A Randomized, Double-blind, Placebo-controlled Phase 3 Study to Assess the Efficacy and Safety of Ad26.COV2.S for the Prevention of SARS-CoV-2-mediated COVID-19 in Adults Aged 18 Years and Older
Phase: PHASE3
Conditions: Participants With or Without Stable Co-morbidities Associated With Progression to Severe COVID-19
Sponsor: Janssen Vaccines & Prevention B.V.

CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date:  27 April 2022
Janssen Vaccines & Prevention B.V.*
Clinical Protocol
Protocol Title
A Randomized, Double-blind, Placebo-controlled Phase 3 Study to Assess the Efficacy and
Safety of Ad26.COV2.S for the Prevention of SARS-CoV-2-mediated COVID-19 in Adults
Aged 18 Years and Older
ENSEMBLE 2
Protocol VAC31518COV3009; Phase 3
AMENDMENT 7
VAC31518 (JNJ-78436735)
* Janssen Vaccines & Prevention B.V. is a Janssen pharmaceutical company of Johnson & Johnson and is
hereafter referred to as the sponsor of the study. The sponsor is identified on the Contact Information page
that accompanies the protocol.
United States (US)sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
Regulatory Agency Identifier Number:
IND: 22657
EudraCT: 2020-003643-29
Status: 
Approved
Date: 
27 April 2022
EDMS number: 
EDMS-RIM-96655, 11.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential. The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or
otherwise.
NCT04614948

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3009Amendment 7
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Status: Approved,  Date:  27 April 2022
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 7 
This document
Amendment 6 
15 October 2021
Amendment 5 
6 May 2021
Amendment 4 
12 March 2021
Amendment 3 
18 December 2020
Amendment 2 
27 November 2020
Amendment 1 
25 September 2020
Original Protocol 
22 August 2020
Amendment 7 (This document)
Overall Rationale for the Amendment:
Vaccine Ad26.COV2.S has received emergency use authorization (EUA) by the United States
(US) Food and Drug Administration (FDA) and conditional marketing authorization by the
European Commission. Vaccine Ad26.COV2.S  has also been authorized in several other
countries/territories worldwide. The epidemic continued and new variants of concern emerged,
and national recommendations introduced booster vaccinations. The primary analysis of the study
that described the double-blind phase has been completed, the primary objectives of the
double-blind phase have been met, and the CSR has been finalized for this part of the study. Further
efficacy evaluations of the open-label data have limitations, due to the unblinding and the loss of
the placebo group. Operational challenges have impacted the feasibility of a strict follow-up of
any COVID-19 episode and active follow-up cannot be sustained. Because of these reasons, the
protocol has been amended to reduce the number of on-site visits and to change the requirements
for new COVID-19 episode reporting by applying a passive follow-up approach. Participants in
the Immunogenicity Subset will continue with the on-site study visits. There are no changes to
follow-up of safety endpoints, including the reporting of adverse events of special interest (AESIs).
Two analyses are still planned for the study, a first analysis will be conducted for the open-label
phase of the study (using the initially designed “active” follow-up of COVID-19 events) and a
second end of study analysis is planned (using a passive follow-up of COVID-19 events).
These and other changes made to the clinical protocol of Study VAC31518COV3009 as part of
Protocol Amendment 7 are listed below, including the rationale for each change and a list of all
applicable sections. Changes made as part of Protocol Amendments 1 to 6 are listed in
Section 10.15.

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3009Amendment 7
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Status: Approved,  Date:  27 April 2022
Section number
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
1.2 Schema
1.3 Schedules of Activities
2.1 Study Rationale
3 OBJECTIVES AND
ENDPOINTS
4.1 Overall Design
4.4 End-of-study Definitionµ
5.5 Criteria for Temporarily
Delaying Administration of Study
Vaccination
6.5 Booster Vaccination
6.10 Prestudy and Concomitant
Therapy
8STUDY ASSESSMENTS AND
PROCEDURES
8.1.2 Procedures in the Event of
(Suspected) COVID-19
8.1.3.4 Case Definition for
Asymptomatic or Undetected
COVID-19
8.1.3.6 Clinical Severity
Adjudication Committee
8.1.4 Immunogenicity Assessments
8.2 Safety Assessments
8.2.1 Physical Examinations (Up to
Amendment 7)
8.2.2 Vital Signs
8.3.1 Time Period and Frequency
for Collecting Adverse Event,
Medically-attended Adverse Event,
Adverse Event of Special Interest,
and Serious Adverse Event
Information
8.9Assessment and Procedures for
Booster Vaccination and Follow-up
After Implementation of Protocol
Amendment 6
9.7 Analyses of the Open-label
Phase
10.2 Appendix 2: Clinical
Laboratory Tests
10.3.6 Committees Structure
10.4.1 Adverse Event Definitions
and Classifications
10.6 Appendix 6: Symptoms of
Infection with Coronavirus-19
(SIC)
10.7 Appendix 7: MRU
Questionnaire
10.8Appendix 8: Medically-
attended COVID-19 (MA-COV)
Form
The number of on-site study visits
has been reduced and management
of new suspected COVID-19
episodes has been changed from
active to passive follow-up, defined
as safety follow-up phone call visits
by the site instead of on-site visits
to document COVID-19 events as
(S)AEs and MAAEs and to record
concomitant therapies associated
with COVID-19.
eCOA has been decommissioned.
The primary analysis of the study
that described the double-blind
phase has been completed. Further
efficacy evaluations of the
open-label data have limitations,
due to the unblinding and the loss
of the placebo group. Moreover,
constant evolution of the
COVID-19 pandemic has impacted
the practical implementation of a
strict follow-up of new suspected
COVID-19 episodes.

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3009Amendment 7
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Status: Approved,  Date:  27 April 2022
Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
3 OBJECTIVES AND
ENDPOINTS
9.1 Statistical Hypotheses
9.7 Analyses of the Open-label
Phase
The endpoints of the open-label
phase and passive follow-up phase
have been adapted and/or added
and more clarification on the open-
label phase has been provided. The
scope and endpoints of the end of
study analysis have been added.
To more clearly describe the
endpoints of the open-label phase,
related to the different cohorts that
are evaluated (one dose, two dose,
and booster cohorts).
In addition, the changes in the
follow-up of new suspected
COVID-19 episodes come with
endpoints specific to the follow-up
phase.
10.4.3 Severity Criteria 
Instructions were added on grading
severity of thrombocytopenia AEs
with platelet counts between
>140,000/µL and <150,000/µL.
Due to a discrepancy in what the
FDA toxicity grading scale and the
Brighton collaboration case
definitions define as abnormal in
terms of platelet counts.
Throughout the protocol. 
Minor errors and inconsistencies
were corrected, and minor
clarifications were added
throughout the protocol.
Correction of minor errors and
inconsistencies. Addition of minor
clarifications. Alignment across
sections in the protocol.

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3009Amendment 7
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Status: Approved,  Date:  27 April 2022
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 8
1. 
PROTOCOL SUMMARY..................................................................................................................... 9
1.1. 
Synopsis........................................................................................................................................... 9
1.2. 
Schema.......................................................................................................................................... 32
1.3. 
Schedules of Activities ................................................................................................................... 33
1.3.1. 
Non-immunogenicity Subset (As of Amendment 7)................................................................... 33
1.3.2. 
Immunogenicity Subset (As of Amendment 7)........................................................................... 34
1.3.3. 
All Participants (Prior to Amendment 7)..................................................................................... 36
1.3.4. 
Open-label Unblinding Visit (Prior to Amendment 7).................................................................. 42
1.3.5. 
Booster Vaccination Visit............................................................................................................ 44
1.3.6. 
Participants With (Suspected) COVID-19................................................................................... 46
1.3.7. 
Participants with a Suspected AESI ........................................................................................... 50
2. 
INTRODUCTION................................................................................................................................ 51
2.1. 
Study Rationale.............................................................................................................................. 54
2.2. 
Background .................................................................................................................................... 57
2.3. 
Benefit-Risk Assessment............................................................................................................... 61
2.3.1 
Risks Related to Study Participation .......................................................................................... 61
2.3.2 
Benefits of Study Participation.................................................................................................... 66
2.3.3 
Benefit-Risk Assessment of Study Participation ........................................................................ 67
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 69
4. 
STUDY DESIGN ................................................................................................................................ 77
4.1. 
Overall Design................................................................................................................................ 77
4.2. 
Scientific Rationale for Study Design............................................................................................. 84
4.2.1. 
Study-specific Ethical Design Considerations ............................................................................ 85
4.3. 
Justification for Dose...................................................................................................................... 86
4.4. 
End-of-study Definition................................................................................................................... 87
5. 
STUDY POPULATION ...................................................................................................................... 87
5.1. 
Inclusion Criteria for the Double-blind Phase and for Newly Enrolled Participants in the
Open-label Phase .......................................................................................................................... 88
5.2. 
Exclusion Criteria for the Double-blind Phase and for Newly Enrolled Participants in the
Open-label Phase .......................................................................................................................... 91
5.3. 
Lifestyle Considerations................................................................................................................. 94
5.4. 
Screen Failures.............................................................................................................................. 94
5.5. 
Criteria for Temporarily Delaying Administration of Study Vaccination ......................................... 95
6. 
STUDY VACCINATION AND CONCOMITANT THERAPY ............................................................. 96
6.1. 
Study Vaccines Administered ........................................................................................................ 96
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 98
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 99
6.4. 
Unblinding and Open-label Phase ............................................................................................... 101
6.5. 
Booster Vaccination ..................................................................................................................... 102
6.6. 
Study Vaccine Compliance .......................................................................................................... 104
6.7. 
Dose Modification......................................................................................................................... 104
6.8. 
Continued Access to Study Vaccine After the End of the Study ................................................. 104
6.9. 
Treatment of Overdose ................................................................................................................ 105
6.10. 
Prestudy and Concomitant Therapy ............................................................................................ 105
6.11. 
Study Vaccination Pausing Rules for Stage 1 ............................................................................. 107

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Status: Approved,  Date:  27 April 2022
7. 
DISCONTINUATION OF STUDY VACCINATION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................. 108
7.1. 
Discontinuation of Study Vaccination........................................................................................... 108
7.2. 
Participant Discontinuation/Withdrawal From the Study.............................................................. 109
7.2.1. 
Withdrawal From the Use of Research Samples ..................................................................... 110
7.3. 
Lost to Follow-up.......................................................................................................................... 110
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................. 110
8.1. 
Efficacy and Immunogenicity Assessments................................................................................. 114
8.1.1. 
Prespecified Criteria for Suspected COVID-19 Prior to Amendment 7.................................... 114
8.1.2. 
Procedures in the Event of (Suspected) COVID-19................................................................. 115
8.1.3. 
Efficacy Assessments............................................................................................................... 123
8.1.4. 
Immunogenicity Assessments .................................................................................................. 127
8.2. 
Safety Assessments..................................................................................................................... 129
8.2.1. 
Physical Examinations (Up to Amendment 7).......................................................................... 129
8.2.2. 
Vital Signs................................................................................................................................. 129
8.2.3. 
Pregnancy Testing.................................................................................................................... 130
8.2.4. 
Clinical Laboratory Assessments ............................................................................................. 130
8.3. 
Adverse Events, Serious Adverse Events, Medically-attended Adverse Events, Adverse
Events of Special Interest, and Other Safety Reporting .............................................................. 131
8.3.1. 
Time Period and Frequency for Collecting Adverse Event, Medically-attended Adverse
Event, Adverse Event of Special Interest, and Serious Adverse Event Information ................ 131
8.3.2. 
Method of Detecting Adverse Events, Medically-attended Adverse Events, Adverse
Events of Special Interest, and Serious Adverse Events ......................................................... 135
8.3.3. 
Follow-up of Adverse Events, Medically-attended Adverse Events, Adverse Events of
Special Interest, and Serious Adverse Events ......................................................................... 136
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ........................................... 136
8.3.5. 
Pregnancy................................................................................................................................. 136
8.3.6. 
Disease-related Events and Disease-related Outcomes Not Qualifying as Adverse
Events or Serious Adverse Events........................................................................................... 137
8.3.7. 
Adverse Events of Special Interest........................................................................................... 137
8.4. 
Virology Assessments.................................................................................................................. 138
8.5. 
Medical Resource Utilization........................................................................................................ 139
8.6. 
Risk Factor Assessment .............................................................................................................. 139
8.7. 
Participant Medical Information Prior to, During and After the Study (Real-world Data)............. 140
8.8. 
Assessment and Procedures After Emergency Use Authorization and Implementation of
Protocol Amendment 4................................................................................................................. 140
8.9. 
Assessment and Procedures for Booster Vaccination and Follow-up After Implementation
of Protocol Amendment 6............................................................................................................. 141
9. 
STATISTICAL CONSIDERATIONS................................................................................................ 143
9.1. 
Statistical Hypotheses.................................................................................................................. 143
9.2. 
Sample Size Determination ......................................................................................................... 143
9.2.1. 
Efficacy (Total Sample Size).................................................................................................... 143
9.2.2. 
Immunogenicity Subset ............................................................................................................ 145
9.2.3. 
Immunogenicity Correlates (Correlates Subset)...................................................................... 145
9.2.4. 
Safety (Safety Subset).............................................................................................................. 145
9.3. 
Participant Information ................................................................................................................. 147
9.4. 
Efficacy Analyses......................................................................................................................... 147
9.4.1. 
Primary Endpoint Evaluation for the Double-blind Phase ........................................................ 148
9.4.2. 
Secondary Endpoints for the Double-blind Phase.................................................................... 149
9.4.3. 
Exploratory Endpoints............................................................................................................... 150
9.4.4. 
Other Analyses ......................................................................................................................... 151
9.5. 
Immunogenicity Analyses ............................................................................................................ 151
9.5.1. 
Immunogenicity Subset ............................................................................................................ 151
9.5.2. 
Correlates of Risk..................................................................................................................... 151
9.6. 
Safety Analysis............................................................................................................................. 151
9.7. 
Analyses of the Open-label Phase............................................................................................... 153

