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C4591001 Clinical Protocol Nov2020 (2) .pdf



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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

A PHASE 1/2/3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLIND,
DOSE-FINDING STUDY TO EVALUATE THE SAFETY, TOLERABILITY,
IMMUNOGENICITY, AND EFFICACY OF SARS-COV-2 RNA VACCINE
CANDIDATES AGAINST COVID-19 IN HEALTHY INDIVIDUALS

Study Sponsor:

BioNTech

Study Conducted By:

Pfizer

Study Intervention Number:

PF-07302048

Study Intervention Name:

RNA-Based COVID-19 Vaccines

US IND Number:

19736

EudraCT Number:

2020-002641-42

Protocol Number:

C4591001

Phase:
1/2/3
Short Title: A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, and
Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Individuals

Page 1

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

TABLE OF CONTENTS
LIST OF TABLES .....................................................................................................................8
1. PROTOCOL SUMMARY .....................................................................................................9
1.1. Synopsis ....................................................................................................................9
1.2. Schema ....................................................................................................................17
1.3. Schedule of Activities .............................................................................................18
1.3.1. Phase 1 ........................................................................................................18
1.3.2. Phase 2/3 .....................................................................................................23
2. INTRODUCTION ...............................................................................................................26
2.1. Study Rationale .......................................................................................................26
2.2. Background .............................................................................................................26
2.2.1. Clinical Overview .......................................................................................27
2.3. Benefit/Risk Assessment .........................................................................................27
2.3.1. Risk Assessment .........................................................................................29
2.3.2. Benefit Assessment .....................................................................................31
2.3.3. Overall Benefit/Risk Conclusion ................................................................31
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................31
3.1. For Phase 1 ..............................................................................................................31
3.2. For Phase 2/3 ...........................................................................................................33
4. STUDY DESIGN.................................................................................................................36
4.1. Overall Design.........................................................................................................36
4.1.1. Phase 1 ........................................................................................................36
4.1.2. Phase 2/3 .....................................................................................................37
4.2. Scientific Rationale for Study Design .....................................................................39
4.3. Justification for Dose ..............................................................................................39
4.4. End of Study Definition ..........................................................................................40
5. STUDY POPULATION ......................................................................................................40
5.1. Inclusion Criteria .....................................................................................................40
5.2. Exclusion Criteria ....................................................................................................41

Page 2

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

5.3. Lifestyle Considerations ..........................................................................................44
5.3.1. Contraception ..............................................................................................44
5.4. Screen Failures ........................................................................................................44
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study
Intervention Administration ......................................................................................44
6. STUDY INTERVENTION ..................................................................................................45
6.1. Study Intervention(s) Administered ........................................................................46
6.1.1. Manufacturing Process ...............................................................................46
6.1.2. Administration ............................................................................................46
6.2. Preparation/Handling/Storage/Accountability ........................................................47
6.2.1. Preparation and Dispensing ........................................................................48
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................48
6.3.1. Allocation to Study Intervention ................................................................48
6.3.2. Blinding of Site Personnel ..........................................................................48
6.3.3. Blinding of the Sponsor ..............................................................................49
6.3.4. Breaking the Blind ......................................................................................50
6.4. Study Intervention Compliance ...............................................................................50
6.5. Concomitant Therapy ..............................................................................................50
6.5.1. Prohibited During the Study .......................................................................50
6.5.2. Permitted During the Study ........................................................................51
6.6. Dose Modification ...................................................................................................51
6.7. Intervention After the End of the Study ..................................................................52
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL ...........................................................................52
7.1. Discontinuation of Study Intervention ....................................................................52
7.2. Participant Discontinuation/Withdrawal From the Study .......................................53
7.2.1. Withdrawal of Consent ...............................................................................53
7.3. Lost to Follow-up ....................................................................................................54
8. STUDY ASSESSMENTS AND PROCEDURES ...............................................................54
8.1. Efficacy and/or Immunogenicity Assessments .......................................................55
8.1.1. Biological Samples .....................................................................................58
8.2. Safety Assessments .................................................................................................58
8.2.1. Clinical Safety Laboratory Assessments (Phase 1 Participants Only) .......59
Page 3

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

8.2.2. Electronic Diary ..........................................................................................59
8.2.2.1. Grading Scales ...........................................................................60
8.2.2.2. Local Reactions .........................................................................60
8.2.2.3. Systemic Events ........................................................................61
8.2.2.4. Fever ..........................................................................................62
8.2.2.5. Antipyretic Medication .............................................................62
8.2.3. Phase 1 Stopping Rules ..............................................................................62
8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19
and Phase 2/3 Stopping Rule ...........................................................................64
8.2.5. Randomization and Vaccination After a Stopping Rule Is Met .................64
8.2.6. Pregnancy Testing ......................................................................................65
8.3. Adverse Events and Serious Adverse Events ..........................................................65
8.3.1. Time Period and Frequency for Collecting AE and SAE Information .......65
8.3.1.1. Reporting SAEs to Pfizer Safety ...............................................66
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF ...................66
8.3.2. Method of Detecting AEs and SAEs ..........................................................66
8.3.3. Follow-up of AEs and SAEs.......................................................................66
8.3.4. Regulatory Reporting Requirements for SAEs...........................................67
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational
Exposure ..........................................................................................................67
8.3.5.1. Exposure During Pregnancy ......................................................67
8.3.5.2. Exposure During Breastfeeding ................................................69
8.3.5.3. Occupational Exposure .............................................................69
8.3.6. Cardiovascular and Death Events ...............................................................70
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not
Qualifying as AEs or SAEs..............................................................................70
8.3.8. Adverse Events of Special Interest .............................................................70
8.3.8.1. Lack of Efficacy ........................................................................70
8.3.9. Medical Device Deficiencies ......................................................................70
8.3.10. Medication Errors .....................................................................................70
8.4. Treatment of Overdose ............................................................................................71
8.5. Pharmacokinetics ....................................................................................................72
8.6. Pharmacodynamics ..................................................................................................72

Page 4

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

8.7. Genetics ...................................................................................................................72
8.8. Biomarkers ..............................................................................................................72
8.9. Immunogenicity Assessments .................................................................................72
8.10. Health Economics .................................................................................................72
8.11. Study Procedures ...................................................................................................72
8.11.1. Phase 1 ......................................................................................................72
8.11.1.1. Screening: (0 to 28 Days Before Visit 1) ................................72
8.11.1.2. Visit 1 – Vaccination 1: (Day 1) .............................................74
8.11.1.3. Visit 2 – Next-Day Follow-up Visit (Vaccination 1): (1
to 3 Days After Visit 1) .....................................................................76
8.11.1.4. Visit 3 – 1-Week Follow-up Visit (Vaccination 1): (6 to
8 Days After Visit 1) .........................................................................78
8.11.1.5. Visit 4 – Vaccination 2: (19 to 23 Days After Visit 1) ...........79
8.11.1.6. Visit 5 – 1-Week Follow-up Visit (Vaccination 2): (6 to
8 Days After Visit 4) .........................................................................81
8.11.1.7. Visit 6 – 2-Week Follow-up Visit (Vaccination 2): (12 to
16 Days After Visit 4) .......................................................................82
8.11.1.8. Visit 7 – 1-Month Follow-up Visit: (28 to 35 Days After
Visit 4) ...............................................................................................83
8.11.1.9. Visit 8 – 6-Month Follow-up Visit: (175 to 189 Days
After Visit 4)......................................................................................84
8.11.1.10. Visit 9 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 4)......................................................................................84
8.11.1.11. Visit 10 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 4)......................................................................................85
8.11.2. Phase 2/3 ...................................................................................................85
8.11.2.1. Visit 1 – Vaccination 1: (Day 1) .............................................85
8.11.2.2. Visit 2 – Vaccination 2: (19 to 23 Days After Visit 1) ...........88
8.11.2.3. Visit 3 – 1-Month Follow-up Visit (After Vaccination 2):
(28 to 35 Days After Visit 2) .............................................................90
8.11.2.4. Visit 4 – 6-Month Follow-up Visit: (175 to 189 Days
After Visit 2)......................................................................................91
8.11.2.5. Visit 5 – 12-Month Follow-up Visit: (350 to 378 Days
After Visit 2)......................................................................................91
8.11.2.6. Visit 6 – 24-Month Follow-up Visit: (714 to 742 Days
After Visit 2)......................................................................................92
Page 5

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

8.12. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction ........................92
8.13. COVID-19 Surveillance (All Participants) ...........................................................93
8.13.1. Potential COVID-19 Illness Visit: (Optimally Within 3 Days After
Potential COVID-19 Illness Onset) .................................................................95
8.13.2. Potential COVID-19 Convalescent Visit: (28 to 35 Days After
Potential COVID-19 Illness Visit) ..................................................................96
8.14. Communication and Use of Technology ...............................................................96
8.15. SARS-CoV-2 NAAT Results From Visits 1 and 2 and Potential COVID-19
Illness Visits ..............................................................................................................97
9. STATISTICAL CONSIDERATIONS ................................................................................98
9.1. Estimands and Statistical Hypotheses .....................................................................98
9.1.1. Estimands ....................................................................................................98
9.1.2. Statistical Hypotheses .................................................................................99
9.1.2.1. Statistical Hypothesis Evaluation for Efficacy ..........................99
9.1.2.2. Statistical Hypothesis Evaluation for Immunogenicity .............99
9.2. Sample Size Determination .....................................................................................99
9.3. Analysis Sets .........................................................................................................101
9.4. Statistical Analyses ...............................................................................................102
9.4.1. Immunogenicity Analyses ........................................................................102
9.4.2. Efficacy Analyses .....................................................................................107
9.4.3. Safety Analyses ........................................................................................109
9.4.4. Other Analyses..........................................................................................110
9.5. Interim Analyses ...................................................................................................111
9.5.1. Analysis Timing........................................................................................114
9.6. Data Monitoring Committee or Other Independent Oversight Committee ...........114
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS ........................................................................................................116
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .............116
10.1.1. Regulatory and Ethical Considerations ..................................................116
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the
Protocol or ICH GCP.......................................................................116
10.1.2. Informed Consent Process ......................................................................117
10.1.3. Data Protection .......................................................................................118

Page 6

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

10.1.4. Dissemination of Clinical Study Data ....................................................118
10.1.5. Data Quality Assurance ..........................................................................119
10.1.6. Source Documents ..................................................................................120
10.1.7. Study and Site Start and Closure ............................................................121
10.1.8. Sponsor’s Qualified Medical Personnel .................................................121
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................123
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting ....................................................................125
10.3.1. Definition of AE .....................................................................................125
10.3.2. Definition of SAE ...................................................................................126
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.....................128
10.3.4. Reporting of SAEs ..................................................................................131
10.4. Appendix 4: Contraceptive Guidance .................................................................132
10.4.1. Male Participant Reproductive Inclusion Criteria ..................................132
10.4.2. Female Participant Reproductive Inclusion Criteria...............................132
10.4.3. Woman of Childbearing Potential ..........................................................133
10.4.4. Contraception Methods ...........................................................................134
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ......136
10.6. Appendix 6: Abbreviations .................................................................................138
10.7. Appendix 7: Stopping and Alert Rules for Enhanced COVID-19 ......................142
10.8. Appendix 8: Criteria for Allowing Inclusion of Participants With Chronic
Stable HIV, HCV, or HBV Infection ......................................................................145
11. REFERENCES ................................................................................................................146

Page 7

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

LIST OF TABLES
Table 1.

