (73.0) 26665 (72.8)
Not reported 103 (0.6) 110 (0.6) 213 (0.6)
Country
Argentina 2561 (14.0) 2539 (13.8) 5100 (13.9)
Brazil 1232 (6.8) 1223 (6.7) 2455 (6.7)
Germany 121 (0.7) 126 (0.7) 247 (0.7)
South Africa 287 (1.6) 279 (1.5) 566 (1.5)
USA 14041 (77.0) 14212 (77.3) 28253 (77.1)
Age group
12-15 Years 46 (0.3) 42 (0.2) 88 (0.2)
16-55 Years 10428 (57.2) 10507 (57.2) 20935 (57.2)
>55 Years 7768 (42.6) 7830 (42.6) 15598 (42.6)
≥65 Years 3980 (21.8) 4038 (22.0) 8018 (21.9)
Age at vaccination (years)
Mean (SD) 50.6 (15.70) 50.4 (15.81) 50.5 (15.76)
Median 52.0 52.0 52.0
Min, max (12, 89) (12, 91) (12, 91)
Note: HIV -positive subjects are included in this summary but not included in the analyses of the overall study objectives.
a.N = number of subjects in the specified group, or the total sample. This value is the denominator for the percentage
calculations.
b.n = Number of subjects with the specified characteristic.
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Page 482.5.4.3.2.1.2. Primary Efficacy – Final Analysis
For the first primary efficacy endpoint, VE for BNT162b2 against confirmed COVID -19 was
evaluated in participants withoutevidence of past SARS-CoV-2 infection before and during
the vaccination regimen. Cases were counted from 7 day s after Dose 2. For the second
primary efficacy endpoint, VE for BNT162b2 against confirmed COVID -19 was evaluated in
participants with orwithoutevidence of past SARS-CoV-2 infection before and during the
vaccination regimen . Cases were counted from 7 day s after Dose 2.
Signs and s ymptoms of COVID -19 cases contributing to efficacy analyses are presented in
the C4591001 Final Analy sis Interim CSR.
2.5.4.3.2.1.2.1. Vaccine Efficacy Without Prior Evidence of SARS- CoV-2 Infection –
7Days After Dose 2 –Final Analysis
As noted above, overwhelming e fficacy was declared at the first (and onl y) interim analy sis
for the first primary efficacy endpoint. A descriptive update based on 170 evaluable cases
accrued at the time of the final anal ysis (of the other efficacy endpoints) is summarized
below.
Amongparticipants without evidence of SARS -CoV-2 infection before and during the
vaccination regimen, VE against confirmed COVID -19 occurring at least 7 day s after Dose 2
was 95.0%, with 8 COVID-19 cases in the BNT162b2 group compared to 162 COVID -19
cases in the placebo group ( Table8). The 95% credi ble interval for the vaccine efficacy was
90.3% to 97.6%, indicating that the true VE is at least 90.3% with a 97.5% probability given
the observed data.
The vaccine efficacy of BNT162b2 for the same primary efficacy endpoint based on the
Dose 2 all -available efficacy population was 95.2%, with 8 and 165 cases in the BNT162b2
and placebo group ( Table9).
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Page 49Table8.Vaccine Efficacy – First COVID -19 Occurrence From 7 Days After Dose 2
–Subjects Without Evidence of Infection Prior to 7 Days After Dose 2 –
Evaluable Efficacy (7 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=18198)Placebo
(Na=18325)
Efficacy Endpoint n1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE
(%)(95%
CIe)Pr (VE >30% |
data)f
First COVID -19 occurrence from
7 days after Dose 282.214 (17411) 1622.222 (17511) 95.0(90.3,
97.6)>0.9999
Abbreviations: N -binding = SARS -CoV-2 nucleoprotein– binding; NAAT = nucleic acid amplification test; SARS -CoV-2
= severe acute respiratory syndrome coronavirus 2; VE = vaccine efficacy.
Note: Subjects who had no serological or virological evidence (prior to 7 days after receipt of the last dose) of past SARS -
CoV-2 infection (ie, N -binding antibody [serum] negative at Visit 1 and SARS-CoV -2 not detected by NAAT [nasal swab]
at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were
included in the analysis.
a.N = number of subjects in the specified group.
b.n1 = Number of subjects meeting the endpoint definition.
c.Totalsurveillance time in 1000 person -years for the given endpoint across all subjects within each group at risk for
the endpoint. Time period for COVID -19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
d.n2 = Number of su bjects at risk for the endpoint.
e.Credible interval for VE was calculated using a beta -binomial model with prior beta (0.700102, 1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details.
f.Posterior probability (Pr) was calculated using a beta -binomial model with prior beta (0.700102, 1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details.
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Page 50Table9.Vaccine Efficacy –First COVID -19 Occurrence From 7 Days After Dose 2
–Subjects Without Evidence of Infection Prior to 7 Days After Dose 2 –
Dose 2 All -Available Efficacy Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=18650)Placebo
(Na=18570)
Efficacy Endpoint n1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE
(%)(95%
CIe)Pr (VE >30% |
data)f
First COVID -19 occurrence from
7 days after Dose 282.266 (17852) 1652.244 (17746) 95.2(90.6,
97.7)>0.9999
Abbreviations: N -binding = SARS -CoV-2 nucleoprotein– binding; NAAT = nucleic acid amplification test; SARS -CoV-2
= severe acute respiratory syndrome coronavirus 2; VE = vaccine efficacy.
Note: Subjects who had no serological or virological evidence (prior t o 7 days after receipt of the last dose) of past SARS -
CoV-2 infection (ie, N -binding antibody [serum] negative at Visit 1 and SARS-CoV -2 not detected by NAAT [nasal swab]
at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were
included in the analysis.
a.N = number of subjects in the specified group.
b.n1 = Number of subjects meeting the endpoint definition.
c.Total surveillance time in 1000 person -years for the given endpoint across all subjects within each group at risk for
the endpoint. Time period for COVID -19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
d.n2 = Number of subjects at risk for the endpoint.
e.Credible interval for VE was c alculated using a beta -binomial model with prior beta (0.700102, 1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details.
f.Posterior probability (Pr) was calculated using a beta -binomial model with prio r beta (0.700102,1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details.
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2.5.4.3.2.1.2.2. Vaccine Efficacy With orWithout Prior Evidence of SARS -CoV-2
Infection –7 Days After Dose 2 – Final Analysis
For the second primary efficacy endpoint, VE for BNT162b2 against confirmed COVID -19
was evaluated in participants with orwithout evidence of prior SARS- CoV-2 infection
through 7 days after Dose 2. Cases were counted from 7 day s after Dose 2.
Among parti cipants with or without evidence of SARS -CoV-2 infection before and during
the vaccination regimen, VE against confirmed COVID -19 occurring at least 7 day s after
Dose 2 was 94.6%, with 9 and 169 cases in the BNT162b2 and placebo groups respectivel y.
The posterior probability of >99.99% for the true VE greater than 30% met the prespecified
success criterion of >98.6% for this endpoint. The 95% credible interval for the vaccine
efficacy was 89.9% to 97.3%, indicating that the true VE is at least 89.9% with a 97.5%
probability given the available data ( Table10). Note that wit h a posterior probability of
98.6%, the true vaccine efficacy is at least 89.2% giventhe available data.
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Page 51The vaccine efficacy of BNT162b2 for the same primary efficacy endpoint based on the
Dose 2 all -available efficacy population was 94.8%, with 9 and 172 cases in the BNT162b2
and placebo group respectively (Table11).
Table10.Vaccine Efficacy – First COVID -19 Occurrence From 7 Days After Dose 2
–Subjects With or Without Evidence of Infection Prior to 7 Days After
Dose 2 –Evaluable Efficacy (7 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=19965)Placebo
(Na=20172)
Efficacy Endpoint n1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE
(%)(95%
CIe)Pr (VE >30% |
data)f
First COVID -19 occurrence from
7 days after Dose 292.332 (18559) 1692.345 (18708) 94.6(89.9,
97.3)>0.9999
Abbreviations: VE = vaccine efficacy.
a.N = number of subjects in the specified group.
b.n1 = Number of subjects meeting the endpoint definition.
c.Total surveillance time in 1000 person -years for the given endpoint across all subjects within each group at risk for
the endpoint. Time period for COVID -19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
d.n2 = Number of subjects at risk for the endpoint.
e.Credible interval for VE was calculated using a beta -binomial model with prior beta (0.700102, 1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details.
f.Posterior probability ( Pr) was calculated using a beta -binomial model with prior beta (0.700102, 1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details.
