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BNT162b2
2.7.3 Summary of Clinical Efficacy
CONFIDENTIAL
Page 12.7.3 SUMMARY OF CLINICAL E FFICAC Y
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Page 2TABLE OF CONTENTS
LIST OF TABLES ................................ ................................ ................................ ..................... 3
LIST OF FIGURES ................................ ................................ ................................ ................... 9
LIST OF ABBREVIATION S................................ ................................ ................................ ..11
2.7.3. SUMMARY OF CLIN ICAL EFFI CACY ................................ ................................ .....13
2.7.3.1. Background and Overview of Clinical Efficacy /Immunogenicity.................... 13
2.7.3.1.1. Overview of the Clinical Development Program ................................ .15
2.7.3.1.1.1. Phase 1/2 Study BNT162 -01 – Study Design and
Conduct ................................ ................................ .............................. 15
2.7.3.1.1.2. Phase 1/2/3 Pivotal Efficacy Study C4591001 –Study
Design and Conduct ................................ ................................ .......... 16
2.7.3.1.2. Methods for the Evaluation of Efficacy –Study C4591001, Phase
2/3................................ ................................ ................................ .................... 19
2.7.3.1.2.1. Objectives and Endpoints for Efficacy Against
Confirmed COVID -19................................ ................................ .......19
2.7.3.1.2.2. Surveillance/Definitions /Case Determination for
Confirmed COVID -19................................ ................................ .......21
2.7.3.1.2.3. Statistical M ethods (Efficacy )................................ ............. 22
2.7.3.1.3. Methods for Evaluation of Immunogenicity ................................ ......... 24
2.7.3.1.3.1. Measurement of the Immune Response .............................. 24
2.7.3.1.3.2. I mmunogenicity Objectives and Endpoints ........................ 26
2.7.3.1.3.3. I mmunogenicity Analy sis Sets ................................ ............ 26
2.7.3.1.3.4. Statistical Analy ses for Immunogenicity ............................ 27
2.7.3.2. Summary of Results of I ndividual Studies ................................ ........................ 27
2.7.3.2.1. Efficacy Against Confirmed COVID -19 - Pivotal Study
C4591001 (Phase 2/3)................................ ................................ ...................... 27
2.7.3.2.1.1. I nterim Analy sis of Efficacy in Study C4591001 ............... 28
2.7.3.2.1.2. Final Anal ysis of Efficacy in Study C4591001 ................... 34
2.7.3.2.1.3. Updated Efficacy Anal yses –Study C4591001 .................. 53
2.7.3.2.2. I mmunogenicity Evaluations ................................ ................................ 70
2.7.3.2.2.1. Phase 1 I mmunogenicity Results – Candidate and
Dose Selection ................................ ................................ ................... 70
2.7.3.2.2.2. Phase 2 I mmunogenicity Results – Study C4591001 .......104
2.7.3.2.2.3. I mmunogenicity Conclusions for BNT162b2 ................... 108
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Page 32.7.3.3. Comparison and Analy ses of Results Across Studies ................................ .....109
2.7.3.4. Analy sis of Clinical Information Relevant to Dosing Recommendations ......109
2.7.3.5. Persistence of Efficacy and/or Tolerance Effects ................................ ............ 109
REFERENCES ................................ ................................ ................................ ...................... 111
2.7.3.6. Appendix ................................ ................................ ................................ ......... 112
Study C4591001 – Efficacy –Interim Anal ysis................................ ................. 112
Study C4591001 – Efficacy –Final Analy sis................................ ..................... 121
Study C4591001 – Efficacy –Updated Anal ysis................................ ............... 144
Study C4591001 – Phase 1 I mmunogenicity ................................ ...................... 169
Study C4591001 – Phase 2 I mmunogenicity ................................ ...................... 175
LIST OF TABLES
Table 1. Primary and Secondary Efficacy Anal yses for Efficacy Against
Confirmed COVID -19 ................................ ................................ .............. 21
Table 2. 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
Analy sis 1 ................................ ................................ ................................ .29
Table 3. Vaccine Efficacy –First COVID -19 Occurrence From 7 Day s After
Dose 2, b y Subgroup – Subjects Without Evidence of Infection
Prior to 7 Da ys After Dose 2 – Evaluable Efficacy Population (7
Days) –Interim Anal ysis 1................................ ................................ .......31
Table 4. Severe COVID -19 Occurrence After Dose 1 –Dose 1 All -Available
Efficacy Population – Interim Anal ysis 1................................ ................. 33
Table 5. 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 Day s) Population .......................... 36
Table 6. 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 Day s) Population ................. 37
Table 7. Vaccine Efficacy –First COVID -19 Occurrence After Dose 1 –
Dose 1 All -Available Efficacy Population ................................ ............... 38
Table 8. 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 ................................ ................................ ................................ .41
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Page 4Table 9. 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 Do se 2 –Evaluable Efficacy (7 Day s)
Population ................................ ................................ ................................ .43
Table 10. Vaccine Efficacy –First COVID -19 Occurrence From 14 Days
After Dose 2 – S ubjects Without Evidence of I nfection Prior to 14
Days After Dose 2 – Evaluable Efficacy (14 Day s) Population ............... 45
Table 11. Vaccine Ef ficacy –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 Efficacy (14 Day s)
Population ................................ ................................ ................................ .46
Table 12. Vaccine Efficacy – First Severe COVID- 19 Occurrence From 7
Days After Dose 2 – Subjects Without Evidence of Infection Prior
to 7 Day s After Dose 2 –Evaluable Efficacy (7 Day s) Population .......... 47
Table 13. 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 ................................ ................................ ...................... 48
Table 14. Vaccine Efficacy – First Severe COVID-19 Occurrence After Dose
1 –Dose 1 All -Available Efficacy Population ................................ ......... 49
Table 15. 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 Day s) Population ......50
Table 16. 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 ................................ ................................ ...................... 51
Table 17. Vaccine Efficacy –First COVID -19 Occurrence From 7 Day s After
Dose 2 –Blinded Placebo-Controlled Follow- up Period –Subjects
Without Evidence of I nfection Prior to 7 Day s After Dose 2 –
Evaluable Efficacy (7 Day s) Population ................................ ................... 55
Table 18. 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 Day s) Population ................................ ................ 56
Table 19. Vaccine Efficacy –First COVID -19 Occurrence After Dose 1 –
Blinded Placebo -Controlled Follow- up Period – Dose 1 All -
Available Efficacy Population ................................ ................................ ..57
Table 20. 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 Day s) Population .......................... 60
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Page 5Table 21. 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 Day s) Population .......................... 62
Table 22. 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 Day s) Population ................................ ...64
Table 23. Vaccine Efficacy – First Severe COVID- 19 Occurrence After Dose
1 – Blinded Placebo -Controlled Follow- up Period –Dose 1 All -
Available Efficacy Population ................................ ................................ ..65
Table 24. Vaccine Efficacy –First Severe CO VID-19 Occurrence Based on
CDC -Definition From 7 Day s 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 ................................ ................................ ...................... 66
Table 25. Vaccine Efficacy – First Severe COVID-19 Occurrence Based on
CDC -Definition After Dose 1 –Blinded Placebo -Controlled
Follow -up Period – Dose 1 All- Available Efficacy Population ............... 67
Table 26. Efficacy Populations –Interim Analy sis 1 ................................ ............. 112
Table 27. Demographic Characteristics –Subjects Without Evidence of
Infection Prior to 7 Day s After Dose 2 –Evaluable Efficacy
Population (7 Day s) –Interim Anal ysis 1................................ .............. 114
Table 28. 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 –Interim
Analy sis 1 ................................ ................................ ............................... 116
Table 29. 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 – Dose 2 All -Available Efficacy
Population – Interim Analy sis 1 ................................ ............................. 117
Table 30. COVID -19 Occurrence From 7 Day s After Dose 2, by Prior SARS -
CoV -2 Status – Evaluable Efficacy Population (7 Day s) –Interim
Analy sis 1 ................................ ................................ ............................... 119
Table 31. COVID -19 Occurrence From 7 Day s After Dose 2, by Prior SARS -
CoV -2 Status – Dose 2 All -Available Efficacy Population –Interim
Analy sis 1 ................................ ................................ ............................... 120
Table 32. Efficacy Populations ................................ ................................ ............... 121
Table 33. Demographic Characteristics –Subjects Without Evidence of
Infection Prior to 7 Day s After Dose 2 –Evaluable Efficacy (7
Days) Population ................................ ................................ .................... 123
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Page 6Table 34. Summary of Signs and Sy mptoms for 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 Day s) Population ........ 125
Table 35. Summary of Signs and Sy mptoms for COVID -19 Occurrence After
Dose 1 –Dose 1 All -Available Efficacy Population .............................. 127
Table 36. Summary of Signs and Sy mptoms for Severe COVID -19
Occurrence After Dose 1 –Dose 1 All -Available Efficacy
Population ................................ ................................ ............................... 128
Table 37. 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 ..................... 129
Table 38. 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 ........... 130
Table 39. Vaccine Efficacy –First COVID -19 Oc currence 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 ................................ ................................ .................... 131
Table 40. Vaccine Efficacy –First COVID -19 Occurrence From 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 ................................ ................................ .................... 133
Table 41. Baseline Charlson Comorbidities –Phase 2/3 (All Subjects) –
Safety Population ................................ ................................ .................... 135
Table 42. 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 ................................ ................................ .................... 137
Table 43. Vaccine Efficacy – First Severe COVID-19 Occurrence Based on
CDC -Definition After Dose 1 –Dose 1 All -Available Efficacy
Population ................................ ................................ ............................... 139
Table 44. Vaccine Efficacy –First COVID -19 Occurrence 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 Day s) Population ................................ ................................ ..140
Table 45. 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 Day s) Popula tion................................ ................. 141
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Page 7Table 46. Vaccine Efficacy –First COVID -19 Occurrence Based on CDC-
Defined S ymptoms From 14 Day s After Dose 2 – Subjects Wi thout
Evidence of Infection Prior to 14 Day s After Dose 2 –Evaluable
Efficacy (14 Day s) Population ................................ ................................ 142
Table 47. Vaccine Efficacy –First COVID -19 Occurrence Based on CDC-
Defined S ymptoms From 14 Day s After Dose 2 – Subjects With or
Without Evidence of I nfection Prior to 14 Day s After Dose 2 –
Evaluable Efficacy (14 Day s) Population ................................ ............... 143
Table 48. Efficacy Populations –Blinded Placebo -Controlled Follow -up
Period ................................ ................................ ................................ ......144
Table 49. Subjects Excluded From Evaluable Efficacy Population Due to
Important Protocol Deviations on or Prior to 7 Days After Dose 2 –
Blinded Placebo -Controlled Follow- up Period ................................ ......146
Table 50. Demographic Characteristics –Blinded Placebo -Controlled Follow-
up Period – Subjects Without Evidence of Infection Prior to 7 Day s
After Dose 2 – Evaluable Efficacy (7 Day s) Population ........................ 148
Table 51. Vaccine Efficacy –First COVID -19 Occurrence From 7 Day s After
Dose 2 –Blinded Placebo- Controlled Follow -up Period –Subjects
Without Evidence of I nfection Prior to 7 Day s After Dose 2 –Dose
2 All- Available Efficacy Population ................................ ...................... 151
Table 52. 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
–Dose 2 All -Available Efficacy Population ................................ .......... 152
Table 53. 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 Efficacy (7 Day s) Population ............... 153
Table54. Vaccine Efficacy –First COVID -19 Occurrence After Dose 1, by
Subgroup –Blinded Placebo -Controlled Follow- up Period –Dose 1
All-Available Efficacy Population ................................ ......................... 156
Table 55. Baseline Charlson Comorbidities –Phase 2/3 Subjects ≥16 Years of
Age –Safet y Population ................................ ................................ ......... 159
Table 56. 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 Day s After Dose 2 – Evaluable Efficacy (7 D ays) Population ............ 161
Table 57. 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 Day s) Population ........................ 163
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Page 8Table 58. 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 ................................ ................................ .................... 164
Table 59. Summary of Signs and Sy mptoms for First 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 Day s) Population ........................ 165
Table 60. Summary of Signs and Sy mptoms for First COVID -19 Occurrence
After Dose 1 – Blinded Placebo -Controlled Follow -up Period –
Dose 1 All -Available Efficacy Population ................................ ............. 167
Table 61. Summary of Signs and Sy mptoms for First Severe COVID -19
Occurrence After Dose 1 –Blinded Placebo -Controlled Follow-up
Period – Dose 1 All -Available Efficacy Population ............................... 168
Table 62. Summary of Geometric Mean Titers/Concentrations – Phase 1, 2
Doses, 21 Day s Apart – BNT162b2 (30 μg)/Placebo –Evaluable
Immunogenicit y Population ................................ ................................ ....169
Table 63. Summary of Geometric Mean Fold Rises From Before Vaccination
to Each Subsequent Time Point –Phase 1, 2 Doses, 21 Day s Apart
–BNT162b2 (30 μg)/Placebo –Evaluable Immunogenicity
Population ................................ ................................ ............................... 171
Table 64. Number ( %) of Subjects Achieving a ≥4 -Fold Rise From Before
Vaccination to Each Subsequent Time Point – Phase 1, 2 Doses, 21
Days Apart –BNT162b2 (30 μg)/Placebo –Evaluable
Immunogenicit y Population ................................ ................................ ....173
Table 65. Immunogenicit y Populations – Phase 2 ................................ .................. 175
Table 66. Demographic Characteristics –Phase 2 – Dose 2 Evaluable
Immunogenicit y Population ................................ ................................ ....176
Table 67. Summary of Geometric Mean Titers/Concentrations – Phase 2 –
Dose 2 Evaluable Immunogenicity Population ................................ ......177
Table 68. Summary of Geometric Mean Fold Rises From Before Vaccination
to Each Subsequent Time Point – Phase 2 – Dose 2 Evaluable
Immunogenicit y Population ................................ ................................ ....178
Table 69. Summary of Geometric Mean Titers/Concentrations by Baseline
SARS -CoV -2 Status – Phase 2 –Dose 2 Evaluable I mmunogenicity
Population ................................ ................................ ............................... 179
Table 70. Summary of Geometric Mean Fold Rises From Before Vaccination
to Each Subsequent Time Point by Baseline SARS -CoV -2 Status –
Phase 2 – Dose 2 Evaluable Immunogenicity Population ...................... 181