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Status: Approved,  Date:  27 April 2022
9.7.1. 
Immunogenicity Analyses......................................................................................................... 153
9.7.2. 
Immunogenicity Correlates (Correlates Subset)...................................................................... 153
9.7.3. 
Safety Analyses........................................................................................................................ 153
9.7.4. 
Efficacy Analyses...................................................................................................................... 153
9.8. 
Interim Analysis and Committees ................................................................................................ 154
9.9. 
Analyses for cohort unblinded due to administration of an authorized/licensed COVID-19
vaccine ......................................................................................................................................... 155
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .......................... 156
10.1. 
Appendix 1: Abbreviations ........................................................................................................... 156
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................................................... 158
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations....................................... 161
10.3.1. 
Regulatory and Ethical Considerations .................................................................................... 161
10.3.2. 
Financial Disclosure.................................................................................................................. 164
10.3.3. 
Informed Consent Process ....................................................................................................... 164
10.3.4. 
Data Protection ......................................................................................................................... 165
10.3.5. 
Long-term Retention of Samples for Additional Future Research............................................ 166
10.3.6. 
Committees Structure............................................................................................................... 166
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data.......................................................... 168
10.3.8. 
Data Quality Assurance............................................................................................................ 169
10.3.9. 
Case Report Form Completion................................................................................................. 169
10.3.10. Source Documents ................................................................................................................... 170
10.3.11. Monitoring ................................................................................................................................. 171
10.3.12. On-Site Audits........................................................................................................................... 172
10.3.13. Record Retention...................................................................................................................... 172
10.3.14. Study and Site Start and Closure ............................................................................................. 172
10.4. 
Appendix 4: Adverse Events, Serious Adverse Events, Adverse Events of Special
Interest, Medically-attended Adverse Events, Product Quality Complaints, and Other
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and
Reporting...................................................................................................................................... 174
10.4.1. 
Adverse Event Definitions and Classifications ......................................................................... 174
10.4.2. 
Attribution Definitions................................................................................................................ 175
10.4.3. 
Severity Criteria........................................................................................................................ 176
10.4.4. 
Special Reporting Situations .................................................................................................... 176
10.4.5. 
Procedures ............................................................................................................................... 177
10.4.6. 
Product Quality Complaint Handling......................................................................................... 178
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality........................................... 179
10.5. 
Appendix 5: Contraceptive Guidance and Collection of Pregnancy Information......................... 180
10.6. 
Appendix 6: Symptoms of Infection with Coronavirus-19 (SIC)................................................... 181
10.7. 
Appendix 7: MRU Questionnaire ................................................................................................. 186
10.8. 
Appendix 8: Medically-attended COVID-19 (MA-COV) Form...................................................... 190
10.9. 
Appendix 9: Toxicity Grading Scale............................................................................................. 196
10.10. Appendix 10: Symptoms of Coronavirus (US Centers for Disease Control and Prevention)...... 199
10.11. Appendix 11: Summary of Guidance from CDC Website on Underlying Medical
Conditions That Lead or Might Lead to Increased Risk for Severe Illness From COVID-19....... 200
10.12. Appendix 12: Risk Factor Assessment........................................................................................ 201
10.12.1. Questionnaire 1 ........................................................................................................................ 201
10.13. Appendix 13: TTS AESI Form...................................................................................................... 202
10.14. Appendix 14: Thrombotic Events to be Reported as Suspected AESIs...................................... 206
10.15. Appendix 15: Protocol Amendment History................................................................................. 207
11.
REFERENCES................................................................................................................................. 234
INVESTIGATOR AGREEMENT............................................................................................................... 239

VAC31518 (JNJ-78436735) 
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Status: Approved,  Date:  27 April 2022
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Vaccination Schedule VAC31518COV3009 - Double-blind Phase .......................................... 79
Table 2: 
Vaccination Schedule VAC31518COV3009 - Open-label Phase............................................. 80
Table 3: 
Sample Size and Distribution of the Immunogenicity Subset Between Active and
Placebo Groups ...................................................................................................................... 127
Table 4: 
Sample Size and Distribution of the Immunogenicity Subset B for the Open-label
Phase...................................................................................................................................... 127
Table 5: 
Immunogenicity Assays .......................................................................................................... 128
Table 6: 
Probability of Observing at Least 1 Adverse Event or Serious Adverse Event at a
Given True Adverse Event Rate in the Active Group (With a Total Sample Size of
Approximately 30,000 Participants)........................................................................................ 146
Table 7: 
Specification of Sequential Statistical Analyses ..................................................................... 149
FIGURES
Figure 1: Schematic Overview of Study VAC31518COV3009 ................................................................ 32
Figure 2: Schema of Cohorts Throughout the VAC31518COV3009 Study:............................................ 74
Figure 3: Decision Tree for COVID-19 Procedures ............................................................................... 116
Figure 4: Diagram of Safety Reporting in the Study .............................................................................. 134

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3009Amendment 7
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Status: Approved,  Date:  27 April 2022
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Randomized, Double-blind, Placebo-controlled Phase 3 Study to Assess the Efficacy and Safety of
Ad26.COV2.S for the Prevention of SARS-CoV-2-mediated COVID-19 in Adults Aged 18 Years and
Older
Ad26.COV2.S (previously known as Ad26COVS1) is a monovalent vaccine composed of a recombinant,
replication-incompetent adenovirus type 26 (Ad26) vector, constructed to encode the severe acute
respiratory syndrome coronavirus-2 (SARS-CoV-2) spike (S) protein.
Information about the disease, correlates of immunity, and safety issues concerning this new
pandemic-causing virus are rapidly evolving. Therefore, it is critical to recognize that the approach outlined
in this document might or will change as insights and discussions evolve.
According to the initial protocol, participants were randomly assigned in a 1:1 ratio in the double-blind
phase to receive 2 doses of Ad26.COV2.S or placebo.
With Protocol Amendment 4, an unblinding visit was introduced at which participants who initially
received placebo in the double-blind phase, and consent, were offered a single dose ofthe Ad26.COV2.S
vaccine (open-label vaccination). Following the unblinding, the study is conducted in an open-label fashion.
After the study pause, the unblinding visit was scheduled as soon as reasonably practicable and preferably
no later than 2 months following local approvals of Protocol Amendment 5 were received.
With Protocol Amendment 6, the study was amended to offer an open-label booster vaccination with a
single dose of Ad26.COV2.S for ongoing consenting and eligible participants who received only a single
Ad26.COV2.S vaccination in the study. Participants who already received 2 vaccinations with
Ad26.COV2.S at the 5x1010 viral particles (vp) dose level or any COVID-19 vaccinations outside of the
study (including the Janssen vaccine) at the time of local approval of Protocol Amendment 6 were not
eligible to receive a booster vaccination with Ad26.COV2.S.
As of Protocol Amendment 7, the number of on-site visits for participants who are not part of the
Immunogenicity Subset is reduced. For these participants, any outstanding on-site visits will be replaced
by phone call visits. No further booster vaccination will be provided in the study. In addition, active
follow-up of new suspected COVID-19 will be replaced by passive surveillance (ie, follow-up phone call
visits by the site instead of on-site study visits to document COVID-19 events as [S]AEs and MAAEs and
to record concomitant therapies associated with COVID-19). During these calls, the protocol-required
safety information (eg, [S]AEs, AESIs, MAAEs 6 months after the last vaccination) is also collected. In
between the scheduled phone calls, participants who experienced a (S)AE, MAAE or AESI are encouraged
to contact the study site.
OBJECTIVES AND ENDPOINTS
1. Double-blind Phase
The primary and secondary objectives and endpoints for the double-blind phase are:
Objectives 
Endpoints
Primary
To demonstrate the efficacy of Ad26.COV2.S  in
the prevention of molecularly confirmeda,
moderate to severe/critical coronavirus disease-
2019 (COVID-19)b, as compared to placebo, in
SARS-CoV-2 seronegative adults
First occurrence of molecularly confirmeda, moderate to
severe/critical COVID-19b, with onset at least 14 days after the
second vaccination (Day 71)

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Objectives 
Endpoints
Secondarye
(The method used to perform hypothesis testing preserving the family wise error rate [FWER] will be specified in
the Statistical Analysis Plan [SAP])
Efficacy
To demonstrate the efficacy of Ad26.COV2.S  in 
the prevention of molecularly confirmeda, 
moderate to severe/critical COVID-19b, as 
compared to placebo, in adults regardless of their
serostatus
 First occurrence of molecularly confirmeda, moderate to
severe/critical COVID-19b, with onset 1 day after the 1st
vaccination
 First occurrence of molecularly confirmeda, moderate to
severe/critical COVID-19b, with onset at least 14 days after
the second vaccination (Day 71)
To evaluate the efficacy of Ad26.COV2.S  in the 
prevention of molecularly confirmeda, moderate to 
severe/critical COVID-19b as compared to placebo 
 
First occurrence of molecularly confirmeda, moderate to
severe/critical COVID-19b with onset 1 day after the 1st
vaccination
 
First occurrence of molecularly confirmeda, moderate to
severe/critical COVID-19b with onset 14 days after the 1st
vaccination (Day 15)
 
First occurrence of molecularly confirmeda, moderate to
severe/critical COVID-19b with onset 28 days after the 1st
vaccination (Day 29)
To assess the effect of Ad26.COV2.S  on
COVID-19 requiring medical intervention (based
on objective criteria) compared to placebo
First occurrence of COVID-19 requiring medical intervention
(such as a composite endpoint of hospitalization, intensive care
unit 
[ICU] 
admission, 
mechanical 
ventilation, 
and
extracorporeal membrane oxygenation [ECMO], linked to
objective measures such as decreased oxygenation, X-ray or
computed tomographic [CT] findings)and linked to any
molecularly confirmeda, COVID-19b,c at least 14 days after the
second vaccination (Day 71)
To assess the effect of Ad26.COV2.S  on
SARS-CoV-2 viral ribonucleic acid (RNA) load
compared 
to 
placebo 
for 
moderate 
to
severe/critical COVID-19b
Assessment of the SARS-CoV-2 viral load by quantitative
reverse-transcriptase polymerase chain reaction (RT-PCR), in
participants with molecularly confirmeda, moderate to
severe/critical COVID-19b by serial viral load measurements
during the course of a COVID-19 episode, at least 14 days after
the second vaccination (Day 71)
To assess the effect of Ad26.COV2.S  on
molecularly confirmeda mild COVID-19c
First occurrence of molecularly confirmeda, mild COVID-19c,
at least 14 days after the second vaccination (Day 71)
To assess the effect of Ad26.COV2.S on
COVID-19 as defined by the United States (US)
Food and Drug Administration (FDA)harmonized
case definitiond
First occurrence of molecularly confirmeda COVID-19d at least
14 days after the second vaccination (Day 71)
To assess the effect of Ad26.COV2.S on all
molecularly 
confirmed 
symptomatic
COVID-19b,c, as compared to placebo
Burden of disease (BOD) endpointf derived from the first
occurrence of molecularly confirmeda symptomatic COVID-
19b,c (meeting the mild, moderate or severe/critical COVID-19
case definition) with onset at least 14 days after the second
vaccination (Day 71)

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Status: Approved,  Date:  27 April 2022
Objectives 
Endpoints
To assess the effect of Ad26.COV2.S  on 
occurrence of confirmed asymptomatic or 
undetected infections with SARS-CoV-2, as 
compared to placeboe

Serologic conversion between baseline and other blood
samples before unblinding visit using an enzyme-linked
immunosorbent assay (ELISA) and/or SARS-CoV-2
immunoglobulin assay that is dependent on the SARS-
CoV-2 nucleocapsid (N) protein

Asymptomatic infection detected by RT-PCR
To assess the efficacy of Ad26.COV2.S in the 
prevention of SARS-CoV-2 infection (both 
symptomatic 
and 
asymptomatic 
infections 
combined, 
that 
are 
serologically 
and/or
molecularly confirmeda), as compared to placebo
First occurrence of SARS-CoV-2 infection (serologically
and/or molecularly confirmeda) with onset at least 14 days after
the second vaccination (Day 71)
Safety
To evaluate safety in terms of serious adverse 
events (SAEs) and adverse events of special 
interest (AESIs) (during the entire study), 
medically-attended adverse events (MAAEs; until 
6 months after the last double-blind vaccination),
and MAAEs leading to study discontinuation
(during the entire study) for all participants
Occurrence and relationship of SAEs and AESIs (during the
entire study), MAAEs (until 6 months after the last double-
blind 
vaccination), 
and 
MAAEs 
leading 
to 
study
discontinuation (during the entire study) for all participants
In a subset of participants, to evaluate the safety 
and reactogenicity in terms of solicited local and 
systemic adverse events (AEs) during 7 days after 
each vaccination, and in terms of unsolicited AEs 
during 28 days after each vaccination
Occurrence, intensity, duration, and relationship of solicited
local and systemic AEs during 7 days following each
vaccination and of unsolicited AEs during 28days following
each vaccination
Immunogenicity
In a subset of participants, to evaluate the 
immunogenicity of Ad26.COV2.S, as compared to 
placebo
Analysis of antibodies binding to the SARS-CoV-2 S protein
by ELISA
a Molecularly confirmed COVID-19 is defined as a positive SARS-CoV-2 viral RNA result by a central laboratory
using RT-PCR-based or other molecular diagnostic test.
b Per case definition for moderate to severe/critical COVID-19 as determined by the Clinical Severity Adjudication
Committee (see below).
c Per case definition for mild COVID-19 as determined by the Clinical Severity Adjudication Committee (see
below).
d Per US FDA harmonized case definition for COVID-19 (see below).
e All secondary efficacy endpoint analyses will occur in seronegative participants unless otherwise indicated in the
statistical analysis plan (SAP).
f For more information and the definition of the BOD endpoint, refer to the body of the protocol.
Exploratory objectives and endpoints, including correlates of protection, evaluation of efficacy in
seropositive participants and/or participants with a SARS-CoV-2 positive RT-PCR or molecular test result,
are included in the body of this protocol.
Based on the changes in the objectives and endpoints, the SAP for the double-blind phase will be amended
and will be provided to the authorities prior to the primary analysis of efficacy of the 2-dose schedule versus
placebo in the double-blind phase.
Hypotheses
The double-blind phase of the study is designed to test the primary hypothesis of vaccine efficacy (VE) in
the per-protocol (PP) population: H0: VE ≤30% versus H1: VE >30% and will be evaluated at a
2.5% one-sided significance level.