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Page 52Table11.Vaccine Efficacy –First COVID -19 Occurrence From 7 Days After Dose 2
–Subjects With or Without Evidence of Infection Prior to 7 Days After
Dose 2 –Dose 2 All -Available Efficacy Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=20488)Placebo
(Na=20459)
Efficacy Endpoint n1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE
(%)(95%
CIe)Pr (VE >30% |
data)f
First COVID -19 occurrence from
7 days after Dose 292.389 (19049) 1722.370 (18971) 94.8(90.2,
97.4)>0.9999
Abbreviations: VE = vaccine efficacy.
a.N = number of subjects in the specified group.
b.n1 = Number of subjects meeting the endpoint definition.
c.Total surveillance time in 1000 person -years for the given endpoint across all subjects within each group at risk for
the endpoint. Time period for COVID -19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
d.n2 = Number of subjects at risk for the endpoint.
e.Credible interval for VE was calculated using a beta-binomial model with prior beta (0.700102, 1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details.
f.Posterior probability (Pr) was calculated using a beta -binomial model with prior beta (0.700102, 1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details.
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All Confirmed Cases of COVID -19 After Dose 1 – All-Available Efficacy Population
A number of confirmed cases of COVID -19 are not captured in the anal yses of the first
primary endpoint for the evaluable efficacy population because they occurred less than
7days after Dose 2, or because they occurred in participants who were excluded fro m the
evaluable efficacy population or who had evidence of infection before or during the
vaccination regimen.
All reports of COVID -19 with onset at any time after Dose 1 are accounted for in Table12,
which provides a summary of cases for all participants in the Dose 1 all -available efficacy
(modified intention -to-treat) population, regardless of evidence of infection before or during
the vaccination regimen. Among the se participants, 50 cases of COVID -19 occurred after
Dose 1 in the BNT162b2 group compared to 275 cases in the placebo group ( Table12).
Notably, in the BNT162b2 group, most cases occurred before Dose 2. The estimated VE
against confirmed COVID -19 occurring after Dose 1 was 82% (2 -sided 95% CI : 75.6 %,
86.9%), with an estimated VE of 52.4% (2 -sided 95% CI : 29.5%, 68.4%) against confirmed
COVID-19 occurring after Dose 1 bu t before Dose 2.
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Page 53Table12.Vaccine Efficacy – First COVID -19 Occurrence After Dose 1 –Dose 1 All -
Available Efficacy Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=21669)Placebo
(Na=21686)
Efficacy Endpoint
Subgroupn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE (%) (95% CIe)
First COVID -19 occurrence after Dose 1 504.015 (21314) 2753.982 (21258) 82.0(75.6, 86.9)
After Dose 1 to before Dose 2 39 82 52.4(29.5, 68.4)
Dose 2 to 7 days after Dose 2 2 21 90.5(61.0, 98.9)
≥7 Days after Dose 2 9 172 94.8(89.8, 97.6)
Abbreviations: VE = vaccine efficacy.
a.N = number of subjects in the specified group.
b.n1 = Number of subjects meeting the endpoint definition.
c.Total surveillance time in 1000 person -years for the given endpoint across all subjects within each group at risk for
the endpoint. Time period for COVID -19 case accrual is from Dose 1 to the end of the surveillance period.
d.n2 = Number of subjects at risk for the endpoint.
e.Confidence interval (CI) for VE is derived based on the Clopper and Pearson method (adjusted for surveillance time
for overall row).
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The early onset of protection is readily apparent in Figure 1, which display s cumulative
incidence for the first COVID -19 occurrence after Dose 1 among all vaccinated participants
based on Dose 1 all -available efficacy (modified intention -to-treat) popul ation. Disease onset
appears to track together for BNT162b2 and placebo until approximately 14 days after
Dose1, at which point the curves diverge, with cases steadily accumulating in the placebo
group, while remaining virtually flat in the BNT162b2 group .The darker -appearing s ymbols
for both BNT162b2 (bluecircles) and placebo (redsquares) curves in Figure 1have an “S”
written inside the open sy mbol, which denotes severe cases; note that there are instances in
which2 cases in the placebo group are “ overlapping ”relative to the placebo curve . Severe
COVID-19 cases reported in the final anal ysisare discussed further in
Section 2.5.4.3.2.1.3.2 .
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Page 54Figure 1.Cumulative Incidence Curves for the First COVID-19 Occurrence After Dose 1 –Dose 1 All -Available Efficacy
Population –Final Analysis
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Page 552.5.4.3.2.1.2.3. Vaccine Efficacy by Subgroup –Final Analysis
Subgroup Analyses by Age, Sex, Race, Ethnicity, and Country
For both primary endpoints, VE was also evaluated for subgroups of participants by age, sex
race, ethnicity, and country (Table13) (withoutevidence of prior infection) and Table14
(withorwithout evidence of prior infection).
Among participants withoutprior evidence of SARS -CoV-2 infection, VE was >93% in all
subgroups, with the exception of “all others” race gr oup (89.3% VE) and Brazil (87.7% VE)
(Table13). Notably , VE was 94.7% (2-sided 95% CI : 66.7%, 99.9%) in participants
≥65years of age (1 case in BNT162b2 group vs 19 cases in placebo group) .
An additional anal ysis of age subgroups showed observed VE in participants ≥75 years of
age was 100% (0 cases in BNT162b2 group vs 5 cases in placebo group ; 2-sided 95%
CI: -13.1%, 100.0%) (Table15).
Among participants with or without prior evidence of SARS -CoV-2 infection, VE was >93%
in all subgroups, with the exception of “all others” race group (78.2% VE) ,Brazil (75.4%
VE), and positive prior SARS -CoV-2 infection at baseline ( -7.1% VE, 1 case in each vaccine
group) (Table14).
Results for t he all-available population were similar; no clinic ally meaningful differences
were observed in VE on the basis of subgroup.
Post Hoc Subgroup Analyses by Risk Status
Post hoc analy ses of efficacy based on risk statuswere performed. Risk assessment included
select comorbidities. At-risk participants were those meeting at least one Charlson
Comorbidity Index condition (see Section2.5.5.5.1 for Charlson comorbidities) or who were
obese(defined as body mass index ≥30kg/m2).
Amongparticipants without prior evidence of SARS -CoV-2 infectionbefore and during the
vaccination regimen ,VE for at-risk participants was 95.3%, as compared with 94.7% for
those not at -risk (Table16). VE for participants ≥65 years of age and at -risk was 91.7%, as
compared with 100% for those ≥65 years of age and not at -risk. VE was similar in obese
(95.4%) and non -obese (94.8%) participants. A summary of VE for groups of participants by
specific comorbidit y is provided in Table 17.
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Page 56Table13.Vaccine Efficacy – First COVID -19 Occurrence From 7 Days After D ose 2, by Subgroup – Subjects Without
Evidence of Infection Prior to 7 Days After Dose 2 –Evaluable Efficacy (7 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=18198)Placebo
(Na=18325)
Efficacy Endpoint
Subgroupn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE (%) (95% CIe)
First COVID -19 occurrence from 7 days after Dose 2
Overall 8 2.214 (17411) 162 2.222 (17511) 95.0 (90.0, 97.9)
Age group (years)
16 to 55 5 1.234 (9897) 114 1.239 (9955) 95.6 (89.4, 98.6)
>55 3 0.980 (7500) 48 0.983 (7543) 93.7 (80.6, 98.8)
≥65 1 0.508 (3848) 19 0.511 (3880) 94.7 (66.7, 99.9)
Sex
Male 3 1.124 (8875) 81 1.108 (8762) 96.4 (88.9, 99.3)
Female 5 1.090 (8536) 81 1.114 (8749) 93.7 (84.7, 98.0)
Race
White 7 1.889 (14504) 146 1.903 (14670) 95.2 (89.8, 98.1)
Black or African American 0 0.165 (1502) 7 0.164 (1486) 100.0 (31.2, 100.0)
All othersf1 0.160 (1405) 9 0.155 (1355) 89.3 (22.6, 99.8)
Ethnicity
Hispanic/Latino 3 0.605 (4764) 53 0.600 (4746) 94.4 (82.7, 98.9)
Non-Hispanic/non -Latino 5 1.596 (12548) 109 1.608 (12661) 95.4 (88.9, 98.5)
Country
Argentina 1 0.351 (2545) 35 0.346 (2521) 97.2 (83.3, 99.9)
Brazil 1 0.119 (1129) 8 0.117 (1121) 87.7 (8.1, 99.7)
USA 6 1.732 (13359) 119 1.747 (13506) 94.9 (88.6, 98.2)
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Page 57Table13.Vaccine Efficacy – First COVID -19 Occurrence From 7 Days After D ose 2, by Subgroup – Subjects Without
Evidence of Infection Prior to 7 Days After Dose 2 –Evaluable Efficacy (7 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=18198)Placebo
(Na=18325)
Efficacy Endpoint
Subgroupn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE (%) (95% CIe)
Abbreviations: N -binding = SARS -CoV-2 nucleoprotein– binding; NAAT = nucleic acid amplification test; SARS -CoV-2 = severe acute respiratory syndrome coronavirus 2; VE
= vaccine efficacy.