Local Reaction Grading Scale ..................................................................60

Table 2.

Systemic Event Grading Scale..................................................................61

Table 3.

Scale for Fever ..........................................................................................62

Table 4.

Power Analysis for Noninferiority Assessment .....................................100

Table 5.

Probability of Observing at Least 1 AE by Assumed True Event
Rates With Different Sample Sizes ........................................................101

Table 6.

Interim Analysis Plan and Boundaries for Efficacy and Futility ............112

Table 7.

Statistical Design Operating Characteristics: Probability of Success
or Failure for Interim Analyses...............................................................113

Table 8.

Statistical Design Operating Characteristics: Probability of Success
for Final Analysis and Overall ................................................................113

Table 9.

Laboratory Abnormality Grading Scale .................................................123

Table 10.

Stopping Rule: Enrollment Is Stopped if the Number of Severe
Cases in the Vaccine Group Is Greater Than or Equal to the
Prespecified Stopping Rule Value (S) ....................................................143

Table 11.

Alert Rule: Further Action Is Taken if the Number of Severe Cases
in the Vaccine Group Is Greater Than or Equal to the Prespecified
Alert Rule Value (A) ..............................................................................144

Page 8

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

1. PROTOCOL SUMMARY
1.1. Synopsis
Short Title: A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, and
Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Individuals
Rationale
A pneumonia of unknown cause detected in Wuhan, China, was first reported in
December 2019. On 08 January 2020, the pathogen causing this outbreak was identified as a
novel coronavirus 2019. The outbreak was declared a Public Health Emergency of
International Concern on 30 January 2020. On 12 February 2020, the virus was officially
named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the WHO
officially named the disease caused by SARS-CoV-2 as coronavirus disease 2019
(COVID-19). On 11 March 2020, the WHO upgraded the status of the COVID-19 outbreak
from epidemic to pandemic, which is now spreading globally at high speed.
There are currently no licensed vaccines to prevent infection with SARS-CoV-2 or
COVID-19. Given the rapid transmission of COVID-19 and incidence of disease in the
United States and elsewhere, the rapid development of an effective vaccine is of utmost
importance.
BioNTech has developed RNA-based vaccine candidates using a platform approach that
enables the rapid development of vaccines against emerging viral diseases, including
SARS-CoV-2. Each vaccine candidate is based on a platform of nucleoside-modified
messenger RNA (modRNA, BNT162b). Each vaccine candidate expresses 1 of 2 antigens:
the SARS-CoV-2 full-length, P2 mutant, prefusion spike glycoprotein (P2 S) (version 9) or a
trimerized SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) (version 5).
The 2 SARS-CoV-2 vaccine candidates that will be tested in this study are therefore:
BNT162b1 (variant RBP020.3): a modRNA encoding the RBD;
BNT162b2 (variant RBP020.2): a modRNA encoding P2 S.
All candidates are formulated in the same lipid nanoparticle (LNP) composition. This study
is intended to investigate the safety, immunogenicity, and efficacy of these prophylactic
BNT162 vaccines against COVID-19.

Page 9

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

Objectives, Estimands, and Endpoints
For Phase 1
Objectives
Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Estimands

Endpoints

Primary:
In participants receiving at least 1 dose
of study intervention, the percentage of
participants reporting:

Local reactions for up to 7 days
following each dose

Systemic events for up to 7 days
following each dose

Adverse events (AEs) from
Dose 1 to 1 month after the last
dose
• Serious AEs (SAEs) from Dose 1
to 6 months after the last dose

Primary:

Local reactions (pain at the
injection site, redness, and
swelling)

Systemic events (fever, fatigue,
headache, chills, vomiting,
diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs

In addition, the percentage of
Hematology and chemistry laboratory
participants with:
parameters detailed in Section 10.2

Abnormal hematology and
chemistry laboratory values 1 and
7 days after Dose 1; and 7 days
after Dose 2

Grading shifts in hematology and
chemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2
Secondary:
Secondary:
In participants complying with the key
protocol criteria (evaluable
participants) at the following time
points after receipt of study
intervention:
7 and 21 days after Dose 1; 7 and 14
days and 1, 6, 12, and 24 months after
Dose 2





Geometric mean titers (GMTs) at SARS-CoV-2 neutralizing titers
each time point
Geometric mean fold rise (GMFR)
from before vaccination to each
subsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination

Page 10

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

Objectives

Estimands







Geometric mean concentrations
(GMCs) at each time point
GMFR from before vaccination to
each subsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
Geometric mean ratio (GMR),
estimated by the ratio of the
geometric mean of SARS-CoV-2
neutralizing titers to the geometric
mean of binding IgG levels at each
time point

Endpoints
S1-binding IgG levels and
RBD-binding IgG levels





SARS-CoV-2 neutralizing titers
S1-binding IgG levels
RBD-binding IgG levels

For Phase 2/3
Objectivesa

Estimands
Primary Efficacy

To evaluate the efficacy of
prophylactic BNT162b2 against
confirmed COVID-19 occurring from
7 days after the second dose in
participants without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluable
participants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To evaluate the efficacy of
prophylactic BNT162b2 against
confirmed COVID-19 occurring from
7 days after the second dose in
participants with and without
evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluable
participants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To define the safety profile of
prophylactic BNT162b2 in the first
360 participants randomized (Phase 2)

In participants receiving at least 1
dose of study intervention, the
percentage of participants reporting:

Local reactions for up to 7 days
following each dose

Systemic events for up to 7 days
following each dose

AEs from Dose 1 to 7 days after
the second dose

SAEs from Dose 1 to 7 days
after the second dose

Endpoints
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locally
confirmed NAAT in participants with
no serological or virological evidence
(up to 7 days after receipt of the
second dose) of past SARS-CoV-2
infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locally
confirmed NAAT

Primary Safety

Page 11







Local reactions (pain at the
injection site, redness, and
swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting,
diarrhea, new or worsened
muscle pain, and new or
worsened joint pain)
AEs
SAEs

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

Objectivesa

Estimands

Endpoints

To define the safety profile of
prophylactic BNT162b2 in all
participants randomized in Phase 2/3

In participants receiving at least
1 dose of study intervention, the
percentage of participants reporting:

Local reactions for up to 7 days
following each dose

Systemic events for up to 7 days
following each dose

AEs from Dose 1 to 1 month
after the second dose
• SAEs from Dose 1 to 6 months
after the second dose





To define the safety profile of
prophylactic BNT162b2 in
participants 12 to 15 years of age in
Phase 3

In participants receiving at least
1 dose of study intervention, the
percentage of participants reporting:

Local reactions for up to 7 days
following each dose

Systemic events for up to 7 days
following each dose

AEs from Dose 1 to 1 month
after the second dose
• SAEs from Dose 1 to 6 months
after the second dose








AEs
SAEs
In a subset of at least 6000
participants:
o Local reactions (pain at the
injection site, redness, and
swelling)
o Systemic events (fever,
fatigue, headache, chills,
vomiting, diarrhea, new or
worsened muscle pain, and
new or worsened joint pain)
Local reactions (pain at the
injection site, redness, and
swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting,
diarrhea, new or worsened
muscle pain, and new or
worsened joint pain)
AEs
SAEs

Secondary Efficacy
To evaluate the efficacy of
prophylactic BNT162b2 against
confirmed COVID-19 occurring from
14 days after the second dose in
participants without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluable
participants) at least 14 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To evaluate the efficacy of
prophylactic BNT162b2 against
confirmed COVID-19 occurring from
14 days after the second dose in
participants with and without
evidence of infection before
vaccination
To evaluate the efficacy of
prophylactic BNT162b2 against
confirmed severe COVID-19
occurring from 7 days and from
14 days after the second dose in
participants without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluable
participants) at least 14 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluable
participants)
• at least 7 days
and
• at least 14 days
after receipt of the second dose of
study intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

Page 12

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locally
confirmed NAAT in participants with
no serological or virological evidence
(up to 14 days after receipt of the
second dose) of past SARS-CoV-2
infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locally
confirmed NAAT

Confirmed severe COVID-19
incidence per 1000 person-years of
follow-up in participants with no
serological or virological evidence (up
to 7 days and up to 14 days after
receipt of the second dose) of past
SARS-CoV-2 infection

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

Objectivesa
To evaluate the efficacy of
prophylactic BNT162b2 against
confirmed severe COVID-19
occurring from 7 days and from
14 days after the second dose in
participants with and without
evidence of infection before
vaccination

To describe the efficacy of
prophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms)
occurring from 7 days and from
14 days after the second dose in
participants without evidence of
infection before vaccination

To describe the efficacy of
prophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms)
occurring from 7 days and from
14 days after the second dose in
participants with and without
evidence of infection before
vaccination

Estimands
In participants complying with the
key protocol criteria (evaluable
participants)
• at least 7 days
and
• at least 14 days
after receipt of the second dose of
study intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluable
participants)
• at least 7 days
and
• at least 14 days
after receipt of the second dose of
study intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluable
participants)
• at least 7 days
and
• at least 14 days
after receipt of the second dose of
study intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

Endpoints
Confirmed severe COVID-19
incidence per 1000 person-years of
follow-up

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locally
confirmed NAAT in participants with
no serological or virological evidence
(up to 7 days and up to 14 days after
receipt of the second dose) of past
SARS-CoV-2 infection

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locally
confirmed NAAT

Secondary Immunogenicity
To demonstrate the noninferiority of
the immune response to prophylactic
BNT162b2 in participants 12 to 15
years of age compared to participants
16 to 25 years of age

GMR, estimated by the ratio of the
geometric mean of SARS-CoV-2
neutralizing titers in the 2 age groups
(12-15 years of age to 16-25 years of
age) 1 month after completion of
vaccination

To evaluate the immune response
over time to prophylactic BNT162b2
and persistence of immune response
in participants with and without
serological or virological evidence of
SARS-CoV-2 infection before
vaccination
To evaluate the immune response
(non-S) to SARS-CoV-2 in
participants with and without
confirmed COVID-19 during the
study
To describe the serological responses
to the BNT vaccine candidate in cases
of:

Confirmed COVID-19

Confirmed severe COVID-19

SARS-CoV-2 infection without
confirmed COVID-19

GMC/GMT, GMFR, and percentage
of participants with titers greater than
defined threshold(s), at baseline and
1, 6, 12, and 24 months after
completion of vaccination

SARS-CoV-2 neutralizing titers in
participants with no serological or
virological evidence (up to 1 month
after receipt of the second dose) of
past SARS-CoV-2 infection

Exploratory




S1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titers



N-binding antibody



S1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titers



Page 13

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

Objectivesa

Estimands

To describe the safety,
immunogenicity, and efficacy of
prophylactic BNT162b2 in
individuals with confirmed stable HIV
disease
To describe the safety and
immunogenicity of prophylactic
BNT162b2 in individuals 16 to 55
years of age vaccinated with study
intervention produced by
manufacturing “Process 1” or
“Process 2”b

a.