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3009Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
12
Status: Approved,  Date:  27 April 2022
The primary endpoint will evaluate the first occurrence of molecularly confirmed, moderate to
severe/critical COVID-19 according to the case definition, with onset at least 14 days after the second
vaccination with Ad26.COV2.S versus placebo, in the PP population, including all events with and without
comorbidities.
If the primary endpoint of the double-blind phase hypothesis testing is successful, secondary objectives will
be evaluated against a null hypothesis employing a lower limit VE>0%. The method to perform hypothesis
testing of primary and secondary objectives preserving the family-wise error rate (FWER) will be specified
in the SAP. The FWER will be controlled at 2.5% 1-sided significance level.
2. Open-label Phase
Schema of Cohorts Throughout the COV3009 Study:
With Protocol Amendment 4, an unblinding visit was introduced at which participants who were initially
assigned to the placebo arm in the double-blind phase, and consent, receive a single dose of Ad26.COV2.S
vaccine (open-label vaccination). Following the unblinding, the study is conducted in an open-label fashion.
After the study pause, the unblinding visit was scheduled as soon as reasonably practicable and preferably
no later than 2 months following local approvals of Protocol Amendment 5 were received.
With Protocol Amendment 6, the open-label phase of the study is extended to include an open-label booster
vaccination with a single dose of Ad26.COV2.S.
With Protocol Amendment 7, requirements for COVID-19 episode reporting are changed, ie, a passive
surveillance approach is adopted, defined as following up on new COVID-19 episodes during scheduled
phone calls with the participants.
2.1 Open-label Active Surveillance Phase
Participants will enter the open-label active phase on the day that the participant received the open-label
vaccination, received a vaccine outside of the study, or is unblinded until the day that the participant
consented to Protocol Amendment 7 or the site stops the electronic clinical outcome assessment (eCOA)
(whichever comes first).
The open-label phase will include 3 main study cohorts, based on the vaccination schedules received during
the open-label phase:
−
Two-dose schedule cohort: participants who received the 2 doses of the Ad26.COV2.S vaccine
according to initial design of the study on Day 1 and Day 57 (Visit 1 and Visit 4), regardless whether
this was before or after unblinding.

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3009Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
13
Status: Approved,  Date:  27 April 2022
− One-dose schedule cohort: participants who received a single dose of the Ad26.COV2.S vaccine in
the context of the open-label vaccination (eg, placebo participants receiving Ad26COV2.S vaccine
during cross-over vaccination) or participants who only received one dose of Ad26COV2.S vaccine
during the double-blind phase of the study. These participants remain in this cohort until they
receive the booster vaccination in the context of Protocol Amendment 6. Participants who will not
receive a booster dose will continue in this cohort.
− Booster dose schedule cohort: participants who, during the course of the study, have received only
a single dose of the Ad26.COV2.S vaccine and received a booster vaccination under Amendment
6, preferably within 6 to 12 months after the initial vaccination, with a minimum of 3 months after
the initial vaccination with Ad26.COV2.S.
Data from participants who received a COVID-19 vaccination outside of the study will be described
separately (other dose cohort).
The main objective of the open-label active phase of the study is to describe COVID-19 outcomes, safety,
and immunogenicity in the different study cohorts. All analyses are descriptive, efficacy evaluations may
be done if feasible, ie, if pre-specified criteria are met, as described in the SAP. Up to the implementation
of Protocol Amendment 7, (suspected) COVID-19 cases are monitored through active surveillance (see
Section 1.3.6.2).
The list of objectives and endpoints of the open-label active surveillance phase are defined below.
Objectives 
Endpoints
Secondary
The secondary safety objective of the double-blind phase (see
secondary double-blind objectives)
The secondary safety endpoint of the double-blind
phase (see secondary double-blind endpoints)
Exploratory
To evaluate symptomatic molecularly confirmeda coronavirus
disease-2019 (COVID-19)b in the different study cohorts.
Incidence of symptomatic COVID-19 cases
starting at 28days after last vaccination
To 
evaluate 
molecularly 
confirmeda 
severe/critical
COVID-19b in the different study cohorts.
Incidence of severe/critical COVID-19 cases
starting at 28days after last vaccination
To evaluate molecularly confirmeda COVID-19 cases that
require medical intervention (based on objective criteria) in
the different study cohorts.
Incidence of COVID-19 cases requiring medical
intervention, starting at 28 days after last
vaccination
To evaluate COVID-19 related death in the different study
cohorts.
Incidence of COVID-19 related deaths starting at
28days after last vaccination
To describe the severity of molecularly confirmeda
breakthrough infections
The severity of COVID-19 cases may be evaluated
by the severity, number, and duration of symptoms
of COVID-19 cases, ratio of severe/critical
COVID-19 cases and ratio of long COVID-19
cases (duration of more than 28 days)
In a subset of participants, to evaluate the immunogenicity of
Ad26.COV2.S
Analysis of antibodies binding to the SARS-CoV-
2 S protein by ELISA

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3009Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
14
Status: Approved,  Date:  27 April 2022
Objectives 
Endpoints
Secondary
In a subset of participants, to further evaluate the 
immunogenicity of Ad26.COV2.S  
 
Immune response to Ad26.COV2.S as
compared to Functional and molecular
antibody placebo characterization including,
but not limited to avidity, Fc-mediated viral
clearance, Fc characteristics, Ig subclass, IgG
isotype, 
antibody 
glycosylation, 
and
assessment of antibody repertoire
 
Original and/or emerging SARS-CoV-2
lineage neutralization as measured by virus
neutralization assay (VNA; wt virus and/or
pseudovirion expressing SARS-CoV-2 S
protein)
 
Adenovirus neutralization as measured by
VNA
 
Analysis of antibodies binding to the
receptor-binding domain (RBD) of the
SARS-CoV-2 S protein
To estimate potential correlate of risk/efficacy in relation to
the primary endpoint of the main study and serious disease,
hospitalization, and death based on immune responses in
breakthrough cases compared to non-infected participants.
 
Analysis of binding antibody titer measured
by S-ELISA and/or MSD assay, as available
for participants having COVID-19 compared
to non-infected participants. and/or MSD
assay
 
Analysis 
of SARS-CoV-2 
neutralizing
antibody titers measured by psVNA or wild-
type VNA, as available for participants
having COVID-19 compared to non-infected
participants.
An attempt to describe the duration of protection following
booster vaccination with Ad26.COV2.S for the primary and
key secondary endpoints of the double blind phase will be
made as outlined in the SAP
Incidence over time of symptomatic COVID-19
cases, severe COVID-19, COVID-19 cases
requiring medical intervention, and COVID-19
related deaths starting 28 days after vaccination
a Molecularly confirmed COVID-19 is defined as a positive SARS-CoV-2 viral RNA result by a central laboratory
using a RT-PCR-based or other molecular diagnostic test.
b Per case definition for mild, moderate or severe/critical COVID-19 or determined by the Clinical Severity
Adjudication Committee (see below).
2.2 Open-label Passive Follow-up Phase
With the implementation of Protocol Amendment 7, the active follow-up of suspected COVID-19 episodes
is replaced by a passive follow-up. Participants will enter this phase on the day of consenting to
Amendment 7 (or with the stop of the eCOA at each study site, whichever comes first) until end of study.
In the passive follow-up phase, the same cohorts as from the open-label active phase are included, and all
data will be descriptively presented by cohort depending on the vaccination schedule received during the
follow-up phase. Since COVID-19 reporting changed from an active approach to a passive approach, the
evaluations will be limited. Efficacy evaluations may be performed if feasible and will be described in the
SAP as applicable.
Passive follow-up of COVID-19 consists of recording of new COVID-19 episodes as SAEs, AEs, or
MAAEs. The information of these AEs is collected during the scheduled phone calls with the participants.

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3009Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
15
Status: Approved,  Date:  27 April 2022
The list of objectives and endpoints of the passive follow-up phase are:
Objectives 
Endpoints
Secondary
The secondary safety objective of the double-blind 
phase (see secondary double-blind objectives) 
 
The secondary safety endpoint of the double-blind
phase (see secondary double-blind endpoints)
during the entire follow-up period
Exploratory
To evaluate COVID-19a in terms of (S)AEs MAAEs, 
hospitalizations and fatal AE linked to COVID-19 in the
different study cohorts
 
SAEs and AEs linked to COVID-19
 
MAAEs linked to COVID-19
 
AEs linked 
to 
COVID-19 that 
require
hospitalization
 
Fatal AEs linked to COVID-19b
In a subset of participants, to evaluate the
immunogenicity of Ad26.COV2.S  in the different study
cohorts
 
Analysis of antibodies binding to the SARS-CoV-
2 S protein by ELISA
 
Analysis of SARS-CoV-2 neutralizing antibody
titers as measured by psVNA and/or wtVNA
If feasible, to estimate a correlate of immunity (correlate
of risk) in relation to the primary endpoint of the main
study and serious disease, hospitalization, and death
based on available immune responses in the different
study cohorts
 
Analysis of binding antibody titer measured by
S-ELISA and/or MSD assay, as available, for
participants having COVID-19 compared to
non-infected participants and/or MSD assay
 
Analysis of SARS-CoV-2 neutralizing antibody
titers measured by psVNA or wtVNA, as
available, for participants having COVID-19
compared to non-infected participants
a Refer to Section 8.3 for the safety follow-up and COVID-19 reporting requirements as of Protocol Amendment 7.
b Fatal AEs linked to COVID-19 as determined by the Clinical Severity Adjudication Committee
Case Definitions
The Clinical Severity Adjudication Committee will be utilized for adjudication of the severity of COVID-19
cases taking into account all available relevant information at the time of adjudication. As of Amendment 7,
the Clinical Severity Adjudication Committee may review all cases based on available data from the passive
follow-up (eg, limited to COVID-19AE/SAE data, CIOMS forms, local laboratory results). Details will be
provided in the revised charter of the Clinical Severity Adjudication Committee. Readjudication will occur
if new information becomes available. The last adjudication for a given case will determine the status of
the case for analysis. The Clinical Severity Adjudication Committee’s decision will be considered the
definitive classification of the case. The role of the Committee and adjudication process will be provided
in the committee’s charter and more details regarding the impact on the analysis will be provided in the
SAP. The case review including severity assessments after implementation of Protocol Amendment 7 may
change and will be reflected in the charter of the committee.
The criteria for suspected COVID-19 are described in the body of the protocol. As several of the
prespecified criteria for suspected COVID-19 overlap with vaccine-related reactogenicity, investigators’
clinical judgement is required to exclude vaccine-related events when assessing suspected COVID-19.
Case Definition for Moderate to Severe/Critical COVID-19
For the primary endpoint (see above), all moderate and severe/critical COVID-19 cases will be considered.