Note: Subjects who had no serological or virological evidence (prior to 7 days after receipt of the last dose) of past SARS -CoV-2 infection (ie, N -binding antibody [serum]
negative at Visit 1 and SARS -CoV-2 not detected by NAAT [nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after
Dose 2 were included in the analysis.
a.N = number of subje cts in the specified group.
b.n1 = Number of subjects meeting the endpoint definition.
c.Total surveillance time in 1000 person -years for the given endpoint across all subjects within each group at risk for the endpoint. Time period for COVID -19case accrual is
from 7 days after Dose 2 to the end of the surveillance period.
d.n2 = Number of subjects at risk for the endpoint.
e.Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for surveillance t ime.
f.All others = American Indian or Alaska native, Asian, Native Hawaiian or other Pacific Islander, multiracial, and not reporte d race categories.
PFIZER CONFIDENTIAL SDTM Creation: 17NOV2020 (09:54) Source Data: adc19ef Table Generation: 18NOV20 20 (15:55)
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Page 58Table14.Vaccine Efficacy – First COVID -19 Occurrence From 7 Days After Dose 2, by Subgroup – Subjects With or
Without Evidence of Infection Prior to 7 Days After Dose 2 – Evaluable Efficacy (7 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=19965)Placebo
(Na=20172)
Efficacy Endpoint
Subgroupn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE (%) (95% CIe)
First COVID -19 occurrence from 7 days after Dose 2
Overall 92.332 (18559) 169 2.345 (18708) 94.6 (89.6, 97.6)
Age group (years)
16 to 55 61.309 (10653) 120 1.317 (10738) 95.0 (88.7, 98.2)
>55 31.022 (7892) 49 1.028 (7956) 93.8 (80.9, 98.8)
≥65 10.530 (4044) 19 0.532 (4067) 94.7 (66.8, 99.9)
Sex
Male 41.183 (9457) 85 1.170 (9342) 95.3 (87.6, 98.8)
Female 51.149 (9102) 84 1.176 (9366) 93.9 (85.2, 98.1)
Race
White 71.975 (15294) 153 1.990 (15473) 95.4 (90.3, 98.2)
Black or African American 00.187(1758) 7 0.188 (1758) 100.0 (30.4, 100.0)
All othersf20.170 (1507) 9 0.167 (1477) 78.2 (-5.4, 97.7)
Ethnicity
Hispanic/Latino 30.637 (5074) 55 0.638 (5090) 94.5 (83.2, 98.9)
Non-Hispanic/non -Latino 61.681 (13380) 114 1.693 (13509) 94.7 (88.1, 98.1)
Country
Argentina 10.366 (2664) 36 0.367 (2684) 97.2 (83.5, 99.9)
Brazil 20.134 (1274) 8 0.132 (1257) 75.4 (-23.5, 97.5)
USA 61.816 (14141) 124 1.830 (14287) 95.1 (89.1, 98.2)
South Africa 0 0.015(362) 1 0.015 (363) 100.0 (-3818.9, 100.0)
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Page 59Table14.Vaccine Efficacy – First COVID -19 Occurrence From 7 Days After Dose 2, by Subgroup – Subjects With or
Without Evidence of Infection Prior to 7 Days After Dose 2 – Evaluable Efficacy (7 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=19965)Placebo
(Na=20172)
Efficacy Endpoint
Subgroupn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE (%) (95% CIe)
Prior SARS -CoV-2 Status
Positive at baselineg1 0.056 (526) 1 0.060 (567) -7.1 (-8309.9, 98.6)
Negative at baseline but positive prior to 7 days after Dose 2h0 0.003 (27) 1 0.004 (34) 100.0 (-6004.9, 100.0)
Negative prior to 7 days after Dose 2i82.214 (17411) 162 2.222 (17511) 95.0 (90.0, 97.9)
Unknown 0 0.059 (595) 5 0.060 (596) 100.0 (-9.6, 100.0)
Abbreviations: N -binding = SARS -CoV-2 nucleoprotein– binding; NAAT = nucleic acid amplification test; SARS-CoV -2 = severe acute respiratory syndrome coronavirus 2; VE
= vaccine efficacy.
a.N = number of subjects in the specified group.
b.n1 = Number of subjects meeting the endpoint definition.
c.Total surveillance time in 1000 person -years for the given endpoint across all subjects within each group at risk for the endpoint. Time period for COVID -19 case accrual is
from 7 days after Dose 2 to the end of the surveillance period.
d.n2 = Number of subjects at risk for the endpoint.
e.Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for surveillance time.
f.All others = American Indian or Alaska native, Asian, Native Hawaiian or other Pacific Islander, multiracia l, and not reported race categories.
g.Positive N -binding antibody result at Visit 1, positive NAAT result at Visit 1, or medical history of COVID -19.
h.Negative N -binding antibody result and negative NAAT result at Visit 1, positive NAAT result at Visit 2 or at unscheduled visit, if any, prior to 7 days after Dose 2.
i.Negative N -binding antibody result at Visit 1, negative NAAT result at Visit 1 and Visit 2, and negative NAAT result at unscheduled visi t, if any, prior to 7 days after Dose
2.
PFIZER CONFIDENTIAL SDTM Creation: 17NOV2020 (09:54) Source Data: adc19ef Table Generation: 18NOV2020 (15:55)
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Page 60Table15.Vaccine Efficacy – First COVID -19 Occurrence From 7 Days After Dose 2, by Requested Subgroup –Subjects
Without Evidence of Infection Prior to 7 Days After Dose 2 – Evaluable Efficacy (7 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=18198)Placebo
(Na=18325)
Efficacy Endpoint
Subgroupn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE (%) (95% CIe)
First COVID -19 occurrence from 7 days after Dose 2
Overall 8 2.214 (17411) 162 2.222 (17511) 95.0 (90.0, 97.9)
Age group (years)
12 to 15 0 0.000 (14) 0 0.000 (13) NE (NE, NE)
16 to 17 0 0.002 (52) 0 0.003 (55) NE (NE, NE)
18 to 64 7 1.703 (13497) 143 1.708 (13563) 95.1 (89.6, 98.1)
65 to 74 1 0.406 (3074) 14 0.406 (3095) 92.9 (53.1, 99.8)
≥75 0 0.102 (774) 5 0.106 (785) 100.0 (-13.1, 100.0)
Race
White 7 1.889 (14504) 146 1.903 (14670) 95.2 (89.8, 98.1)
Black or African American 0 0.165 (1502) 7 0.164 (1486) 100.0 (31.2, 100.0)
American Indian or Alaska native 0 0.011 (100) 1 0.010 (96) 100.0 (-3429.0, 100.0)
Asian 1 0.092 (764) 4 0.093 (769) 74.6 (-156.6, 99.5)
Native Hawaiian or other Pacific Islander 0 0.006 (46) 1 0.003 (29) 100.0 (-2266.9, 100.0)
Multiracial 0 0.042 (414) 1 0.036 (359) 100.0 (-3231.3, 100.0)
Not reported 0 0.010 (81) 2 0.012 (102) 100.0 (-563.3, 100.0)
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Page 61Table15.Vaccine Efficacy – First COVID -19 Occurrence From 7 Days After Dose 2, by Requested Subgroup –Subjects
Without Evidence of Infection Prior to 7 Days After Dose 2 – Evaluable Efficacy (7 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=18198)Placebo
(Na=18325)
Efficacy Endpoint
Subgroupn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE (%) (95% CIe)
Abbreviations: N -binding = SARS -CoV-2 nucleoprotein– binding; NAAT = nucleic acid amplification test; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; VE
= vaccine efficacy.
Note: Subjects who had no serological or virological evidence (prior to 7 days after receipt of the last dose) of past SARS -CoV-2 infection (ie, N -binding antibody [serum]
negative at Visit 1 and SARS -CoV-2 not detected by NAAT [nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after
Dose 2 were included in the analysis.
a.N = number of subjects in the specified group.
b.n1 = Number of subjects meeting the endpoint definition.
c.Total surveillance time in 1000 person -years for the given endpoint across all subjects within each group at risk for the endpoint. Time period for COVID -19 case accrual is
from 7 days after Dose 2 to the end of the surveillance period.
d.n2 = Number of subjects at risk for the endpoint.
e.Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for surveillance time.