Endpoints


All safety, immunogenicity, and
efficacy endpoints described
above



All safety endpoints described
above
SARS-CoV-2 neutralizing titers



HIV-positive participants in Phase 3 will not be included in analyses of the objectives, with the
exception of the specific exploratory objective.
See Section 6.1.1 for a description of the manufacturing process.

b.

Overall Design
This is a Phase 1/2/3, multicenter, multinational, randomized, placebo-controlled,
observer-blind, dose-finding, vaccine candidate–selection, and efficacy study in healthy
individuals.
The study consists of 2 parts: Phase 1: to identify preferred vaccine candidate(s) and dose
level(s); Phase 2/3: an expanded cohort and efficacy part. These parts, and the progression
between them, are detailed in the schema (Section 1.2).
The study will evaluate the safety, tolerability, and immunogenicity of 2 different
SARS-CoV-2 RNA vaccine candidates against COVID-19 and the efficacy of 1 candidate:


As a 2-dose (separated by 21 days) schedule;



At various different dose levels in Phase 1;



In 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3: ≥12
years of age [stratified as 12-15, 16-55, or >55 years of age]).

Dependent upon safety and/or immunogenicity data generated during the course of this
study, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
in Phase 1 may be started at the next highest dose, groups may not be started, groups may be
terminated early, and/or groups may be added with dose levels below the lowest stated dose
or intermediate between the lowest and highest stated doses.
The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.

Page 14

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

Number of Participants
Each group in Phase 1 will comprise 15 participants (12 receiving active vaccine and
3 receiving placebo). In this phase, 13 groups will be studied, corresponding to a total of
195 participants.
The vaccine candidate selected for Phase 2/3, BNT162b2 at a dose of 30 µg, will comprise
21,999 vaccine recipients. The 12- to 15-year stratum will comprise up to approximately
2000 participants (1000 vaccine recipients) enrolled at selected investigational sites. It is
intended that a minimum of 40% of participants will be in the >55-year stratum. An equal
number of participants will receive placebo, ie, randomized in a 1:1 ratio.
Intervention Groups and Duration
The study will evaluate a 2-dose (separated by 21 days) schedule of various different dose
levels of 2 investigational RNA vaccine candidates for active immunization against
COVID-19 in 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3:
≥12 years of age [stratified as 12-15, 16-55, or >55 years of age]):


BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 20 µg, 30 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 20 µg, 30 µg

The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.
Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Phase 1
dosing arms that are not evaluated in Phase 2/3.
Data Monitoring Committee or Other Independent Oversight Committee
The study will utilize an IRC, an internal Pfizer committee that will review data to allow
dose escalation or changes to continuation of specific groups.
An external data monitoring committee (DMC) will be formed and will review cumulative
unblinded data throughout the study.
Statistical Methods
The sample size for Phase 1 of the study is not based on any statistical hypothesis testing.
For Phase 2/3, the VE evaluation will be the primary objective. The VE is defined as
VE = 100 × (1 – IRR), where IRR is calculated as the ratio of the first confirmed COVID-19
illness rate in the vaccine group to the corresponding illness rate in the placebo group. With
assumptions of a true VE of 60% and 4 IAs planned, 164 COVID-19 cases will provide 90%

Page 15

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

power to conclude true VE >30%. This would be achieved with a total 43,998 participants
(21,999 vaccine recipients), based on the assumption of a 1.3% per year incidence in the
placebo group, accrual of 164 primary-endpoint cases within 6 months, and 20% of the
participants being nonevaluable. If the attack rate is much higher, case accrual would be
expected to be more rapid, enabling the study’s primary endpoint to be evaluated much
sooner. The total number of participants enrolled in Phase 2/3 may vary depending on the
incidence of COVID-19 at the time of the enrollment, the true underlying VE, and a potential
early stop for efficacy or futility.
VE will be evaluated using a beta-binomial model and the posterior probability of VE being
>30% will be assessed.
In Phase 3, up to approximately 2000 participants are anticipated to be 12 to 15 years of age.
Noninferiority of immune response to prophylactic BNT162b2 in participants 12 to 15 years
of age to response in participants 16 to 25 years of age will be assessed based on the GMR of
SARS-CoV-2 neutralizing titers using a 1.5-fold margin. A sample size of 200 evaluable
participants (or 250 vaccine recipients) per age group will provide a power of 90.8% to
declare the noninferiority in terms of GMR (lower limit of 95% CI for GMR >0.67).
The primary safety objective will be evaluated by descriptive summary statistics for local
reactions, systemic events, AEs/SAEs, and abnormal hematology and chemistry laboratory
parameters (Phase 1 only), for each vaccine group. A 3-tier approach will be used to
summarize AEs in Phase 2/3.
Except for the objective to assess the noninferiority of immune response in participants 12 to
15 years of age compared to participants 16 to 25 years of age, the other immunogenicity
objectives will be evaluated descriptively by GMT, GMC, GMFR, percentage of participants
with ≥4-fold rise, percentage of participants with ≥ specified threshold, and GMC ratio, and
the associated 95% confidence intervals (CIs), for SARS-CoV-2 neutralizing titers,
S1-binding IgG levels, and/or RBD-binding IgG levels at the various time points.

Page 16

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

1.2. Schema
Phase 1

For each vaccine candidate

(4:1 randomization active:placebo)

Age: 18-55 y

Age: 65-85 y

Low-dose-level 2-dose group (n=15)
IRC (safety)

IRC (safety

Low-dose-level 2-dose group (n=15)

after Dose 1)
Mid-dose-level 2-dose group (n=15)
IRC (safety)

IRC (safety

Mid-dose-level 2-dose group (n=15)

after Dose 1)
High-dose-level 2-dose group (n=15)
IRC (safety

High-dose-level 2-dose group (n=15)

after Dose 1)
IRC choice of group(s) for Phase 2/3
(safety & immunogenicity after Doses 1 and 2)

Phase 2/3
Single vaccine candidate
Safety and immunogenicity analysis of
Age: ≥12
Phase 2 data (first 360 participants)
(Stratified 12-15, 16-55, or >55)
by unblinded team (these participants
BNT162b2 30 µg or placebo 2 doses
will also be included in Phase 3
(n~21,999 per group, total n~43.998)
analyses)
Abbreviation: IRC = internal review committee.

Page 17

(1:1 randomization active:placebo)

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or
assessments required to protect the well-being of the participant.
1.3.1. Phase 1
An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 10 (24-month follow-up visit) that COVID-19 is suspected.
Visit Number

Screening

1

Visit Description

Screening

Vax 1

Visit Window (Days)

0 to 28
Days
Before
Visit 1

Day 1

1 to 3
Days
After
Visit 1

6 to 8
Days
After
Visit 1

19 to 23
Days
After
Visit 1

6 to 8
Days
After
Visit 4

X

X

X

X

X

Obtain informed consent

X

Assign participant number

X

Obtain demography and
medical history data

X

Obtain details of medications
currently taken

X

Perform physical examination

X

2

3

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)
(Vax 1)

4
Vax 2

5

6

7

8

9

10

Unplanned

Unplanned

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent
(Vax 2) (Vax 2)
up Visit up Visit
Visita
Visit

Page 18

12 to 16 28 to 35 175 to
350 to
714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4
COVID-19 Illness Visit
Illness
Onset

X

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

Visit Number

Screening

1

Visit Description

Screening

Vax 1

Visit Window (Days)

0 to 28
Days
Before
Visit 1

Day 1

1 to 3
Days
After
Visit 1

6 to 8
Days
After
Visit 1

19 to 23
Days
After
Visit 1

6 to 8
Days
After
Visit 4

Measure vital signs
(including body temperature)

X

X

X

X

X

X

~10 mL

~10 mL

~10 mL

~10 mL

Collect blood sample for
hematology and chemistry
laboratory testsb

~10 mL

Collect screening blood
sample for HIV, HBsAg,
HBc Ab, and HCV Ab tests

~10 mL

Serological test for prior
COVID-19 infection

~20 mL

Perform urine pregnancy test
(if appropriate)

X

Obtain nasal (midturbinate)
swab(s)c

4
Vax 2

X

X

X

X

X

Confirm eligibility

X

X

Collect prohibited medication
use

X

Review hematology and
chemistry results

X

Review temporary delay
criteria

X
X

X

X

5

6

7

8

9

10

Unplanned

Unplanned

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent
(Vax 2) (Vax 2)
up Visit up Visit
Visita
Visit
12 to 16 28 to 35 175 to
350 to
714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4
COVID-19 Illness Visit
Illness
Onset
X

X
X

X

X

X

X

X

X
X

X

3

X

Collect nonstudy vaccine
information

Confirm use of contraceptives
(if appropriate)

2

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)
(Vax 1)

X

X

X

X

X

X

X

X

X

X

X
X

X

X

Page 19

X

X

X

X

X

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

Visit Number

Screening

1

Visit Description

Screening

Vax 1

Visit Window (Days)

0 to 28
Days
Before
Visit 1

Day 1

Obtain randomization number
and study intervention
allocation
Collect blood sample for
immunogenicity assessment

2

3

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)
(Vax 1)
1 to 3
Days
After
Visit 1

4
Vax 2

6 to 8
Days
After
Visit 1

19 to 23
Days
After
Visit 1

~50 mL

~50 mL

5

6

8

9

10

Unplanned

Unplanned

6 to 8
Days
After
Visit 4

12 to 16 28 to 35 175 to
350 to
714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4
COVID-19 Illness Visit
Illness
Onset

X

~50 mL

Administer study intervention

X

X

Assess acute reactions for at
least 30 minutes after study
intervention administrationd

X

X

Explain participant
communication methods
(including for e-diary
completion), assist the
participant with downloading
the app, or issue provisioned
device, if required

X

Provide thermometer and
measuring device

X

~50 mL ~50 mL ~50 mL ~20 mL
+
+
+
optionale optionale optionale
~170 mL ~170 mL ~170 mL