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3009Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
16
Status: Approved,  Date:  27 April 2022
Case Definition for Moderate COVID-19
 
A SARS-CoV-2 positive RT-PCR or molecular test result from any available respiratory tract sample
(eg, nasal swab sample, sputum sample, throat swab sample, saliva sample) or other sample
AND at any time during the course of observationa:
Any 1 of the following new or worsening signs
or symptoms:
OR
Any 2 of the following new or worsening signs or
symptoms:
 
Respiratory rate ≥20 breaths/minute
 
Abnormal saturation of oxygen (SpO2)
but still >93% on room air at sea level*
 
Clinical or radiologic evidence of
pneumonia
 
Radiologic evidence of deep vein
thrombosis (DVT)
 
Shortness of breath or difficulty
breathing 
 
Fever (≥38.0°C or ≥100.4°F)
 
Heart rate ≥90 beats/minute
 
Shaking chills or rigors
 
Sore throat
 
Cough
 
Malaise as evidenced by 1 or more of the
following**:
- Loss of appetite
- Generally unwell
- Fatigue
- Physical weakness
 
Headache
 
Muscle pain (myalgia)
 
Gastrointestinal symptoms (diarrhea,
vomiting, nausea, abdominal pain)**
 
New or changing olfactory or taste
disorders
 
Red or bruised looking feet or toes
* SpO2 criteria will be adjusted according to altitude per the investigator judgement.
** Having 2 or more elements of a symptom (eg, vomiting and diarrhea or fatigue and loss of appetite) is counted only as 1 symptom
for the case definition. To meet the case definition, a participant would need to have at least 2 different symptoms.
Case Definition for Severe/Critical COVID-19
 
A SARS-CoV-2 positive RT-PCR or molecular test result from any available respiratory tract sample
(eg, nasal swab sample, sputum sample, throat swab sample, saliva sample) or other sample
AND any 1 of the following at any time during the course of observationa:
 
Clinical signs at rest indicative of severe systemic illness (respiratory rate ≥30 breaths/minute, heart
rate ≥125 beats/minute, oxygen saturation (SpO2) ≤93% on room air at sea level*, or partial pressure
of oxygen/fraction of inspired oxygen (PaO2/FiO2) <300 mmHg)
* SpO2 criteria will be adjusted according to altitude per the investigator judgement.
 
Respiratory failure (defined as needing high-flow  oxygen, non-invasive ventilation, mechanical
ventilation, or extracorporeal membrane oxygenation [ECMO])
a Until Amendment 7, participants will be asked to undertake the COVID-19 procedures until 14 days after symptom
onset (COVID-19 Day 15) or until resolution of the COVID-19 episode, whichever comes last (see
Section 8.1.2).

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3009Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date:  27 April 2022
 
Evidence of shock (defined as systolic blood pressure <90 mmHg, diastolic blood pressure <60 mmHg,
or requiring vasopressors)
 
Significant acute renal, hepatic, or neurologic dysfunction
 
Admission to the ICU
 
Death
Case Definition for Mild COVID-19
 
A SARS-CoV-2 positive RT-PCR or molecular test result from any available respiratory tract sample
(eg, nasal swab sample, sputum sample, throat swab sample, saliva sample) or other sample
AND at any time during the course of observationa:
 
One of the following symptoms: fever (≥38.0°C or ≥100.4°F), sore throat, malaise (loss of appetite,
generally unwell, fatigue, physical weakness), headache, muscle pain  (myalgia), gastrointestinal
symptoms, cough, chest congestion, runny nose, wheezing, skin rash, eye irritation or discharge, chills,
new or changing olfactory or taste disorders, red or bruised looking feet or toes, or shaking chills or
rigors.
A case is considered mild when it meets the above case definition but not the moderate to severe/critical
definition.
US FDA Harmonized Case Definition for COVID-19
If a participant presents with symptoms as those listed by the US FDA harmonized case definition (see
appendix to the protocol), the investigator (or designated medically trained clinician) should assess if these
are suggestive of COVID-19:
 
A SARS-CoV-2 positive RT-PCR or molecular test result from any available respiratory tract sample
(eg, nasal swab sample, sputum sample, throat swab sample, saliva sample) or other sample; AND
 
COVID-19 symptoms consistent with those defined by the US FDA harmonized case definition at the
time of finalization of this protocol: fever or chills, cough, shortness of breath or difficulty breathing,
fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny
nose, nausea or vomiting, diarrhea.
Case Definition for Asymptomatic or Undetected COVID-19
If a participant does not fulfil the criteria for suspected COVID-19 based on signs and symptoms, which
would classify them as mild or moderate to severe/critical by the protocol definitions mentioned above,
AND
 
has a SARS-CoV-2 positive RT-PCR or molecular test result from any available respiratory tract
sample (eg, nasal swab sample, sputum sample, throat swab sample, saliva sample) or other sample
OR
 
develops a positive serology (non-S protein) test
Then, the participant will be considered to have experienced asymptomatic or undetected COVID-19.
a Until Amendment 7, participants will be asked to undertake the COVID-19 procedures until 14 days after symptom
onset (COVID-19 Day 15) or until resolution of the COVID-19 episode, whichever comes last (see
Section 8.1.2).

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3009Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
18
Status: Approved,  Date:  27 April 2022
For any case definition to be considered for classification of COVID-19 there needs to be at least one
SARS-CoV-2 positive RT-PCR or molecular test result from any available respiratory tract sample
(eg, nasal swab sample, sputum sample, throat swab sample, saliva sample) that is confirmed by the central
laboratory. It is possible that not all samples can be confirmed at the time of the analysis. Hence a sensitivity
analysis may be performed using all RT-PCR or molecular test result, regardless of the confirmation by the
central laboratory.
As of Amendment 7, severity assessment by the CSAC may still be performed and will be based on the
data collected through the passive follow-up (eg, hospitalization reported in the context of SAEs). The
scope of the severity review may change and will be described in the charter.
OVERALL DESIGN
This is a multicenter, randomized, double-blind, placebo-controlled, Phase 3, pivotal efficacy and safety
study in adults ≥18 years of age. The efficacy, safety, and immunogenicity of Ad26.CoV2.S will be
evaluated in participants living in, or going to, locations with high risk for acquisition of SARS-CoV-2
infection after administration of 2 doses of study vaccine.
Initial immunogenicity and safety data (28 days post dose 1 data from Cohort 1a and available data from
Cohort 3) from study VAC31518COV1001 have demonstrated that a single dose of Ad26.COV2.S at
5×1010 vp and 1×1011 vp induces an immune response that meets prespecified minimum criteria and has an
acceptable safety profile. The sponsor has therefore decided to proceed with an Ad26.COV2.S dose level
of 5×1010 vp in its Phase 3 studies. Even though a single-dose regimen in study VAC31518COV1001
showed good immunogenicity that may already protect against COVID-19, data from other vaccines using
the Ad26 platform suggest that a secondvaccination may potentially result in an increased and more durable
immune response, providing justification for the evaluation of a 2-dose regimen in this study. The single
dose regimen will be further evaluated in study VAC31518COV3001.
Participants will be randomized in parallel in a 1:1 ratio in the double-blind phase of the study to receive
Ad26.COV2.S or placebo intramuscularly (IM) as shown in the table below. Ad26.COV2.S will be
administered at a dose level of 5×1010 vp.
Following Ad26.COV2.S EUA in the US, all participants from countries where Protocol Amendment 4 is
approved by both the Health Authority and the IEC/IRB will be unblinded at the on-site or remote
unblinding visit. The unblinding of all participants and vaccination of placebo recipients may be conducted
as soon as reasonably practicable and preferably no later than 2 months after local approvals of Protocol
Amendment 5 have been received. Investigators will be encouraged to follow local health authority
guidelines on prioritization of immunization. If a scheduled study visit is planned within 2 months of the
local approval of Protocol Amendment 5, the unblinding visit may be combined with this planned study
visit. Every effort should be made to combine the unblinding visit with a scheduled visit; otherwise, it must
be done as an unscheduled visit. In the event that the unblinding takes place at a scheduled visit, procedures
that would be duplicated should be done only once.
Participants from the placebo arm enrolled during the double-blind phase will be offered to receive a
single dose of Ad26.COV2.S vaccine (open-label vaccination), unless they met certain vaccination
discontinuation rules during the double-blind phase of the study.
Participants from the Ad26.COV2.S arm enrolled during the double-blind phase will continue in the
same arm to receive their second dose, if applicable.
Newly enrolled participants in the open-label phase under Amendment 4 will be randomized in a 1:1
ratio to receive either 1 dose or 2 doses of Ad26.COV2.S. vaccine. After the study pause, the unblinding
visit was scheduled as soon as reasonably practicable and preferably no later than 2 months following local
approvals of Protocol Amendment 5 were received.

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3009Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
19
Status: Approved,  Date:  27 April 2022
As of implementation of Protocol Amendment 6, all ongoing eligible participants who received only a
single vaccination with Ad26.COV2.S in the study will be offered a single booster dose of Ad26.COV2.S
vaccine (5×1010 vp) (see table below). Participants who already received 2 vaccinations with Ad26.COV2.S
at the 5x1010 vp dose level or any COVID-19 vaccinations outside of the study (including the Janssen
vaccine) at the time of local approval of Protocol Amendment 6 are not eligible to receive a booster
vaccination with Ad26.COV2.S. The booster vaccination will be administered in the open-label phase of
the study, preferably within 6 to 12 months after the participant’s first Ad26.COV2.S vaccination in the
study. If this is not possible, the booster vaccination should not occur earlier than 3 months after the
participant’s first Ad26.COV2.S vaccination. The Booster Vaccination Visit should preferably coincide
with the participant’s next scheduled visit (ie, Visit 7 or Visit 8 for the majority of participants) from the
original Schedule of Activities (SoA). If not operationally feasible to coincide with an existing visit, an
unscheduled visit may be planned. After the booster vaccination visit, participants will continue procedures
and visits as in the original SoA. All participants (whether they consent to the booster vaccination or not)
will be encouraged to remain in the study and will be monitored for safety, immunogenicity, and efficacy
according to their original schedule.
With Amendment 7, active follow-up of suspected COVID-19 will be replaced by passive surveillance
(ie, follow-up phone call visits by the site instead of on-site study visits to document new COVID‑19 events
as [S]AEs and MAAEs) and to record concomitant therapies associated with COVID-19, if available.
During these calls, the protocol required safety information (eg, [S]AEs, AESIs, MAAEs 6 months after
the last vaccination) are also collected.
Vaccination Schedule VAC31518COV3009 –Double-blind Phase
Group  
N 
Day 1 
Day 57
1 
Approx.15,000 
Ad26.COV2.S (5×1010 vp) 
Ad26.COV2.S (5×1010 vp)
2 
Approx. 15,000 
Placebo 
Placebo
N  number of participants; vp  virus particles.
Note: It is intended that a minimum of approximately 30% of recruited participants will be ≥60 years of age and approximately
20% of recruited participants will be ≥18 to <40 years of age.
Vaccination Schedule VAC31518COV3009 –Open-label Phase
Group  N* 
Day 1 
Day 57 
Unscheduled
Unblinding
visit**/Day 1 for
newly enrolled
participants***
Booster Vaccination
Preferably Vac 1 +
6-12 months
Minimally Vac 1 +
3 months*****
1 
Approx. 
15,000 
Ad26.COV2.S 
(5×1010 vp) 
Ad26.COV2.S
(5×1010 vp) 
Ad26.COV2.S
(5×1010 vp)
2 
Approx.
15,000 
Placebo*** 
Placebo****
Ad26.COV2.S 
(5×1010vp)
N  number of participants; vp  virus particles.
Note: It is intended that a minimum of approximately 30% of recruited participants will be ≥60 years of age and approximately
20% of recruited participants will be ≥18 to <40 years of age.
* It is possible that there might be over enrollment of participants in this study.
** All participants will be unblinded (informed whether they received placebo or Ad26.COV2.S) at the on site or remote
unblinding visit following EUA in the US and approval of Protocol Amendment 4 by the local Health Authority and
IEC/IRB, and the study will continue as an open label study. Participants who were in the placebo arm will be offered to
receive a single dose of Ad26.COV2.S 5×1010 vp. After the study pause, the unblinding visit should be scheduled as soon as
reasonably practicable and preferably no later than 2 months following local approvals of Protocol Amendment 5 have been
received. The unblinding visit may be combined with the next planned study visit, if appropriate.
*** Newly enrolled participants will be randomized to Group 1 (to receive two doses of Ad26.COV2.S) or to Group 2 (to receive
one dose of Ad26.COV2.S on Day 1 instead of 2 doses of placebo (there will be no administration of placebo on Day 57).
**** Vaccination at Day 57 is not applicable for participants who were unblinded after the placebo vaccination at Day 1 and
prior to receiving the second placebo vaccination.
*****Following implementation of Protocol Amendment 6, all ongoing eligible participants who received only 1 Ad26.COV2.S
vaccination in the study will be offered 1 Ad26.COV2.S booster vaccination. Participants who already received 2 vaccinations
with Ad26.COV2.S at the 5x1010 vp dose level or any COVID 19 vaccinations outside of the study (including the Janssen

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vaccine) at the time of local approval of Protocol Amendment 6 are not eligible to receive a booster vaccination with
Ad26.COV2.S.
A staggered enrollment strategy will be used in the double-blind phase:
 
Stage 1: Initially, approximately 1,000 participants without comorbidities that are associated with
increased risk of progression to severe COVID-19 (including approximately 500 Ad26.COV2.S
recipients and approximately 500 placebo recipients) will be enrolled.
 