PFIZER CONFIDEN TIAL SDTM Creation: 17NOV2020 (09:54) Source Data: adc19ef Table Generation: 23NOV2020 (16:38)
(Cutoff Date: 14NOV2020, Snapshot Date: 16NOV2020) Output File: ./nda2 unblinded/C4591001 EUA FAEF RR/adc19ef ve cov 7pd2 wor q sg eval
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Page 62Table16.Vaccine Efficacy – First COVID -19 Occurrence From 7 Days After Dose 2, by Risk Status –Subjects Without
Evidence of Infection Prior to 7 Days After Dose 2 – Evaluable Efficacy (7 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=18198)Placebo
(Na=18325)
Efficacy Endpoint
Subgroupn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE (%) (95% CIe)
First COVID -19 occurrence from 7 days after Dose 2
Overall 8 2.214 (17411) 162 2.222 (17511) 95.0 (90.0, 97.9)
At riskf
Yes 4 1.025 (8030) 86 1.025 (8029) 95.3 (87.7, 98.8)
No 4 1.189 (9381) 76 1.197 (9482) 94.7 (85.9, 98.6)
Age group (years) and at risk
16-64 and not at risk 4 0.962 (7671) 69 0.964 (7701) 94.2 (84.4, 98.5)
16-64 and at risk 3 0.744 (5878) 74 0.746 (5917) 95.9 (87.6, 99.2)
≥65 and not at risk 0 0.227 (1701) 7 0.233 (1771) 100.0 (29.0, 100.0)
≥65 and at risk 1 0.281 (2147) 12 0.279 (2109) 91.7 (44.2, 99.8)
Obeseg
Yes 3 0.763 (6000) 67 0.782 (6103) 95.4 (86.0, 99.1)
No 5 1.451 (11406) 95 1.439 (11404) 94.8 (87.4, 98.3)
Age group (years) and obese
16-64 and not obese 4 1.107 (8811) 83 1.101 (8825) 95.2 (87.3, 98.7)
16-64 and obese 3 0.598 (4734) 60 0.609 (4789) 94.9 (84.4, 99.0)
≥65 and not obese 1 0.343 (2582) 12 0.338 (2567) 91.8 (44.5, 99.8)
≥65 and obese 0 0.165 (1265) 7 0.173 (1313) 100.0 (27.1, 100.0)
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Page 63Table16.Vaccine Efficacy – First COVID -19 Occurrence From 7 Days After Dose 2, by Risk Status –Subjects Without
Evidence of Infection Prior to 7 Days After Dose 2 – Evaluable Efficacy (7 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=18198)Placebo
(Na=18325)
Efficacy Endpoint
Subgroupn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE (%) (95% CIe)
Abbreviations: N -binding = SARS -CoV-2 nucleoprotein –binding; NAAT = nucleic acid amplification test; SARS -CoV-2 = severe acute respiratory syndrome coronavirus 2; VE
= vaccine efficacy.
Note: Subjects who had no serological or virological evidence (prior to 7 days after receipt of the last dos e) of past SARS -CoV-2 infection (ie, N -binding antibody [serum]
negative at Visit 1 and SARS -CoV-2 not detected by NAAT [nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after
Dose 2 were included in the analysis.
a.N = number of subjects in the specified group.
b.n1 = Number of subjects meeting the endpoint definition.
c.Total surveillance time in 1000 person -years for the given endpoint across all subjects within each group at risk for the endpoint. Time period for COVID-19 case accrual is
from 7 days after Dose 2 to the end of the surveillance period.
d.n2 = Number of subjects at risk for the endpoint.
e.Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for surveillance time.
f.At risk is defined as having at least one of the Charlson Comorbidity Index (CMI) category or obesity (BMI ≥30 kg/m2).
g.Obese is defined as BMI ≥30 kg/m2.
PFIZER CONFIDENTIAL SDTM Creation: 17NOV2020 (09:54) Source Data: adc19ef Table Generation: 24NOV2020 (17:41)
(Cutoff Date: 14NOV2020, Snapshot Date: 16NOV2020) Output File: ./nda2_unblinded/C4591001_EUA_FAEF_RR/adc19ef_ve_cov_7pd2_wo_ rg_eval
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Page 64Table17.Vaccine Efficacy – First COVID -19 Occurrence From 7 Days After Dose 2, by Comorbidity Status –Subjects
Without Evidence of Infection Prior to 7 Days After Dose 2 –Evaluable Efficacy (7 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=18198)Placebo
(Na=18325)
Efficacy Endpoint
Subgroupn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE (%) (95% CIe)
First COVID -19 occurrence from 7 days after Dose 2
Overall 8 2.214 (17411) 162 2.222 (17511) 95.0 (90.0, 97.9)
Comorbidity
No comorbidity 4 1.189 (9381) 76 1.197 (9482) 94.7 (85.9, 98.6)
Any comorbidityf4 1.025 (8030) 86 1.025 (8029) 95.3 (87.7, 98.8)
Any malignancy 1 0.092 (704) 4 0.090 (681) 75.7 (-145.8, 99.5)
Cardiovascular 0 0.067 (534) 5 0.062 (492) 100.0 (-0.8, 100.0)
Chronic pulmonary disease 1 0.175 (1374) 14 0.171 (1358) 93.0 (54.1, 99.8)
Diabetes 1 0.176 (1372) 19 0.176 (1374) 94.7 (66.8, 99.9)
Obese (≥30.0 kg/m2) 3 0.763 (6000) 67 0.782 (6103) 95.4 (86.0, 99.1)
Hypertension 2 0.567 (4413) 44 0.567 (4437) 95.4 (82.6, 99.5)
Diabetes (including gestational diabetes) 1 0.177 (1381) 20 0.178 (1384) 95.0 (68.7, 99.9)
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Page 65Table17.Vaccine Efficacy – First COVID -19 Occurrence From 7 Days After Dose 2, by Comorbidity Status –Subjects
Without Evidence of Infection Prior to 7 Days After Dose 2 –Evaluable Efficacy (7 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=18198)Placebo
(Na=18325)
Efficacy Endpoint
Subgroupn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE (%) (95% CIe)
Abbreviations: N-binding = SARS -CoV-2 nucleoprotein– binding; NAAT = nucleic acid amplification test; SARS -CoV-2 = severe acute respiratory syndrome coronavirus 2; VE
= vaccine efficacy.
Note: Subjects who had no serological or virological evidence (prior to 7 days after receipt of the last dose) of past SARS-CoV -2 infection (ie, N -binding antibody [serum]
negative at Visit 1 and SARS -CoV-2 not detected by NAAT [nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days afte r
Dose 2 were included in the analysis.
a.N = number of subjects in the specified group.
b.n1 = Number of subjects meeting the endpoint definition.
c.Total surveillance time in 1000 person -years for the given endpoint across all subjects wi thin each group at risk for the endpoint. Time period for COVID -19 case accrual is
from 7 days after Dose 2 to the end of the surveillance period.
d.n2 = Number of subjects at risk for the endpoint.
e.Confidence interval (CI) for VE is derived b ased on the Clopper and Pearson method adjusted for surveillance time.
f.Subject who had 1 or more comorbidities that increase the risk of severe COVID -19 disease: defined as subjects who had at least one of the Charlson comorbidity index
category or BMI ≥30 kg/m2.
PFIZER CONFIDENTIAL SDTM Creation: 17NOV2020 (09:54) Source Data: adc19ef Table Generation: 29NOV2020 (21:33)
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Page 662.5.4.3.2.1.3. Secondary Efficacy – Final Analysis
2.5.4.3.2.1.3.1. Vaccine Efficacy For COVID -19 Occurring at Least14 Days After
Dose2 –Final Analysis
Participants Without Evidence of Infection Before and During Vaccination Regimen
For this efficacy endpoint, participants with positive or unknown NAAT results at any illness
visit prior to 14 day s after Dose 2 were not included in the evaluation for efficacy .
Among participants without evidence of SARS -CoV-2 infection before and duri ng the
vaccination regimen, VE against confirmed COVID -19 occurring at least 14 days after
Dose2 was 94.2%, with 8 and 139 cases in the BNT162b2 and placebo groups respectivel y
(Table18). The posterior probability of >99.99% for the true VE greater than 30% met the
prespecified success criterion of >98.6% for this endpoint. The 95% credible interval for the
vaccine efficacy was 88.7% to 97.2%, indicating that the true VE is at least 88.7% with a
97.5% probability given the available data.