X

Review reactogenicity e-diary
data (daily review is optimal
during the active diary period)
Review ongoing
reactogenicity e-diary

7

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent
(Vax 2) (Vax 2)
up Visit up Visit
Visita
Visit

X

X

Page 20

~20 mL

~20 mL

~20 mL

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

Visit Number

Screening

1

Visit Description

Screening

Vax 1

2

3

Visit Window (Days)

0 to 28
Days
Before
Visit 1

Day 1

1 to 3
Days
After
Visit 1

6 to 8
Days
After
Visit 1

19 to 23
Days
After
Visit 1

6 to 8
Days
After
Visit 4

X

X

X

X

X

X

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)
(Vax 1)

4
Vax 2

5

6

7

8

9

10

Unplanned

Unplanned

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent
(Vax 2) (Vax 2)
up Visit up Visit
Visita
Visit
12 to 16 28 to 35 175 to
350 to
714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4
COVID-19 Illness Visit
Illness
Onset

symptoms and obtain stop
dates
Collect AEs and SAEs as
appropriate
Collect e-diary or assist the
participant to delete
application

X

X

X

X

X
X

Page 21

X

X

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

Visit Number

Screening

1

Visit Description

Screening

Vax 1

Visit Window (Days)

0 to 28
Days
Before
Visit 1

Day 1

2

3

Next- 1-Week
Day
FollowFollow- up Visit
up Visit (Vax 1)
(Vax 1)
1 to 3
Days
After
Visit 1

6 to 8
Days
After
Visit 1

4
Vax 2

19 to 23
Days
After
Visit 1

5

6

7

8

9

10

Unplanned

Unplanned

1-Week 2-Week 1-Month 6-Month
1224Potential
Potential
Follow- Follow- Follow- Follow- Month Month COVID-19 COVID-19
up Visit up Visit up Visit up Visit Follow- FollowIllness
Convalescent
(Vax 2) (Vax 2)
up Visit up Visit
Visita
Visit
6 to 8
Days
After
Visit 4

12 to 16 28 to 35 175 to
350 to
714 to Optimally 28 to 35 Days
Days
Days 189 Days 378 Days 742 Days Within 3
After
After
After
After
After
Days
After
Potential
After
Visit 4
Visit 4
Visit 4
Visit 4
Potential
COVID-19
Visit 4
COVID-19 Illness Visit
Illness
Onset

Collection of
COVID-19–related clinical
and laboratory information
(including local diagnosis)

X

X

Abbreviations: e-diary = electronic diary; HBc Ab = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HCV Ab = hepatitis C virus antibody;
HIV = human immunodeficiency virus; NAAT = nucleic acid amplification test; vax = vaccination.

a.
b.
c.
d.
e.

The COVID-19 illness visit may be conducted as an in-person or telehealth visit.
Hematology: hemoglobin, complete blood count with differential, and platelets. Blood chemistry: alanine aminotransferase (ALT), aspartate
aminotransferase (AST), alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), and creatinine.
Two swabs will be taken at Visits 1 and 4. One will be tested (if possible at the site, otherwise at the central laboratory) within 24 hours and vaccination will
only proceed if it is NAAT-negative for SARS-CoV-2 genomes. The second will be sent to the central laboratory for potential later testing.
The first 5 participants in in each group will be observed at the site for at least 4 hours after study intervention administration. Further vaccination will
commence no sooner than 24 hours after the fifth participant received his or her vaccination.
An optional blood draw of ~170 mL will be taken at 1 of the visits (from selected participants who consent) for exploratory COVID-19 research.

Page 22

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

1.3.2. Phase 2/3
An unplanned potential COVID-19 illness visit and unplanned potential COVID-19 convalescent visit are required at any time
between Visit 1 (Vaccination 1) and Visit 6 (24-month follow-up visit) that potential COVID-19 symptoms are reported, including
MIS-C.
Visit Number
Visit Description

Visit Window (Days)

1

Day 1b

Obtain informed consent

X

Assign participant number

X

Obtain demography and medical history data
Perform clinical assessment

c

2

Vaccination 1 Vaccination 2

3

4

5

6

1-Month
Follow-up
Visit

6-Month
Follow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
Potential
COVID-19
COVID-19
Illness Visita Convalescent
Visit

175 to 189
Days After
Visit 2

350 to 378
Days After
Visit 2

714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

X

X

X

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2

X
X

Measure height and weight

X

Measure temperature (body)

X

X

Perform urine pregnancy test (if appropriate)

X

X

Confirm use of contraceptives (if appropriate)

X

X

X

Collect nonstudy vaccine information

X

X

X

X

X

X

X

X

X

~20 mL/
~10 mL

~20 mL/
~10 mL

~20 mL/
~10 mL

~20 mL/
~10 mL

Collect prohibited medication use

X

Confirm eligibility

X

X

Review temporary delay criteria

X

X

Obtain nasal (midturbinate) swab

Unplanned

X

For participants who are HIV-positive, record latest
CD4 count and HIV viral load

Collect blood sample for immunogenicity
assessmentd

Unplanned

~20 mL/
~10 mL
X

X

X

~20 mL/
~10 mL
X

Page 23

X

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

Visit Number
Visit Description

Visit Window (Days)

1

2

Vaccination 1 Vaccination 2

Day 1b

3

4

5

6

1-Month
Follow-up
Visit

6-Month
Follow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
Potential
COVID-19
COVID-19
Illness Visita Convalescent
Visit

175 to 189
Days After
Visit 2

350 to 378
Days After
Visit 2

714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

Xf

Xf

Xf

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2

Obtain randomization number and study
intervention allocation

X

Administer study intervention

X

X

Assess acute reactions for at least 30 minutes after
study intervention administration

X

X

Explain participant communication methods
(including for e-diary completion), assist the
participant with downloading the app, or issue
provisioned device, if required

X

Provide/ensure the participant has a thermometer
(all participants) and measuring device
(reactogenicity subset participants only)

X

Unplanned

Unplanned

X

Review reactogenicity e-diary data (daily review is
optimal during the active diary period)e
Review ongoing reactogenicity e-diary symptoms
and obtain stop datese
Collect AEs and SAEs as appropriate

X

X

X

X

X

Collect e-diary or assist the participant to delete
application

X

Page 24

X

Xf

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

Visit Number
Visit Description

Visit Window (Days)

1

2

Vaccination 1 Vaccination 2

Day 1b

3

4

5

6

1-Month
Follow-up
Visit

6-Month
Follow-up
Visit

12-Month
Follow-up
Visit

24-Month
Follow-up
Visit

Potential
Potential
COVID-19
COVID-19
Illness Visita Convalescent
Visit

175 to 189
Days After
Visit 2

350 to 378
Days After
Visit 2

714 to 742
Days After
Visit 2

Optimally 28 to 35 Days
Within 3
After
Days After
Potential
Potential
COVID-19
COVID-19
Illness Visit
Illness Onset

19 to 23 Days 28 to 35 Days
After Visit 1 After Visit 2

Collection of COVID-19–related clinical and
laboratory information (including local diagnosis)

Unplanned

X

Unplanned

X

Abbreviations: HIV = human immunodeficiency virus; e-diary = electronic diary.

a.
b.
c.
d.
e.
f.

The COVID-19 illness visit may be conducted as an in-person or telehealth visit.
The visit may be conducted across 2 consecutive days; if so, all steps from assessing the inclusion and exclusion criteria onwards must be conducted on the
same day.
Including, if indicated, a physical examination.
20 mL is to be collected from participants ≥16 years of age; 10 mL is to be collected from participants 12 to 15 years of age.
Reactogenicity subset participants only.
Any AEs occurring up to 48 hours after the blood draw must be recorded (see Section 8.3.1).

Page 25

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

2. INTRODUCTION
The BNT162 RNA-based COVID-19 vaccines are currently being investigated for
prevention of COVID-19 in healthy individuals.
2.1. Study Rationale
The purpose of the study is to rapidly describe the safety, tolerability, and immunogenicity of
2 BNT162 RNA-based COVID-19 vaccine candidates against COVID-19, and the efficacy
of 1 candidate, in healthy individuals. There are currently no licensed vaccines to prevent
infection with SARS-CoV-2 or COVID-19. Given the global crisis of COVID-19 and fast
expansion of the disease in the United States and elsewhere, the rapid development of an
effective vaccine is of utmost importance.
2.2. Background
In December 2019, a pneumonia outbreak of unknown cause occurred in Wuhan, China.
In January 2020, it became clear that a novel coronavirus (2019-nCoV) was the underlying
cause. Later in January, the genetic sequence of the 2019-nCoV became available to the
World Health Organization (WHO) and public (MN908947.3), and the virus was categorized
in the Betacoronavirus subfamily. By sequence analysis, the phylogenetic tree revealed a
closer relationship to severe acute respiratory syndrome (SARS) virus isolates than to another
coronavirus infecting humans, the Middle East respiratory syndrome (MERS) virus.
SARS-CoV-2 infections and the resulting disease, COVID-19, have spread globally,
affecting a growing number of countries.
On 11 March 2020, the WHO characterized the COVID-19 outbreak as a pandemic.1
The WHO Situation Update Report dated 30 March 2020 noted 693,224 confirmed cases
with 33,106 deaths globally, including 142,081 confirmed cases with 2457 deaths in the
Americas.2 The United States currently has the most reported cases globally. At the time of
this communication, the number of confirmed cases continues to rise globally. There are
currently no vaccines or effective antiviral drugs to treat SARS-CoV-2 infections or the
disease it causes, COVID-19.3
A prophylactic, RNA-based SARS-CoV-2 vaccine provides one of the most flexible and
fastest approaches available to immunize against the emerging virus.4,5
The development of an RNA-based vaccine encoding a viral antigen, which is then expressed
by the vaccine recipient as a protein capable of eliciting protective immune responses,
provides significant advantages over more traditional vaccine approaches. Unlike live
attenuated vaccines, RNA vaccines do not carry the risks associated with infection and may
be given to people who cannot be administered live virus (eg, pregnant women and
immunocompromised persons). RNA-based vaccines are manufactured via a cell-free in
vitro transcription process, which allows an easy and rapid production and the prospect of
producing high numbers of vaccination doses within a shorter time period than achieved with
traditional vaccine approaches. This capability is pivotal to enable the most effective
response in outbreak scenarios.

Page 26

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

Two SARS-CoV-2–RNA lipid nanoparticle (RNA-LNP) vaccines based on a platform of
nucleoside-modified messenger RNA (modRNA, BNT162b) will be evaluated in this study.
Each vaccine candidate expresses 1 of 2 antigens: the SARS-CoV-2 full-length, P2 mutant,
prefusion spike glycoprotein (P2 S) (version 9) or a trimerized SARS-CoV-2 spike
glycoprotein-receptor binding domain (RBD) (version 5). The 2 SARS-CoV-2 vaccine
candidates that will be tested in this study are therefore:


BNT162b1 (variant RBP020.3): nucleoside-modified messenger RNA (modRNA)
with blunted innate immune sensor–activating capacity and augmented expression
encoding the RBD.