Stage 2: After a vaccination pause in Stage 1 to allow the Independent Data Monitoring Committee
(IDMC)to examine Day 3 safety data (ie, from Day 1 to Day 3; including safety data from the ongoing
studies), if no safety concerns are identified enrollment will proceed, expanding enrollment to include
participants with and without comorbidities that are associated with increased risk of progression to
severe COVID-19in 2 age-dependent subgroups (≥18 years to <60 years of age and ≥60 years of age).
Comorbidities (or risk factors)that are or might be associated with an increased risk of progression to severe
COVID-19a include: moderate-to-severe asthma; chronic lung diseases such as chronic obstructive
pulmonary disease (COPD) (including emphysema and chronic bronchitis), idiopathic pulmonary fibrosis
and cystic fibrosis; diabetes (including type 1 or type 2); serious heart conditions, including heart failure,
coronary artery disease, congenital heart disease, cardiomyopathies, and pulmonary hypertension; moderate
to severe high blood pressure; obesity (body mass index [BMI] ≥30 kg/m2); chronic liver disease, including
cirrhosis; sickle cell disease; thalassemia; cerebrovascular disease; neurologic conditions (dementia); end
stage renal disease; organ transplantation; cancer; human immunodeficiency virus (HIV) infection and
other immunodeficiencies; hepatitis B infection; sleep apnea; and participants who live in nursing homes
or long-term care facilities.
The duration of individual participation, including screening, will be maximum 2 years and 3 months.
Consenting for the open-label and/or booster vaccination will not prolong the study duration for an
individual participant. If a participant is unable to complete the study, but has not withdrawn consent, an
early exit visit will be conducted. The end-of-study is considered as the completion of the last visit for the
last participant in the study.
Key efficacy assessments include the surveillance for COVID-19-like signs and symptoms, recording of
COVID-19-related hospitalizations and complications, and the laboratory confirmation of SARS-CoV-2
infection by a molecular assay (based on RT-PCR) and by anti-SARS-CoV-2 serology. Immunogenicity
assessments, and especially assessments of the humoral immune responses with emphasis on neutralizing
and binding antibodies will also be performed.
Key safety assessments will include the monitoring of solicited and unsolicited AEs (in the Safety Subset
only), and the collection of SAEs, and MAAEs, and AESIs in all participants. Up to Amendment 7, the
viral load of SARS-CoV-2 will be assessed in confirmed COVID-19 cases. Medical resource utilization
(MRU) following vaccination will be recorded for all participants with molecularly confirmed,
symptomatic COVID-19.
Additional characteristics related to current work situation, living situation, and community interactions
will be collected for risk factor analysis, if allowed per local regulations. For consenting participants in the
US, medical data (electronic health records, claims and laboratory data from other care settings) from 5
years prior to study enrollment until 5 years after study completion may be accessed utilizing tokenization
aCenters for Disease Control and Prevention (CDC). Coronavirus Disease 2019 (COVID-19) Groups at Higher Risk
for Severe Illness. https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/groups-at-higher-risk.html.
(Accessed: 19 July 2020). In this study, former or current smoking/vaping and mild hypertension (according to the
Toxicity Grading Scale in the body of this document) will not be considered as a comorbidity. Gestational diabetes
was deleted from the list since it is not applicable as pregnant women are not to participate in the study.

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and matching procedures (ie, the generation of anonymous identifiers or “tokens” [hashed and encrypted
combinations of identifying elements] to allow linking of participant data from different sources without
compromising the participant’s confidentiality). These data together with data collected as part of the study
(as specified in the Schedules of Activities), may be used for exploratory analyses to enhance our
understanding of the impact of prior medical history on the response to immunization and the impact of
immunization on efficacy and duration of efficacy as well as adverse events that may occur during and after
completion of the study. Concomitant therapies associated with COVID-19 are also to be reported as of
Amendment 7.
As of Amendment 7, participants will continue to be required to report safety events, such as SAEs, AESIs,
MAAEs. The active follow-up of new suspected COVID-19 episodes will be replaced by passive follow-up,
defined as follow-up phone call visits by the site instead of on-site study visits to document COVID-19
events as SAEs, AEs, or MAAEs.
Up to Amendment 7, until completion of Visit 8, each participant will be asked at least twice a week,
through the electronic clinical outcome assessment (eCOA), if they have experienced any new symptoms
or health concerns that could be related to infection with SARS-CoV-2. As ofcompletion of Visit 8, until
the end of the 2-year follow-up period, the frequency of this (suspected) COVID-19 surveillance (symptom
check) through the eCOA will decrease to once every 2 weeks. All participants will be monitored for safety,
including enhanced disease and SAEs until the last study visit and including MAAEs up to 6 months after
the last Ad26.COV2.S dose. Every effort will be made to document the status of all participants that are
lost to follow-up due to not completing the eCOA and for whom hospitalization has not been recorded. As
from Amendment 7, the eCOA will be decommissioned (passive follow-up approach). The eCOA will be
stopped based on approval of Amendment 7 at each study site.
Enrolled participants will be counselled on SARS-CoV-2 infection prevention each time that they have a
contact with site staff, in line with local guidelines. At the time of study entry, each participant will need to
indicate to the study site, in case they would get infected with SARS-CoV-2, the identity and location of
their routine medical care physician and/or facility and the identity and location of where they would obtain
emergency care and hospitalization if necessary. If this information is not available, a plan for where such
care could be obtained should be developed. If a participant should have COVID-19 and their symptoms
deteriorate, they will be instructed to go to the Health Care Professional (HCP) or hospital that has been
identified in advance.
Up to Amendment 7, all participants with COVID-19-like signs or symptoms meeting the prespecified
criteria for suspected COVID-19 and all participants with at least one positive RT-PCR test for SARS-
CoV-2 on COVID-19 Day 1-2 and Day 3-5 visits should undertake the COVID-19 procedures until 14 days
after symptom onset (COVID-19 Day 15) or until resolution of the COVID-19 episode, whichever comes
last. However, participants with COVID-19-like signs or symptoms meeting the prespecified criteria for
suspected COVID-19 should stop the COVID-19 procedures as soon as it is confirmed that both nasal
swabs collected on COVID-19 Day 1-2 and Day 3-5 are negative for SARS-CoV-2. Resolution of the
COVID-19 episode is defined as having 2 consecutive SARS-CoV-2 negative nasal swabs and
2 consecutive days with no COVID-19-related signs or symptoms. At the time of resolution of the
COVID-19 episode, the collected information will be applied against the clinical case definition. As from
Amendment 7, this active follow-up approach will no longer be pursued and will be replaced by passive
follow-up. Passive follow-up of COVID-19 consists of recording of new COVID-19 episodes as SAEs,
AEs, or MAAEs. The information of these AEs is collected during the scheduled phone calls with the
participants. Positive COVID-19 laboratory findings should be reported in the eCRF, if available
(eg, positive PCR results, positive nasal swab). The assay methodology should be mentioned.
All necessary precautions (as per local regulation) should be taken to protect medical staff and other
contacts of participants who are suspected to have COVID-19 until proven negative by molecular
techniques or who are positive AND meet the prespecified criteria for suspected COVID-19 on COVID-19
Day 1-2 and Day 3-5 until they are no longer positive. In the event of a confirmed SARS-CoV-2 infection,

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the participant and participant’s medical care provider and/or local health authorities (if required) will be
notified, and the participant will be asked to adhere to the appropriate measures and restrictions as defined
by local regulations.
An IDMC will be commissioned for this study.
NUMBER OF PARTICIPANTS
Overall, a target ofapproximately 30,000 adult participants (≥18to <60 years of age and ≥60 years of age,
with and without relevant comorbidities) will be randomly assigned in this study, under the assumption that
the annualized incidence of moderate to severe/critical COVID-19(meeting the COVID-19 case definition
for the primary endpoint) will be approximately 1% to 4% at the start of the study. Every effort will be
made to identify regions of high SARS-CoV-2 activity and populations within these regions with high risk
of exposure to the virus will be enrolled. Recruitment for high incidence populations will also take into
account age. Per stage, participants will be enrolled in 2 subgroups (≥18 to <60 years of age and ≥60 years
of age). Enrollment may be stopped if the primary endpoint is reached.
This sample size takes into consideration the uncertainty of the epidemiological situation in combination
with the ability to provide a high probability (approximately 90%) to reach a time to signal within 15 months
of the last study for a vaccine with an assumed 65% VE or higher. Efforts will be made to ensure good
representation in terms of race, ethnicity, and gender.
Of the total sample size, a minimum of approximately 30% of recruited participants will be ≥60 years of
age and approximately 20% of recruited participants will be <40 years of age. Details on the possible blinded
sample-size reassessment will be described in the statistical analysis plan (SAP).
The overall recruitment target is of approximately 30,000 participants. Up to 10% of additional participants
may be recruited to partially compensate for increased fraction unblinded prior to unblinding visit and/or
increased seroprevalence rates and/or drop-outs.
INTERVENTION GROUPS AND DURATION
In the double-blind phase, participants will be vaccinated at the study site according to the schedules
detailed above:
 
Ad26.COV2.S supplied at a concentration of 1×1011 vp/mL in single-use vials, with an extractable
volume of 0.5 mL, and dosed at 5×1010 vp
 
Placebo: 0.9% sodium chloride (NaCl) solution
For blinding purposes during the double-blind phase, all participants will receive a vaccination at Day 1
and at Day 57, using the same volume (ie, 0.5 mL).
In the open-label phase, all newly randomized participants will receive either 1 dose (Day 1) or 2 doses
(Day 1 and Day 57) of Ad26.COV2.S. For participants already enrolled, upon unblinding of the study
vaccine allocation, participants in the placebo arm will receive a single dose of Ad26.COV2.S provided
they have not met certain vaccination discontinuation criteria. Participants in the active arm who have not
yet received their second vaccination at the time of unblinding, will receive the second vaccination at
Day 57 in an open-label fashion, if applicable. Upon implementation of Protocol Amendment 6, all ongoing
consenting and eligible participants who received onlya single Ad26.COV2.S vaccination in the study, will
be offered a single Ad26.COV2.S booster vaccination. Participants who already received 2 vaccinations
with Ad26.COV2.S at the 5x1010 vp dose level or any COVID-19 vaccinations outside of the study
(including the Janssen vaccine) at the time of local approval of Protocol Amendment 6 are not eligible to
receive a booster vaccination with Ad26.COV2.S.

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Before the actual participant unblinding, all of the previously available data should be complete and
accurate in participant’s electronic case report form (eCRF).
EFFICACY EVALUATIONS
Up to Amendment 7, identification and molecular confirmation of SARS-CoV-2 infection and symptomatic
COVID-19 will be performed throughout the study.
The occurrence of COVID-19-related hospitalization and COVID-19-related complications (such as but
not limited to hyperinflammatory syndrome, pneumonia, neurological or vascular complications, severe
neurological or vascular events, acute respiratory distress syndrome, renal complications, sepsis, septic
shock, death)a will be monitored throughout the study.
For the primary objective, all moderate to severe/critical COVID-19 cases will be considered.
As a secondary objective, VE in the prevention of asymptomatic SARS-CoV-2 infection and mild
COVID-19 will be analyzed.
For samples collected prior to implementation of Amendment 7, an immunologic test for SARS-CoV-2
seroconversion (ELISA and/or SARS-CoV-2 immunoglobulin assay) based on SARS-CoV-2 N protein,
may be performed to identify cases of asymptomatic infection. This assay will be performed on samples
obtained at Day 1 (before the 1st vaccination) and 14 days, 6 months, and 1 year (Visit 8) after the second
vaccination. Additionally, this assay will be performed on blood samples obtained at the unblinding visit
(before open-label vaccination) and at the Booster Vaccination Visit (before booster vaccination).
IMMUNOGENICITY EVALUATIONS
Up to Amendment 7, blood will be collected from all non-Immunogenicity Subset participants for humoral
immunogenicity assessments at Day 1 (before the 1st vaccination) and 14 days, 6 months, and 1 year after
the second vaccination.
During the double-blind phase, an Immunogenicity Subset was defined (approximately 400 participants),
from which blood will be collected for analysis of humoral immune responses before each vaccination, 28
days after the 1st vaccination and 14 days, 6 months, 1 year, 18months, and 2 years after the second
vaccination.
For a total of approximately 400 participants in the new Immunogenicity Subset, blood will be collected
for analysis of humoral immune responses at baseline and at Day 71, Week 32, and Week 60 after the first
vaccination.
Up to Amendment 7, all participants will have a blood sample taken at the time of the unblinding visit
(before open-label vaccination) and at the Booster Vaccination Visit (before booster vaccination) for
analysis of immune responses, regardless of whether they were part of the Immunogenicity Subset in the
double-blind phaseb.
Up to Amendment 7, for participants with suspected or confirmed COVID-19 (ie, meeting prespecified
criteria on COVID-19 Day 1-2 and Day 3-5 and/or a SARS-CoV-2 positive sample on COVID-19 Days 1-2
or 3-5), blood will be collected on COVID-19 Day 3-5 and on COVID-19 Day 29 for immunogenicity
a 
World Health Organization  (WHO). Clinical management of severe acute respiratory infection (SARI) when
COVID-19 disease is suspected. Interim guidance, 13 March 2020. https://www.who.int/docs/default-
source/coronaviruse/clinical-management-of-novel-cov.pdf. Accessed 12 May 2020.
b The unblinding visit and the Booster Vaccination Visit may be combined with the scheduled study visit and
procedures that would be duplicated should be done only once. If a blood draw is already planned in the scheduled
visit, then no additional blood draw is needed.