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Page 9LIST OF FIGURES
Figure 1. Cumulative I ncidence Curves for the First COVID- 19 Occurrence
After Dose 1 – Dose 1 All -Available Efficacy Population ....................... 39
Figure 2. Cumulative I ncidence Curves for th e First COVID -19 Occurrence
After Dose 1– Blinded Placebo -Controlled Follow -up Period –
Dose 1 All -Available Efficacy Population ................................ ............... 58
Figure 3. Frequency and Magnitude of BNT162b2 -Induced CD4+ and CD8+
T cell Responses Against Full -length S protein ................................ .......73
Figure 4. Dura bility of BNT162b2 -Induced T Cell Responses ............................... 75
Figure 5. S-specific CD4+ T Cells Producing the Indicated Cy tokines in
Response to S Protein Pool 1 as a Fraction of Total Cy tokine -
Producing S -Specific CD4+ T Cells –BNT162b2, Adults 18 -55
Years of Age ................................ ................................ ............................. 77
Figure 6 . S- specific CD4+ T Cells Producing the Indicated Cy tokines in
Response to S Protein Pool 1 as a Fraction of Total Cy tokine -
Producing S -Specific CD4+ T Cells (10 to 30 µg BNT162b2 Older
Participant Dose Groups)................................ ................................ .......... 78
Figure 7. Persistence of S -specific CD4+ and CD8+ T Cells Producing the
Indicated C ytokines (IFN and IL -2) as a Fraction of Total
Circulating CD4+ and CD8+ T cells –30 µg B NT162b2 Dose
Group in Younger (a) and Older (b) Participants ................................ .....80
Figure 8. BNT162b1 –Functional 50% SARS -CoV -2 Neutralizing Antibody
Titers (VN 50) –IMM – Adults 18 to 55 Years of Age ............................. 82
Figure 9. BNT162b2 -Functional 50% SARS -CoV -2 Neutralizing Antibody
Titers (VN 50) -IMM - Adults 18 to 55 Years of Age and 56 to 85
Years of Age ................................ ................................ ............................. 83
Figure 10. BNT162b1 – Fold Increase From Baseline in Functional 50%
SARS -CoV -2 Neutralizing Antibod y Titers (VN 50) –IMM –Adults
18 to 55 Years of Age ................................ ................................ ............... 85
Figure 11. BNT162b2 – Fold Increase from Baseline in Functional 50%
SARS -CoV -2 Neutralizing Antibod y Titers (VN 50) –IMM –Adults
18 to 55 Years of Age ................................ ................................ ............... 85
Figure 12. Geometric Mean Titers and 95% CI : SARS -CoV -2 Neutralization
Assay -NT50 –Phase 1, 2 Doses, 21 Day s Apart – 18-55 Years of
Age – BNT162b1 – Evaluable Immunogenicit y Population .................... 89
Figure 13. Geometric Mean Titers and 95% CI : SARS -CoV -2 Neutralization
Assay -NT50 –Phase 1, 2 Doses, 21 Day s Apart – 65-85 Years of
Age – BNT162b1 – Evaluable Immunogenicit y Population .................... 90
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Page 10Figure 14. Geometric Mean Titers and 95% CI : SARS -CoV -2 Neutralization
Assay -NT50 –Phase 1, 2 Doses, 21 Day s Apart – 18-55 Years of
Age – BNT162b2 – Evaluable Immunogenicit y Population .................... 92
Figure 15. Geometric Mean Titers and 95% CI : SARS -CoV -2 Neutralization
Assay -NT50 –Phase 1, 2 Doses, 21 Day s Apart – 65-85 Years of
Age – BNT162b2 – Evaluable Immunogenic ity Population .................... 93
Figure 16. Geometric Mean Concentrations and 95% CI : SARS -CoV -2 RBD -
binding IgG Level Assay – Phase 1, 2 Doses, 21Days Apart – 18-
55 Years of Age – BNT162b1 – Evaluable Immunogenicity
Population ................................ ................................ ................................ .95
Figure 17. Geometric Mean Concentrations and 9 5% CI : SARS -CoV -2 RBD -
binding IgG Level Assay – Phase 1, 2 Doses, 21 Days Apart – 65-
85 Years of Age, BNT162b1 – Evaluable Immunogenicity
Population ................................ ................................ ................................ .96
Figure 18. Geometric Mean Concentrations and 95% CI : SARS -CoV -2 S1-
binding IgG Level Assay – Phase 1, 2 Doses, 21 Days Apart – 18-
55 Years of Age – BNT162b2 – Evaluable Immunogenicity
Population ................................ ................................ ................................ .97
Figure 19. Geometric Mean Concentrations and 95% CI : SARS -CoV -2 S1-
binding IgG Level Assay – Phase 1, 2 Doses, 21 Days Apart – 65-
85 Years of Age – BNT162b2 – Evaluable Immunogenicity
Population ................................ ................................ ................................ .98
Figure 20. 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 ........................... 101
Figure 21. 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 ........................... 102
Figure 22. Geometric Mean Titers: SARS -CoV -2 Neutralization Assay -NT50
–Evaluable Immunogenicity Population (Study C4591001, Phase
2)................................ ................................ ................................ ............. 106
Figure 23. Geometric Mean Concentrations: SARS -CoV -2 S1-binding IgG
Level Assay – Evaluable Immunogenicit y Population (Study
C4591001, Phase 2)................................ ................................ ................ 107
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Page 11LIST OF ABBREVIATIONS
Abbreviation Definition
BMI body mass index
CDC (US) Centers for Disease Control and Prevention
CEFMHC -class I restricted peptides originating from CMV, EBV, and flu (influenza)
virus
CEFTMHC -class II restricted peptides originating from CMV, EBV, Flu (influenza)
virus and tetanus toxin
CI confidence interval
CMV cytomegalovirus
CoV coronavirus
COVID -19 coronavirus disease 2019
CSR clinical study report
DBP diastolic blood pressure
EBV Epstein -Barr- virus
ECMO extracorporeal membrane oxygenation
ELISpot enzyme -linked immuno -spot
FACS fluorescence -activated cell sorting
FDA (US) Food and Drug Administration
FIH first-in-human
FiO 2 fraction of inspired oxygen
GMC geometric mean concentration
GMFR geometric mean -fold rise
GMT geometric mean titer
HBV hepatitis B virus
HCV hepatitis C virus
HCS human convalescent serum
HIV human immunodeficiency virus
HLA human leukocyte antigen
ICS intracellular cytokine staining
ICU intensive care unit
IFN interferon
IgG immunoglobulin G
IgM immunoglobulin M
IL interleukin
IMMImmunogenicity set, defined as all participants who received at least one dose of
study vaccine and had at least one post -baseline immunogenicity assessment
IRC (US Study C4591001) internal review committee
IRR illness rate ratio
LLOQ lower limit of quantitation
LNP lipid nanoparticle
MHC major histocompatibility complex
modRNA nucleoside- modified messenger RNA
mRNA messenger RNA
NAAT nucleic acid amplification test
N-binding SARS -CoV- 2 nucleoprotein binding
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Page 12Abbreviation Definition
P2 S SARS -CoV- 2 full -length, P2 mutant, prefusion spike glycoprotein
PaO 2 partial pressure of oxygen, arterial
PBMC peripheral blood mononuclear cell
Pr posterior probability
RBD receptor binding domain
RNA ribonucleic acid
RNA -LNP RNA lipid nanoparticle
RR respiratory rate
RT-PCR reverse transcription –polymerase chain reaction
S protein, S SARS -CoV- 2 spike protein
SAP statistical analysis plan
SARS severe acute respiratory syndrome
SARS -CoV-2 SARS coronavirus -2; virus causing the disease COVID- 19
SBP systolic blood pressure
SCE summary of clinical efficacy
SPO 2 oxygen saturation as measured by pulse oximetry
USA United States
Th1/Th2 helper T cell type 1/type 2
VE vaccine efficacy
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Page 132.7.3. SUMMARY OF CLINICAL EFFICACY
Pfizer and BioNTech have developed an investigational vaccine intended to prevent
Coronavirus Disease 2019 (COVID -19) caused by the virus ,SARS -CoV -2. The vaccine ,
BNT162b2, is anucleoside -modified m RNA -based vaccine formulated in lipid nanoparticles
(LNPs) thatencodes the SARS -CoV -2 full -length, P2 mutant, prefusion spike gl ycoprotein
(P2 S) .
This Summary of Clinical Efficacy (SCE) summarizes data from evaluations of efficacy and
immunogenicit y performed in 2 clinical studies of B NT162b2 that support the present
marketing application . The proposed indication and dosing administration for BNT162b2
(30µg)are:
Proposed indication : Active immunization to prevent COVI D-19 in individuals 16 years of
age and older
Dosing administration :administered intramuscularly as a series of two doses (0.3 mL each)
3 weeks apart.
The present submission comprises 2 studies conducted in individual s ≥12years of age .
Thesubmission includes data from:
Phase 1 of the first -in-human (FIH) dose-ranging study , BNT162 -01; and
Phase 1, 2, and 3 of the pivotal efficacy study , C4591001.
The studies are currently ongoing, and therefore data included in the submission and
presented in this SCE are interim. Additional data will be provided in subse quent
submissions.
2.7.3.1. Background and Overview of Clinical Efficacy/Immunogenicity
The core innovation of mRNA-based vaccines is based on in vivo delivery 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.1,2,3BioNTech has developed multiple RNA -LNP platforms, including
nucleoside -modified RNA (modRNA) ,which has blunted innate immune sensor activating
capacity and th us augmented antigen expression. Two modRNA vaccine candidates were
evaluated in both the FIH dose -ranging stud y,conducted in German y(BNT162 -01),and in
the Phase 1, dose -ranging portion of Study C4591001, conducted in the United States . The
vaccines wer e:
BNT162b1, which encodes a fragment of the SARS -CoV -2 S glycoprotein that contains
the receptor binding domain (RBD) ; and
BNT162b2, which encodes thefull-length SARS -CoV -2 S glycoprotein with mutations
thatstabilize S in an antigenicall y optimal prefu sion conformation that exposes
neutralization -sensitive sites (P2 S).
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Page 14Based on safet y and immunogenicity results from both of these studies, as well as nonclinical
data, a single candidate and dose level (BNT162b2, at 30 µg )was selected for further
development.
In Phase 2/3 of Study C4591001, the efficacy of BNT162b2 was evaluated using a case
accrual design. Based on initial assumptions regarding the COVID -19 attack rate in the
placebo group and the anticipated non-evaluable rate among all participa nts, it was estimated
that efficacy could be de monstrated in a population of approximately 43,998 participants
(21,999 per group). Recruitment was expanded beyond the United States to include study
centers in Argentina, Brazil, Germany, Turkey , and South Africa .Initially , 4interim analy ses
were planned after accrual of 32, 62, 92, and 120 confirmed COVID -19 cases for the first
primary efficacy endpoint . At each interim analy sis, Vaccine efficacy (VE) was to be
evaluated for the first primary objective only (ie,VE for the subgroup of participants with no
serological or virological evidence of SARS -CoV -2 infection prior to vaccination and up to
7days after receipt of the second dose). Overwhelming efficacy could be declared if the
success criteri onfor the first primary endpoint wasmetat any of the 4 interim analy ses, or
the study could be stopped for lack of benefit if the futility criterion was met at any of the
first 3 interim analyses. The final analy siswas to be performed with accrual of
164confirmed cases for the first primary efficacy endpoint .
For operational reasons, the first planned IA was not performed. Amendment 9 to the
C4591001 protocol eliminated the planned interim anal ysis at 32 cases and provided for
3interim analy sesto be p erformed after accrual of at least 62, 92, and 120 cases . Thereafter,
case accumulation was so rapid that the planned analy sis at 62 cases was performed after
94 cases had been confirmed, and acc rual of the 164 cases for the final analy sis followed
soon thereafter.
At the interim anal ysis(data cutoff date : 04 November 2020), the success criterion for the
first primary endpoint was met, confirming the efficacy of BNT162b2 in preventing disease
caused by SARS -CoV -2 virus in individuals ≥16 yearsof age . The results from this interim
analysis of the first primary endpoint are included in this SCE ,along with the results from
analyses of all the other primary and secondary efficacy endpoints, which were conducted
after accrual of at least 164cases (final analysis data cutoff date: 14 November 2020) .
Inaddition, updated descriptive efficacy anal yses based on an accrued 1165 confirmed cases
of COVID -19 during blinded placebo- controlled follow -up(data cutoff date: 13 March
2021) were conducted.
Analy ses o f immunogenicity in Study C4591001 include data from adults ≥18 y ears of age
up to 6 months after Dose 2 in Phase 1 and up to 1 month after Dose 2 in Phase 2 .
Content of the Summary of Clinical Efficacy
This SCE provides an overview of the 2 studies included in the submission, describing study
design and conduct, methods for evaluating vaccine efficacy and immunogenicity , and
results from the efficacy and immunogenicit y analyses , as outlined below .
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Page 15Content Section
Overview of study design and conduct for both studies Section 2.7.3.1.1
Methods for the evaluation of efficacy (Study C4591001) Section 2.7.3.1.2
Methods for the evaluation of immunogenicit y for both studies Section 2.7.3.1.3
Results of efficacy evaluations (Study C4591001) Section 2.7.3.2 .1
Results of immunogenicity evaluations
Phase 1 Candidate and dose selection (BNT162 -01, C4591001) Section 2.7.3.2.2.1
Phase 2 Immunogeni city results (C4591001) Section 2.7.3.2.2.2
2.7.3.1.1. Overview of the Clinical Development Program
This section provides an overview of stud y design and conduct for Phase 1/2 study
BNT162 -01 (Section 2.7.3.1.1.1 ) and Phase 1/2/3 study C4591001 ( Section 2.7.3.1.1.2 ).
Methods for the evaluation of efficacy , including the statistical analy ses performed, are
described for Study C4591001 in Section 2.7.3.1.2 ; and methods for the evaluation of
immunogenicit y, including the statistical an alyses performed, are described for both studies
in Section 2.7.3.1.3 .
2.7.3.1.1.1. Phase 1/2 Study BNT162-01 – Study Design and Conduct
Study BNT162-01 , conducted in German y,is an ongoing, FIH, open -label, dose -level finding
study designed to evaluate the safety and immunogenicity of several different candidate
vaccines at various dose levels in order to identify vaccine candidates and dose levels for
further evaluation.
The study initially enrolled healthy adults 18 to 55 years of age , but the protocol was later
amended to include adults 56 to 85 y ears of age , with data evaluated separately for the 2 age
groups .Healthy participants with preexisting stable disease, defined as disease not requiring
significant change in therapy or hospitalization for worsening disease during the 6 weeks
prior to enrollment, were eligible for the study . Individuals with certain medical conditions
that could affect participant safet y or evaluation of vaccine safety or immunogenicity were
excluded. A complete list of inclusion and exclusion criteria is available in the protocol
(Module 5.3.5.1 BNT162 -01 Protocol Section 5).
Study BNT162-01 evaluated 4 different vaccine candidates using various mRNA platforms.
However, because onl y the 2 modRN A candidates were ultimatel y selected for progression
in the development program, the 2 candidates based on other RNA platforms are not
discussed further herein.
For each vaccine candidate, participants were to receive escalating /de-escalating dose levels
(12participants per dose level), with progression to subsequent dose levels based on review
of safet y data b y a Safet y Review Committee. Each modRNA vaccine was administered as a
2-dose regimen, given 21 days apart, with dose levels as follows :
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Page 16For adults 18 to 55 y ears of age:
BNT162b1 : 1, 3, 10, 20, 30, 50, and 60 µg
BNT162b2 : 1, 3, 10, 20, and 30µg
Note that based on the tolerability profile after the first dose of BNT162b1 at 60 μg, the
Safety Review Committee recommended that a second dose at 60 µg not be administered.
For adults 56 to 85 years of age:
BNT162b1: 10, 20, 30 µg
BNT162b2: 10, 20, 30 µg
Blood samples for evaluation of immunogenicity wereto be collected at baseline
(immediately before Dose 1); 7 and 21 day s after Dose 1 ; and 7, 14, 21, 28, 63, and 162 day s
after Dose 2.
Immune responses were principally evaluated based on functional antibody titers determined
using the SARS -CoV -2 neutralization assay . In addition, cell -mediated immune response
assay s were used to characte rize T cell responses at baseline and approximately 7days after
Dose 2. For information on immunogenicit y evaluation methods, refer to Section 2.7.3.1.3 .
2.7.3.1.1.2. Phase 1/2/3 Pivotal Efficacy Study C4591001 –Study Design and Conduct
Study C4591001 is theongoing Phase 1/2/3, randomized, placebo -controlled, observer -blind
study in health y individual s≥12years of age .Phase 1 , conducted in the United States,
comprised the dose -finding, vaccine candidate –selection portion of the study , while efficacy
was evaluated in the Phase 2/3 portion of the study , in which enrollment was expanded to
include sites in Argentina, Brazil, German y, Turkey, andSouth Africa .
The study is observer -blinded, as the ph ysical appearance of the investigational vaccine
candidates and the placebo may differ. The participant, investigator, study coordinator, and
other site staff areblinded ; at the study site, onl y the dispenser(s)/administrator(s) of the
study vaccines are unblinded. To facilitate rapid review of data in real time, sponsor staff
were unblinded to vaccine allocation for the participants in Phase 1.