BNT162b2 (variant RBP020.2): nucleoside-modified messenger RNA (modRNA) as
above, but encoding P2 S.

The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2.
2.2.1. Clinical Overview
Prior to this study, given clinical data from other similarly formulated uRNA liposomal
vaccines from BioNTech in oncology trials6 and recent published results from clinical trials
using modRNA influenza vaccines by Moderna,7 the BNT162 vaccines were expected to
have a favorable safety profile with mild, localized, and transient effects. BNT162 vaccines
based on modRNA have now been administered to humans for the first time in this study and
the BNT162-01 study conducted in Germany by BioNTech, at doses between 1 µg and
100 µg. The currently available safety and immunogenicity data are presented in the BNT162
IB.
2.3. Benefit/Risk Assessment
There is an ongoing global pandemic of COVID-19 with no preventative or therapeutic
options available. While there were no data available from clinical trials on the use of
BNT162 vaccines in humans at the outset of this study, available nonclinical data with these
vaccines, and data from nonclinical studies and clinical trials with the same or related RNA
components, or antigens, supported a favorable risk/benefit profile. Anticipated AEs after
vaccination were expected to be manageable using routine symptom-driven standard of care
as determined by the investigators and, as a result, the profile of these vaccine candidates
supported initiation of this Phase 1/2/3 clinical study.
Updates as part of protocol amendment 6:


In order for the overall Phase 3 study population to be as representative and
diverse as possible, the inclusion of participants with known chronic stable HIV,
HCV, or HBV infection is permitted. Individuals with chronic viral diseases are at
increased risk for COVID-19 complications and severe disease. In addition, with
the currently available therapies for their treatment, many individuals with chronic
stable HIV, HCV, and HBV infections are unlikely to be at higher safety risk as a

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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

participant in this vaccine study than individuals with other chronic stable medical
conditions.


All participants with chronic stable HIV disease will be included in the
reactogenicity subset (see Section 8.2.2).

Updates as part of protocol amendment 7:


The minimum age for inclusion in Phase 3 is lowered to 12 years, therefore
allowing the inclusion of participants 12 to 15 years of age.



For individuals 12 to 15 years of age, the immune responses in this age group may
be higher and reactogenicity is expected to be similar to younger adults 18 to 25
years of age. Inclusion of individuals 12 to 15 years of age was based upon a
satisfactory blinded safety profile in participants 18 to 25 years of age.



All participants 12 to 15 years of age will be included in the reactogenicity subset
(see Section 8.2.2).

More detailed information about the known and expected benefits and risks and reasonably
expected AEs of BNT162 RNA-based COVID-19 vaccines may be found in the IB, which is
the SRSD for this study.

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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

2.3.1. Risk Assessment
Potential Risk of Clinical
Significance

Summary of Data/Rationale for Risk

Mitigation Strategy

Study Intervention: BNT162 RNA-Based COVID-19 Vaccine
Potential for local reactions (injection
site redness, injection site swelling,
and injection site pain) and systemic
events (fever, fatigue, headache,
chills, vomiting, diarrhea, muscle
pain, and joint pain) following
vaccination.

These are common adverse reactions seen
with other vaccines, as noted in the FDA
Center for Biologics Evaluation and
Research (CBER) guidelines on toxicity
grading scales for healthy adult volunteers
enrolled in preventive vaccine clinical
trials.8

The Phase 1 study design includes the use of controlled vaccination and
dose escalation to closely monitor and limit the rate of enrollment to ensure
participant safety. The study employs the use of a reactogenicity e-diary to
monitor local reactions and systemic events in real time. Stopping rules are
also in place. The first 5 participants in each group in Phase 1 will be
observed for 4 hours after vaccination to assess any immediate AEs. All
other participants will be observed for at least 30 minutes after vaccination.

Unknown AEs and laboratory
abnormalities with a novel vaccine.

This study is one of the first 2
parallel-running clinical studies with the
BNT162 vaccine candidates and as such
there are no clinical data available for this
vaccine.

The Phase 1 study design includes the use of controlled vaccination and
dose escalation to closely monitor and limit the rate of enrollment to ensure
participant safety. An IRC (in Phase 1) and DMC (throughout the study)
will also review safety data. Stopping rules are also in place. The first 5
participants in each group in Phase 1 will be observed for 4 hours after
vaccination to assess any immediate AEs. All other participants will be
observed for at least 30 minutes after vaccination.

Potential for COVID-19
enhancement.

Disease enhancement has been seen
following vaccination with respiratory
syncytial virus (RSV), feline coronavirus,
and Dengue virus vaccines.

Phase 1 excludes participants with likely previous or current COVID-19. In
Phase 2/3, temporary delay criteria defer vaccination of participants with
symptoms of potential COVID-19. All participants are followed for any
potential COVID-19 illness, including markers of severity, and have blood
samples taken for potential measurement of SARS-CoV-2 antigen-specific
antibody and SARS-CoV-2 neutralizing titers.

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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

Potential Risk of Clinical
Significance

Summary of Data/Rationale for Risk

Mitigation Strategy

Study Procedures
Participants will be required to attend Without appropriate social distancing and
healthcare facilities during the global PPE, there is a potential for increased
exposure to SARS-CoV-2.
SARS-CoV-2 pandemic.
Venipuncture will be performed
during the study.

There is the risk of bleeding, bruising,
hematoma formation, and infection at the
venipuncture site.

Page 30

Pfizer will work with sites to ensure an appropriate COVID-19 prevention
strategy. Potential COVID-19 illness visits can be conducted via telehealth,
without the need for an in-person visit, if required, with the participant
performing a self-swab.
Only appropriately qualified personnel would obtain the blood draw.

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

2.3.2. Benefit Assessment
Benefits to individual participants may include:


Receipt of a potentially efficacious COVID-19 vaccine during a global pandemic



Access to COVID-19 diagnostic testing



Contributing to research to help others in a time of global pandemic

2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in this
study, the potential risks identified in association with BNT162 RNA-based COVID-19
vaccine are justified by the anticipated benefits that may be afforded to healthy participants.
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS
3.1. For Phase 1
Objectives
Primary:
To describe the safety and tolerability
profiles of prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Estimands

Endpoints

Primary:
In participants receiving at least 1 dose
of study intervention, the percentage of
participants reporting:

Local reactions for up to 7 days
following each dose

Systemic events for up to 7 days
following each dose

Adverse events (AEs) from
Dose 1 to 1 month after the last
dose
• Serious AEs (SAEs) from Dose 1
to 6 months after the last dose

Primary:

Local reactions (pain at the
injection site, redness, and
swelling)

Systemic events (fever, fatigue,
headache, chills, vomiting,
diarrhea, new or worsened muscle
pain, and new or worsened joint
pain)

AEs

SAEs

In addition, the percentage of
Hematology and chemistry laboratory
participants with:
parameters detailed in Section 10.2

Abnormal hematology and
chemistry laboratory values 1 and
7 days after Dose 1; and 7 days
after Dose 2

Grading shifts in hematology and
chemistry laboratory assessments
between baseline and 1 and 7 days
after Dose 1; and before Dose 2
and 7 days after Dose 2

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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

Objectives
Secondary:
To describe the immune responses
elicited by prophylactic BNT162
vaccines in healthy adults after 1 or 2
doses

Estimands
Secondary:
In participants complying with the key
protocol criteria (evaluable
participants) at the following time
points after receipt of study
intervention: 7 and 21 days after Dose
1; 7 and 14 days and 1, 6, 12, and 24
months after Dose 2











Endpoints
Secondary:

Geometric mean titers (GMTs) at SARS-CoV-2 neutralizing titers
each time point
Geometric mean fold rise (GMFR)
from before vaccination to each
subsequent time point after
vaccination
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
S1-binding IgG levels and RBDGeometric mean concentrations
binding IgG levels
(GMCs) at each time point
GMFR from prior to first dose of
study intervention to each
subsequent time point
Proportion of participants
achieving ≥4-fold rise from before
vaccination to each subsequent
time point after vaccination
Geometric mean ratio (GMR),

estimated by the ratio of the
geometric mean of SARS-CoV-2 •
neutralizing titers to the geometric •
mean of binding IgG levels at
each time point

Page 32

SARS-CoV-2 neutralizing titers
S1-binding IgG levels
RBD-binding IgG levels

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

3.2. For Phase 2/3
Objectivesa

Estimands
Primary Efficacy

Endpoints

To evaluate the efficacy of
prophylactic BNT162b2 against
confirmed COVID-19 occurring from
7 days after the second dose in
participants without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluable
participants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locally
confirmed NAAT in participants with
no serological or virological evidence
(up to 7 days after receipt of the
second dose) of past SARS-CoV-2
infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locally
confirmed NAAT

To evaluate the efficacy of
prophylactic BNT162b2 against
confirmed COVID-19 occurring from
7 days after the second dose in
participants with and without
evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluable
participants) at least 7 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To define the safety profile of
prophylactic BNT162b2 in the first
360 participants randomized (Phase 2)

In participants receiving at least 1
dose of study intervention, the
percentage of participants reporting:

Local reactions for up to 7 days
following each dose

Systemic events for up to 7 days
following each dose

AEs from Dose 1 to 7 days after
the second dose

SAEs from Dose 1 to 7 days
after the second dose



To define the safety profile of
prophylactic BNT162b2 in all
participants randomized in Phase 2/3

In participants receiving at least
1 dose of study intervention, the
percentage of participants reporting:

Local reactions for up to 7 days
following each dose

Systemic events for up to 7 days
following each dose

AEs from Dose 1 to 1 month
after the second dose

SAEs from Dose 1 to 6 months
after the second dose





AEs
SAEs
In a subset of at least 6000
participants:
o Local reactions (pain at the
injection site, redness, and
swelling)
o Systemic events (fever,
fatigue, headache, chills,
vomiting, diarrhea, new or
worsened muscle pain, and
new or worsened joint pain)

To define the safety profile of
prophylactic BNT162b2 in
participants 12 to 15 years of age in
Phase 3

In participants receiving at least
1 dose of study intervention, the
percentage of participants reporting:

Local reactions for up to 7 days
following each dose

Systemic events for up to 7 days
following each dose

AEs from Dose 1 to 1 month
after the second dose



Local reactions (pain at the
injection site, redness, and
swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting,
diarrhea, new or worsened
muscle pain, and new or
worsened joint pain)
AEs
SAEs

Primary Safety



SAEs from Dose 1 to 6
months after the second dose

Page 33











Local reactions (pain at the
injection site, redness, and
swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting,
diarrhea, new or worsened
muscle pain, and new or
worsened joint pain)
AEs
SAEs