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assessments, including the assays summarized in the table below. As from Amendment 7, active follow-up
will no longer be pursued and blood sampling for this purpose will no longer be performed.
Immunogenicity Assays
Humoral Assays 
Purpose
Supportive of Secondary Objectives
SARS-CoV-2 binding antibodies to S 
protein (ELISA)
Analysis of antibodies binding to SARS-CoV-2 S protein
SARS-CoV-2 seroconversion based 
on antibodies to N protein (ELISA
and/or SARS-CoV-2
Immunoglobulin assay)
Analysis of antibodies binding to SARS-CoV-2 N protein
Supportive of Exploratory Objectives
SARS-CoV-2 neutralization (VNA) 
Analysis of neutralizing antibodies to the wild-type or variant virus,
and/or pseudovirion expressing S protein
SARS-CoV-2 binding antibodies to S 
protein (MSD) 
Analysis of antibodies binding to SARS-CoV-2 S protein (different
than the assays supportive of the secondary objectives) and the
receptor-binding domain (RBD) of SARS-CoV-2 S protein
Functional and molecular antibody 
characterization 
Analysis of antibody characteristics including, but not limited to,
avidity, crystallizable fragment (Fc)-mediated viral clearance, Fc
characteristics, immunoglobulin (Ig) subclass, IgG isotype, antibody
glycosylation, and assessment of antibody repertoire
Adenovirus neutralization (VNA) 
Adenovirus neutralization assay to evaluate neutralizing antibody
responses against the Ad26 vector
Binding antibodies to other 
coronaviruses (MSD) 
Analysis of antibodies binding to coronaviruses other than
SARS-CoV-2
Ad26  adenovirus type 26; ELISA  enzyme linked immunosorbent assay; Fc  crystallizable fragment; Ig(G) 
immunoglobulin (G); MSD  Meso Scale Discovery; N
nucleocapsid; RBD  receptor binding domain; S  spike; SARS
CoV 2  severe acute respiratory syndrome coronavirus 2; VNA  virus neutralization assay.
In areas where seroprevalence is predicted to be high, a screening serologic test for past or current infection
with SARS-CoV-2 may be performed (in a local laboratory), at the discretion of the sponsor, to restrict the
proportion of seropositive participants in the study.
For samples collected prior to implementation ofAmendment 7, a serologic test for past or current infection
with SARS-CoV-2 may be performed for all participants at Day 1 (before the 1st vaccination) and 14 days
(Visit 5), 6 months (Visit 7)and 1 year (Visit 8) after the second vaccination. All participants in the
open-label phase will have 1 blood sample taken at the unblinding visit (before open-label vaccination)and
at the Booster Vaccination Visit (before booster vaccination), except when the previous blood sampling for
the serologic test occurred within 5 days of the visit.a Samples for the serologic tests will be sent to a central
laboratory for testingb. Participants who test positive will be informed of the result by the study staff.
SAFETY EVALUATIONS
The first 1,000 participants will remain under observation at the study site for at least 30 minutes after each
vaccination to monitor for the development of acute reactions. If at the time of the Day 3 safety review of
a The unblinding visit and the Booster Vaccination Visit may be combined with the scheduled study visit and
procedures that would be duplicated should be done only once. If a blood draw is already planned in the scheduled
visit, then no additional blood draw is needed.
b Vaccination with Ad26.COV2.S may interfere with some serologic assays utilized at local community health
clinics/commercial laboratories, by seeking and identifying the spike protein in the vaccine and rendering a false
positive result. For this reason, participants will be encouraged to not seek testing outside the study. If a participant
requires testing outside of the protocol-mandated testing schedule, the site will guide them on the appropriate assay
that identifies the viral nucleocapsid protein (and not the spike protein).

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the initial 1,000 participants no acute reactions have been observed, the observation period at the study site
may be reduced to at least 15 minutes, except where local authorities require a longer observation period
(eg, Belgium), after each vaccination for the remaining participants in the study.
Solicited and unsolicited AEs collected as part of Safety subset will be collected in the eCRF up to the
unblinding visit.
For all participants (throughout the study regardless of any protocol amendmentunless specified otherwise):
 
(S)AEs that are related to study procedures or that are related to non-investigational sponsor products
will be reported from the time a signed and dated informed consent form (ICF) is obtained until the
end of the study/early withdrawal.
 
Clinically relevant medical events not meeting the above criteria and occurring between first signing
of the ICF and moment of 1st vaccination will be collected on the Medical History eCRF page as
pre-existing conditions.
 
All SAEs and all AEs leading to study discontinuation or discontinuation of study vaccination
(regardless of the causal relationship) are to be reported from the moment of 1st vaccination until
completion of the participant’s last study-related procedure, which may include contact for safety
follow-up. The sponsor will evaluate any safety information that is spontaneously reported by an
investigator beyond the time frame specified in the protocol.
 
MAAEs are defined as AEs with medically-attended visits including hospital, emergency room, urgent
care clinic, or other visits to or from medical personnel for any reason. Routine study visits will not be
considered medically-attended visits. New onset of chronic diseases will be collected as part of the
MAAEs. MAAEs are to be reported for all participants from the moment of 1st vaccination until
6 months after the last vaccination (including the open-label vaccination or booster vaccination,
whichever comes last), except for MAAEs leading to study discontinuation which are to be reported
during the entire study.
 
Special reporting situations, whether serious or non-serious, will be recorded for each vaccination from
the time of vaccination until 28 days post-vaccination.
 
From the time of local approval of Protocol Amendment 5 onwards, TTS is considered to be an AESI.
Suspected AESIs (thrombotic events and thrombocytopenia [defined as platelet count below
150,000/µLa]) will be reported from the moment of vaccination until the end of the study/early
withdrawal. An AESI Assesment Committee with appropriate expertise will be established to evaluate
each suspected AESI and determine whether it is a case of TTS.
 
All AEs will be followed until resolution or until clinically stable.
For all participants, as of Amendment 7:
 
A passive follow-up approach is adopted, defined as follow-up phone call visits by the site instead of
on-site study visits to document new COVID‑19 events as SAEs, AEs or MAAEs. Participants may
also contact the site at any time in between scheduled visits to report a safety concern
(eg, hospitalization) or COVID-19 episodes.
 
Concomitant medications for these events should be reported.
a Reference for definition of thrombocytopenia: Updated Proposed Brighton Collaboration process for developing a
standard case definition for study of new clinical syndrome X, as applied to Thrombosis with Thrombocytopenia
Syndrome (TTS). 18 May 2021. https://brightoncollaboration.us/wp-content/uploads/2021/05/TTS-Interim-Case-
Definition-v10.16.3-May-23-2021.pdf. Accessed: 02 September 2021.

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 
If a COVID-19 confirmatory laboratory or assay read-out is available, this should be reported in the
eCRF (self-reported or as part of CIOMS form). The method of the laboratory or assay read-out should
be documented.
For participants in the Safety Subset (applicable to double-blind phase only):
 
Solicited AEs, collected through an e-Diary, will be recorded from the time of each vaccination until
7 days post-vaccination. If these solicited signs and symptoms are not resolved by that time, the
participant will continue to complete the e-Diary until Day 29 post-vaccination or until they are
resolved, whichever comes first.
 
All other unsolicited AEs, whether serious or non-serious, will be recorded from the time of each
vaccination until 28 days post-vaccination. Unsolicited AEs with the onset date outside the timeframe
defined above (>28 days after previous study vaccination), which are ongoing on the day of the
subsequent vaccination, should be recorded as such.
After the unblinding visit, participants in the Safety Subset will stop the collection of solicited AEs and will
not continue in the Safety Subset for any subsequent vaccination. Newly enrolled participants in the
open-label phase will not participate in the Safety subset.
STATISTICAL METHODS
Sample Size Calculation
Efficacy (Total Sample Size)
For the double-blind phase, the sample size is determined using the following assumptions:
 
a VE for molecularly confirmed, moderate to severe/critical SARS-CoV-2 infection of 65%.
 
type 1 error rate α = 2.5% to evaluate VE of the vaccine regimen
 
a randomization ratio of1:1 for active versus placebo.
Events are defined as first occurrence of molecularly confirmed, moderate to severe/critical COVID-19
according to the case definition (see above) in the Per-protocol Efficacy population at least 14 days after
the second vaccination (Day 71) with study vaccine.
Under the assumptions above, a total of 104 events will provide approximately 90% power to reject the null
hypothesis of H0: VE≤30%, according to the primary endpoint case definition of moderate to severe/critical
COVID-19.
If the primary hypothesis testing is successful, secondary objectives will be evaluated against a null
hypothesis employing a lower limit VE>0%. The method to perform hypothesis testing of primary and
secondary objectives preserving the FWER will be specified in the SAP. The FWER will be controlled at
2.5%.
The sample size is approximately 15,000/group (approximately 30,000 in total) and is determined based on
an estimated annualized incidence rate of moderate to severe/critical COVID-19 of 1 to 4% at the start of
the study.
The operating characteristics of the study design, statistical methods, study monitoring rules and efficacy
evaluation specified in this protocol with the chosen event and sample sizes will be described in a separate
modeling and simulation report and will be added to the SAP before the first participant is vaccinated. The
SAP will be amended before primary analysis of the double-blind phase. Upon implementation of Protocol
Amendment 6, the SAP will be amended before the next scheduled analysis.

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To maximize power for the secondary objectives and evaluations in subgroups, any interim testing was
abandoned, and a single analysis planned at the end of the double-blind phase.
The overall recruitment target is approximately 30,000 participants. Up to 10% of additional participants
may be recruited to partially compensate for increased fraction unblinded prior to unblinding visit and/or
increased seroprevalence rates and/or drop-outs.
Immunogenicity Correlates (Correlates Subset)
Correlates will be assessed in a subset where immune responses and/or transcriptome modifications are
measured in all vaccine recipients who experience a SARS-CoV-2 event, and in random samples of vaccine
recipients who have not been infected, in a 1:5 ratio. The goal of this case–control study is to assess
correlates of risk of SARS-CoV-2 infection (and potential other secondary endpoints) in the vaccine group
by comparing vaccine-induced immune responses and transcriptome modifications associated with
COVID-19. Also, placebo participants will be included in this subset (placebo infected, seropositive [based
on N-protein] non-infected and seronegative non-infected), if feasible.
Safety (Safety Subset)
Solicited and unsolicited AEs will be captured only in the Safety Subset, ie, approximately
6,000 participants (~3,000 from the active group, ~3,000 from the placebo group; and including at least
2,000 from the older age group [≥60 years of age] if feasible).
The aim is to recruit up to 6,000 participants in the safety subset. At the time of writing the Protocol
Amendment 4, the target recruitment has not been completed yet. Every effort will be made to reach the
target of 6,000 participants, but the final number of participants recruited in the safety subset may be less
due to unblinding of the participants. After an individual participant has been unblinded, he/she is no longer
considered as part of the Safety Subset and no further solicited/unsolicited symptoms that are specific to
the Safety Subset will be collected. All other safety reporting requirements applicable for all participants
will be maintained (eg, [S]AEs leading to discontinuation, MAAEs, AESIs, and special reporting
situations).
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:

Full Analysis Set (FAS): All randomized participants with at least 1 documented study vaccine
administration, regardless of the occurrence of protocol deviations and serostatus at enrollment.
Analyses of safety will be performed on the FAS. Vaccine efficacy analyses can be repeated using the
FAS.

Safety Subset: subset of the FAS for the analysis of solicited and unsolicited AEs.
Per-protocol Efficacy (PP) populationa: Participants in the FAS who receive 2 doses of study
vaccine and who are seronegative at the time of 1st vaccination and at Day 71, and who have no other
major protocol deviations that were judged to possibly impact the efficacy of the vaccine before
unblinding. The PA of VE will be based on the PP population. In the double-blind phase, the PP will
be the main analysis population for efficacy analyses.

Per-protocol Immunogenicity (PPI) populationa: All randomized participants who receive 2 doses
of study vaccine in the double-blind phase, including those who are part of the ImmunogenicitySubset
a If a participant would be vaccinated out of window due to a study pause or any other reason, this will not by default
be a reason for excluding this participant from the PP and PPI population. A sensitivity analysis might also be
performed. Further details will be described in the SAP. This analysis set will only be applied to the double-blind
phase.