Table18.Vaccine Efficacy – First COVID -19 Occurrence From 14 Days After Dose 2
–Subjects Without Evidence of Infection Prior to 14 Days After Dose 2 –
Evaluable Efficacy (14 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=18175)Placebo
(Na=18261)
Efficacy Endpoint n1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE
(%)(95%
CIe)Pr (VE >30% |
data)f
First COVID -19 occurrence from
14 days after Dose 281.887 (16612) 1391.893 (16663) 94.2(88.7,
97.2)>0.9999
Abbreviations: N -binding = SARS -CoV-2 nucleoprotein– binding; NAAT = nucleic acid amplification test; SARS -CoV-2
= severe acute respiratory syndrome coronavirus 2; VE = vaccine efficacy.
Note: Subjects who had no serological or virological evidence (prior to 14 days after receipt of the last dose) of past
SARS-CoV-2 infection (ie, N -binding antibody [serum] negative at Visit 1 and SARS -CoV-2 not detected by NAAT
[nasal swab] at Visits 1 an d 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 14 days after Dose 2
were included in the analysis.
a.N = number of subjects in the specified group.
b.n1 = Number of subjects meeting the endpoint definition.
c.Total surveillance time in 1000 person -years for the given endpoint across all subjects within each group at risk for
the endpoint. Time period for COVID -19 case accrual is from 14 days after Dose 2 to the end of the surveillance period.
d.n2 = Number of subjects at risk for the endpoint.
e.Credible interval for VE was calculated using a beta -binomial model with prior beta (0.700102, 1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details.
f.Posterior probability (Pr) was calculated using a beta -binomial model with prior beta (0.700102, 1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details.
PFIZER CONFIDENTIAL SDTM Creation: 17NOV2020 (09:48) Source Data: adc19ef Table Generation: 17NOV2020
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Page 67Participants With or Without Evidence of Infection Beforeand During Vaccination
Regimen
Among participants with or without evidence of SARS- CoV-2 infection before and during
the vaccination regimen, VE against confirmed COVID -19 occurring at least 14 day s after
Dose 2 was 94.4%, with 8 and 144 cases in the BNT1 62b2 and placebo groups respectivel y
(Table19). The posterior probability of >99.99% for the true VE greater than 30% met the
prespecified success criterion of >98.6% for this endpoint. The 95% credible interval for the
vaccine efficacy was 89.1% to 97.3%, indicating that the true VE is at least 89.1% with a
97.5% probability given the available data.
Table19.Vaccine Efficacy – First COVID -19 Occurrence From 14 Days After Dose 2
–Subjects With or Without Evidence of Infection Prior to 14 Days After
Dose 2 –Evaluable Efficacy (14 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=19965)Placebo
(Na=20171)
Efficacy Endpoint n1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE
(%)(95%
CIe)Pr (VE >30% |
data)f
First COVID -19 occurrence from
14 days after Dose 281.984 (17645) 1441.995 (17746) 94.4(89.1,
97.3)>0.9999
Abbreviations: VE = vaccine efficacy.
a.N = number of subjects in the specified group.
b.n1 = Number of subjects meeting the endpoint definition.
c.Total surveillance time in 1000 person-years for the given endpoint across all subjects within each group at risk for
the endpoint. Time period for COVID -19 case accrual is from 14 days after Dose 2 to the end of the surveillance period.
d.n2 = Number of subjects at risk for the end point.
e.Credible interval for VE was calculated using a beta -binomial model with prior beta (0.700102, 1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details.
f.Posterior probability (Pr) was calc ulated using a beta -binomial model with prior beta (0.700102, 1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details.
PFIZER CONFIDENTIAL SDTM Creation: 17NOV2020 (09:48) Source Data: adc19ef Table Generatio n: 17NOV2020
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Page 682.5.4.3.2.1.3.2. Efficacy forSevere COVID -19Cases –Final Analysis
Efficacy Against Severe COVID-19 (≥7Days After Dose 2)
Participants W ithout Evidence of Infection Before and During Vaccination Regimen
For this efficacy endpoint, participants with positive or unknown NAAT results at any illness
visit prior to 7 day s after Dose 2 were not included in the e valuation for efficacy .
Among participants without evidence of SARS -CoV-2 infection before and during the
vaccination regimen, the estimated VE against severe COVID- 19 occurring at least 7 days
after Dose 2 was 66.4%, with 1 and 3 cases in the BNT162b2 and placebo groups
respectivel y (Table20). The posterior probability for the true vaccine efficacy greater than
30% is 74.29%, which did not meet the prespecified success criterion of >98.6% for this
endpoint due to the small number of severe cases observed after Dose 2 in the study .
Consequently , statistical testing of subsequent secondary endpoints (ie, the additional
secondary endpoints related to severe disease with pre -specified control of overall ty pe 1
error) ended. However, descriptive summaries for the additional endpoints are provided.
Table20.Vaccine Efficacy – First Severe COVID -19 Occurrence From 7 Days After
Dose 2 –Subjects Without Evidence of Infection Prior to 7 Days After Dose
2 –Evaluable Efficacy (7 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=18198)Placebo
(Na=18325)
Efficacy Endpoint n1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE
(%)(95% CIe)Pr (VE >30% |
data)f
First severe COVID-19
occurrence from 7 days after
Dose 212.215 (17411) 32.232 (17511) 66.4(-124.8, 96.3) 0.7429
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Page 69Table20.Vaccine Efficacy – First Severe COVID -19 Occurrence From 7 Days After
Dose 2 –Subjects Without Evidence of Infection Prior to 7 Days After Dose
2 –Evaluable Efficacy (7 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=18198)Placebo
(Na=18325)
Efficacy Endpoint n1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE
(%)(95% CIe)Pr (VE >30% |
data)f
Abbreviations: N -binding = SARS -CoV-2 nucleoprotein– binding; NAAT = nucleic acid amplification test; SARS -CoV-2
= severe acute respiratory syndrome coronavirus 2; VE = vaccine efficacy.
Note: Subjects who had no serological or virological evidence (prior to 7 days after receipt of the last dose) of past SARS -
CoV-2 infection (ie, N -binding antibody [serum] negative at Visit 1 and SARS -CoV-2 not detected by NAAT [nasal swab]
at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were
included in the analysis.
a.N = number of subjects in the specified group.
b.n1 = Number of subjects meeting the endpoint definition.
c.Total surveillance time in 1000 person -years for the given endpoint across all subjects within each group at risk for
the endpoint. Time period for COVID -19 case accrual is from 7 days afte r Dose 2 to the end of the surveillance period.
d.n2 = Number of subjects at risk for the endpoint.
e.Credible interval for VE was calculated using a beta -binomial model with prior beta (0.700102, 1) adjusted for
surveillance time. Refer to the s tatistical analysis plan, Appendix 2, for more details.
f.Posterior probability (Pr) was calculated using a beta -binomial model with prior beta (0.700102, 1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details.
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Participants W ith orWithout Evidence of Infection Before and During Vaccination Regimen
Among participants with or without evidence of SARS- CoV-2 infection before and during
the vaccination regimen, VE against severe COVID- 19 occurring at least 7 days after Dose 2
was 66.3%, with 1 and 3 cases in the BNT162b2 and placebo groups respectively (Table21).
The posterior probability for the true vaccine efficacy greater than 30% is 74.19%.
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Page 70Table21.Vaccine Efficacy – First Severe COVID -19 Occurrence From 7 Days After
Dose 2 –Subjects With or Without Evidence of Infection Prior to 7 Days
After Dose 2 –Evaluable Efficacy (7 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=19965)Placebo
(Na=20172)
Efficacy Endpoint n1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE
(%)(95% CIe)Pr (VE >30% |
data)f
First severe COVID-19
occurrence from 7 days after
Dose 212.333(18566) 32.358 (18733) 66.3(-125.5, 96.3) 0.7419
Abbreviations: VE = vaccine efficacy.
a.N = number of subjects in the specified group.
b.n1 = Number of subjects meeting the endpoint definition.
c.Total surveillance time in 1000 person-years for the given endpoint across all subjects within each group at risk for
the endpoint. Time period for COVID -19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
d.n2 = Number of subjects at risk for the endp oint.
e.Credible interval for VE was calculated using a beta -binomial model with prior beta (0.700102, 1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details.
f.Posterior probability (Pr) was calcu lated using a beta -binomial model with prior beta (0.700102, 1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details.
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All Confirmed Cases of Severe COVID -19 After Dose 1 – All- Available Population
Among participants in the all -available efficacy population, 1 case of severe COVID-19
occurred after Dose 1 in the BNT162b2 group compared to 9 cases in the placebo group
(Table22). The estimated VE against severe COVID- 19 occurring after Dose 1 was 88.9%
(2-sided 95% CI: 20.1%, 99.7%), with an estimated VE of 75.0% (1 case in BNT162b2 and
4cases in placebo groups) against severe COVID -19 occurring at least 7 days after Dos e 2.