2.7.3.1.1.2.1. Phase 1 of Study C4591001
Initiated shortl y after the FIH stud yBNT162 -01, Phase 1 of Study C4591001 evaluated
escalating dose levels of BNT162b1 and BNT162b2 in healthy adults 18 to 55 y ears of age or
65 to 85 y ears of age. As in Study BNT162-01, h ealthy participants with preexisting stable
disease were eligible, although individuals with certain medical conditions or situations that
could affect participant safet y or evaluation of vaccine safety or immunogenicity were
excluded. These included individuals at high risk for severe COVID -19 (eg , those with
hypertension, diabetes mellitus, chronic pulmonary , liver, or kidney disease); and individuals
who were immunocompromised (including infection with HIV or receipt of sy stemic
corticoster oids); and those with autoimmune disease, HCV, or HBV). Individuals with a
SARS -CoV -2 NAAT- positive nasal swab within 24 hours before receipt of study
intervention or a p ositive serological test for SARS -CoV -2 IgM and/or IgG antibodies at the
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Page 17screening visit were excluded. A complete list of inclusion and exclusion criteria is available
in the protocol (Module 5.3.5.1 C4591001 Protocol Section 5).
Study vaccine was administered using the same 2- dose regimen as in Study BNT162 -01
(21days apart). Aninternal review committee (IRC) reviewed safet y data to allow dose
escalation or changes to continuation of dosing in specified groups. Escalation between dose
levels was based on IRC review of at least 7 -day post–Dose 1 safet y data in this study and/or
the Phase 1 study conducted in German y (BNT162 -01).
Each vaccine and dose level was first evaluated in a group of participants 18-55 years of age
(randomized 4:1, with 12 receiving active vaccine and 3 receiving placebo). A given vaccine
and dose level was administered to groups of participants 65-85 years of age (12 receiving
active vaccine and 3 receiving placebo) only after the I RC had reviewed safety data for the
RNA platform at the same, or a higher, dose level in the 18- to 55 -year age group and
deemed them acceptable. Further details regarding controlled enrollment to ensure safet y at
each dose level, progression between dose levels, and stopping rules areprovided in the
protocol ( Module 5.3.5.1 C4591001 Protocol Section 4.1 ).
The following vaccine candidates and dose levels were evaluated in Phase 1:
BNT162b1: 10, 20, 30, and 100 µg
BNT162b2: 10, 20, and 30 µg
The IRCrecommended that a second dose of BNT162b1 at 100 µg not be administered due
toreactogenicity after the first dose (see Module 5.3.5.1 C4591001 Efficacy Final Analy sis
Interim CSR Section 9.8 and Section 12.1 ). Participants in this group instead received a
second dose of BNT162b1 at the 10 -µg dose level ,and the 100 -µg dose level was not
administered to older adults receiving BNT162b1.
Blood for i mmunogenicity evaluations wascollected immediately before Dose 1 and at visits
taking place approximately 7 and 21 day s after Dose 1; at 7, 14, and 28 days after Dose 2,
and at 6, 12, and 24 months after Dose 2. Immune responses were evaluated using the SARS -
CoV -2 neut ralization assay and antigen specific (S 1-binding or RBD -binding) IgG level
assay s. Refer to Section 2.7.3.1.3 for information on immunogenicit y evaluation methods.
2.7.3.1.1.2.2. Phase 2/3 of Study C4591001
Study Population
Initiall y, participant s enrolled in Phase 2/3 were to be 18 to 85 y ears of age, in 2age strata:
18 to 55 years (“younger participant s”) and 56 to 85 y ears (“older participants ”). It was
intended that a minimum of 40% of participan tswould be in the >55-years stratum .
Theprotocol was later amended to lower the minimum age of participants to 16 years and to
remove the upper age limit (Protocol Amendment 6, 08 September 2020). Protocol
Amendment 7 (06 October 2020) allowed for enrollment of adolescents 12 to 15 years of age
as an additional age stratum .The 12- to 15 -year stratum was expected to comprise up to
approximately 2000 participants enrolled at selected investigational sites. Note that both of
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Page 18these amendments were implemented after Phase 2 of the study had been fully enrolled
(N=360 participants) , and therefore the Phase 2 study population include donly adults 18 to
85 years of age.
Enrollment criteria for Phase 2/3 were defined to ensure a broad stud y population
representative of the “real -world” populations expected to receive the registered vaccine .
Health y participants with preexisting stable disease, defined as disease not requiring
significant change in therapy or hospitalization for worsening disease during the 6 weeks
before enrollment, were eligible for the study . Individuals were to be, in the judgment of the
investigator, at higher risk for acquiring COVID -19 (including, but not limited to, use of
mass transpor tation, relevant demographics, and frontline essential workers) .Individuals
with medical conditions placing them at high risk of severe COVID -19 or in occupations
with high risk of exposure to SARS -CoV -2 were eligible for the stud y. Also included were
individuals with previous clinical or microbiological diagnosis of COVID -19or with
evidence of current or prior infection based on serology or nasal swab. Immunocompromised
individuals were excluded, including those receiving immunosuppressive therap y or s ystemic
corticosteroids (inhaled/nebulized corticosteroids were permitted). Initially, known infection
with human immunodeficiency virus (HIV), hepatitis C virus ( HCV), or hepatitis B virus
(HBV) were exclusionary ; however, Amendment 6 (08 September 2020) allowed enrollment
of individuals with stable HIV, hepatitis B, or hepatitis C. Additional selection criteria are
described in the protocol ( Module 5.3.5.1 C4591001 Protocol Section 5 ).
Vaccine A dministration
Based on review of safety and immunogenicit y results through 1 week post -Dose 2 in both
Study BNT162- 01 and Study C4591001 Phase 1, as well as key results from non -human
primate studies, the vaccine selected for efficacy evaluation in Phase 2/3 of Study C4591001
was BNT162b2 at the 30 µgdose level.
Participant s were randomized in a 1:1 ratio to receive either:
BNT162b2 (30µg); or
Placebo (normal saline).
Vaccines were administered by an unblinded administrator . Participant s received a 2 -dose
regimen, administered approximately 21 day s apart, at Visit 1 and at Visit 2, with Visit 2
intended to take place 19 to 23 day s after Visit 1.
Scheduled Assessments
Blood samples were collected from a ll participant s for immunogenicit y assessments
immediately before Dose 1and 1 month after Dose 2 (Visit 3) . Sample swill also be collected
at follow-up visits scheduled at 6 months, 12 months, and 24 months after Dose 2.
Nasal (midturbinate) swabs for de tection of SARS- CoV -2 were performed at Visit 1 and at
Visit 2.
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Page 19The complete schedule of study activities, including all efficacy , immunogenicity , and safety
evaluations is available in the protocol ( Module 5.3.5.1 C4591001 Protocol Section 1.3).
Definition of Phase 2
Phase 2 of the stud y comprised the collection and evaluation of safet y and immunogenicit y
data for 360 of the earliest enrollees into the Phase 2/3 portion of the study, selected for
balance between the younger (18 to 55 years of age) and older (56 to 85 years of age)
protocol -defined strata within each vaccine group (BNT162b2 or placebo) .Immunogenicit y
data for the 360 Phase 2 participants through 1 month after Dose 2 are presented below in
Section 2.7.3.2.2.2 .These participants were also included in the efficacy evaluation of the
Phase 3 portion of the study .
2.7.3.1.2. Methods for the Evaluation of Efficacy – Study C4591001, Phase 2/3
Efficacy against confirmed COVID -19 was ev aluated in Phase 2/3 of Study C4591001 using
a case -accrual design. Under the assumption of a true vaccine efficacy (VE)rate of ≥60%
after the second dose of study intervention ,a target of 164 first primary -endpoint cases of
confirmed COVID -19 due to SARS -CoV -2 occurring at least 7 daysafter Dose 2 were
sufficient to provide 90% power to conclude true VE >30% with high probability .
Assuming a COVID -19 attack rate of 1. 3% per year in the placebo group, accrual of 164 first
primary -endpoint cases within 6 months, an estimated 20% nonevaluable rate, and 1:1
randomization, the required sample size was expected to be approximately 17,600 evaluable
participants per group or 21,999 BNT162b2 recipients randomized in a 1:1 ratio with
placebo, for a total sample size of 43,998. This wasthe number of participants initially
targeted for Phase 2/3 and could be adjusted based on advice from the data monitoring
committee’s analyses of case accumulation and the percentage of participants who are
seropositive at baseline.
Ongoing s urveillance for potential cases of COVID -19required participants who experienced
symptoms of COVID- 19 (as specified in the protocol) to contact the site immediately for
assessment a nd case confirmation based on protocol- specified criteria (seeSection
2.7.3.1.2.2 ).
2.7.3.1.2.1. Objectives and Endpoints for Efficacy Against Confirmed COVID -19
The primary efficacy objectives of the Phase 2/3 portion of the study were:
To evaluate the efficacy of BNT162b2 against confirmed COVID -19occurring from
7days after the second dose
in participants without evidence of infection before and during vaccination regimen
(first primary objective), and
in participants with or without evidence of infection before and during vaccination
regimen (second primary objective).
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Page 20Secondary efficacy objectives were:
To evaluate the efficacy of BNT162b2 against confirmed COVID -19occurring from
14days after the second dose
in participants without evidence of infection before and during vaccination regimen;
in participants with orwithout evidence of infection before and during vaccination
regimen.
To evaluate the efficacy of BNT162b2 against confirmed severe COVID -19occurring
from 7days and from 14 days after the second dose
in participants without evidence of infection before and during vaccination regimen;
in participants with orwithout evidence of infection before and during vaccination
regimen.
To describe the efficacy of BNT162b2 a gainst confirmed COVID -19 (according to the
CDC -defined s ymptoms) occurring from 7 days and from 14 days after the second dose
in participants without evidence of infection before and during vaccination regimen;
in participants with orwithout evidence of infection before and during vaccination
regimen.
In addition, post hoc analy ses (not specified in the protocol) were performed to describe the
efficacy of BNT162b2 against confirmed severe COVID -19 (according to the CDC -defined
severe symptoms ).
The endpoint for each analy siswas the incidence of disease ( confirmed COVID -19,
confirmed severe COVID 19 , or confirmed COVID -19 according to the CDC -defined
symptoms) per 1000 person- years of follow -up based on a nasal (midturbinate) swab positive
for SARS -CoV- 2 as determined by nucleic acid amplification test (NAAT) (central
laboratory or locally confirmed). Onl yfirst occurrences of COVID -19with onset of
symptoms at least 7 day sor 14 day s after Dose 2 were included in the analy ses.
The anal yses were perf ormed for endpoints as shown in Table 1.
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Page 21Table 1. Primary and Secondary Efficacy Analyses for Efficacy Against
Confirmed COVID -19
Efficacy A gainst Confirm ed:Occurring From
(Days after Dose 2)Incidence in Participants With/Without
Infection Before and During
Vaccination Regim en
Prim ary Efficacy Endpoints
COVID -19
First primary endpoint 7 days With out
Second primary endpoint With orWithout
Secondary Efficacy Endpoints
COVID -19 14 days With out
With orWithout
Severe COVID -19 7 days With out
With orWithout
14 days With out
With orWithout
CDC -Defined COVID -19 7 days With out
With orWithout
14 days With out
With orWithout
2.7.3.1.2.2. Surveillance/Definitions /Case Determination for Confirmed COVID -19
Participants who developed an y of the potential COVID -19 symptoms listed in the protocol
(Module 5.3.5.1 C4591001 Protocol Section 8.13) were to contact the site immediately and,
if confirmed, participate in an in- person or telehealth visit as soon as possible, optimally
within 3 day s of s ymptom onset. At the visit, in vestigators were to collec t clinical
information and results from local standard -of-care tests sufficient to confirm a diagnosis of
COVID -19.
Confirmation of Infection with SARS -CoV-2: Investigators were to obtain a nasal swab
(mid -turbinate) to be tested at a central laboratory using a reverse transcription– polymerase
chain reaction (RT -PCR) test (Cepheid; FDA approved under emergency use authorization )
to detect SARS- CoV -2. If the evaluation was conducted b y telehealth, the participant was to
self-collect a nasal swab and ship for assessment at the central laboratory . The central
laboratory nucleic acid amplification –based test (NAAT) result was to be used for the case
definition, unless no result wasavailable from the central laboratory , in which case a local
NAAT result could be used if it was obtained using oneof the following assay s:
Cepheid Xpert Xpress SARS -CoV -2
Roche cobas SARS -CoV -2 real -time RT -PCR test (EUA200009/A001)
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Page 22Abbott Molecular/RealTime SARS -CoV -2 assay (EUA200023/A001) .
Confirmed COVID -19was defined (per FD A guidance)4asthe presence of at least 1 of the
following s ymptoms and apositive SARS -CoV -2 NAAT (determined b y the central
laboratory or at a local testing facility using an acceptable test) during , or within 4 day s
before or after, the s ymptomatic period:
fever; new or increased cough; new or increased shortness of breath; chills;
new or increased muscle pain; new loss of taste or smell; sore throat; diarrhea;
vomiting.
Confirmed COVID -19 (according to the CDC -defined symptoms) was defined as abov e,
adding the following to the list of sy mptoms :
fatigue; headache; nasal congestion or runn y nose ; nausea.5
Confirmed severe COVID -19was defined (per FDA guidance)4as confirmed COVID -19
and the presence of at least 1 of the following:
Clinical signs at rest indicative of severe s ystemic illness (RR ≥30 breaths per minute,
HR ≥125 beats per minute, SpO2 ≤ 93% on room air at sea level, or PaO2/FiO2
<300 mmHg);
Respiratory failure (defined as needing high -flow oxy gen, noninvasive ventilation,
mechanical ventilation, or ECMO);
Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiring vasopressors);
Signif icant acute renal, hepatic, or neurologic dy sfunction *;
Admission to an I CU;
Death.
For post hoc anal yses (not specified in the protocol), confirmed severe COVID -19
(according to the CDC- defined severe symptoms) was defined as COVID -19 illness events
that resulted in hospitalization, admission to the ICU, intubation or mechanical ventilation,
or death.6
2.7.3.1.2.3. Statistical Methods (Efficacy)
2.7.3.1.2.3.1. Efficacy Analysis Dataset s
The efficacy evaluations were performed using data for the evaluable efficacy population ,
which included all eligible randomized participants who receive dall vaccinations as
randomized, with Dose 2 received within the predefined window (19 -42 day s after Dose 1) ,
and ha dno other important protocol deviations as determined b y the clinician onor before
7days after Dose 2 (for 7 -day post vaccina tion efficacy endpoint s) or on or before 14 day s
after Dose 2 (for 14 -day post vaccination efficacy endpoint s).
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Page 23Efficacy evaluations were also performed for the Dose 1 all -available efficacy population
(all randomized participants who receive dat least 1 vaccination ) and the Dose 2 all -available
efficacy population (allrandomized participants who receive d 2vaccination doses).
Vaccine efficacy evaluation sfor the primary endpoints were also performed forsubgroups of
participants b y age, race, ethnicity , sex, and country , as well as by risk status and by
comorbidity status. I n addition, in analy ses of cases among participants with or without
evidence of prior infection, efficacy evaluations for the pri mary endpoints were also
performed for subgroups of participants b y baseline SARS -CoV -2 infection status.
2.7.3.1.2.3.2. Statistical Analyses for Efficacy
Interim and Final Analyses
The assessment of efficacy against confirmed COVID -19 was event -driven. Initially,
4interim analy ses were planned to be performed by an unblinded statistical team supporting
the data monitoring committee after accrual of 32, 62, 92, and 120 confirmed COVID -19
cases for the first primary endpoint , with the final anal ysis performed after accrua l of at least
164 cases. For operational reasons, the first planned IA (after 32 cases) was not performed.