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and for whom immunogenicity data are available, excluding participants with major protocol
deviations expected to impact the immunogenicity outcomes. In addition, for participants who
experience a SARS-CoV-2 event (molecularly confirmed), samples taken after the event and samples
taken outside protocol windows will not be taken into account in the assessment of the
immunogenicity. The PPI population is the primary immunogenicity population. For key tables,
sensitivity immunogenicity analyses will also be performed on the FAS, including participants who
are part of the Immunogenicity Subset for whom immunogenicity measures are available. Excluded
samples might be taken into account as well in the sensitivity analysis. Analyses of vaccine
immunogenicity and immune correlates of risk will be based on PPI.
The populations for the open-label active and open-label passive follow-up phase are described in the SAP.
The list of major protocol deviations to be excluded from the efficacy for the double blind analysis and/or
immunogenicity analyses will be specified in the SAP and/or this list will be reported into protocol
deviation dataset of the clinical database before database lock and unblinding.
Efficacy Analyses
The study will have 3 timepoints for efficacy analyses:
1. 
The primary efficacy analysis of the double-blind phase is planned to be performed when all
participants have reached the open-label phase/been unblinded. Depending on the operational
implementation of unblinding visits, as well as the stage of the pandemic, the analysis may be
conducted when a minimum of 90% of the study population have reached the open-label phase/been
unblinded.
After the primary analysis, additional analyses to support health authority interactions may be planned,
if deemed appropriate.
During the open-label phase, 2 analyses can be performed:
2. 
The open-label active phase analysis
3. 
An end-of-study analysis is planned 1 year after a minimum of 90% of the enrolled study population
have reached Visit 8or discontinued earlier and will be conducted upon completion of the last active
participant visit. Depending on the timing of approval of Amendment 7 across study sites, the
open-label active phase analysis may be combined with the end-of-study analysis. All boosted
participants will have at least 6 months safety follow-up.
Additional analyses may be conducted to support health authority interactions and/or based on public health
demand in case of emerging variants.
Primary Endpoints for the Double-blind Phase
The double-blind phase of the study is designed to test the primary hypothesis of VE in the PP population:
H0: VE ≤30% versus H1: VE >30%.
The primary endpoint will evaluate the first occurrence of molecularly confirmed, moderate to
severe/critical COVID-19 according to the case definition with onset at least 14 days after the second
vaccination (Day 71) with Ad26.COV2.S versus placebo, separately, in the PP population, including all
events from both age groups, with and without comorbidities.
Participants included in the seronegative analysis set are those participants with a negative SARS-CoV-2
serology test result at baseline.

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The unblinding visit marks for a participant the end of the double-blind phase, and the start of the open-label
phase. For a given participants, all data up to the unblinding visit will be incorporated in the analysis of the
double-blind phase.
The minimum criteria that may trigger the primary analysis before at least 90% of participants are unblinded
is if the prespecified harm boundaries have been crossed.
Evaluation of the Primary Endpoint
A successful primary efficacy conclusion will require establishing the hypothesis H1: VE>30% for the
primary endpoint.
Exact Poisson regression will be used to estimate the VE and associated CI taking into account the
follow-up time. To evaluate the primary null hypothesis: H0: VE ≤30% versus H1: VE >30% for the
primary endpoint, 95% 2-sided confidence interval based on Poisson regression model will be used.
The primary efficacy analysis will pool data across populations (with and without comorbidities) to evaluate
the primary and secondary objectives. In addition, these will be supplemented with a subgroup analysis for
age and comorbidities employing a descriptive summary, including 95% confidence intervals to describe
the VE in each subpopulation.
In addition, to assess potential time-effects of VE, the Kaplan-Meier method will be used to plot the
estimated cumulative incidence rates over time for the vaccine and placebo groups. This method will be
used to estimate cumulative VE  over time, defined as [(1 minus ratio (vaccine/placebo) of cumulative
incidence by time t)×100%].
Secondary Endpoints for the Double-blind Phase
All secondary endpoint analyses for the double-blind phase will occur in the PP analysis set, in seronegative
participants unless otherwise indicated.
The multiple testing strategy and the timing of the hypothesis testing to evaluate the secondary objectives
will be detailed in the SAP separately.
Analysis of the Open-label Phase: Open-label Active Phase and Open-label Passive Follow-up Phase
Safety, immunogenicity, and efficacy endpoints following the open-label and/or booster vaccination will
be descriptively summarized by the different cohorts for the different phases.
Additional analyses may be conducted to support health authority interactions and/or based on public health
demand in case of emerging variants.
If deemed feasible, efficacy of the booster vaccination may be explored by comparing efficacy data after
boosting to data in the absence of booster, on the same primary regimen.
Feasibility will be assessed based on data availability as well as adjustments for potential confounding in
the statistical analysis. It will be explored if adjustment for potential confounding factors is feasible (based
on risk factors identified in the analysis of the double-blind phase/and or literature) in each comparison.
This may include, but is not limited to age, presence of co-morbidities as well as the spatiotemporal
evolution ofvariants and the epidemic.
All details will be provided in the SAP.

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Status: Approved,  Date:  27 April 2022
Immunogenicity Analyses
For the double-blind phase, no formal statistical testing of the immunogenicity data is planned. All
immunogenicity analyses will be performed on the PPI set. Key  tables might be repeated for the FAS
(including samples that are excluded from the PPI analysis). For the open-label active and open-label
passive follow-up phase, no statistical testing of the immunogenicity data is planned. All details regarding
the analysis will be described in the SAP.
Safety Analyses
No formal statistical testing of safety data is planned. Safety data by vaccination group and based on the
FAS will be analyzed descriptively. The analysis of solicited and unsolicited AEs will be restricted to a
subset of the FAS (ie, the Safety Subset [double-blind phase]). For SAEs, AESIs, and MAAEs the full FAS
is considered. New onset of chronic diseases will be collected as part of the MAAEs.
Interim Analyses and Committees
The primary analysis of the double-blind phase will be performed after at least 90% of participants are
unblinded and have moved from the double-blind phase to the open-label phase.
In addition to the current objectives and endpoints outlined for the double-blind analyses, the sponsor may
conduct a preliminary and descriptive assessment of efficacy to assess the impact of the vaccine on possible
emerging variants that may arise in the current epidemic situation.  This analysis, if needed, will be
performed by the independent statistical group that is supporting the IDMC of the trial (SSG). The sponsor
personnel directly involved in the oversight and conduct of the trial will be kept blinded. The results can
only be shared with the Sponsor Committee and regulatory authorities upon request.
The study will be formally monitored by an IDMC. In general, the IDMC will monitor safety data on a
regular basis to ensure the continuing safety of the participants. The IDMC will review unblinded data.
The IDMC will review Day 3 safety data (ie, from Day 1 to Day 3; including safety data from the ongoing
studies) from participants enrolled in Stage 1, before enrollment of participants in Stage 2. Enrollment will
not be paused during other safety reviews. The IDMC responsibilities, authorities, and procedures will be
documented in the IDMC Charter.
Continuous monitoring for vaccine-associated enhanced disease will be performed through the SSG who
will look at each of the diagnosed FAS COVID-19 events. Vaccine harm monitoring will be performed for
severe/critical COVID-19/death endpoint based on the FAS. As these events will be monitored in real-time,
and, after each confirmed respective case, the SSG will assess if a stopping boundary is reached.
Specifically, monitoring for a higher rate of severe/critical disease or death in the vaccine group compared
to the placebo group starts at the 5th event and at each additional event until the harm boundary is reached
or until the primary analysis is triggered. If the stopping boundary is met, then the SSG immediately informs
the Chair of the IDMC through secure communication procedures. At this point the IDMC will convene
and provide a recommendation to the Sponsor Committee. As such, the potential harm monitoring is in
real-time, resulting in the earliest indication of harm possible as soon as data come in.
The monitoring rules will be detailed in the IDMC charter, with the statistical details in the SAP.
The SAP will describe the planned analyses in greater detail.
Unblinding due to availability of an authorized/licensed COVID-19 vaccine
As data from VAC31518COV3001 have suggested that a single dose of Ad26.COV2.S is highly efficacious
against severe disease, hospitalization, and death, it is considered ethical to offer a single dose of the active
vaccine to the placebo controls in this study. Hereby, an unblinding visit will be scheduled to inform all

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Status: Approved,  Date:  27 April 2022
participants about their study vaccine allocation as well as to offer placebo recipients Ad26.COV2.S after
EUA in the US and approval of Protocol Amendment 4 by the local Health Authority and IEC/IRB.
All data will be analyzed separately from the point of unblinding, for safety, efficacy, and immunogenicity
analysis, as described in the SAP.

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1.2. 
Schema
Figure 1: Schematic Overview of Study VAC31518COV3009
Active  Ad26.COV2.S; incl.  including; LTFU  long term follow up; rand.  randomization; Th  T helper cell type 1/2.
a Available safety data from all ongoing studies with Ad26.COV2.S will be taken into account.
A screening phase of up to 28 days is included, however, screening may also be performed prior to randomization on the day of vaccination.
The enrollment for Stage 1 and Stage 2 will be staggered. In both stages, participants will be enrolled in 1 of the 2 age dependent subgroups (≥18 years to <60 years of age or ≥60 years of
age). Once Stage 2 is initiated, participants with and without relevant comorbidities can be recruited. It is intended that a minimum of approximately 30% of recruited participants will
be ≥60 years of age and approximately 20% of recruited participants will be ≥18 to <40 years of age. The analysis of the data will not be staggered: the primary analysis will be based
on pooled data from both stages of the study.
Refer to Section 2.1 for details on initiation of study VAC31518COV3009based on data from study VAC31518COV1001.
Refer to the Investigator’s Brochure (IB) for details about the VAC31518COV1001 study.40,41
Refer to Section 5.2 for details on the relevant comorbidities.
Note: Upon implementation of Amendment 4, all participants from double blind phase will be unblinded and the study will continue as an open label study. Participants who received
either one dose or two doses of placebo at that time will be offered to receive a single dose of Ad26.COV2.S, under the conditions delineated in Section 6.4. Participants from the
Ad26.COV2.S arm enrolled during the double blinded phase, will continue in the same arm to receive their second dose, if applicable (refer to Section 6.4).
*Upon implementation of Protocol Amendment 6, all ongoing participants in the study who received only a single vaccination with Ad26.COV2.S in the study will be offered a single
booster dose of Ad26.COV2.S vaccine under the conditions delineated in Section 6.5. Participants who already received 2 vaccinations with Ad26.COV2.S at the 5x1010 vp dose level
or any COVID 19 vaccinations outside of the study (including the Janssen vaccine) at the time of local approval of Protocol Amendment 6 are not eligible to receive a booster
vaccination with Ad26.COV2.S.

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Status: Approved,  Date:  27 April 2022
AE = adverse event; AESI = adverse event of special interest; COVID-19 = coronavirus disease-2019; d = day(s); ICF = informed consent form; m = month(s);
MAAE = medically-attended adverse event; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus-2; w = week(s); y = year(s).
1.3.3. 
All Participants (Prior to Amendment 7)
Phase Screeninga 
Study Period  
Long-term Follow-up
Visit #b 
1 
2 
3 
4** 
5 
6 c 
7ii 
8ii 
9 
10 
Exitd
Visit Timing 
Vac 1
Vac 1
+ 28 d
Vac 2**
Visit 4 
+ 14 d  
Visit 4 
+ 28 d  
Visit 4 
+ 24 w  
Visit 4 
+52 w  
Visit 4 
+78 w 
Visit 4
+104 w
Visit Day/Week
Day -28 to
1
Day 1 
Day 29* 
Day 57 
Day 71* 
Day 85*
Week 32*
(6m post 
Day 57)
Week 60*
(1y post 
Day 57)
Week 86*
(18m post 
Day 57)
Week 112*
(2y post
Day  57)
Visit Window  
±3 d 
±14 d 
±3 d 
±3 d 
-106 to
+28 
days
±21 d 
±28 d 
±28 d
Visit Type 
Screening
Vaccine
1
Safety
and
Immuno 
Vaccine 
2 
Safety and  
Immuno
Safety
Safety 
and 
Immuno 
Safety
and
Immuno
Safety and 
Immuno 
Safety and
Immuno 
Early
Exit
Informed consente 

Inclusion/exclusion criteria 
 
#,f
Demographics 

Risk factor assessmentg 
 
# 
 
 
 

Optional consent to access medical data in
US only
 
 
 
h
Relevant medical historyi/prestudy therapiesj 
 
#
Body weight and height 

Vital signsj 
 
 
Body temperaturek 
 
# 
 
# 
 
 
 
 
 
 
l
Urine pregnancy testm 
 
# 
 
# 
 
 
 
 
 
Pulse oximetry 
 
# 
 
 
 
 
 
 
 
Randomization 
#
Nasal sample collection for SARS CoV 2 
testingn 
#
Blood sample collection for screening
serological test for anti SARS CoV 2 
antibodyo

MRU questionnaire (baseline version)p 
#
Pre vaccination symptomsq 
# 
#
eCOA training and set upr 
#
Distribution of thermometer 
# 
 
 
 
 
 
 
 
Distribution of pulse oximeters 
# 
 
 
 
 
 
 
 
Distribution of MA COV form  
t 
# 
 
 
 
 
 
 
 