In addition to the C4591001 protocol specified definition of severe COVID -19(provided in
Section 2.5.4.1.1.3 ), a post hoc efficacy analysis for severe COVID-19 cases was conducted
using the CDC definition of severe COVID -19 (hospitalization, admission to the I CU,
intubation or mechanical ventilation, or death ).18Inthis analy sis,the Dose 1 all -available
efficacy population, 1 case of severe COVID-19 occurred after Dose1 in the BNT162b2
group compared to 14 cases in the placebo group ( Table23). The estimated VE against
severe COVID -19 occurring after Dose 1 was 92.9% (2-sided 95% CI: 53.2%, 99.8%), with
an estimated VE of 100.0% against severe COVID -19 occurring at least 7 days after Dose 2
(nocases in the BNT162b2 group and 5cases in the placebo group).
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Page 71Table22.Vaccine Efficacy – First Severe COVID -19 Occurrence After Dose 1 –Dose
1 All-Available Efficacy Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=21669)Placebo
(Na=21686)
Efficacy Endpoint
Subgroupn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE (%) (95% CIe)
First severe COVID- 19 occurrence after
Dose 114.021 (21314) 94.006 (21259) 88.9 (20.1, 99.7)
After Dose 1 to before Dose 2 0 4 100.0 (-51.5, 100.0)
Dose 2 to 7 days after Dose 2 0 1 100.0 (-3800.0, 100.0)
≥7 Days after Dose 2 1 4 75.0 (-152.6, 99.5)
Abbreviations: VE = vaccine efficacy.
a.N = number of subjects in the specified group.
b.n1 = Number of subjects meeting the endpoint definition.
c.Total surveillance time in 1000 person -years for the given endpoint across all subjects within each group at risk for
the endpoint. Time period for COVID -19 case accrual is from Dose 1 to the end o f the surveillance period.
d.n2 = Number of subjects at risk for the endpoint.
e.Confidence interval (CI) for VE is derived based on the Clopper and Pearson method (adjusted for surveillance time
for overall row).
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Page 72Table23.Vaccine Efficacy – First Severe COVID -19 Occurrence Based on CDC -
Definition After Dose 1 –Dose 1 All -Available Efficacy Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=21669)Placebo
(Na=21686)
Efficacy Endpoint
Subgroupn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE
(%)(95% CIe)
First Severe COVID -19 occurrence based on
CDC-definition after Dose 114.018 (21299) 144.001 (21238) 92.9 (53.2, 99.8)
After Dose 1 to before Dose 2 1 8 87.5 (6.8, 99.7)
Dose 2 to 7 days after Dose 2 0 1 100.0(-3800.0, 100.0)
≥7 Days after Dose 2 0 5 100.0 (-9.1, 100.0)
Abbreviations: VE = vaccine efficacy.
a.N = number of subjects in the specified group.
b.n1 = Number of subjects meeting the endpoint definition.
c.Total surveillance time in 1000 person -years for the given endpoint across all subjects within each group at risk for
the endpoint. Time period for COVID -19 case accrual is from Dose 1 to the end of the surv eillance period.
d.n2 = Number of subjects at risk for the endpoint.
e.Confidence interval (CI) for VE is derived based on the Clopper and Pearson method (adjusted for surveillance time
for overall row).
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Participants W ithout Evidence of Infection Before and During Vaccination Regimen
(14Days) –Severe–Evaluable Efficacy Population
For this efficacy endpoint, participants with positive or unknown NAAT results at any illness
visit prior to 14 days after Dose 2 were not included in the evaluation for efficacy .
Among participants without evidence of SARS -CoV-2 infection before and during the
vaccination regimen, the estimated VE against severe COVID- 19 occurring at least 14 day s
after Dose 2 was 66.4%, with 1 and 3 cases in the BNT162b2 and placebo groups
respectively (Table24). The posterior probability for the true vaccine efficacy greater than
30% is 74.32%.
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Page 73Table24.Vaccine Efficacy – First Severe COVID -19 Occurrence From 14 Days After
Dose 2 –Subjects Without Evidence of Infection Prior to 14 Days After
Dose 2 –Evaluable Efficacy (14 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=18175)Placebo
(Na=18261)
Efficacy Endpoint n1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE
(%)(95% CIe)Pr (VE >30% |
data)f
First severe COVID-19
occurrence from 14 days after
Dose 211.888 (16612) 31.901 (16663) 66.4(-124.7, 96.3) 0.7432
Abbreviations: N -binding = SARS -CoV-2 nucleoprotein –binding; NAAT = nucleic acid amplification test; SARS -CoV-2
= severe acute respiratory syndrome coronavirus 2; VE = vaccine efficacy.
Note: Subjects who had no serological or virological evidence (prior to 14 days after receipt of the last do se) of past
SARS-CoV-2 infection (ie, N -binding antibody [serum] negative at Visit 1 and SARS -CoV-2 not detected by NAAT
[nasal swab] at Visits 1 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 14 days after Dose 2
were include d in the analysis.
a.N = number of subjects in the specified group.
b.n1 = Number of subjects meeting the endpoint definition.
c.Total surveillance time in 1000 person -years for the given endpoint across all subjects within each group at ri sk for
the endpoint. Time period for COVID -19 case accrual is from 14 days after Dose 2 to the end of the surveillance period.
d.n2 = Number of subjects at risk for the endpoint.
e.Credible interval for VE was calculated using a beta -binomial mod el with prior beta (0.700102, 1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details.
f.Posterior probability (Pr) was calculated using a beta -binomial model with prior beta (0.700102, 1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details.
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Participants With or Without Evidence of Infection Before and During Vaccination Regimen
(14Days) –Severe–Evaluable Efficacy Population
Among participants with or without evidence of SARS- CoV-2 infection before and during
vaccination phase, VE against severe COVID -19 occurring at least 14 day s after Dose 2 was
66.3%, with 1 and 3 cases in the BNT162b2 and placebo groups respectively ( Table25). The
posterior probability for the true vaccine efficacy greater than 30% is 74.18%.
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Page 74Table25.Vaccine Efficacy – First Severe COVID -19 Occurrence From 14 Days After
Dose 2 –Subjects With or Without Evidence of Infection Prior to 14 Days
After Dose 2 –Evaluable Efficacy (14 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=19965)Placebo
(Na=20171)
Efficacy Endpoint n1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE
(%)(95% CIe)Pr (VE >30% |
data)f
First severe COVID-19
occurrence from 14 days after
Dose 211.985 (17652) 32.007 (17792) 66.3(-125.6, 96.3) 0.7418
Abbreviations: VE = vaccine efficacy.
a.N = number of subjects in the specified group.
b.n1 = Number of subjects meeting the endpoint definition.
c.Total surveillance time in 1000 person -years for the given endpoint across all subjects within each group at risk for
the endpoint. Time period for COVID -19 case accrual is from 14 days after Dose 2 to the end of the surveillance period.
d.n2 = Number of subjects at risk for the endpoint.
e.Credible interval for VE was calculated using a beta -binomial model with prior beta (0.700102, 1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details.
f.Posterior probability (Pr) was calculated using a beta -binomial model with prior beta (0.700102, 1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details.
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2.5.4.3.2.1.3.3. Efficacy forCOVID-19 perCDC Definition –Final Analysis
Efficacy Against COVID -19 Based on CDC -Defined Symptoms (≥7Days After Dose 2)
Participants W ithout Evidence of Infection Before and During Vaccination Regimen –
CDCDefined – 7 Days
For this efficacy endpoint, participants with positive or unknown NAAT results at any illness
visit prior to 7 day s after Dose 2 were not included in the evaluation for efficacy .
Among participants without evidence of SARS -CoV-2 infection before and during the
vaccination regimen, VE against CDC- defined COVID -19 occurring at least 7 day s after
Dose 2 was 95.1% (2- sided 95% CI: 90.2%, 97.9%), with 8 and 165 cases in the BNT162b2
and placebo groups respectively (Table26).
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Page 75Table26.Vaccine Efficacy – First COVID -19 Occurrence Based on CDC- Defined
Symptoms From 7 Days After Dose 2 –Subjects Without Evidence of
Infection Prior to 7 Days After Dose 2 –Evaluable Efficacy (7 Days)
Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=18198)Placebo
(Na=18325)
Efficacy Endpoint n1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE
(%)(95% CIe)
First COVID -19 occurrence based on CDC-
defined symptoms from 7 days after Dose 282.213 (17399) 1652.220 (17495) 95.1(90.2, 97.9)
Abbreviations: N -binding = SARS -CoV-2 nucleoprotein– binding; NAAT = nucleic acid amplification test; SARS -CoV-2
= severe acute respiratory syndrome coronavirus 2; VE = vaccine efficacy.