Amendment 9 to the C4591001 protocol eliminated the planned interim analy sis at 32 cases
and provided for 3interim analy ses to be performed after ac crual of at least 62, 92, and
120cases for the first primary endpoint . At each of the IAs ,vaccine efficacy with respect to
the first primary efficacy endpoint was to be assessed . At the final analy sis(atleast 164
cases) vaccine efficacy with respect to all efficacy endpoints w asto be assessed .
VE against confirmed COVID -19 was estimated by 100 × (1 – IRR), where I RR was the
ratio of COVID -19 illness rate in the BNT162b2 group to the corresponding illness rate in
the pla cebo group . The Bay esian 95% credible interval and the posterior probability for the
true vaccine efficacy greater than 30% conditioning on the available data, i e,
P[VE >30%| data], were calculated using a beta -binomial model and a pre -specified
minimally informative beta distribution as prior. The calculation of posterior probability and
95% credible interval were adjusted for surveillance time. All efficacy endpoints were to be
analyzed using the same Bay esian approach unless stated otherwise.
If the poste rior probability of VE>30% were greater than 99.5%at an y pre-planned interim
analysis, or greater than 98.6%at the final anal ysis, the vaccine efficacy of BNT162b2 would
bedeclared.
If the predicted posterior probability of demonstrating vaccine efficac y at the final anal ysis
were less than 5.0%at the anal yses after accrual of at least 62 and at least 92 cases , the study
would stop for lack of benefit (futility ).
For the subgroup anal yses of the efficacy endpoint s, and for the anal yses of efficacy for
COVID -19 case s determined according to the CDC- defined s ymptoms, VE and the 2 -sided
95% CI for VE wasderived based on the Clopper and Pearson method adjusted for
surveillance time.
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Page 24Updated Efficacy Analyses
Updated efficacy analy ses were performed for COVID -19 cases accrued during blinded
placebo- controlled follow -up, up to the data cutoff date (13 March 2021). Updated
descriptive efficacy analy ses were conducted for the primary efficacy endpoints, including
subgroup anal yses, and for secondary efficac y endpoints of severe disease and CDC -defined
severe disease cases occurring ≥7 day s after Dose 2. The anal yses for cases of COVID -19
occurring ≥14 day s after Dose 2 were not updated.
Thepoint estimate of VE in the blinded follow -up period and associated 2-sided 95%
CIwasderived using the Clopper Pearson method adjusted for surveillance time, and the
posterior probability (ie, P[VE >30%| data]) wasprovided for the primary endpoints and
secondary endpoints of severe disease.
Additional details of the anal ysis methods are provided in Module 5.3.5.1 C4591001
6-Month Update Interim CSR Appendix 16.1.9 SAP Section 5.1.1 and Section 6 .
2.7.3.1.3. Methods for Evaluation of Immunogenicity
2.7.3.1.3.1. Measurement of the Immune Response
Serological Assays
Blood samples were collected for immunogenicity assessments at the visits specified in the
protocol s (Module 5.3.5.1 C4591001 Protocol Section 1.3; Module 5.3.5.1 BNT162 -01
Protocol Section 1.3). In both studies BNT162 -01 and C4591001, immune responses were
evaluated using 3serological assay s: the SARS -CoV -2 neutralization assay, the S1 -binding
IgG level assay , and the RBD- binding IgG level assay .7,8
Details regarding the neutralization and binding assays are available in Module 2.7.1
Summary of Biopharmaceutic Studies and A ssociated Anal ytical Methods and
Module 5.3.1.4 Reports of Bioanaly tical and Analytical Methods for Human Studies.
Human Convalescent Sera Panel for Serology Comparisons
To facilitate interpretation of immunogenicit y data generated in both studies , a human
convalescent serum (HCS) panel was obtained from Sanguine Biosciences (Sherman Oaks,
CA), MT Group (Van Nuy s, CA), and Pfizer Occupational Health and Wellness (Pearl River,
NY).7,8The 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 as ymptomatic . The serum donors had predominantl y had symptomatic
infections (35 of 38) , including 1 who had been hospitalized. Data for SARS -CoV -2 serum
neutralizing titers ( geometric mean titers, GMT s) from the two clinical studies were
compared with data for GMTs determined for the HCS panel.
CD4+ and CD8+ T Cell Responses
In addition, in Study BNT162 -01, T cell mediated immune responses were evaluated using
Enzy me-Linked Immuno -Spot (ELI Spot) andintracellular cy tokine staining (ICS)visualized
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Page 25with fluorescence -activated cell sorting (FACS) .Blood samples for evaluation of T cell
responses were collected at baseline (before Dose 1) and at the visit that was to take place
approximately 7 day s after Dose 2 (~Day 29).
Cell mediated immune response data were also evaluated in post hoc anal yses (not specified
in the protocol) using blood collected for general research purposes on approximately Day 43
(21 day s after Dose 2) Day 85 (63 day s after Dose 2) and Day 184 (162 day s after Dose 2).
Tcell responses were evaluated atthese later time points for only a small number of
participants who received BNT162b2 at doses of 10, 20, or 30 µg.
ELISpot
The ELISpot assay wasused to measure the frequency of cy tokine -secreting cells in sample s
of peripheral blood mononuclear cells (PBMCs) obtained from whole blood samples of
vaccinated participants . Briefl y, PBMCs enriched forCD4+ orCD8+ effector cells are
placed in ELISpot plates pre-coated with antibodies specific for IFN-γand are incubated
overnight (≥18 hours) with peptides originating from the vaccine antigens (ie, from RBD or
full-length S protein). IFN-secreted by CD4+ or CD8+ c ells in response to stimulat ionby
the peptides is bound to the plate by the coating antibody . After incubation, the plates are
developed b y addition of alkaline phosphatase conjugated secondary anti-IFN-γ antibod y
followed b y enz yme substrate ; each spot corresponds to the IFN -secret ed by a single cell.
Developed plates are read by an AID ELISpot Reader. Details of the ELISpot assay are
available in the analy tical interim report (Module 5.3.5.1 BNT162-01 Interim CSR Appendix
16.1.14 GA-RB-022- 01A v3).
For benchmarking, the T cell responses (IFN- secretion) after stimulation by peptides
derived from the vaccine antigens were compared to those after stimulation by recall antigens
in the following assay peptide mixtures:
CEF : MHC -class I restricted peptides originating from CMV, EBV, and Fluvirus
(cytomegalovirus, Epstein- Barr virus, and influenza virus ), which are expected to
stimulate IFN -γ production from CD8+ T cells in the majority of donors ; the peptides
included in this pool are short peptides which mainly stimulate CD8+ T cel ls.
CEFT : MHC -class II restricted peptides originating from CMV, EBV, Flu (influenza )
virus and Tetanus toxin, which are expected to stimulate IFN-γ production from CD4+
Tcells in the majority of donors.
Intracellular Cytokine Staining with FACS
Intracellular cy tokine staining (ICS) is a flow cy tometry -based assay to detect the production
and accumulation of cy tokines intracellularl y upon cell stimulation. PBMCs obtained from
vaccinated participants were restimulated in a round- bottom 96 -well plat e with synthetic
peptides covering the encoded antigen s (RBD or full -length S protein). After stimulation of
PBMCs, inhibitors of protein transport were added to retain the produced cytokines within
the cells. In order to discriminate between antigen -speci fic CD4 and CD8 Tcell responses,
fluorescentl y labelled antibodies for CD4 andCD8 were used for staining of extracellular
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Page 26surface markers. Next, PBMCs were fixed (with paraformaldeh yde) and subsequently
permeabilized for intracellular staining of CD4 andCD8, and of produced cy tokines using
fluorescentl y labelled, cytokine -specific antibodies (IFNγ, IL- 2 and IL -4). After the staining
procedure, cells were analy zed using FACS on a flow cy tometer to visualize the proportions
of vaccine antigen -specific Th1 and Th2 CD4+ T cells and cy totoxic CD8+ T cells producing
each cy tokine. For benchmarking , PBMCs from recovered COVID -19 patients were used.
Details of the ICS/flow cytometry assay are available in the interim technical report, Module
5.3.5.1 BNT162-01 Interim CSR Appendix 16.1.14 – R-20-0235 v2.0 (for BNT162b1) and
R-20 -0241 v 3.0(for BNT162b2).
2.7.3.1.3.2. Immunogenicity Objectives and Endpoints
The methods described below appl y to both Study BNT162- 01 and Study C4591001, except
as noted. The immunogenicity object ives and endpoints are listed for each study in
Module 5.3.5.1 BNT162 -01 Protocol Section 3 and in Module 5.3.5.1 C4591001 Protocol
Section 3 .
For the immunogenicit y serological assay results (neutralizing titers , S1-binding IgGlevels ,
and RBD -binding IgGlevels ), the estimands included:
Geometric mean concentrations (GMCs) or geometric mean titers (GMTs) at protocol
specified time points; (Note that GMT data were summarized for 50% neutralizing
titers and for 90% neutralizing titers. The estimand of princ ipal interest is the 50%
neutralizing titer. The 90% neutralizing titer was primarily intended to assist in
differentiation of the candidate vaccines in Phase 1, if needed, for the purpose of
candidate selection. Results for 90% neutralizing titers are ava ilable in the CSR, but
will not be discussed in this SCE.)
Geometric mean fold -rise (GMFR) from before vaccination to subsequent protocol
specified time points;
Proportion of participants achieving ≥4-fold rise from before vaccination to
subsequent protocol -specified time point after vaccination (Study BNT162 -01 and
Study C4591001 Phase 1 only ).
2.7.3.1.3.3. Immunogenicity Analysis Sets
In Stud y BNT162 -01, immunogenicit y evaluations were performed for the immunogenicit y
set (IMM), defined as all participants who received at least one dose of study vaccine and
had at least one post- baseline immunogenicity assessment .
In Stud y C4591001, immunogenicity anal yses are primarily based on the Dose 1 and Dose 2
evaluable immunogenicity populations. Additional anal yses were to be performed based on
the all -available populations if there was a large enough difference in sample size between
the all -available immunogenicity population and the evaluable immunogenicity population.
Thecriteria for each population are shown below . Participants were anal yzed according to
the vaccine group to which they were randomized.
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Page 27Dose 1 evaluable
immunogenicityFor Phase 1 only , all eligible randomized participants who receive dthe vaccine to
which they are randomly assigned at the first do se, have at least 1 valid and
determinate immunogenicity result from the blood collection w ithin an appropriate
window after Dose 1 (same as visit window, ie, within 19 -23days after Dose 1), and
have no other important protocol deviations as determined by the clinician.
Dose 2 evaluable
immunogenicityAll eligible randomized participants who receive 2 doses of the vaccine to which
they are randomly assigned, with Dose 2 received within the predefined w indow
(19-42 days after Dose 1), have at least 1 valid and determinate immunogenicity
result from the blood collection within an appropriate w indow after Dose 2 (6 -8 days
after Dose 2 for Phase 1 and within 28 -42 days after Dose 2 fo r Phase 2/3), and have
no other important protocol deviations as determined by the clinician.
Dose 1 all -available
immunogenicityFor Phase 1 only , all randomized participants who receive at least 1 dose of the
study intervention with at least 1 valid and determinate immunogenicity result after
Dose 1 but before Dose 2.
Dose 2 all -available
immunogenicityAll random ized participants who receive at least 1 dose of the study intervention
with at least 1 valid and determinate immunogenicity result after Dose 2.
2.7.3.1.3.4. Statistical Analyses for Immunogenicity
For immunogenicity results of SARS -CoV -2 neutralizing titers and S1 -or RBD- binding IgG
concentration s, the GMT s and GMCs were calculated as the mean of the assay results after
making the log arithm transformation and then expo nentiating the mean to express results on
the original scale. Two-sided 95% CIs were obtained by taking log transforms of the titers,
calculating the 95% CI with reference to Student’s t-distribution, and then exponentiating the
confidence limits.
GMFRs were defined as the post -vaccination assay result divided by the pre -vaccination
result. GMFRs were calculated as the mean of the difference of logarithmically transformed
neutralization titers or antibody levels (later result minus earlier result) and ex ponentiating
the mean. The associated 2- sided 95% CIs were obtained by constructing CI s using Student’s
t-distribution for the mean difference on the natural log scale and exponentiating the
confidence limits.
The exact 2-sided 95% CI sfor binary endpoints were computed using the F distribution
(Clopper -Pearson).9
Further details of the analy ses are available in the SAP s (Module 5.3.5.1 C4591001 6-Month
Update Interim CSR Appendix 16.1.9 SAP Section 5 and Section 6 ; and Module 5.3.5.1
BNT162 -01Interim CSR Appendix 16.1.9 SAP Section 6 ). Titers/concentrations below the
lower limit of quantitation ( LLOQ )or denoted as below the level of quantitation were set to
0.5 × LLOQ for anal ysis.
2.7.3.2. Summary of Results of Individual Studies
2.7.3.2.1. Efficacy Against Confirmed COVID -19 - Pivotal Study C4591001 (Phase 2/3)
The e fficacy of BNT162b2 in preventing COVID -19 among participants without evidence of
SARS -CoV -2 infection before and during vaccination regimen was demonstrated at the first
interim analy sis,which was conduc ted after accrual of at least 62cases (cutoff date
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Page 2804November 2020). The results from this anal ysis, which evaluated the first primary
efficacy endpoint onl y, are provided in Section 2.7.3.2.1.1
The final analy sis of efficacy was conducted after accrual of at least 164 cases for the first
primary efficacy endpoint (cutoff date, 14 November 2020). The results from these anal yses
are pr ovided in Section 2.7.3.2.1.2 .
Updated descriptive efficacy analy ses were performed for COVID-19 cases accrued during
blinded placebo -controlled follow -up, up to the cutoff date of 13 March 2021. The results
from these ana lyses are provided in Section 2.7.3.2.1.3 .
Details of results from the interim and final efficacy analyses are provide dinModule 5.3.5.1
C4591001 Efficacy Final Analy sis Interim CSR Section 11.1 and are summarized below.
Details of results from the updated efficacy analy sesare provided in Module 5.3.5.1
C4591001 6- Month Update Interim CSR Section 11.1.2 and are summarized below.
2.7.3.2.1.1. Interim Analysis of Efficacy in Study C4591001
2.7.3.2.1.1.1. Efficacy Populations – Interim Analysis
For the first primary efficacy endpoint, VE for BNT162b2 against confirmed COVID -19 was
evaluated in participants without evidence of prior SARS- CoV -2 infection before and during
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 th isevaluation for VE. Cases were counted
from 7 day s after Dose 2.
In the interim analysis, the proportions of participants included in the evaluable efficacy
population were similar in the BNT162b2 and placebo groups (Table 26). 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 4 2days
after Dose 1) . There were 302 participants (1.4%) in the BNT162b2 group and
52 participants (0.2%) in the placebo group excluded for having important protocol
deviations ator prior to 7 days after Dose 2.
Demographics of participants in the interi m analysis evaluable efficacy population for
participants without evidence of infection before and during the vaccination regimen were
similar between the BNT162b2 and placebo groups ( Table 27). This anal ysispopulation had
generall y similar demographics compared to the safet y population. Demographic
characteristics for the interim anal ysis Dose 2 all -available efficacy population were similar
to those for the evaluable e fficacy population.
2.7.3.2.1.1.2. Primary Efficacy Results – Interim Analysis
2.7.3.2.1.1.2.1. Vaccine Efficacy in Participants Without Prior Evidence of SARS -CoV -2
Infection –7 Days After Dose 2 – 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 ( Table 26).
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Page 29As 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 ( Table 2).
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 prior SARS -CoV -2 infection before and during vaccination regimen with cases
counted from 7 day s after Dose 2.
VE of BNT162b2 was 95.5% with a 99.99% posterior probability for the true VE being
>30% conditioning on available data, to overwhelmingly meet the prespecified 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 pr imary 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 (Table 28).
Table 2.Vaccin e 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 24 1.722 (15899) 90 1.732 (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.