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

Objectivesa

Estimands
Secondary Efficacy

To evaluate the efficacy of
prophylactic BNT162b2 against
confirmed COVID-19 occurring from
14 days after the second dose in
participants without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluable
participants) at least 14 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To evaluate the efficacy of
prophylactic BNT162b2 against
confirmed COVID-19 occurring from
14 days after the second dose in
participants with and without
evidence of infection before
vaccination

In participants complying with the
key protocol criteria (evaluable
participants) at least 14 days after
receipt of the second dose of study
intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To evaluate the efficacy of
prophylactic BNT162b2 against
confirmed severe COVID-19
occurring from 7 days and from 14
days after the second dose in
participants without evidence of
infection before vaccination

In participants complying with the
key protocol criteria (evaluable
participants)
• at least 7 days
and
• at least 14 days
after receipt of the second dose of
study intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluable
participants)
• at least 7 days
and
• at least 14 days
after receipt of the second dose of
study intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluable
participants)
• at least 7 days
and
• at least 14 days
after receipt of the second dose of
study intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]
In participants complying with the
key protocol criteria (evaluable
participants)
• at least 7 days
and
• at least 14 days
after receipt of the second dose of
study intervention:
100 × (1 – IRR) [ratio of active
vaccine to placebo]

To evaluate the efficacy of
prophylactic BNT162b2 against
confirmed severe COVID-19
occurring from 7 days and from 14
days after the second dose in
participants with and without
evidence of infection before
vaccination

To describe the efficacy of
prophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms)
occurring from 7 days and from 14
days after the second dose in
participants without evidence of
infection before vaccination

To describe the efficacy of
prophylactic BNT162b2 against
confirmed COVID-19 (according to
the CDC-defined symptoms)
occurring from 7 days and from 14
days after the second dose in
participants with and without
evidence of infection before
vaccination

Page 34

Endpoints
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locally
confirmed NAAT in participants with
no serological or virological evidence
(up to 14 days after receipt of the
second dose) of past SARS-CoV-2
infection
COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locally
confirmed NAAT

Confirmed severe COVID-19
incidence per 1000 person-years of
follow-up in participants with no
serological or virological evidence (up
to 7 days and up to 14 days after
receipt of the second dose) of past
SARS-CoV-2 infection

Confirmed severe COVID-19
incidence per 1000 person-years of
follow-up

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locally
confirmed NAAT in participants with
no serological or virological evidence
(up to 7 days and up to 14 days after
receipt of the second dose) of past
SARS-CoV-2 infection

COVID-19 incidence per 1000
person-years of follow-up based on
central laboratory or locally
confirmed NAAT

PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

Objectivesa

Estimands
Secondary Immunogenicity

To demonstrate the noninferiority of
the immune response to prophylactic
BNT162b2 in participants 12 to 15
years of age compared to participants
16 to 25 years of age

GMR, estimated by the ratio of the
geometric mean of SARS-CoV-2
neutralizing titers in the 2 age groups
(12-15 years of age to 16-25 years of
age) 1 month after completion of
vaccination

To evaluate the immune response
over time to prophylactic BNT162b2
and persistence of immune response
in participants with and without
serological or virological evidence of
SARS-CoV-2 infection before
vaccination

GMC/GMT, GMFR, and percentage
of participants with titers greater than
defined threshold(s), at baseline and
1, 6, 12, and 24 months after
completion of vaccination

Endpoints
SARS-CoV-2 neutralizing titers in
participants with no serological or
virological evidence (up to 1 month
after receipt of the second dose) of
past SARS-CoV-2 infection

Exploratory



S1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titers

To evaluate the immune response
(non-S) to SARS-CoV-2 in
participants with and without
confirmed COVID-19 during the
study



N-binding antibody

To describe the serological responses
to the BNT vaccine candidate in cases
of:

Confirmed COVID-19

Confirmed severe COVID-19

SARS-CoV-2 infection without
confirmed COVID-19
To describe the safety,
immunogenicity, and efficacy of
prophylactic BNT162b2 in
individuals with confirmed stable
HIV disease
To describe the safety and
immunogenicity of prophylactic
BNT162b2 in individuals 16 to 55
years of age vaccinated with study
intervention produced by
manufacturing “Process 1” or
“Process 2”b



S1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titers

a.
b.





All safety, immunogenicity, and
efficacy endpoints described
above



All safety endpoints described
above
SARS-CoV-2 neutralizing titers



HIV-positive participants in Phase 3 will not be included in analyses of the objectives, with the
exception of the specific exploratory objective.
See Section 6.1.1 for description of the manufacturing process.

This protocol will use a group of internal case reviewers to determine whether certain
investigator-reported events meet the definition of disease-related efficacy endpoints, using
predefined endpoint criteria.
For those AEs that are handled as disease-related efficacy endpoints (which may include
death), a DMC will conduct unblinded reviews on a regular basis throughout the trial
(see Section 9.6).

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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

Any AE that is determined by the internal case reviewers NOT to meet endpoint criteria is
reported back to the investigator site of incidence. Refer to Section 8.3.1.1 for instructions
on how to report any such AE that meets the criteria for seriousness to Pfizer Safety.
4. STUDY DESIGN
4.1. Overall Design
This is a multicenter, multinational, Phase 1/2/3, randomized, placebo-controlled,
observer-blind, dose-finding, vaccine candidate–selection, and efficacy study in healthy
individuals.
The study consists of 2 parts. Phase 1: to identify preferred vaccine candidate(s) and dose
level(s); Phase 2/3: an expanded cohort and efficacy part. These parts, and the progression
between them, are detailed in the schema (Section 1.2).
The study will evaluate the safety, tolerability, and immunogenicity of 2 different
SARS-CoV-2 RNA vaccine candidates against COVID-19 and the efficacy of 1 candidate:


As a 2-dose (separated by 21 days) schedule;



At various different dose levels in Phase 1;



In 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3: ≥12
years of age [stratified as 12-15, 16-55, or >55 years of age]).

Dependent upon safety and/or immunogenicity data generated during the course of this
study, or the BioNTech study conducted in Germany (BNT162-01), it is possible that groups
in Phase 1 may be started at the next highest dose, groups may not be started, groups may be
terminated early, and/or groups may be added with dose levels below the lowest stated dose
or intermediate between the lowest and highest stated doses.
The study is observer-blinded, as the physical appearance of the investigational vaccine
candidates and the placebo may differ. The participant, investigator, study coordinator, and
other site staff will be blinded. At the study site, only the dispenser(s)/administrator(s) are
unblinded.
To facilitate rapid review of data in real time, sponsor staff will be unblinded to vaccine
allocation for the participants in Phase 1.
4.1.1. Phase 1
Each group (vaccine candidate/dose level/age group) will comprise 15 participants;
12 participants will be randomized to receive active vaccine and 3 to receive placebo.
For each vaccine candidate/dose level/age group, the following apply:


Additional safety assessments (see Section 8.2)

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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001



Controlled enrollment (required only for the first candidate and/or dose level studied):


No more than 5 participants (4 active, 1 placebo) can be vaccinated on the first
day



The first 5 participants must be observed by blinded site staff for at least 4 hours
after vaccination for any acute reactions



Vaccination of the remaining participants will commence no sooner than 24 hours
after the fifth participant received his or her vaccination



Application of stopping rules



IRC review of safety data to determine escalation to the next dose level in the 18- to
55-year age cohort:


Escalation between dose levels will be based on IRC review of at least 7-day
post–Dose 1 safety data in this study and/or the BioNTech study conducted in
Germany (BNT162-01)



Note that, since both candidates are based upon the same RNA platform, dose
escalation for the second candidate studied may be based upon the safety profile
of the first candidate studied being deemed acceptable at the same, or a higher,
dose level by the IRC

Groups of participants 65 to 85 years of age will not be started until safety data for the RNA
platform have been deemed acceptable at the same, or a higher, dose level in the 18- to
55-year age cohort by the IRC.
In this phase, 13 groups will be studied, corresponding to a total of 195 participants.
The IRC will select 1 vaccine candidate that, in Phase 1, has an established dose level per age
group based on induction of a post–Dose 2 immune response, including neutralizing
antibodies, which is expected to be associated with protection against COVID-19, for
progression into Phase 2/3.
4.1.2. Phase 2/3
On the basis of safety and/or immunogenicity data generated during the course of this study,
and/or the BioNTech study conducted in Germany (BNT162-01), 1 vaccine candidate was
selected to proceed into Phase 2/3. Participants in this phase will be ≥12 years of age,
stratified as follows: 12 to 15 years, 16 to 55 years, or >55 years. The 12- to 15-year stratum
will comprise up to approximately 2000 participants enrolled at selected investigational sites.
It is intended that a minimum of 40% of participants will be in the >55-year stratum.
Commencement of each age stratum will be based upon satisfactory post–Dose 2 safety and
immunogenicity data from the 18- to 55-year and 65- to 85-year age groups in Phase 1,

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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

respectively. The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose
of 30 µg.
Phase 2/3 is event-driven. Under the assumption of a true VE rate of ≥60%, after the second
dose of investigational product, a target of 164 primary-endpoint cases of confirmed
COVID-19 due to SARS-CoV-2 occurring at least 7 days following the second dose of the
primary series of the candidate vaccine will be sufficient to provide 90% power to conclude
true VE >30% with high probability. The total number of participants enrolled in Phase 2/3
may vary depending on the incidence of COVID-19 at the time of the enrollment, the true
underlying VE, and a potential early stop for efficacy or futility.
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 BNT162b2 vaccine candidate selected for Phase 2/3 is expected to
comprise approximately 21,999 vaccine recipients. This is the number of participants
initially targeted for Phase 2/3 and may be adjusted based on advice from DMC analyses of
case accumulation and the percentage of participants who are seropositive at baseline.
Dependent upon the evolution of the pandemic, it is possible that the COVID-19 attack rate
may be much higher, in which case accrual would be expected to be more rapid, enabling the
study’s primary endpoint to be evaluated much sooner.
The first 360 participants enrolled (180 to active vaccine and 180 to placebo, stratified
equally between 18 to 55 years and >55 to 85 years) will comprise the “Phase 2” portion.
Safety data through 7 days after Dose 2 and immunogenicity data through 1 month after
Dose 2 from these 360 participants will be analyzed by the unblinded statistical team,
reviewed by the DMC, and submitted to appropriate regulatory authorities for review.
Enrollment may continue during this period and these participants would be included in the
efficacy evaluation in the “Phase 3” portion of the study.
In Phase 3, up to approximately 2000 participants, enrolled at selected sites, are anticipated
to be 12 to 15 years of age. Noninferiority of immune response to prophylactic BNT162b2
in participants 12 to 15 years of age to response in participants 16 to 25 years of age will be
assessed based on the GMR of SARS-CoV-2 neutralizing titers using a 1.5-fold margin. A
sample size of 200 evaluable participants (or 250 vaccine recipients) per age group will
provide a power of 90.8% to declare the noninferiority in terms of GMR (lower limit of 95%
CI for GMR >0.67). A random sample of 250 participants from each of the 2 age groups
(12 to 15 years and 16 to 25 years) will be selected as an immunogenicity subset for the
noninferiority assessment.
The initial BNT162b2 was manufactured using “Process 1”; however, “Process 2” was
developed to support an increased scale of manufacture. In the study, each lot of
“Process 2”-manufactured BNT162b2 will be administered to approximately 250 participants
16 to 55 years of age. The safety and immunogenicity of prophylactic BNT162b2 in
individuals 16 to 55 years of age vaccinated with “Process 1” and each lot of “Process 2”
study intervention will be described. A random sample of 250 participants from those