Note: Subjects who had no serological or virological evidence (prior to 7 days after receipt of the last dose) of past SARS -
CoV-2 infection (ie, N -binding antibody [serum] negative at Visit 1 and SARS-CoV -2 not detected by NAAT [nasal swab]
at Visits 1 and 2), and had negative NAAT(nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were
included in the analysis.
a.N = number of subjects in the specified group.
b.n1 = Number of subjects meeting the endpoint definition.
c.Total surveillance time in 1000 person-years for the given endpoint across all subjects within each group at risk for
the endpoint. Time period for COVID -19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
d.n2 = Number of subjects at risk for the end point.
e.Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for surveillance time.
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Participants W ith orWithout Evidence of Infection Before and During Vaccination Regimen
–CDC Defined –7 Days
Among participants with orwithout evidence of SARS -CoV-2 infection before and during
the vaccination regimen, VE against CDC- defined COVID -19 occurring at least 7 day s after
Dose 2 was 94.7% (2- sided 95% CI: 89.8%, 97.6%), with 9 and 172 cases in the BNT1 62b2
and placebo groups respectively (Table27).
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Page 76Table27.Vaccine Efficacy – First COVID -19 Occurrence Based on CDC- Defined
Symptoms From 7 Days After Dose 2 –Subjects With o r Without Evidence
of Infection Prior to 7 Days After Dose 2 –Evaluable Efficacy (7 Days)
Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=19965)Placebo
(Na=20172)
Efficacy Endpoint n1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE
(%)(95% CIe)
First COVID -19 occurrence based on CDC- defined
symptoms from 7 days after Dose 292.330 (18544) 1722.343 (18690) 94.7(89.8, 97.6)
Abbreviations: VE = vaccine efficacy.
a.N = number of subjects in the specified group.
b.n1 = Number of subjects meeting the endpoint definition.
c.Total surveillance time in 1000 person -years for the given endpoint across all subjects within each group at risk for
the endpoint . Time period for COVID -19 case accrual is from 7 days after Dose 2 to the end of the surveillance period.
d.n2 = Number of subjects at risk for the endpoint.
e.Confidence interval (CI) for VE is derived based on the Clopper and Pearson method ad justed for surveillance time.
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Efficacy Against COVID -19 Based on CDC -Defined Symptoms ( ≥14 Days After Dose 2)
Amongparticipants without and with or without evidence of SARS -CoV-2 infection before
and during the vaccination regimen , observed VE results against CDC -defined COVID -19
occurring at least 14 days after Dose 2 were similar to those occurring at least 7 day s after
Dose 2.
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Page 772.5.4.3.2.2. Efficacy Conclusions –Final Analysis
Final Analysis of Efficacy in the Evaluable Efficacy Population
In the final efficacy analysis, among participants without evidence of SARS -CoV-2 infection
before and during the vaccination regimen, VE against confirmed COVID -19 occurring at
least 7days after Dose 2 was 95.0%, with 8 COVID -19 cases in the BNT162b2 gro up
compared to 162 COVID -19 cases in the placebo group. The 95% credible interval for the
vaccine efficacy was 90.3% to 97.6%.
For the second primary endpoint, VE against confirmed COVID -19 occurring at least 7 days
after Dose 2 in participants with or without evidence of SARS -CoV-2 infection before and
during the vaccination regimen was 94.6%, with 9 and 169 cases in the BNT162b2 and
placebo groups respectively . The posterior probability of >99.99% for the true VE greater
than 30% met the prespecified success criterion of >98.6% for this endpoint. The 95%
credible interval for the vaccine efficacy was 89.9% to 97.3%.
Observed VE was very high for the first primary efficacy endpoint across subgroups of age,
sex, race, ethnicity, and country, as VE was >93% in all subgroups, with the exception of “all
others” race group (89.3% VE) and Brazil (87.7% VE).
For the secondary efficacy endpoint analyses, observed VE against confirmed COVID-19
occurring at least 14 day s after Dose 2 in participants without evidence of SARS-CoV-2
infection before and during the vaccination regimen, was 94.2%, with 8 and 139 cases in the
BNT162b2 and placebo groups respectively. The posterior probability of >99.99% for the
true VE >30% met the prespecified success criterion of >98.6% f or this endpoint. The 95%
credible interval for the vaccine efficacy was 88.7% to 97.2%.
Similarly, among participants with or without evidence of SARS- CoV-2 infection before and
during the vaccination regimen, VE against confirmed COVID -19 occurring at l east 14 day s
after Dose 2 was 94.4%, with 8 and 144 cases in the BNT162b2 and placebo groups
respectivel y. The posterior probability of >99.99% for the true VE >30% met the
prespecified success criterion of >98.6% for this endpoint. The 95% credible interv al for the
vaccine efficacy was 89.1% to 97.3%.
Amongparticipants without evidence of SARS -CoV-2 infection before and during the
vaccination regimen , observed VE of 66.3% against severe COVID -19 occurring at least
7days after Dose 2 did not meet the pres pecified success criterion of the posterior probability
>98.6%, due to the small number of severe cases (1 in the BNT162b2 group, 3 in the placebo
group) observed after Dose 2 in the study .
The efficacy anal yses using CDC defined sy mptoms to identify a COVID-19 case gave
similar efficacy results as the primary endpoints.
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Page 78Final Analysis of Efficacy in the All-Available Efficacy Population
The early onset of protection is readily apparent from cumulative incidence curves, which
show that disease onset tra cks conjointly for BNT162b2 and placebo until approximately
14days after Dose 1, at which point the curves diverge, with cases steadil y accumulating in
the placebo group, while remaining virtually flat after BNT162b2.
Among all participants, regardless of evidence of infection before or during the vaccination
regimen, 50 cases of COVID-19 occurred after Dose 1 in the BNT162b2 group compared
with 275 cases in the placebo group, indicating an estimated VE of 82% (2 -sided 95% CI:
75.6%, 86.9%) against confirm ed COVID -19 occurring after Dose 1, with VE of 52.4%
(95%CI: 29.5%, 68.4%) between Dose 1 and Dose 2 .
Among the total of 10 severe COVID- 19 cases observed after Dose 1, onl y 1severe case was
seen in BNT162b2 recipients compared to 9 severe COVID -19 casesin placebo recipients;
these results, as well as case splits between Dose 1 and Dose 2 and after Dose 2, were
consistent with overall efficacy seen against COVID -19. Similar results were observed when
using the CDC definition of severe disease.
Overall Co nclusions from Final Analysis of Efficacy
Final efficacy results show that BNT162b2 at 30 µg provided protection against COVID -19
in participants with or without evidence of prior infection with SARS -CoV-2, including
across demographic subgroups, with sev ere cases observed predominantly in the placebo
group.
2.5.4.3.3. Updated Analysis of Efficacy in Study C4591001
Updated analy ses of 1165 confirmed cases in blinded placebo- controlled follow -up from
Dose 1 to the data cutoff date (13 March 2021) evaluated duration of protection . Updated
efficacy data for the Phase 3 portion of Study C4591001 were anal yzed for all enrolled
participants who met the protocol- specified criteria for efficacy evaluation. Data are
summarized for the efficacy populations.
COVID-19 case evaluation for primary and secondary efficacy endpoints is discussed in
Section 2.5.4.1 . Efficacy endpoints evaluated confirmed COVID -19 cases in partic ipants
either without or with or without evidence of past SARS-CoV-2 infection before and during
the vaccination regime n. Participants with positive or unknown NAAT results at any illness
visit prior to either 7 days after Dose 2 were not included in the e valuation for VE. Cases
were counted from 7 days after Dose 2.
Efficacy population characteristics in the updatedanalysis are presented in Section 2.5.4.3.3.1 ,
and results of the updatedanalysis are presented in Section 2.5.4.3.3.2 and Section 2.5.4.3.3.3
(VE for participants either withoutor with or without prior evidence of SARS -CoV-2 infection,
respectivel y), Section 2.5.4.3.3.4 (VE in demographic, risk, and comorbidity subgroups), and
Section 2.5.4.3.3.5 (VEforsevere disease as defined by the FDA and by the CDC ).
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Page 792.5.4.3.3.1. Efficacy Populations –Updated Analysis
Disposition and Data Sets Analyzed
The proportions of participants included in the updated efficacy populations w eresimilar in
the BNT162b2 and placebo groups (Table28).
Most particip ants who were excluded from the evaluable efficacy population had not
received all vaccinations as randomized or did not receive Dose 2 within the predefined
window (ie, 19 to 42 days after Dose 1). There were 240 participants in the BNT162b2 group
and 60 participants in the placebo group excluded for having important protocol deviation s
on or prior to 7 day s after Dose 2. In the BNT162b2 group, most of these deviations were
related to improper administration of the investigational product (203 participants, as
compared with 23 participants in the placebo group) .Specificall y,in the BNT162b2 group
most PDs were due to dosing/administration errors (errors in dilution of the vaccine,
76 participants) or administration of investigational product that was deemed not suitable for
use (temperature excursions in shipment or storage a t the distributor, 110 participants) that
would have not applied to placebo .