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Page 30Table 2.Vaccin e 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
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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2.7.3.2.1.1.2.2. Vaccine Efficacy by Subgroup – Interim Analysis
VEin 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
(Table 3). Results for t he Dose 2 all -available population were similar, demonstrating no
clinically meaningful differences in VE on the basis of subgroup ( Table 29).
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Page 31Table 3.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 4 1.722 (15899) 90 1.732 (16010) 95.5 (88.1, 98.8)
Age group (years)
16 to 55 2 0.954 (8994) 67 0.959 (9040) 97.0 (88.7, 99.6)
>55 2 0.767 (6905) 23 0.773 (6970) 91.2 (64.6, 99.0)
Sex
Male 2 0.874 (8115) 38 0.865 (8029) 94.8 (79.8, 99.4)
Female 2 0.848 (7784) 52 0.867 (7981) 96.1 (85.1, 99.5)
Race
White 4 1.477 (13399) 85 1.491 (13530) 95.3 (87.4, 98.7)
Black or African American 0 0.124 (1263) 4 0.124 (1277) 100.0 (-51.8, 100.0)
All othersf0 0.121 (1237) 1 0.118 (1203) 100.0 (-3690.1, 100.0)
Ethnicity
Hispanic/Latino 1 0.464 (4389) 34 0.459 (4342) 97.1 (82.7, 99.9)
Non-Hispanic/non -Latino 3 1.247 (11418) 56 1.262 (11570) 94.6 (83.3, 98.9)
Country
Argentina 0 0.271 (2436) 28 0.266 (2402) 100.0 (86.2, 100.0)
Brazil 0 0.087 (878) 2 0.087 (879) 100.0 (-432.5, 100.0)
USA 4 1.360 (12384) 60 1.376 (12530) 93.3 (81.8, 98.2)
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 prior to 7 days after Dose 2 were included in the
analysis.
Note: Data from sub jects 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 = numb er 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 f or 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 to the s urveillance
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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Page 32Table 3.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)
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2.7.3.2.1.1.3. Additional Descriptive Efficacy Results – Interim Analysis
2.7.3.2.1.1.3.1. Vaccine Efficacy by Ba seline 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, ther e were 2 participants in the evaluable efficacy
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
(Table 30).
Results were similar for the Dose 2 all -available population (ie, 1 participant with COVI D-19
in each group was baseline SARS- CoV -2 positive; all others were SARS -CoV -2 negative up
to 7days after Dose 2) (Table 31).
2.7.3.2.1.1.3.2. Vaccine Efficacy for Severe COVID -19 Cases – Interim Analysis
Severe cases of COVID -19 were evaluated from after Dose 1 onwards, and were reported for
the Dose 1 all -available efficacy popu lation (see efficac yanalysis populations in (Section
2.7.3.2.1.1 ).
As of the time of the interim analy sis efficacy , atotal of 7 severe cases of COVID -19 were
reported as occurring from Dose 1 onwards ( Table 4). All of these severe cases were reported
in the placebo group. Of these, 5 of 7 severe cases were reported as occurring after Dose 1
and prior to Dose 2; the remaining 2 cases were reported ≥7 day s after Dose 2.
Of these 7 severe cases reported in the placebo group, all were confirmed as being SARS -
CoV -2 negative at baseline.
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Page 33Table 4.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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2.7.3.2.1.1.4. Efficacy Conclusions From the Interim Analysis – Study C4591001
The first primary efficacy objective met success criteria at the first interim analysis
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 infection
before and during vaccination regimen, and a >99.99% posterior probability for the true VE
being >30%, conditioning on available data.
There w ereno clinicall y meaningful difference sin VE for the first primary efficacy endpoint
by participant subgroup, as VE was >90% across age groups, for both male and female
participants, acr oss race/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.
A total of 7 severe cases of COVID -19 were reported 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 day s
after Dose 2. All severe cases were r eported in placebo recipients and none were reported in
BNT162b2 recipients. None were baseline positive for SARS- CoV -2.
The interim anal ysis efficacy results suggest BNT162b2 at 30 µg provided protection against
COVID -19 overall and across subgroups of pa rticipants who had no evidence of prior
infection with SARS -CoV -2, with severe cases observed exclusively in the placebo group.
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Page 342.7.3.2.1.2. Final Analysis of Efficacy in Study C4591001
Efficacy data for the Phase 3 portion of Study C4591001 were anal yzed for all enrol led
participants who met the protocol- specified criteria for efficacy evaluation, with a final
analysis cutoff date of 14 November 2020.
COVID -19 case evaluation for primary and secondary efficacy endpoints is discussed in
Section 2.7.3.1.2 .
2.7.3.2.1.2.1. Efficacy Populations – Final Analysis
The proportions of participants included in the final anal ysis efficacy populations was simil ar
in the BNT162b2 and placebo groups ( Table 32). 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
311participants in the BNT162b2 group and 60 participants in the placebo group excluded
for having important protocol deviations on or prior to 7 days after Dose 2. In the BNT162b2
group, m ost of these deviations were rela ted to improper administration of the investigat ional
product (263 participants, as compared with 20 participants in the placebo group); among
these, most exclusions in the BNT162b2 group were due to dosing/administration errors
(105 participants) or admin istration of investigational product that was deemed not suitable
for use b y the contractor who distributed the vaccine to study sites (144 participants).
Demographics of participants in the final anal ysis evaluable efficacy population for
participants w ithout evidence of infection prior to 7 days after Dose 2 were similar between
BNT162b2 and placebo groups (Table 33). This analy sispopulation had generall y similar
demographics compared to the safet y population. Demographic characteristics for the final
analysis 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 those for the Dose 2
evaluable efficacy (7 days) population.
2.7.3.2.1.2.2. Signs and Symptoms of COVID -19
The criteria for COVID -19case determination are described in Section 2.7.3.1.2.2 .
The signs and sy mptoms reported for cases contributing to the anal ysis for the first primary
efficacy endpoint (8 cases in the BNT162b2 group and 162 cases in the placebo group) are
summariz ed in Table 34.These include cases occurring at least 7 day s after the second
vaccination among participants in the evaluable efficacy population who had no evidence of
SARS -CoV -2 infection before or during the vaccination regimen . Most of these participants
reported new or increased cough, and other s ymptoms reported most frequently were new or
increased muscle pain, fever, and sore throat. New or increased shortness of breath was
reported for 25 participants (15.4%) in the placebo group and for no participants who
received BNT162b2.
Table 35summarizes the signs and s ymptoms for all cases of COVID -19 occurring at any
time after Dose 1 (50 cases in the BNT162b2 group and 275 cases in the placebo group).
These include cases occurr ing among participants in the Dose 1 all- available efficacy
population, regardless of evidence of SARS -CoV -2 infection before or during the vaccination
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Page 35regimen. Most participants reported 2 or more s ymptoms, and the most frequently reported
symptoms were sim ilar to those for the primary efficacy analysis population.
All participants with severe COVID -19 occurring at any time after Dose 1 (1 case in the
BNT162b2 group and 9 cases in the placebo group) experienced clinical signs at rest
indicative of severe s ystemic illness (RR ≥30 breaths per minute, HR ≥125 beats per minute,
SpO2 ≤93% on room air at sea level, or PaO2/FiO2 <300 mm Hg) ; respiratory failure and
admission to an I CU were each reported for 3 participants (33.3%) in the placebo group
(Table 36).
Complete details of signs and sy mptoms for all efficacy populations and analy ses are
provided in the CSR.
2.7.3.2.1.2.3. Primary Efficacy Results –Final Analysis
For the first primary efficacy endpoint, VE for BNT162b2 against confirmed COVID -19 was
evaluated in participants without evidence of prior SARS -CoV -2 infection before and during
vaccination regimen. Cases were counted from 7 day s after Dose 2. For the sec ond primary
efficacy endpoint, VE for BNT162b2 against confirmed COVID -19 was evaluated in
participants with orwithout evidence of prior SARS -CoV -2 infection before and during
vaccination regimen . Cases were counted from 7 day s after Dose 2.
Secondary efficacy endpoints evaluated confirmed COVID -19 cases in participants either
without or with orwithout evidence of prior SARS -CoV -2 infection before and during
vaccination regimen . Cases were counted from 7 day s after Dose 2 or from 14 day s after
Dose 2 . Secondary efficacy endpoints are described in Section 2.7.3.1.2.1 .
2.7.3.2.1.2.3.1. Vaccine Efficacy Without Prior Evidence of SARS- CoV -2 Infection –
7Days After Dose 2 –Final Analysis
Among participants without evidence of SARS -CoV -2 infection before and during
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 ( Table 5). 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 effic acy endpoint based on the
Dose 2 all -available efficacy population was 95.2%, with 8 and 165 cases in the BNT162b2
and placebo group, respectively (Table 37).
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Page 36Table 5.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 28 2.214 (17411) 162 2.222 (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 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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2.7.3.2.1.2.3.2. 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 or without 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
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
poster ior 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 ( Table 6). Note that wit h a posterior probability of
98.6%, the true vaccine efficacy is at least 89.2% given the available data.
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Page 37The 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 (Table 38).
Table 6.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 29 2.332 (18559) 169 2.345 (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 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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2.7.3.2.1.2.3.3. Vaccine Efficacy for All Confirmed Cases of COVID-19 After Dose 1 –
Dose 1 All -Available Po pulation
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 e xcluded from 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 Table 7,
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 these participants, 50 cases of COVID -19 occurred af ter
Dose 1 in the BNT162b2 group compared to 275 cases in the placebo group. 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
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Page 38estimated VE of 52.4% (2 -sided 95% CI: 29.5%, 68.4%) against confirmed COVID -19
occurring after Dose 1 but before Dose 2.
Table 7.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 50 4.015 (21314) 275 3.982 (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 ac crual 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) population. Disease onset
appears to track together for BNT162b2 and placebo until approximately 14 day s after
Dose 1, 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 (blue circles) and placebo (red squares) curves in Figure 1have an “S”
written inside the open sy mbol, which denotes severe cases. Severe COVID -19 cases
reported in the final analysis are discussed further in Section 2.7.3.2.1.2.4.2 .
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Page 39Figure 1.Cumulative Incidence Curves for the First COV ID-19 Occurrence After Dose 1 – Dose 1 All -Available Efficacy
Population
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Page 402.7.3.2.1.2.3.4. Vaccine Efficacy by Subgroup –Final Analysis
For both primary endpoints, VE was also evaluated for subgroups of participants by age, sex ,
race/ethnicity , and country for participants without evidence of prior infection and for
participants with orwithou t evidence of prior infection.
Among participants without prior evidence of SARS- CoV -2 infection before and during
vaccination regimen, V E was >93% in all subgroups, with the exception of “all others” race
group (89.3% VE) and Brazil (87.7% VE) ( Table 8). VE for additi onal age subgroups and for
all racial groups is provided in Table 39. Notabl y, in participants ≥65 y ears of age ,VE wa s
94.7% (1 case in BNT162b2 group vs 19 cases in placebo group ; 2-sided 95% CI : 66.7%,
99.9%) (Table 8), and VEin par ticipants ≥75 y ears of age was 100% (0 cases in BNT162b2
group vs 5 cases in placebo group+ ; 2-sided 95% CI : -13.1%, 100.0%) (Table 39).
Among partici pants with or without prior evidence of SARS -CoV -2 infection before and
during vaccination regimen, 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) ( Table 40).
Results for t he all -available population were similar; no clinicall y meaningful differences
were observed in VE on the basis of subgroup.
Post Hoc Subgroup Analyses by Risk Status
Post hoc analy ses of efficacy by risk status were performed. For these analyses, a t-risk
participants were defined as those who had at least one Charlson Comorbidity Index
condition or who were obese (defined as bod y mass index ≥30kg/m2). For a summary of
Charlson comorbidit ies among all participants at study entry , seeTable 41.
Among participants without prior evidence of SARS -CoV -2 infection before and during the
vaccination regimen , VE for participants at risk was 95.3%, as compared with 94.7% for
those not at risk ( Table 9). VE for participants ≥65 years of age and at risk was 91.7%, as
compared with 100% for those ≥65 y ears 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 co -morbidity is provided in Table 42.
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Page 41Table 8.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 (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 42Table 8.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 (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 t he 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 gr oup 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, multiracial, and not reporte d race categories.
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Page 43Table 9.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 44Table 9.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.
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Page 452.7.3.2.1.2.4. Secondary Efficacy Results – Final Analysis
2.7.3.2.1.2.4.1. Vaccine Efficacy for COVID -19 ( ≥14 Days After Dose 2)
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 during
vaccination regimen, VE against confirmed COVID -19 occurring at least 14 days after Dose
2 was 94.2%, with 8 and 139 cases in the BNT162b2 and placebo groups respectively
(Table 10). The posterior probability of >99.99% for the true VE greater than 30% met th e
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.
Table 10.Vaccine Efficacy – First CO VID-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 28 1.887 (16612) 139 1.893 (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 and 2), and had negative NAAT (nasal swab) at any unscheduled visit prior to 14 days af ter 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 us ing 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 (0.70 0102, 1) adjusted for
surveillance time. Refer to the statistical analysis plan, Appendix 2, for more details.
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Page 46Participants With or Without Evidence of Infection Before and During Vaccination
Regimen
Among participants with or without evidence of SARS- CoV -2 infection before and during
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 BNT162b2 and placebo groups respectively
(Table 11). 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%, indic ating that the true VE is at least 89.1% with a
97.5% probability given the available data.
Table 11.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 -19occurrence from
14 days after Dose 28 1.984 (17645) 144 1.995 (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 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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2.7.3.2.1.2.4.2. Vaccine 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 evaluation for efficacy .
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Page 47Among participants without evidence of SARS -CoV -2 infection before and during
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 (Table 12). 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.
Table 12.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 21 2.215 (17411) 3 2.232 (17511) 66.4 (-124.8, 96.3) 0.7429
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 infec tion (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 per iod 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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Participants W ith or Without Evidence of Infection Before and During Vaccination Regimen
Among participants with or without evidence of SARS- CoV -2 infection before and during
vaccination regimen, VE against severe COVID -19 occurring at least 7 days after Dose 2
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Page 48was 66.3%, with 1 and 3 cases in the BNT162b2 and placebo groups respectively (Table 13).
The posterior probability for the true vaccine efficacy greater than 30% is 74.19%.
Table 13.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 21 2.333 (18566) 3 2.358 (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 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. Re fer 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 Dose 1 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
(Table 14). 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% against severe COVID-19
occurring at least 7 days after Dose 2 (1 case in the BNT162b2 group and 4 cases in the
placebo group) .
In addition, a post hoc analy sis was conducted for efficacy against severe cas es of
COVID -19 using the CDC definition of severe COVID -19 (hospitalization, admission to the
intensive care unit (I CU), intubation or mechanical ventilation, or death).6In this analy sisin
the Dose 1 all -available efficacy population, 1 case of severe COVID-19 occurred after
Dose 1 in the BNT162b2 group compared to 14 cases in the placebo group ( Table 43).The
estimated VE against severe COVID -19 occurring after Dose 1 was 92.9% (2- sided 95% CI:
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Page 4953.2%, 99.8%), with an estimated VE of 100.0% against severe COVID -19 occurring at least
7days after Dose 2 (no cases in the BNT162b2 group and 5 cases in the placebo group).
Table 14.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 11 4.021 (21314) 9 4.006 (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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Efficacy Against Severe COVID-19 (≥14 Days After Dose 2)
Participants W ithout Evidence of Infection Before and During Vaccination Regimen
(14Days) –Severe
For this efficacy endpoint, participants with positive or unknown NAAT results at any illness
visit prior to 14 day s after Dose 2 wer e not included in the evaluation for efficacy .
Among participants without evidence of SARS -CoV -2 infection before and during
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
respectivel y (Table 15). The posterior probability for the true vaccine efficacy greater than
30% is 74.32%.
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Page 50Table 15.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 21 1.888 (16612) 3 1.901 (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 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 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.