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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
Protocol C4591001

vaccinated with study intervention produced by manufacturing “Process 1” will be selected
for this descriptive analysis.
Participants are expected to participate for up to a maximum of approximately 26 months.
The duration of study follow-up may be shorter among participants enrolled in Phase 1
dosing arms that are not evaluated in Phase 2/3.
4.2. Scientific Rationale for Study Design
Additional surveillance for COVID-19 will be conducted as part of the study, given the
potential risk of disease enhancement. If a participant experiences symptoms, as detailed in
Section 8.13, a COVID-19 illness and subsequent convalescent visit will occur. As part of
these visits, samples (nasal [midturbinate] swab and blood) will be taken for antigen and
antibody assessment as well as recording of COVID-19–related clinical and laboratory
information (including local diagnosis).
Human reproductive safety data are not available for BNT162 RNA-based COVID-19
vaccines, but there is no suspicion of human teratogenicity based on the intended mechanism
of action of the compound. Therefore, the use of a highly effective method of contraception
is required (see Appendix 4).
4.3. Justification for Dose
Because of the requirement for a rapid response to the newly emerged COVID-19 pandemic,
sufficient data were not available to experimentally validate the dose selection and initial
starting dose. Therefore, the original planned starting dose of 10 µg (for both BNT162b1 and
BNT162b2) in this study was based on nonclinical experience with the same RNAs encoding
other viral antigens (such as influenza and HIV antigens). The general safety and
effectiveness of uRNA and modRNA platforms have been demonstrated in oncological
clinical trials with different administration routes (NCT02410733, NCT03871348). Doses of
up to 400 µg total uRNA have been administered IV as RNA lipoplex (RNA-LPX) and doses
of up to 1000 µg total naked modRNA have been administered intratumorally, both without
signs of unpredictable overstimulation of the immune system.
Based on nonclinical data of the RNA components, with other liposomes or in conjunction
with the lipid nanoparticles as will be tested clinically in this study, it was expected that
doses in the 1- to 5-µg range would be immunogenic and induce neutralizing antibodies;
however, it was anticipated that 3- to 10-fold higher doses would likely be required to elicit a
stronger antibody response. Based on previous clinical and nonclinical experience, it was
expected that doses of up to 100 µg would be well tolerated.
Update as part of protocol amendment 2: preliminary experience in this study and the
BioNTech study conducted in Germany (BNT162-01) suggests that, for vaccine candidates
based on the modRNA platform, a dose level between 30 µg and 100 µg warrants
consideration. Therefore, a 50-µg dose level is formally included for BNT162b1 and
BNT162b2.

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Update as part of protocol amendment 3: as data have become available from this study and
the BNT162-01 study in Germany, it was decided:


To not study the BNT162a1 and BNT162c2 vaccine candidates at this time, so these
candidates have been removed from the protocol; and



That lower dose levels of BNT162b1 and BNT162b2 warrant consideration.
Therefore, a 20-µg dose level is formally included for both candidates.

Update as part of protocol amendment 4: the 50-µg dose level for BNT162b1 and BNT162b2
is removed and the 100-µg dose level for BNT162b2 is removed; similar dose levels of
BNT162b3 may be studied as for BNT162b1 and BNT162b2.
Update as part of protocol amendment 5: the vaccine candidate selected for Phase 2/3
evaluation is BNT162b2 at a dose of 30 µg. BNT162b3 will not be studied.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of
the study, including the last visit. Note that participants enrolled in Phase 1 in groups that do
not proceed to Phase 2/3 may be followed for fewer than 24 months (but no less than
6 months after the last vaccination).
The end of the study is defined as the date of last visit of the last participant in the study.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled. The
following eligibility criteria are designed to select participants for whom participation in the
study is considered appropriate. All relevant medical and nonmedical conditions should be
taken into consideration when deciding whether a particular participant is suitable for this
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male or female participants between the ages of 18 and 55 years, inclusive, and 65 and
85 years, inclusive (Phase 1), or ≥12 years (Phase 2/3), at randomization. Note that
participants <18 years of age cannot be enrolled in the EU.


Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female
(Section 10.4.2) participants.

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Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, vaccination
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Healthy participants who are determined by medical history, physical examination
(if required), and clinical judgment of the investigator to be eligible for inclusion in the
study.
Note: Healthy participants with preexisting stable disease, defined as disease not
requiring significant change in therapy or hospitalization for worsening disease during
the 6 weeks before enrollment, can be included. Specific criteria for Phase 3 participants
with known stable infection with human immunodeficiency virus (HIV), hepatitis C virus
(HCV), or hepatitis B virus (HBV) can be found in Section 10.8.
4. Phase 2/3 only: Participants who, in the judgment of the investigator, are at higher risk
for acquiring COVID-19 (including, but not limited to, use of mass transportation,
relevant demographics, and frontline essential workers).
Informed Consent:
5. Capable of giving personal signed informed consent/have parent(s)/legal guardian
capable of giving signed informed consent as described in Appendix 1, which includes
compliance with the requirements and restrictions listed in the ICD and in this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Other medical or psychiatric condition including recent (within the past year) or active
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study
participation or, in the investigator’s judgment, make the participant inappropriate for the
study.
2. Phases 1 and 2 only: Known infection with human immunodeficiency virus (HIV),
hepatitis C virus (HCV), or hepatitis B virus (HBV).
3. History of severe adverse reaction associated with a vaccine and/or severe allergic
reaction (eg, anaphylaxis) to any component of the study intervention(s).
4. Receipt of medications intended to prevent COVID-19.
5. Previous clinical (based on COVID-19 symptoms/signs alone, if a SARS-CoV-2 NAAT
result was not available) or microbiological (based on COVID-19 symptoms/signs and a
positive SARS-CoV-2 NAAT result) diagnosis of COVID-19.

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6. Phase 1 only: Individuals at high risk for severe COVID-19, including those with any of
the following risk factors:


Hypertension



Diabetes mellitus



Chronic pulmonary disease



Asthma



Current vaping or smoking



History of chronic smoking within the prior year



Chronic liver disease



Stage 3 or worse chronic kidney disease (glomerular filtration rate
<60 mL/min/1.73 m2)



Resident in a long-term facility



BMI >30 kg/m2



Anticipating the need for immunosuppressive treatment within the next 6 months

7. Phase 1 only: Individuals currently working in occupations with high risk of exposure to
SARS-CoV-2 (eg, healthcare worker, emergency response personnel).
8. Immunocompromised individuals with known or suspected immunodeficiency, as
determined by history and/or laboratory/physical examination.
9. Phase 1 only: Individuals with a history of autoimmune disease or an active autoimmune
disease requiring therapeutic intervention, including but not limited to: systemic or
cutaneous lupus erythematosus, autoimmune arthritis/rheumatoid arthritis, Guillain-Barré
syndrome, multiple sclerosis, Sjögren’s syndrome, idiopathic thrombocytopenia purpura,
glomerulonephritis, autoimmune thyroiditis, giant cell arteritis (temporal arteritis),
psoriasis, and insulin-dependent diabetes mellitus (type 1).
10. Bleeding diathesis or condition associated with prolonged bleeding that would, in the
opinion of the investigator, contraindicate intramuscular injection.
11. Women who are pregnant or breastfeeding.
Prior/Concomitant Therapy:
12. Previous vaccination with any coronavirus vaccine.
13. Individuals who receive treatment with immunosuppressive therapy, including cytotoxic
agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned
receipt throughout the study. If systemic corticosteroids have been administered short
term (<14 days) for treatment of an acute illness, participants should not be enrolled into

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the study until corticosteroid therapy has been discontinued for at least 28 days before
study intervention administration. Inhaled/nebulized (except for participants in
Phase 1 – see exclusion criterion 14), intra-articular, intrabursal, or topical (skin or eyes)
corticosteroids are permitted.
14. Phase 1 only: Regular receipt of inhaled/nebulized corticosteroids.
15. Receipt of blood/plasma products or immunoglobulin, from 60 days before study
intervention administration or planned receipt throughout the study.
Prior/Concurrent Clinical Study Experience:
16. Participation in other studies involving study intervention within 28 days prior to study
entry and/or during study participation.
17. Previous participation in other studies involving study intervention containing lipid
nanoparticles.
Diagnostic Assessments:
18. Phase 1 only: Positive serological test for SARS-CoV-2 IgM and/or IgG antibodies at
the screening visit.
19. Phase 1 only: Any screening hematology and/or blood chemistry laboratory value that
meets the definition of a ≥ Grade 1 abnormality.
Note: With the exception of bilirubin, participants with any stable Grade 1 abnormalities
(according to the toxicity grading scale) may be considered eligible at the discretion of
the investigator. (Note: A “stable” Grade 1 laboratory abnormality is defined as a report
of Grade 1 on an initial blood sample that remains ≤ Grade 1 upon repeat testing on a
second sample from the same participant.)
20. Phase 1 only: Positive test for HIV, hepatitis B surface antigen (HBsAg), hepatitis B
core antibodies (HBc Abs), or hepatitis C virus antibodies (HCV Abs) at the screening
visit.
21. Phase 1 only: SARS-CoV-2 NAAT-positive nasal swab within 24 hours before receipt of
study intervention.
Other Exclusions:
22. Investigator site staff or Pfizer/BioNTech employees directly involved in the conduct of
the study, site staff otherwise supervised by the investigator, and their respective family
members.