Table28.Efficacy Populations – Blinded Placebo -Controlled Follow -up Period
Vaccine Group (as
Randomized)
BNT162b2 (30
μg)
na(%)Placebo
na(%)Total
na(%)
Randomizedb23219 (100.0) 23210 (100.0) 46429 (100.0)
Dose 1 all -available efficacy population 23140 (99.7) 23137 (99.7) 46277 (99.7)
Subjects without evidence of infection before Dose 1 22200 (95.6) 22191 (95.6) 44391 (95.6)
Subjects excluded from Dose 1 all-available efficacy population 79 (0.3) 73 (0.3) 152 (0.3)
Reason for exclusionc
Did not receive at least 1 vaccination 58 (0.2) 51 (0.2) 109 (0.2)
Data considered potentially unreliable due to lack of PI oversight
identified as significant quality event21 (0.1) 22 (0.1) 43 (0.1)
Dose 2 all -available efficacy population 22771 (98.1) 22741 (98.0) 45512 (98.0)
Subjects without evidence of infection prior to 7 days after Dose 2 21544 (92.8) 21470 (92.5) 43014 (92.6)
Subjects excluded from Dose 2 all -available efficacy population 448 (1.9) 469 (2.0) 917 (2.0)
Reason for exclusionc
Did not receive 2 vaccinations 384 (1.7) 443 (1.9) 827 (1.8)
Data considered potentially unreliable due to lack of PI oversight
identified as significant quality event21 (0.1) 22 (0.1) 43 (0.1)
Unblinded prior to 7 days after Dose 2 45 (0.2) 11 (0.0) 56 (0.1)
Evaluable efficacy (7 days) population 22255 (95.8) 22410 (96.6) 44665 (96.2)
Subjects without evidence of infection prior to 7 days after Dose 2 21069 (90.7) 21175 (91.2) 42244 (91.0)
Subjects excluded from evaluable efficacy (7 days) population 964 (4.2) 800 (3.4) 1764 (3.8)
Reason for exclusionc
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Page 80Table28.Efficacy Populations – Blinded Placebo -Controlled Follow -up Period
Vaccine Group (as
Randomized)
BNT162b2 (30
μg)
na(%)Placebo
na(%)Total
na(%)
Randomized but did not meet all eligibility criteria 33 (0.1) 30 (0.1) 63 (0.1)
Data considered potentially unreliable due to lack of PI oversight
identified as significant quality event21 (0.1) 22 (0.1) 43 (0.1)
Did not receive all vaccinations as randomized or did not receive
Dose 2
within the predefined window (19 -42 days after Dose 1)732 (3.2) 748 (3.2) 1480 (3.2)
Unblinded prior to 7 days after Dose 2 45 (0.2) 11 (0.0) 56 (0.1)
Had other important protocol deviations on or prior to 7 days after
Dose 2240 (1.0) 60 (0.3) 300 (0.6)
Note: HIV -positive subjects are included in this summary but not included in the analyses of the overall study objectives.
a.n = Number of subjects with the specified characteristic.
b.These values are the denominators for the percentage calculations.
c.Subjects may have been excluded for more than 1 reason.
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Demographics
Demographics of participants in the updatedevaluable efficacy population for participants
without evidence of infection prior to 7 days after Dose 2 were similar in the BNT162b2 and
placebo groups (Table29). This anal ysispopulation had generally similar demographics
compared to the safet y population (refer to Section 2.5.5.5.1).
Demographic characteristics for the Dose 1all-available efficacy population and for
participants with or without evidence of infection prior to 7days after Dose 2 ( evaluable
efficacy [7 days] population ) were similar to the evaluable efficacy (7 days) population .
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Page 81Table29.Demographic Characteristics – Blinded Placebo -Controlled Follow -up
Period–Subjects Without Evidence of Infection Prior to 7 Days After Dose
2 –Evaluable Efficacy (7 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=21069)
nb(%)Placebo
(Na=21175)
nb(%)Total
(Na=42244)
nb(%)
Sex
Male 10824 (51.4) 10689 (50.5) 21513 (50.9)
Female 10245 (48.6) 10486 (49.5) 20731 (49.1)
Race
White 17458 (82.9) 17604 (83.1) 35062 (83.0)
Black or African American 1799 (8.5) 1812 (8.6) 3611 (8.5)
American Indian or Alaska Native 188 (0.9) 182 (0.9) 370 (0.9)
Asian 959 (4.6) 949 (4.5) 1908 (4.5)
Native Hawaiian or other Pacific Islander 55 (0.3) 31 (0.1) 86 (0.2)
Multiracial 522 (2.5) 489 (2.3) 1011 (2.4)
Not reported 88 (0.4) 108 (0.5) 196 (0.5)
All othersc1812 (8.6) 1759 (8.3) 3571 (8.5)
Racial Designation
Japanese 78 (0.4) 74 (0.3) 152 (0.4)
Ethnicity
Hispanic/Latino 5241 (24.9) 5217 (24.6) 10458 (24.8)
Non-Hispanic/non -Latino 15725 (74.6) 15846 (74.8) 31571 (74.7)
Not reported 103 (0.5) 112 (0.5) 215 (0.5)
Country
Argentina 2624 (12.5) 2617 (12.4) 5241 (12.4)
Brazil 1326 (6.3) 1314 (6.2) 2640 (6.2)
Germany 238 (1.1) 242 (1.1) 480 (1.1)
South Africa 307 (1.5) 297 (1.4) 604 (1.4)
Turkey 231 (1.1) 226 (1.1) 457 (1.1)
USA 16343 (77.6) 16479 (77.8) 32822 (77.7)
Age group (years)
12 to 15 1005 (4.8) 978 (4.6) 1983 (4.7)
16 to 55 11753 (55.8) 11824 (55.8) 23577 (55.8)
>55 8311 (39.4) 8373 (39.5) 16684 (39.5)
≥65 4245 (20.1) 4296 (20.3) 8541 (20.2)
16 to 17 344 (1.6) 334 (1.6) 678 (1.6)
16 to 25 1657 (7.9) 1668 (7.9) 3325 (7.9)
16 to 64 15819 (75.1) 15901 (75.1) 31720 (75.1)
18 to 64 15475 (73.4) 15567 (73.5) 31042 (73.5)
55 to 64 4499 (21.4) 4493 (21.2) 8992 (21.3)
65 to 74 3392 (16.1) 3442 (16.3) 6834 (16.2)
≥75 853 (4.0) 854 (4.0) 1707 (4.0)
75 to 85 848 (4.0) 848 (4.0) 1696 (4.0)
>85 5 (0.0) 6 (0.0) 11 (0.0)
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Page 82Table29.Demographic Characteristics – Blinded Placebo -Controlled Follow -up
Period–Subjects Without Evidence of Infection Prior to 7 Days After Dose
2 –Evaluable Efficacy (7 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=21069)
nb(%)Placebo
(Na=21175)
nb(%)Total
(Na=42244)
nb(%)
Comorbiditiesd
Yes 9390 (44.6) 9411 (44.4) 18801 (44.5)
No 11679 (55.4) 11764 (55.6) 23443 (55.5)
Age at vaccination (years)
Mean (SD) 48.3 (17.41) 48.2 (17.41) 48.3 (17.41)
Median 50.0 50.0 50.0
Min, max (12, 89) (12, 91) (12, 91)
Note: HIV -positive subjects are included in this summary but not included in the analyses of the overall study objectives.
a.N = number of subjects in the specified group, or the total sample. This value is the denominator for the percentage
calculations.
b.n = Number of subjects with the specified characteristic.
c.All others = American Indian or Alaska nativ e, Asian, Native Hawaiian or other Pacific Islander, multiracial, and not
reported race categories.
d.Number of subjects who have 1 or more comorbidities that increase the risk of severe COVID -19 disease: defined as
subjects who had at least one of t he Charlson comorbidity index category or BMI ≥30 kg/m2(≥16 Years of age) or BMI
≥95thpercentile (12 -15 Years of age).
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data: adsl Table Generation: 19A PR2021
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(Cutoff Date: 13MAR2021, S napshot Date: 25MAR2021) Output File:
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2.5.4.3.3.2. Vaccine Efficacy Without Prior Evidence of SARS- CoV-2 Infection – 7 Days
After Dose 2 –Updated Analysis
Among participants withoutevidence of SARS -CoV-2 infection before and during the
vaccination regimen, the estimated VE again
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