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Participants W ith or Without Evidence of Infection Before and During Vaccination Regimen
(14Days) –Severe
Among participants with or without evidence of SARS -CoV -2 infection before and during
vaccination regimen, VE against severe COVID -19 occurring at least 14 day s after Dose 2
was66.3%, with 1 and 3 cases in the BNT162b2 and placebo groups respecti vely (Table 16).
The posterior probability for the true vaccine efficacy greater than 30% is 74. 18%.
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Page 51Table 16.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 21 1.985 (17652) 3 2.007 (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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2.7.3.2.1.2.4.3. Vaccine Efficacy for COVID -19 Cases per CDC 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 –CDC
Defined – 7 Days
For this efficacy endpoint, participants with positive or unknown NAAT results at any illness
visit prior to 7 day s afte r Dose 2 were not included in the evaluation for efficacy .
Among participants without evidence of SARS -CoV -2 infection before and during
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, respectivel y (Table 44).
Participants With and Without Evidence of Infection Before and During Vaccination
Regimen–CDC Defined –7 Days
Among participants with and without evidence of SARS -CoV -2 infection before and during
vaccination regimen, VE against CDC- defined COVID -19 occurring at least 7 day s after
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Page 52Dose 2 was 94.7% (2- sided 95% CI: 89.8%, 97.6%), with 9 and 172 cases in the BNT162b2
and placebo groups, respectivel y (Table 45).
Efficacy Against COVID -19 Based on CDC -Defined Symptoms ( ≥14 Days After Dose 2)
Among participants without and with or without evidence of SARS -CoV -2 infection before
and during 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 ( Table 46and Table 47).
2.7.3.2.1.2.5. Efficacy Conclusions From the Final Analysis – Study C4591001
Evaluable Efficacy Population
In the final efficacy analy sis, among participants without evidence of SARS -CoV -2 infection
before and during 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 group compared
to 162 COVI D-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 withou t evidence of SARS -CoV -2 infection before and
during 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 endpoints, observed VE against confirmed COVID- 19 occurring
at least 14 days after Dose 2 in participants without evidence of SARS -CoV -2 infection
before and during vaccination regimen, was 94.2%, with 8 and 139 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 thi s 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 vaccination regimen, VE against confirmed COVID -19 occurring at least 14 da ys
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 greater than 30% met the
prespecified success criterion of >98.6% for this endpoint. The 95% credible inte rval for the
vaccine efficacy was 89.1% to 97.3%.
Among participants without evidence of SARS -CoV -2 infection before and during
vaccination regimen , observed VE of 66.3% against severe COVID -19 occurring at least
7days after Dose 2 did not meet the prespe cified success criterion of the posterior probability
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Page 53>98.6%, due to the small number of severe cases (1 in the BNT162b2 group, 3 in the placebo
group) observed within the prespecified timeframe of ≥7 Day safter Dose 2 in the study .
The efficacy anal yses using CDC defined sy mptoms to identify COVID -19 case s and severe
COVID -19 cases gave similar efficacy results as the analyses using the protocol -defined
symptoms .
All-Available Efficacy Population
The early onset of protection is readily apparent from cumulative incidence curves, which
show that disease onset tracks 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 estimate d VE of 82% (2 -sided 95% CI:
75.6%, 86.9%) against confirmed 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 1 severe case was
seen in BNT162b2 recipients compared to 9 severe COVID- 19 cases in 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.
In conclusion, the final effic acy results show that BNT162b2 at 30 µg provided protection
against COVID -19 in participants who had no evidence of prior infection with SARS -CoV -2,
including across demographic subgroups, with severe cases observed predominantly in the
placebo group.
2.7.3.2.1.3. Updated Efficacy Analyses –Study C4591001
Updated descriptive efficacy analy ses were performed using all cases accrued during the
blinded placebo -controlled follow -up through the cutoff date of 13 March 2021. Updated
efficacy anal yses were conducted for the primary efficacy endpoints, including subgroup
analyses, and for secondary efficacy endpoints of severe disease and CDC -defined severe
disease.
2.7.3.2.1.3.1. Efficacy Populations – Updated Analysis
The proportions of participants included in the updated anal ysis efficacy populations w ere
similar in the BNT162b2 and placebo groups ( Table 48). Most particip ants who were
excluded from the evaluable efficacy population had not recei ved all vaccinations as
randomized or did not receive Dose 2 within the predefined window (ie, 19 to 42 day s after
Dose 1). There were 240 participants in the BNT162b2 group and 60 participants in the
placebo group excluded for having important protocol de viations 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 (2 03 participants, as compared with
23 participants in the placebo group); among these, most exclusions in the BNT162b2 group
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Page 54were due to dosing/administration errors ( 76participants) or administration of investigational
product that was deemed not suitable for use by the contractor who distributed the vaccine to
study sites (110 participants) Table 49. These were administration errors that could not have
applied to participants who received placebo: eg, errors in dilution of the vaccine or
temperature excur sions.
Demographic characteristics of participants in the updated analysis evaluable efficacy
population for participants without evidence of infection prior to 7 day s after Dose 2 were
similar in the BNT162b2 and placebo groups ( Table 50). This anal ysispopulation had
generall y similar demographic characteristics compared to the safet y population.
2.7.3.2.1.3.2. Efficacy Results –Updated Analyses
As described above, based on results for the first primary efficacy endpoint, overwhelming
efficacy was declared at the first (and onl y) interim analysis ( Section 2.7.3.2.1.1.2.1 ) and was
confirmed at the final analy sis (Section 2.7.3.2.1.2.3.1 ). A descriptive update bas ed on a total
of 927confirmed cases for the first primary endpoint accrued during blinded placebo -
controlled follow -up, up to the data cutoff date of 13 March 2021, is summarized below.
The results presented are for the evaluable efficacy populations, except as noted.
2.7.3.2.1.3.2.1. Vaccine Efficacy Against Confirmed COVID -19 Occurring at Least
7Days After Dose 2 – Evaluable Efficacy Population -Updated Analysis
Participants Without Evidence of SARS -CoV -2 Infection
Among participants without evidence of SARS -CoV -2 infection before and during the
vaccination regimen, the estimated VE against confirmed COVID -19 occurring at least
7days after Dose 2 was 91.3%, with 77 COVID -19 cases in the BNT162b2 group compared
to 850 cases in the placebo group ( Table 17). The 2-sided 95% CI for vaccine efficacy was
89.0% to 93.2%. The posterior probability forthe true VE being greater than 30% ,given the
available data ,was >99 .99%.
The estimated VE of BNT162b2 for the same efficacy endpoint based on the Dose 2
all-available efficacy population was 91.4% (2-sided 95% CI: 89.1%, 93.3%) , with 78 and
866 cases in the BNT162b2 and placebo group, respectively (Table 51).
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Page 55Table 17.Vaccine Efficacy – First COVID -19 Occurrence From 7 Days After Dose 2 –
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=20998)Placebo
(Na=21096)
Efficacy Endpointn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE (%) (95% CIe)Pr (VE >30% |
data)f
First COVID -19 occurrence
from 7 days after Dose 2776.247 (20712) 8506.003 (20713) 91.3 (89.0, 93.2) >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 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 (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 = Numbe r 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 t he 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. 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.
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Participants With or Without Evidence of SARS- CoV -2 Infection
Among participants with or without evidence of SARS- CoV -2 infection before and during
the vaccination regimen, estimated VE against confirmed COVID -19 occurring at least
7days after Dose 2 was 9 1.1%, with 81 and 873cases in the BNT162b2 and placebo group s,
respectivel y (Table 18). The 2-sided 95% CI for vaccine efficacy was 88.8% to 93.0% .
Theposterior probability for the true VE being greater than 30% ,given the available data ,
was >99 .99%.
The estimated VEof BNT162b2 for the same endpoint based on the Dose 2 all -available
efficacy population was 91.2% (2-sided 95% CI: 88.9%, 93.0%) , with 82 and 889cases in
the BNT162b2 and placebo group, respectively (Table 52).
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Page 56Table 18.Vaccine Efficacy – First 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 Days After Dose 2 – Evaluable
Efficacy (7 Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=22166)Placebo
(Na=22320)
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 281 6.509 (21642) 873 6.274 (21689) 91.1 (88.8,
93.0)>0.9999
Abbreviation: 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. Posterior probabil ity (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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2.7.3.2.1.3.2.2. Vaccine Efficacy for All Confirmed Cases of COVID-19 After Dose 1 –
Dose 1 All -Available Po pulation –Updated Analysis
A number of confirmed cases of COVID -19 are not captured in the anal yses of the primary
endpoint sfor the evaluable efficacy population because they either occurred in participants
who were excluded from the evaluable efficacy population, or occurred less than 7 days after
Dose 2.
All reports of COVID -19 with onset at any time after Dose 1 are accounted for in Table 19,
which provides a summ ary of VE for confirmed cases for all participants in the Dose 1
all-available efficacy (modified intention -to-treat) population adjusted for surveillance time ,
regardless of evidence of infection before or during the vaccination regimen. Among these
participants, 131cases of COVID -19 occurred after Dose 1 in the BNT162b2 group
compared to 1034 cases in the placebo group. The estimated VE against confirmed
COVI D-19 occurring at any time after Dose 1 was 87.8% (2 -sided 95% CI: 85.3%, 8 9.9%) .
In this population, the estimated VE against all cases occurring ≥7 day s after Dose 2 was
91.2%. The estimated VE was 91.7% for cases occurring from ≥11 day s after Dose 1 to
before Dose 2, 96.2% for cases occurring from ≥7 day s after Dose 2 to <2 months after
Dose 2, 90.1% for the period from ≥2months to <4 months after Dose 2, and 8 3.7% for the
period ≥4 months after Dose 2.
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Page 57Table 19.Vaccine Efficacy – First COVID -19 Occ urrence After Dose 1 –Blinded
Placebo- Controlled Follow -up Period – Dose 1 All -Available Efficacy
Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=23040)Placebo
(Na=23037)
Efficacy Endpoint
Subgroupn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE
(%)(95% CIe)
First COVID -19 occurrence after Dose 1 131 8.412 (22505) 1034 8.124 (22434) 87.8 (85.3, 89.9)
After Dose 1 to before Dose 2 46 1.339 (22505) 110 1.331 (22434) 58.4 (40.8, 71.2)
After Dose 1 to <11 days after Dose 1 41 0.677 (22505) 50 0.675 (22434) 18.2 (-26.1, 47.3)
≥11 Days after Dose 1 to before Dose 2 5 0.662 (22399) 60 0.656 (22369) 91.7 (79.6, 97.4)
Dose 2 to 7 days after Dose 2 3 0.424 (22163) 35 0.422 (22057) 91.5 (72.9, 98.3)
≥7 Days after Dose 2 82 6.649 (22132) 889 6.371 (22001) 91.2 (88.9, 93.0)
≥7 days after Dose 2 to <2 Months after
Dose 212 2.923 (22132) 312 2.884 (22001) 96.2 (93.3, 98.1)
≥2 Months after Dose 2 to <4 Months
after Dose 246 2.696 (20814) 449 2.593 (20344) 90.1 (86.6, 92.9)
≥4 Months after Dose 2 24 1.030 (12670) 128 0.895 (11802) 83.7 (74.7, 89.9)
Abbreviation: 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.
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The early onset of protection is readily apparent in Figure 2, which display s cumulative
incidence for the first COVID -19 occurrence after Dose 1 among all vaccinated participants
based on Dose 1 all -availa ble efficacy (modified intention -to-treat) population. Disease onset
appears to track together for BNT162b2 and placebo until approximately 11days after
Dose 1(consistent with the data shown in Table 19), at which point the curves diverge, with
cases steadil y accumulating in the placebo group, while remaining virtually flat in the
BNT162b2 group.
The darker -appearing s ymbols for both BNT162b2 (blue circles) and placebo (red squares)
curves in Figure 2 have an “S” written inside the open sy mbol, which denotes severe cases.
Severe COVID -19 cases reported in the updated analy sis are discussed further in Section
2.7.3.2.1.3.2.4 .
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Page 58Figure 2. Cumulative Incidence Curves for the First COVID- 19 Occurrence After Dose 1– Blinded Placebo- Controlled Follow -
up Period – Dose 1 All -Available Efficacy Population
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Page 592.7.3.2.1.3.2.3. Vaccine Efficacy by Subgroup – Updated Analysis
For both primary endpoints, VE was also evaluated for subgroups of participants by age, sex,
race/ethnicity , and country , as well as for groups of subjects by risk status and comor bidities.
Overall, the results show high rates of VE based on subgroup anal yses.
Subgroups of Age, Sex, Race/Ethnicity, and Country
In the evaluable efficacy population, a mong participants without evidence of SARS -CoV -2
infection before and during the vaccination regimen, estimated VE was ≥90% in most
subgroups ,similar to the 91.3% overall VE ( Table 20). High VE was a lso observed across
age groups, with a n estimated VE of 100.0% in 12 to 15 year olds, 90.6% in 16 to 64 y ear
olds, 94.5% in those ≥65 y ears, and 96.2% in those ≥75 years of age. Estimated VEs were
87.6% among Asian and 88.5% among Hispanic/Latino participants; the estimated VE was
92.6% in the United States, 86.5% in Argentina, 86.2% in Brazil, and 100.0% in South
Africa, German y, and Turkey .
Similar results were observed for subgroup anal yses among participants with or without
evidence of SARS -CoV -2 infection before and during the vaccination regimen (Table 53).
Inanalyses for the Dose 1 all-available efficacy population, which included all confirmed
cases occurring at an y time after Dose 1, no clinically meaningfu l differences among the
subgroups were identified ( Table 54).
Subgroup ana lyses included evaluation of VE by prior SARS -CoV -2 status at baseline.
Thenumber of participants with positive prior SARS -CoV -2 status at baseline was relatively
small, and the 95% CIs for the estimated VEs in these subgroup anal yses were very wide;
therefore, the data must be interpreted with caution. However, the results may provide som e
information regarding the benefits of vaccination for individuals with prior SARS -CoV -2
infection.
Participants with positive prior SARS -CoV -2 status at bas eline were defined as those with
positive N -binding antibody or NAAT results at Visit 1 or a medic al history of COVID -19.
In the evaluable efficacy anal ysis for this subgroup, the estimated VE against cases occurring
≥7 day s after Dose 2 was 46.9% (3cases BNT162b2; 6 cases placebo) ( Table 53), and in the
all-available efficacy analy sis the estimated VE against cases occurring at any time after
Dose 1 was 19.2% (13 cases BNT162b2, 17 cases placebo) (Table 54).
It is import ant to note that the subgroup defined above includes participants with both past
infections (positive N- binding antibody ) and current infections (NAAT positive) .Since it is
reasonable to expect that vaccination m ay be less effective in participants currentl y infected
with SARS -CoV -2 at Visit 1, it may be relevant to examine VE specificall y in participants
who were positive for N -binding only (and were not NAAT -positive) at Visit 1. In the
evaluable efficacy anal ysis for these participants, the estimated VE against cases occurring
≥7 day s after Dose 2 was 58.9% (2cases BNT162b2; 5 cases placebo) ( Table 53), and in the
all-available efficacy analy sis the estimated VE against cases occurring at any time after
Dose 1 was 70.5% (2 cases BNT162b2, 7 cases placebo) (Table 54).Therefore, estimates of
VE areconsiderably higher in partic ipants who were positive for N- binding antibody only,
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Page 60suggesting that vaccination provides a benefit for individuals with previous SARS -CoV -
infection.