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5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that
the participant has selected an appropriate method of contraception for the individual
participant and his or her partner(s) from the permitted list of contraception methods
(see Appendix 4, Section 10.4.4) and will confirm that the participant has been instructed in
its consistent and correct use. At time points indicated in the SoA, the investigator or
designee will inform the participant of the need to use highly effective contraception
consistently and correctly and document the conversation and the participant’s affirmation in
the participant’s chart (participants need to affirm their consistent and correct use of at least 1
of the selected methods of contraception). In addition, the investigator or designee will
instruct the participant to call immediately if the selected contraception method is
discontinued or if pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but
are not subsequently randomly assigned to study intervention. A minimal set of screen
failure information is required to ensure transparent reporting of screen failure participants to
meet the CONSORT publishing requirements and to respond to queries from regulatory
authorities. Minimal information includes demography, screen failure details, eligibility
criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened under a different participant number.
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention
Administration
The following conditions are temporary or self-limiting and a participant may be vaccinated
once the condition(s) has/have resolved and no other exclusion criteria are met.
1. Current febrile illness (body temperature ≥100.4°F [≥38°C]) or other acute illness within
48 hours before study intervention administration. This includes current symptoms that
could represent a potential COVID-19 illness:


New or increased cough;



New or increased shortness of breath;



Chills;



New or increased muscle pain;



New loss of taste/smell;



Sore throat;

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PF-07302048 (BNT162 RNA-Based COVID-19 Vaccines)
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Diarrhea;



Vomiting.

2. Receipt of any seasonal or pandemic influenza vaccine within 14 days, or any other
nonstudy vaccine within 28 days, before study intervention administration.
3. Anticipated receipt of any seasonal or pandemic influenza vaccine within 14 days, or any
other nonstudy vaccine within 28 days, after study intervention administration.
4. Receipt of short-term (<14 days) systemic corticosteroids. Study intervention
administration should be delayed until systemic corticosteroid use has been discontinued
for at least 28 days. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin or
eyes) corticosteroids are permitted.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s),
placebo, medical device(s), or study procedure(s) intended to be administered to a study
participant according to the study protocol.
The study will evaluate a 2-dose (separated by 21 days) schedule of various different dose
levels of 2 investigational RNA vaccine candidates for active immunization against
COVID-19 in 3 age groups (18 to 55 years of age, 65 to 85 years of age, and ≥12 years of
age [stratified as 12-15, 16-55, or >55 years of age]).
These 2 investigational RNA vaccine candidates, with the addition of saline placebo, are the
3 potential study interventions that may be administered to a study participant:


BNT162b1 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the RBD):
10 µg, 20 µg, 30 µg, 100 µg



BNT162b2 (BNT162 RNA-LNP vaccine utilizing modRNA and encoding the P2 S):
10 µg, 20 µg, 30 µg



Normal saline (0.9% sodium chloride solution for injection)

The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.

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6.1. Study Intervention(s) Administered
Intervention Name

Type
Dose Formulation

BNT162b1
(BNT162 RNA-LNP
vaccine utilizing
modRNA)
Vaccine
modRNA

BNT162b2
(BNT162 RNA-LNP
vaccine utilizing
modRNA)
Vaccine
modRNA

Saline Placebo

Placebo
Normal saline (0.9%
sodium chloride solution
for injection)
Unit Dose Strength(s)
250 µg/0.5 mL
250 µg/0.5 mL
N/A
Dosage Level(s)a
10-, 20-, 30-, 100-µg
10-, 20-, 30-µg
N/A
Route of Administration Intramuscular injection
Intramuscular injection
Intramuscular injection
Use
Experimental
Experimental
Placebo
IMP or NIMP
IMP
IMP
IMP
Sourcing
Provided centrally by the Provided centrally by the Provided centrally by the
sponsor
sponsor
sponsor
Packaging and Labeling Study intervention will be Study intervention will be Study intervention will be
provided in a glass vial as provided in a glass vial as provided in a glass or
open-label supply. Each
open-label supply. Each
plastic vial as open-label
vial will be labeled as
vial will be labeled as
supply. Each vial will be
required per country
required per country
labeled as required per
requirement
requirement
country requirement
a. Dependent upon safety and/or immunogenicity data generated during the course of this study, or the
BioNTech study conducted in Germany (BNT162-01), it is possible that groups may be started at the next
highest dose, groups may not be started, groups may be terminated early, and/or groups may be added
with dose levels below the lowest stated dose or intermediate between the lowest and highest stated doses.

The vaccine candidate selected for Phase 2/3 evaluation is BNT162b2 at a dose of 30 µg.
6.1.1. Manufacturing Process
The scale of the BNT162b2 manufacturing has been increased to support future supply.
BNT162b2 generated using the manufacturing process supporting an increased supply
(“Process 2”) will be administered to approximately 250 participants 16 to 55 years of age,
per lot, in the study. The safety and immunogenicity of prophylactic BNT162b2 in
individuals 16 to 55 years of age vaccinated with material generated using the existing
manufacturing process “Process 1,” and with material from lots generated using the
manufacturing process supporting increased supply, “Process 2,” will be described.
In brief, the process changes relate to the method of production for the DNA template that
RNA drug substance is transcribed from, and the RNA drug substance purification method.
The BNT162b2 drug product is then produced using a scaled-up LNP manufacturing process.
6.1.2. Administration
Participants will receive 1 dose of study intervention as randomized at each vaccination visit
(Visits 1 and 4 for Phase 1 participants, Visits 1 and 2 for Phase 2/3 participants) in
accordance with the study’s SoA. The volume to be administered may vary by vaccine
candidate and dose level; full details are described in the IP manual.

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Study intervention should be administered intramuscularly into the deltoid muscle, preferably
of the nondominant arm, by an unblinded administrator.
Standard vaccination practices must be observed and vaccine must not be injected into blood
vessels. Appropriate medication and other supportive measures for management of an acute
hypersensitivity reaction should be available in accordance with local guidelines for standard
immunization practices.
Administration of study interventions should be performed by an appropriately qualified,
GCP-trained, and vaccine-experienced member of the study staff (eg, physician, nurse,
physician’s assistant, nurse practitioner, pharmacist, or medical assistant) as allowed by
local, state, and institutional guidance.
Study intervention administration details will be recorded on the CRF.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study interventions received and any discrepancies are
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only
authorized site staff may supply or administer study intervention. All study interventions
must be stored in a secure, environmentally controlled, and monitored (manual or
automated recording) area in accordance with the labeled storage conditions with access
limited to the investigator and authorized site staff. At a minimum, daily minimum and
maximum temperatures for all site storage locations must be documented and available
upon request. Data for nonworking days must indicate the minimum and maximum
temperatures since previously documented for all site storage locations upon return to
business.
3. Any excursions from the study intervention label storage conditions should be reported to
Pfizer upon discovery along with any actions taken. The site should actively pursue
options for returning the study intervention to the storage conditions described in the
labeling, as soon as possible. Once an excursion is identified, the study intervention must
be quarantined and not used until Pfizer provides permission to use the study
intervention. Specific details regarding the definition of an excursion and information the
site should report for each excursion will be provided to the site in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage conditions
stated on the label.
5. Study interventions should be stored in their original containers.
6. See the IP manual for storage conditions of the study intervention.

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7. The investigator, institution, or the head of the medical institution (where applicable) is
responsible for study intervention accountability, reconciliation, and record maintenance
(ie, receipt, reconciliation, and final disposition records), such as the IPAL or
sponsor-approved equivalent. All study interventions will be accounted for using a study
intervention accountability form/record.
8. Further guidance and information for the final disposition of unused study interventions
are provided in the IP manual. All destruction must be adequately documented. If
destruction is authorized to take place at the investigator site, the investigator must ensure
that the materials are destroyed in compliance with applicable environmental regulations,
institutional policy, and any special instructions provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of
discovery as described in the IP manual.
6.2.1. Preparation and Dispensing
See the IP manual for instructions on how to prepare the study intervention for
administration. Study intervention should be prepared and dispensed by an appropriately
qualified and experienced member of the study staff (eg, physician, nurse, physician’s
assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as allowed by
local, state, and institutional guidance. A second staff member will verify the dispensing.
Study intervention and placebo will be prepared by qualified unblinded site personnel
according to the IP manual. The study intervention will be administered in such a way to
ensure the participants remain blinded.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
Allocation (randomization) of participants to vaccine groups will proceed through the use of
an IRT system (IWR). The site personnel (study coordinator or specified designee) will be
required to enter or select information including but not limited to the user’s ID and
password, the protocol number, and the participant number. The site personnel will then be
provided with a vaccine assignment and randomization number. The IRT system will
provide a confirmation report containing the participant number, randomization number, and
study intervention allocation assigned. The confirmation report must be stored in the site’s
files.
The study-specific IRT reference manual and IP manual will provide the contact information
and further details on the use of the IRT system.
6.3.2. Blinding of Site Personnel
In this observer blinded study, the study staff receiving, storing, dispensing, preparing, and
administering the study interventions will be unblinded. All other study and site personnel,
including the investigator, investigator staff, and participants, will be blinded to study

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intervention assignments. In particular, the individuals who evaluate participant safety will
be blinded. Because the BNT162 RNA-based COVID-19 vaccine candidates and placebo
are different in physical appearance, the study intervention syringes will be administered in a
manner that prevents the study participants from identifying the study intervention type based
on its appearance.
The responsibility of the unblinded dispenser and administrator must be assigned to an
individual or individuals who will not participate in the evaluation of any study participants.
Contact between the unblinded dispenser and study participants and unblinded administrator
and study participants should be kept to a minimum. The remaining site personnel must not
know study intervention assignments.
6.3.3. Blinding of the Sponsor
To facilitate rapid review of data in real time, sponsor staff will be unblinded to study
intervention allocation for the participants in Phase 1. The majority of sponsor staff will be
blinded to study intervention allocation in Phase 2/3. All laboratory testing personnel
performing serology assays will remain blinded to study intervention assigned/received
throughout the study. The following sponsor staff, who will have no part in the blinded
conduct of the study, will be unblinded in Phase 2/3 (further details will be provided in a data
blinding plan):


Those study team members who are involved in ensuring that protocol requirements
for study intervention preparation, handling, allocation, and administration are
fulfilled at the site will be unblinded for the duration of the study (eg, unblinded study
manager, unblinded clinical research associate).



Unblinded clinician(s), who are not direct members of the study team and will not
participate in any other study-related activities, will review unblinded protocol
deviations.



An unblinded team supporting interactions with, and analyses for, the DMC
(see Section 9.6). This will comprise a statistician, programmer(s), a clinical
scientist, and a medical monitor who will review cases of severe COVID-19 as they
are received, and will review AEs at least weekly for additional potential cases of
severe COVID-19 (see Section 8.2.3).



An unblinded submissions team will be responsible for preparing unblinded analyses
and documents to support regulatory activities that may be required while the study is
ongoing. This team will only be unblinded at the group level and not have access to
individual participant assignments. The programs that produce the summary tables
will be developed and validated by the blinded study team, and these programs will
be run by the unblinded DMC team. The submissions team will not have access to
unblinded COVID-19 cases unless efficacy is achieved in either an interim analysis or
the final analysis, as determined by the DMC.

Page 49


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