Table 20.Vaccine Efficacy – First COVID -19 Occu rrence From 7 Days After Dose 2,
by Subgroup –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=20998)Placebo
(Na=21096)
Efficacy Endpoint
Subgroupn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE (%) (95% CIe)
First COVID -19 occurrence from 7 days
after Dose 2
Overall 77 6.247 (20712) 850 6.003 (20713) 91.3 (89.0, 93.2)
Age group (years)
12 to 15 0 0.154 (1001) 16 0.147 (972) 100.0 (75.3, 100.0)
16 to 55 52 3.593 (11517) 568 3.439 (11533) 91.2 (88.3, 93.5)
>55 25 2.499 (8194) 266 2.417 (8208) 90.9 (86.3, 94.2)
≥65 7 1.233 (4192) 124 1.202 (4226) 94.5 (88.3, 97.8)
16 to 17 0 0.061 (342) 10 0.057 (331) 100.0 (58.2, 100.0)
16 to 25 8 0.482 (1629) 80 0.466 (1622) 90.3 (80.0, 96.0)
16 to 64 70 4.859 (15519) 710 4.654 (15515) 90.6 (87.9, 92.7)
18 to 64 70 4.798 (15177) 700 4.597 (15184) 90.4 (87.7, 92.6)
55 to 64 21 1.399 (4426) 157 1.334 (4388) 87.3 (79.8, 92.3)
65 to 74 6 0.994 (3350) 98 0.966 (3379) 94.1 (86.6, 97.9)
≥75 1 0.239 (842) 26 0.237 (847) 96.2 (76.9, 99.9)
75 to 85 1 0.238 (837) 25 0.235 (841) 96.0 (75.9, 99.9)
>85 0 0.001 (5) 1 0.001 (6) 100.0 (-4055.9, 100.0)
Sex
Male 42 3.246 (10637) 399 3.047 (10433) 90.1 (86.4, 93.0)
Female 35 3.001 (10075) 451 2.956 (10280) 92.4 (89.2, 94.7)
Race
White 67 5.208 (17186) 747 5.026 (17256) 91.3 (88.9, 93.4)
Black or African American 4 0.545 (1737) 48 0.527 (1737) 91.9 (78.0, 97.9)
American Indian or Alaska Native 0 0.041 (186) 3 0.037 (176) 100.0 (-119.0, 100.0)
Asian 3 0.260 (946) 23 0.248 (934) 87.6 (58.9, 97.6)
Native Hawaiian or other Pacific
Islander0 0.015 (54) 1 0.008 (30) 100.0 (-1961.2, 100.0)
Multiracial 3 0.151 (518) 22 0.128 (476) 88.5 (61.6, 97.8)
Not reported 0 0.026 (85) 6 0.030 (104) 100.0 (2.8, 100.0)
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Page 61Table 20.Vaccine Efficacy – First COVID -19 Occu rrence From 7 Days After Dose 2,
by Subgroup –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=20998)Placebo
(Na=21096)
Efficacy Endpoint
Subgroupn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE (%) (95% CIe)
All othersf6 0.494 (1789) 55 0.451 (1720) 90.0 (76.9, 96.5)
Ethnicity
Hispanic/Latino 29 1.786 (5161) 241 1.711 (5120) 88.5 (83.0, 92.4)
Non-Hispanic/non -Latino 47 4.429 (15449) 609 4.259 (15484) 92.6 (90.0, 94.6)
Not reported 1 0.032 (102) 0 0.033 (109) -∞ (NA, NA)
Country
Argentina 15 1.012 (2600) 108 0.986 (2586) 86.5 (76.7, 92.7)
Brazil 12 0.406 (1311) 80 0.374 (1293) 86.2 (74.5, 93.1)
Germany 0 0.047 (236) 1 0.048 (242) 100.0 (-3874.2, 100.0)
South Africa 0 0.080 (291) 9 0.074 (276) 100.0 (53.5, 100.0)
Turkey 0 0.027 (228) 5 0.025 (222) 100.0 (-0.1, 100.0)
USA 50 4.674 (16046) 647 4.497 (16094) 92.6 (90.1, 94.5)
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.
f. All others = American India n or Alaska native, Asian, Native Hawaiian or other Pacific Islander, multiracial, and not
reported race categories.
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Subgroup Analyses by Risk Status and Comorbidities
Analyses of efficacy by risk status were performed. For these anal yses, at -risk participants
were de fined as those who had at least one Charlson Comorbidity Index condition or who
were obese (defined as body mass index ≥30 kg/m2). For a summary of Charlson
comorbidities among all participants ≥16 y ears of age at study entry , see Table 55.
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Page 62Among participants without evidence of SARS -CoV -2 infection before and during
vaccination regimen, estimated VE was similar for participants at risk (91.6% ) and
participants not at risk ( 91.0% ) (Table 21). The estimated VE for participants ≥65 y ears of
age and at risk was 91.8%, as compared with 98.1% for those ≥65 y ears of age and not at
risk. Estimated VE was similar in obese (91.6%) and non -obese (91.1%) participants. When
evaluated b y type of comorbidity , estimated VE was >85% for participants with each
comorbidity evaluated, including an y malignancy, cardiovascular disease, chronic pulmonary
disease, diabetes, obesity, and hy pertension (Table 56).
Table 21.Vaccine Efficacy – First COVID -19 Occurrence From 7 Days After Dose 2,
by Risk Status –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=20998)Placebo
(Na=21096)
Efficacy Endpoint
Subgroupn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE (%) (95% CIe)
First COVID -19 occurrence from 7
days after Dose 2
Overall 77 6.247 (20712) 850 6.003 (20713) 91.3 (89.0, 93.2)
Atriskf
Yes 35 2.797 (9167) 401 2.681 (9136) 91.6 (88.2, 94.3)
No 42 3.450 (11545) 449 3.322 (11577) 91.0 (87.6, 93.6)
Age group (years) and at risk
12-15 and not at risk 0 0.121 (788) 11 0.116 (769) 100.0 (61.9, 100.0)
12-15 and at risk 0 0.034 (213) 5 0.032 (203) 100.0 (-2.0, 100.0)
16-64 and not at risk 41 2.776 (8887) 385 2.661 (8886) 89.8 (85.9, 92.8)
16-64 and at risk 29 2.083 (6632) 325 1.993 (6629) 91.5 (87.5, 94.4)
≥65 and not at risk 1 0.553 (1870) 53 0.546 (1922) 98.1 (89.2, 100.0)
≥65 and at risk 6 0.680 (2322) 71 0.656 (2304) 91.8 (81.4, 97.1)
Obeseg
Yes 27 2.103 (6796) 314 2.050 (6875) 91.6 (87.6, 94.6)
No 50 4.143 (13911) 536 3.952 (13833) 91.1 (88.1, 93.5)
Age group (years) and obese
12-15 and not obese 0 0.135 (878) 13 0.131 (867) 100.0 (68.3, 100.0)
12-15 and obese 0 0.019 (123) 3 0.016 (105) 100.0 (-104.8, 100.0)
16-64 and not obese 46 3.178 (10212) 444 3.028 (10166) 90.1 (86.6, 92.9)
16-64 and obese 24 1.680 (5303) 266 1.624 (5344) 91.3 (86.7, 94.5)
≥65 and not obese 4 0.829 (2821) 79 0.793 (2800) 95.2 (87.1, 98.7)
≥65 and obese 3 0.404 (1370) 45 0.410 (1426) 93.2 (78.9, 98.7)
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Page 63Table 21.Vaccine Efficacy – First COVID -19 Occurrence From 7 Days After Dose 2,
by Risk Status –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=20998)Placebo
(Na=21096)
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 prio r 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. Includes subjects who had at least one of the Charlson Comorbidity Index (CMI) category or obesity (BMI ≥30 kg/m2
[≥16 Years of age] or BMI ≥95thpercentile [12 -15 Years of age]).
g. Subjects (≥16 Years of age) who had BMI ≥30 kg/m2. For 12 through 15 years age group, obesity is defined as a BMI
at or above the 95thpercentile. Refer to the CDC growth charts at
https://www.cdc.gov/growthcharts/html_charts/bmiagerev htm.
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2.7.3.2.1.3.2.4. Vaccine Efficacy for Severe COVID -19 Cases – Updated Analysis
Efficacy Against Severe COVID-19 (≥7Days After Dose 2)
Among participants without evidence of SARS -CoV -2 infection before and during the
vaccination regimen, the estimated VE against severe COVID-19 as defined by FDA
occurring at least 7 day s after Dose 2 was 95.3% (2-sided 95% CI: 71.0% , 99.9 %), with
1and 21cases in the BNT162b2 and placebo groups ,respectivel y (Table 22). The posterior
probability for the true vaccine efficacy being greater than 30% ,given the available data ,was
>99.99%.
The same number of severe cases were reported among participants with or without evidence
of SARS -CoV -2 infection before and during the vaccination regimen (1 case in the BNT162
group and 21 cases in the placebo group) , and the estimated VE was the same (95.3%)
(Table 57).
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Page 64Table 22.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 Days After Dose 2 – Eval uable Efficacy (7
Days) Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=20998)Placebo
(Na=21096)
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 21 6.257 (20712) 21 6.120 (20713) 95.3 (71.0,
99.9)>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 detecte d 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 surveil lance 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. 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 Severe COVID -19 (As Defined by FDA) After Dose 1 –
All-Available Efficacy Population
Among participants in the Dose 1 all -available efficacy (modified intention- to-treat)
population , 1 case of severe COVID -19 as defined by FDA occurred after Dose 1 in the
BNT162b2 group compared to 30cases in the placebo group ( Table 23). The estimated VE
against severe COVID -19 occurring after Dose 1 was 96.7% (2 -sided 95% CI : 80.3%,
99.9%).
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Page 65Table 23.Vaccine Efficacy – First Severe COVID -19 Occurrence After Dose 1 –
Blinded Placebo -Controlled Follow -up Period – Dose 1 All -Available
Efficacy Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=23040)Placebo
(Na=23037)
Efficacy Endpoint
Subgroupn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE (%) (95% CIe)
First severe COVID-19 occurrence after
Dose 11 8.439 (22505) 30 8.288 (22435) 96.7 (80.3, 99.9)
After Dose 1 to before Dose 2 0 1.351 (22505) 6 1.360 (22435) 100.0 (14.5, 100.0)
Dose 2 to 7 days after Dose 2 0 0.425 (22170) 1 0.423 (22070) 100.0 (-3783.5, 100.0)
≥7 Days after Dose 2 1 6.663 (22142) 23 6.505 (22048) 95.8 (73.9, 99.9)
Abbreviation: 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 sur veillance time.
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2.7.3.2.1.3.2.5. Vaccine Efficacy for Severe COVID -19 Cases per CDC Definition –
Updated Analysis
In addition, a supportive analysis was conducted for efficacy against severe cases of
COVID -19 using the CDC definition of severe COVID -19 (hospitalization, admission to the
intensive care unit (I CU), intubation or mechanical ventilation, or death).6
Among efficacy evaluable participants without evidence of SARS -CoV -2 infection before
and during the vaccination regimen, the estimated VE against CDC -defined severe
COVID -19 occurring at least 7 day s after Dose 2 was 100.0 %(2-sided 95% CI : 88.1%,
100.0 %), with 0 and 32cases in the BNT162b2 and placebo groups, respectively (Table 24).
The same num ber of CDC -defined severe cases were reported among efficacy evaluable
participants with or without evidence of SARS- CoV -2 infection before and during the
vaccination regimen (Table 58).
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Page 66Table 24.Vaccine Efficacy – First Severe COVID -19 Occurrence Based on CDC -
Definition From 7 Days After Dose 2 –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=20998)Placebo
(Na=21096)
Efficacy Endpoint n1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE (%) (95% CIe)
First severe COVID-19 occurrence based on
CDC -definition from 7 days after Dose 20 6.250 (20688) 32 6.108 (20680) 100.0 (88.1, 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.
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 prio r 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.
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All Confirmed Cases of CDC -Defined Severe COVID -19 After Dose 1 – All- Available
Efficacy Population
Among participants in the Dose 1 all -available efficacy population, 1 case of CDC -defined
severe COVID -19 occurred after Dose 1 (but before Dose 2)in the BNT162b2 group
compared to 45 cases in the placebo group ( Table 25). The estimated VE against severe
CDC -defined COVID -19 occurring after Dose 1 was 97.8% (2 -sided 95% CI: 8 7.2%,
99.9%).
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Page 67Table 25.Vaccine Efficacy – First Severe COVID -19 Occurrence Based on CDC -
Definition After Dose 1 –Blinded Placebo -Controlled Follow -up Period –
Dose 1 All -Available Efficacy Population
Vaccine Group (as Randomized)
BNT162b2 (30 μg)
(Na=23040)Placebo
(Na=23037)
Efficacy Endpoint
Subgroupn1bSurveillance
Timec(n2d)n1bSurveillance
Timec(n2d)VE
(%)(95% CIe)
First Severe COVID -19 occurrence based
on CDC -definition after Dose 11 8.427 (22473) 45 8.269 (22394) 97.8 (87.2, 99.9)
After Dose 1 to before Dose 2 1 1.348 (22473) 11 1.355 (22394) 90.9 (37.1, 99.8)
Dose 2 to 7 days after Dose 2 0 0.424 (22141) 1 0.422 (22030) 100.0 (-3781.6, 100.0)
≥7 Days after Dose 2 0 6.654 (22113) 33 6.491 (22008) 100.0 (88.5, 100.0)
Abbreviation: 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 base d on the Clopper and Pearson method adjusted for surveillance time.
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2.7.3.2.1.3.3. Signs and Symptoms of COVID -19
The signs and sy mptoms reported for cases contributing to the anal ysis for the first primary
efficacy endpoint (77 cases in the BNT162b2 group and 850 cases in the placebo g roup) are
summarized in Table 59. These include cases occurring at least 7 day s after the second
vaccination among participants in the evaluable efficacy population who had no evidence of
SARS -CoV -2 infection before or during the vaccination regimen. In this analy sis, the
proportions of participants reporting only 1 symptom were 36.4% in the BNT162b2 group,
compared with 20.9% in the placebo group; and 15.6% of participants in the BNT162b2
group reported 4 or more sy mptoms, compared with 30.8% of participants in the placebo
group. Most participants reported new or increased cough (63.9% of s ymptomatic cases
overall), and other s ymptoms reported most frequently were new or increased muscle pain
(45.2%), sore throat (38.6%), new loss of taste or smell (36.0%), and fever (35.9%).
Table 60summarizes the signs and s ymptoms for all cases of COVID -19 occurring at any
time after Dose 1 (131 cases in the BNT162b2 group and 1034 cases in the placebo group).
These include cases occurring among participants in the Dose 1 all -available efficacy
population, regardless of evidence of SARS -CoV -2 infection before or during the vaccination
regimen. The proport ions of participants reporting 4 or more s ymptoms were 19.1% in the
BNT162b2 group compared with 30.0% of participants in the placebo group. The most
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Page 68frequentl y reported s ymptoms were similar to those for the anal ysis of the first primary
efficacy endpoint .
The signs and sy mptoms reported for all confirmed cases of FDA -defined severe COVID -19
reported at an y time after Dose 1 (in the all-available population) (1 case in the BNT162b2
group and 30 cases in the placebo group) are summarized in Table 61. The participan t who
was diagnosed with severe COVID -19 after receiving BNT162b2 had one sy mptom, SpO2
≤93%. Among the 30 severe cases in the placebo group, 63.3 % had clinical signs at rest
indicative of severe s ystemic illness (RR ≥30 breaths per minute, HR ≥125 beats per minute,
SpO2 ≤93% on room air at sea level, or PaO2/FiO2 <300 mm Hg); 46.7% had respiratory
failure (defined as needing high -flow ox ygen, noninvasive ventilation, mechanical
ventilation, or ECMO), and 26.7% were admitted to an I CU.
2.7.3.2.1.3.4. Efficacy Conclusions From the Updated Analyses –Study C4591001
Updated Analysis –Efficacy Against Confirmed COVID -19
In the updated descriptive efficacy anal ysis (cutoff date 13 March 2021), a mong
participants in the evaluable efficacy population without evidence of SARS -CoV -2
infection before and during the vaccination regimen, the estimated VE against confirmed
COVID -19 occurring at least 7 days after Dose 2 was 91.3% (95% CI: 89.0%. 93.2%),
with 77 cases in the BNT162b2 group and 850 cases in the placebo group. Among
participants with or without evidence of SARS- CoV -2 infection before and during the
vaccination regimen, the estimated VE against confirmed COVID -19 occu rring at least
7days after Dose 2 was 91.1% (95% CI: 88.8%, 93.0%), with 81 and 873 cases in the
BNT162b2 and placebo groups, respectively.
All cases of confirmed COVID -19 are accounted for in the anal yses of VE in the
all-available (modified intention -to-treat) population (regardless of evidence of infection
before or during the vaccination regimen). In this anal ysis, estimated VE against all cases
occur ring at any time after Dose 1 was 87.8% (2 -sided 95% CI : 85.3%, 89.9%), with
131cases in the BNT162b2 group and 1034 cases in the placebo group.
In the all -available (modified intention -to-treat) population , the estimated VE against all
cases occurring ≥7 days after Dose 2 was 9 1.2%. The estimated VE was 91.7% for cases
occurring from ≥11days after Dose 1 to before Dose 2, 96.2% for cases occurring from
≥7 day s after Dose 2 to <2 months after Dose 2, 90.1 % for the period from ≥2months to
<4 months after Dose 2, and 8 3.7% for the period ≥4 months after Dose 2.
Efficacy Against Severe Cases of COVID-19
Among participants without evidence of SARS -CoV -2 infection before and during the
vaccination regimen (evaluable efficacy population) , the estimated VE against FDA
defined severe COVID -19 (protocol defin ition) occurring at least 7 days after Dose 2 was
95.3% (2 -sided 95% CI: 71.0%, 99.9%), with 1 and 21 cases in the BNT162b2 and
placebo groups, respectively . Similarly , the estimated VE was also 95.3% (2-sided
95% CI: 70.9%, 99.9%) among participants with or w ithout evidence of SARS -CoV -2
infection, also with 1 and 21 cases in the BNT162b2 and placebo groups, respectivel y.
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Page 69Among participants without evidence of SARS -CoV -2 infection before and during the
vaccination regimen (evaluable efficacy population), the e stimated VE against CDC -
defined severe COVID -19 occurring at least 7 days after Dose 2 was 100.0% (2- sided
95% CI : 88.1%, 100.0%), with 0 and 32 cases in the BNT162b2 and placebo groups,
respectivel y. Similarly, the estimated VE was also 100.0% (2-sided 95% CI: 88.0%,
100.0%) among participants with or without evidence of SARS- CoV -2 infection, also
with 0 and 32 cases in the BNT162b2 and placebo groups, respectively
Among participants in the Dose 1 all -available efficacy population (regardless of
evidence of infection before or during the vaccination regimen) , estimated VE against
severe cases of COVID -19 (as defined b y FDA) occurring at an y time after Dose 1 was
96.7% (2 -sided 95% CI: 80.3%, 99.9%), with 1 case of severe COVID -19 in the
BNT162b2 group compared to 30 cases in the placebo group.
Efficacy in Demographic and Risk Subgroups
Among participants without evidence of SARS -CoV -2 infection before and during the
vaccination regimen (efficacy evaluable population) VE against COVID- 19 occurring at least
7 day s after Dose 2 was evaluated, with results as follows:
Estimated VE was ≥90% in most subgroups, similar to the 91.3% overall estimated VE.
High VE was observed across age subgroups, with a n estimated VE of 100.0% in 12 to
15year olds, 90.6% in 16 to64 year olds, 94.5% in those ≥65 y ears, and 96.2% in those
≥75years of age.
The estimated VE was 86.5% in Argentina, 86.2% in Brazil, 92.6% in the United States,
and 100.0% in South Africa, German y, and Turkey.
The e stimated VE was similar for participa nts at risk (91.6%) and participants not at risk
(91.0%). Estimated VE for participants ≥65 y ears of age and at risk was 91.8%, as
compared with 98.1% for those ≥65 y ears of age and not at risk. Estimated VE was
similar in obese (91.6%) and non -obese (91.1 %) participants. When evaluated by type of
comorbidity , estimated VE was >85% for participants with each comorbidity evaluated,
including an y malignancy, cardiovascular disease, chronic pulmonary disease, diabetes,
obesity , and h ypertension.
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Page 702.7.3.2.2. Immunogeni city Evaluations
In this section, immunogenicity results are first summarized for Phase 1 data from Study
BNT162 -01 (Section 2.7.3. 2.2.1.1 ) and Study C4591001 (Section 2.7.3.2.2.1.2 ), including
discussion of the rationale for the selection of the vaccine candidate and dose level to take
forward into Phase 2/3 of Study C4591001 (Section 2.7.3.2.2.1.3 ).Subsequently , results
from Study C4591001 are presented for the analyses of immunogenicity data for the
360partic ipants in Phase 2 (Section 2.7.3.2.2.2 ).
2.7.3.2.2.1. Phase 1 Immunogenicity Results – Candidate and Dose Selection
2.7.3.2.2.1.1. Study BNT162-01 – Phase 1
Study BNT1 62-01 is currently ongoing, and immunogenicity results reported here are for
interim data.
This submission includes serology results (SARS -CoV -2 neutralizing titers and antigen -
specific binding IgG levels) through the cutoff date of 23 October 2020 . For participants
18to 55 y ears of age (y ounger age group), serology data are available up to Day 43 (21 day s
after Dose 2) for BNT162b1 recipients and up to Day 85 (63 day s after Dose 2) for
BNT162b2 recipients. Serology data are also available up to Day 29 (7 days after Dose 2)for
individuals 56 to 85 y ears of age (older age group) who received BNT162b2 at the 20 µg
dose level.
This submission also includes T cell response data with cutoff dates as follows:
ELISpot data: 02 March 2021;
ICS data: 17 Novemb er 2020 for BNT162b1 and 02 March 2021 for BNT162b2.
T cell response data are available for all participants with evaluable data at Day 29 (7 day s
after Dose 2) and up to Day 184 for a subset of participants who received BNT162b2 at 10,
20, or30 µg .
2.7.3.2.2.1.1.1. Disposition and Demographics - Study BNT162 -01
BNT162b1 – Younger Participants 18 to 55 Years of Age
A total of 84 participants in the 18 to 55 y ears age group received Dose 1 of BNT162b1,
12ineach of the 7 dose level groups (1, 3, 10, 20, 30, 50, 60 µg), and 69 of these participants
received Dose 2 of BNT162b1. Based on the Safety Review Committee’s determination,
none of the 12 participants in the 60 µggroup received the second dose, due to
reactogenicity ; however, these participants continued in the s tudy.Three participants were
withdrawn from the study before the administration of Dose 2 (1 in the 10 µggroup due to an
adverse event of malaise considered not related to study vaccine b y the investigator; 1 in the
20 µggroup due to withdrawal b y parti cipant; and 1 in the 50 µg group due to private
reasons). One additional participant in the 20 µggroup was withdrawn from the study after
Dose 2 due to private reasons.
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Page 71Among the 84 younger participants who received at least 1 dose of study vaccine, the m ean
age was approximately 38 y ears (range, 19 to 55 years); 52% of participants were male, 96%
were white, and 98% were non -Hispanic.
BNT162b1 – Older Participants 56 to 85 Years of Age
A total of 36 participants in the older age group (56 to 85 y ears of age) received Dose 1 of
BNT162b1 (12 at each dose level: 10, 20, and 30 µg). At the time of data cutoff, a ll of these
participants had received Dose 2, except for 1 participant in the 20 µggroup, who was
continuing in the study .Among the 36 older participants who received at least 1 dose of
BNT162b1 , the mean age was approximately 66 y ears (range, 56 to 76); 64% were female,
and all were white and non- Hispanic.
BNT162b2 –Younger Partici pants 18 to 55 Years of Age
A total of 60 younger participants (18 to 55 y ears of age )received Dose 1 of BNT162b 2,
12ineach of the 5 dose level groups (1, 3, 10, 20, 30 µg). All of these participants also
received Dose 2 of BNT162b2 , except for 2 partic ipants who were withdrawn from the stud y
(one participant in the 1 µg group due to withdrawal by participant ,andone partic ipant in the
10µg group due to an adverse event of nasopharyngitis, considered not related to study
vaccine b y the investigator ).
Among the 60 younger participants who received at least 1 dose of BNT162b2 , the mean age
was approximately 40 y ears (range, 19 to 55); 57% of participants were female, and allwere
white and non -Hispanic.
BNT162b 2 –Older Participants 56 to 85 Years of Age
A total of 36 older participants (56 to 85 years of age) r eceived both doses of BNT162 b2,
12in each of the 3 dose level groups (10, 20, and 30 µg). At the time of data cutoff none of
these participants had been prematurel y discontinued from the stud y. Am ong these
participants, the mean age was approximately 65 years (range, 56 to 84); 54% were female;
and all were white and non -Hispanic.
2.7.3.2.2.1.1.2. T Cell Response Data –Study BNT162-01
T cell mediated immune responses were evaluated using Enzy me-Linked Immuno -Spot
(ELISpot) and intracellular cy tokine staining (ICS) visualized with fluorescence -activated
cell sorting (FACS). Blood samples for evaluation of T cell responses were collected per
protocol at baseline (before Dose 1) and at the visit that was to take place approximately
7days after Dose 2 (Day 29).Cell mediated immune response data were also evaluated in
post hoc anal yses (not specified in the protocol) using blood collected for general research
purposes on approximately Day 43 (21 day s after Dose 2) Day 85 (63 day s after Dose 2) and
Day 184 (162 day s after Dose 2). T cell responses were evaluated at these later time points
for only a small number of participants who received BNT162b2 at doses of 10, 20, or 30 µg.
Based on the ELISpot and intracellular cy tokine staining assay results described below,
BNT162b1 and BNT162b2 induced poly-functional and pro- inflammatory CD4+/CD8+
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Page 72T cell responses in most participants in both the older and younger age groups .
Re-stimulat ion of PBMCs with peptide pools representing the encoded antigens (RBD or
full-length S protein) demonstrated a helper response characterized by a robust IFNγ/IL -2
response and onl y minor IL -4 production . This cytokine profile indicates a favorable Th1
response and onl y a minimal Th2 immune response.
SARS -CoV -2specific CD4+ and CD8+ T cell responses - ELISpot
At the ELISpot data cutoff date, e valuable ELISpot data were available f or 97 participants
who received BNT162b1 :70 in the y ounger age group (at 1, 3, 10, 20, 30 , 50, 60 µg)and
27 in the older age group (at 10, 20, 30 µg ). For BNT162b2, ELISpot data were available
for76participants who received BNT162b2 : 47 younger participants (at 1, 3, 10, 20, 30 µg),
and 29 older participants (at 10, 20, 30 µg).
Overall, for both BNT162b1 and BNT162b2, based on data for Day 29, the T cell response
rate and the magnitude of the responses as measured by ELISpot were similar across dose
levels of 10 µg and higher and were similar between y ounger and older parti cipants. Results
are shown in Figure 3(a) for the BNT162b2 group.
Among participants who received both Dose 1 and Dose 2, BNT162b1 induced strong
SARS -CoV -2 RBD -specifi c CD4+T cell responses in 96.7% (59/61) of younger participants
and in 100% (27/27) of older participants; CD8+responses were induced in 77.0% (47/ 61) of
younger participants and in 77. 8% (21/27) of older participants. In contrast, T cell responses
were detected less often and were lower in magnitude in 9 y ounger participants who received
only Dose 1 in the 60 μg dose group (55.6% for CD4+and 66.7% for CD8+),indicating the
importance of a booster dose.
BNT162b2 induced strong SARS- CoV -2 S protein -speci fic CD4+ T cell responses in all
participants in both the younger (47/47) and older (29/29) age groups. CD8+ T cell responses
were induced in 95.7% (45/47) of y ounger participants and 82.8% (24/29) of older
participants. Despite the slightly lower CD8+ imm unogenicit y rate in older participants, the
magnitude of the BNT162b2 -induced responses was comparable to those induced in younger
participants receiving 30 μg of BNT162b2. These T cell responses were directed against
different parts of the antigen ,includ ing non -RBD sequences, indicating the induction of
multi- epitopic responses by BNT162b2 in both age groups.
For both BNT162b1 and BNT162b2, w hile the magnitude of the responses varied among
individuals, in participants with the strongest responses, post -vaccination CD4+Tcell
responses to pools of S protein peptides were more than 10 -fold the memory responses to
peptides of CMV, EBV, influenza virus and tetanus toxoid observed in the same participants ,
and CD8+Tcell responses were comparable with memory responses against the viral antigen
peptides in the same participants . Results for BNT162b2 are shown in Figure 3(b).
Complete results for the ELISpot data are presented in Module 5.3.5.1 BNT162-01 Interim
CSR Appendix 16.1.14 Report R-20-0244 v3.0 and Report GA -RB-022- 01A v3.0.
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Page 73Figure 3.Frequency and Magnitude of BNT162b2 -Induced CD4+ and CD8+ T cell
Responses Against Full -length S protein
PBMCs obtained on Day 1 (pre- Dose 1) and on Day 29 (7 days post -Dose 2) w ere analyzed in exvivo IFN
ELISpot (for details see GA-RB-022
-01A). Common pathogen T cell epitope pools CEF (CMV, EBV, and
influenza virus HLA class I epitopes) and CEFT (CMV, EBV, influenza virus, and tetanus toxoid HLA class II
epitopes) served to assess general T cell reactivity, cell culture medium served as negative control. Each dot
represents the sum of normalized mean spot count from duplicate w ells stimulated w ith two peptide pools
corresponding to the full -length wt S protein for one study subject, after subtraction of the medium -only control.
a, Ratios above post -vaccination data points are the number of subjects with detectable CD4+or CD8+Tcell
responses within the total number of tested subjects per dose group . b, S protein -specific CD4+and CD8+Tcell
responses in al l subjects w ith a positive response to S protein (n=46 adults, 29 older adults for CD4+and n=43
adults, 24 older adults for CD8+Tcell responses) and their baseline CEFT -and CEF -specific T cell responses.
Note: CD4 data from 1 adult subject from the 20 µg group and CD8 data from two adult subjects from the
20µg group could not be normalized and hence have not been included in the plots. Horizontal lines represent
the median of each group. Source: Report R -20-0244 v3.0
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Page 74Durability of BNT162b2 -Induced CD4+ and CD8+ T Cell R esponses -ELISpot
Figure 4illustrate sthedurability of the CD4+ and CD8+ T cell responses induced b y
BNT162b2 among younger partici pants (N = 20) at doses of 10, 20, and 30 µg and among
older participants (N=4) receiving 10 µg. T cell responses decreased from Day 29 to Day 85
(63days after Dose 2), but on Day 184 (162 day s after Dose 2) both CD4+ and CD8+ T cell
responses were still detectable in the majority of participants at levels higher than, or in the
range of ,recall antigen memory responses (CEF and CEFT in the figure) (Figure 4).
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Page 75Figure 4.Durability of BNT162b2 -Induced T Cell Responses
PBMCs obtained on Day 1 (before Dose 1), Day 29, Day 85, and Day 184 (7 , 63, and 162 days post-Dose 2,
respectively), were analyzed in exvivo IFN ELISpot (for details see GA -RB-022
-01A). Common pathogen T
cell epitope pools CEF (CMV, EBV, and influenza virus HLA class I epitopes) and CEFT (CMV, EBV,
influenza virus, and tetanus toxoid HLA class II epitope s) served to assess general T cell reactivity, cell culture
medium served as negative control. Each dot represents the sum of normalized mean spot count from duplicate
wells stimulated with two peptide pools corresponding to the full -length wild -type S protein for one study
participant, after subtraction of the medium -only control. Ratios above post -vaccination data points are the
number of participants with detectable CD4+or CD8+Tcell responses within the total number of tested
participants per dose group and time point. Source: R eport R -20-0244 v3.0.
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