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Status: Approved,  Date:  27 April 2022
h. 
For US participants only, at Day 29 or any time thereafter, the participant will be asked for optional consent to allow access to their medical data (electronic health
records, claims, laboratory data from other care settings) from 5 years prior to study enrollment until 5 years after study completion utilizing tokenization and
matching procedures (see Section 4.2 and Section 8.7)Participants will be informed that consent can be withdrawn at any given time. The sponsor will then
remove the token generated and any associated linked real-world data (Section 4.2.1)
i. 
Only relevant medical history is to be collected, in particular: congenital abnormalities, history of cancer, history of immunodeficiency or conditions treated with
immunomodulators, major psychiatric illness, major cardiovascular or lung diseases, history of an allergy to vaccination, ongoing relevant comorbidities as per
investigator’s judgement, history of any comorbidity known to be associated with an increased risk of progression to severe COVID-19, and history of hepatitis B
or hepatitis C infection.
Participants with stable/well-controlled HIV infection are allowed to enroll in the study (see Section 5.1). These participants will be encouraged to have HIV RNA
viral load and CD4 cell count assessed at least twice a year and to provide these data for inclusion in the eCRF.
j. 
Prestudy therapies are only to be recorded for participants with relevant comorbidities and participants aged ≥60 years. For these participants, all prestudy therapies
(excluding vitamins, herbal supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special diets, and exercise regimens)
administered up to 30 days before the 1st vaccination must be recorded at screening. Prestudy therapies linked to inclusion and exclusion criteria (eg, flu vaccine)
should be recorded.
Vital signs may be measured at the discretion of the investigator. Under special circumstances such as high altitude, the investigator should assess baseline
respiratory rate and other vital signs, as appropriate.
k. 
Body temperature will be measured preferably via the oral route, or in accordance with the local standard of care.
l. 
If within 7 days of the vaccination.
m. For participants of childbearing potential only. Collection ofurine pregnancy test results at Day 57 is only applicable for participants who will be vaccinated at this
visit. Note: Participants who are pregnant and previously received placebo during the double blind phase may be vaccinated with Ad26.COV2.S (single dose
regimen), if allowed by local regulations for emergency use of the vaccines and if the investigator considers that the potential benefits outweigh any potential risks
to the mother and fetus (see Section 6.4).
n. 
Diagnostic molecular RT-PCR test for SARS-CoV-2 infection (from nasal swab collected prior to vaccination on Day 1) will be performed at a central laboratory
on a retrospective basis. These baseline results will not be available in real time, and thus cannot be used to inform participants at time of enrollment.
o. 
In areas where seroprevalence is high based on baseline humoral immunogenicity samples collected and analyzed by a central laboratory, a screening serologic test
for past or current infection with SARS-CoV-2 may be performed (in a local laboratory) at the discretion of the sponsor to restrict the proportion of seropositive
participants in the study. This procedure should not be performed unless the site is instructed to implement the test by the Sponsor. The decision will be based on
Sponsor-assessed local seroprevalence.
p. 
MRU over the last 3 months before the 1st vaccination will be collected by interview with the participant and recorded in the eCRF.
q. 
Investigator must check for acute illness or body temperature ≥38.0°C/100.4°F at the time of vaccination. If any of these events occur within 24 hours prior to the
planned vaccination, the vaccination can be rescheduled as long as this is within the allowed window. If the vaccination visit cannot be rescheduled within the
allowed window or the contraindications to vaccination persist, the sponsor should be contacted for further guidance. Collection of pre-vaccination symptoms at
Day 57 is only applicable for participants who will be vaccinated at this visit.
r. 
Participants will complete the eCOA using an application on their own eDevice (smartphone or tablet) if their device is compatible with the application or using
the web portal.
All eCOA assessments should be conducted/completed before any tests, procedures, or other consultations to prevent influencing participant responses.
If a participant is unable to complete the eCOA, a study staff member or the participant’s caregiver can collect information on the participant’s behalf as detailed in
Section 8.1.2.
s. 
All participants will be provided a pulse oximeter at baseline to measure blood oxygen saturation and pulse rate during a COVID-19 episode (see Section 1.3.4).

VAC31518 (JNJ-78436735) 
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Status: Approved,  Date:  27 April 2022
t. 
The Medically-attended -COV form (Appendix 8) will be provided to the participant at the 1st vaccination visit and should be completed by the medical care
provider or the study site personnel during medical visits for COVID-19 or COVID-19 complications.
u. 
The SIC questionnaire asks the participant if he/she had any of the prespecified signs or symptoms (see Appendix 6) during the past 24 hours (including highest
temperature in the last 24 hours), and (when applicable) to rate the severity. Baseline SIC questionnaire (Visit 2) must be completed the same day as vaccination 1,
before vaccination.
v. 
The first 1,000 participants will remain under observation at the study site for at least 30 minutes after each vaccination to monitor for the development of acute
reactions. If at the time of the Day 3 safety review of the initial 1,000 participants no acute reactions have been observed, the observation period at the study site
may be reduced to at least 15 minutes, except where local regulations require a longer observation period (eg, Belgium), after each vaccination for the remaining
participants in the study. For participants in the Safety Subset, any solicited local (at injection site) and systemic AEs, unsolicited AEs, SAEs, and concomitant
therapies will be documented by study-site personnel following this observation period. Participants will be allowed to leave the study site after it is documented
that the post-vaccination observation period is complete.
Post-vaccination observation at Day 57 is only applicable for participants who will be vaccinated at this visit.
w. Until completion of Visit 8, each participant will be asked at least twice a week, through the eCOA, if they have experienced any new symptoms or health concerns
that could be related to infection with SARS-CoV-2. As ofcompletion of Visit 8, until the end of the 2-year follow-up period, the frequency of this (suspected)
COVID-19 surveillance (symptom check) through the eCOA will decrease to once every 2 weeks. Sites should reach out to a participant if the participant fails to
complete the surveillance question upon any of these reminders. The questionnaire will be accessible on the eCOA platform in between scheduled reminders and
participants will be encouraged to answer the surveillance question in the eCOA as soon as possible after the onset of COVID-19-like symptoms. Every effort will
be made to document the status of all participants that are lost to follow-up due to not completing the eCOA and for whom hospitalization has not been recorded.
If a participant develops COVID-19-like signs and symptoms, refer to Section 1.3.4 and Section 8.1.2.
Enrolled participants will be counselled on SARS-COV-2 infection prevention each time that they have a contact with site staff, in line with local guidelines.
At the time of study entry, each participant will need to indicate to the study site, in case they would get infected with SARS-CoV-2, the identity and location of
their routine medical care physician and/or facility and the identity and location of where they would obtain emergency care and hospitalization if necessary. If this
information is not available, a plan for where such care could be obtained should be developed. If a participant should have COVID-19 and their symptoms
deteriorate, they will be instructed to go to the HCP or hospital that has been identified in advance.
x. 
MAAEs are to be reported for all participants from the moment of the 1st vaccination until 6 months after the last vaccination (including the open-label vaccination
or booster vaccination, whichever comes last), except for MAAEs leading to study discontinuation which are to be reported during the entire study. New onset of
chronic diseases will be collected as part of the MAAEs.
y. 
All (S)AEs related to study procedures or non-investigational sponsor products will be reported from the time a signed and dated ICF is obtained until the end of
the study/early withdrawal. All other SAEs are to be reported from the moment of vaccination until completion of the participant’s last study-related procedure.
AEs leading to study discontinuation or discontinuation of study vaccination (regardless of the causal relationship) are to be reported from the moment of the 1st
vaccination until completion of the participant’s last study-related procedure. Applicable from the time of local approval of Protocol Amendment 5 onwards:
Suspected AESIs are to be reported from the moment of vaccination until completion of the participant’s last study-related procedure (see Section 8.3.1). Special
reporting situations, whether serious or non-serious, are to be recorded for each vaccination from the time of vaccination until 28 days post-vaccination.
Participants will be reminded once a month to contact the study site in case of an SAE.
z. 
Refer to Section 6.10 for collection and recording of concomitant therapies associated with SAEs, solicited and unsolicited AEs, suspected AESIs, and MAAEs.
aa. Blood sample for humoral immunity at Day 1 (before the 1st vaccination) and 14 days,6 months, and 1 year (Visit 8) after the second vaccination also include
sample for sero-confirmation of SARS-CoV-2 infection.
bb. Blood samples for immunogenicity will only be taken if the early exit visit is at least 10 days after the previous immunogenicity blood draw
cc. To be collected only from participants receiving Ad26.COV2.S. Whole blood samples will be used for immediate measurement of a platelet count (as part of a
complete blood count if applicable)in a local laboratory or substitute for local laboratory, depending on local feasibility towards turnaround time of sample

VAC31518 (JNJ-78436735) 
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Status: Approved,  Date:  27 April 2022
processing. Serum samples will be derived from the whole blood sample and stored for potential future coagulation-related testing in a central laboratory if the
participant experiences a suspected AESI (see Section 10.2, Appendix 2).
dd. Blood samples for humoral immunity at Day 1 (before the 1st vaccination) and 14 days, 6 months, and 1 year after the second vaccination also include sample for
sero-confirmation of SARS-CoV-2 infection. Samples will be collected for 400 participants at selected sites.
ee. A subset of participants (N=6,000; Safety Subset) will record solicited signs and symptoms (including body temperature) in an e-Diary via the eCOA from the time
of each vaccination until 7 days post-vaccination. If these solicited signs and symptoms are not resolved by that time, the participant will continue to complete the
e-Diary until Day 29 post-vaccination or until they are resolved, whichever comes first. After the unblinding visit, participants in the Safety Subset will stop the
collection of solicited AEs and will not continue in the Safety Subset for any subsequent vaccination. Newly enrolled participants in the open-label phase will not
participate in the Safety Subset.
ff. 
All other unsolicited AEs will be reported for each vaccination from the time of vaccination until 28 days post-vaccination. In order to perform the safety
assessment after approximately 1,000 participants have been vaccinated in Stage 1, participants will be asked to reach out to the study site as soon as possible in
case they experience a serious or severe adverse event.
gg. If within 28 days of the previous vaccination.
hh. A ruler to measure local injection site reactions will be distributed to each participant in the Safety Subset.
ii. 
With implementation of Protocol Amendment 6, all ongoing participants who received only a single Ad26.COV2.S vaccination in the study will be offered to
receive a single booster Ad26.COV2.S vaccination (as specified in Section 1.3.5), under the conditions delineated in Section 6.5. Participants who already received
2 vaccinations with Ad26.COV2.S at the 5x1010 vp dose level or any COVID-19 vaccinations outside of the study (including the Janssen vaccine) at the time of
local approval of Protocol Amendment 6 are not eligible to receive a booster vaccination with Ad26.COV2.S. The booster vaccination will be administered in the
open label phase of the study, preferably within 6 to 12 months after the participant’s first Ad26.COV2.S vaccination in the study. If this is not possible, the
booster vaccination should not occur earlier than 3 months after the participant’s first Ad26.COV2.S vaccination. The Booster Vaccination Visit should preferably
coincide with the participant’s next scheduled visit (ie, Visit 7 or Visit 8for the majority of participants). If not operationally feasible to coincide with an existing
visit, an unscheduled visit may be planned. After the booster vaccination visit, participants will continue procedures and visits as in the original SoA.
AE = adverse event; AESI = adverse event of special interest; approx. = approximate; cont. = continuous; COVID-19 = coronavirus disease-2019; d = day(s); eCOA =
electronic clinical outcome assessment; eCRF = electronic case report form; ePRO = electronic patient-reported outcome; ICF = informed consent form; MAAE =
medically-attended adverse event; MRU = medical resource utilization; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus-2;
SIC = Symptoms of Infection with Coronavirus-19; vac = vaccination; w = week(s).

VAC31518 (JNJ-78436735) 
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Status: Approved,  Date:  27 April 2022
1.3.4. 
Open-label Unblinding Visit (Prior to Amendment 7)
Visit # 
Unblinding visita
Unblinding 
Vaccinationn
Visit Window
Preferably no later than 2 months of local Protocol 
Amendment 5 approval 
Preferably no later than 2 months of local Protocol
Amendment 5 approval
Visit Type 
On-site / Remoteb 
On-site
Informed reconsentb 

Unblinding 

Body temperaturec 
 
#
Urine pregnancy testd 
 
#
Nasal sample collection for SARS-CoV-2 testinge 
#
Blood sample for humoral immunogenicity and 
SARS-CoV-2 serology, mLf
 
#10 mL
Clinical lab blood sample (whole blood), mLg 
 
#7 mL
Pre-vaccination symptomsh 
 
#
Vaccination  
i 
 

Post-vaccination observation  
j 
 

MAAE recordingk 
 

(S)AE recordingl 
 

Concomitant therapiesm 
 

# pre vaccination
a. 
After Ad26.COV2.S EUA in the US and approval of Protocol Amendment 4 by the local Health Authority and the IEC/IRB, all participants enrolled during the
double-blind phase will be invited for an on-site unblinding visit and the study will continue as an open-label study. This visit is also applicable to participants
already unblinded during the double-blind phase of the study. After the study pause, the unblinding visit can be done at a scheduled or unscheduled visit but
preferably during a planned visit, within 2 months of the local approval of Amendment 5. If this is not operationally feasible, an unscheduled visit may be planned.
If the unblinding visit is combined with a scheduled visit, the procedures of the scheduled visit should be completed as well, with the exception of solicited
symptoms collection in the safety subset (please refer to Section 8.3.1 and Section 8.3.2). However, procedures that would be duplicated should be done only once.
All participants will be encouraged to remain in the study and will be followed for efficacy, safety, and immunogenicity, as originally planned. All participants will
be counselled to continue practicing other public health/preventive measures that were introduced at the start of this pandemic (eg, social distancing, face masks,
frequent hand washing), in compliance with local and national guidelines. After the unblinding visit, participants will resume procedures depicted in Schedule of
Activities, Section 1.3.3.
b. 
Signing of the ICF should be done before any visit-related procedure. In case the unblinding occurs remotely, participants should be provided with the ICF, the
investigator will review the content with the participant, and the ICF should be signed electronically or at the next on-site study visit. Investigators will be
encouraged to follow local health authority guidelines on prioritization of immunization.
c. 
Body temperature will be measured preferably via the oral route, or in accordance with the local standard of care.
d. 
For participants of childbearing potential only. Applicable for participants who will receive vaccination at the unblinding visit. Participants who are pregnant and
previously received placebo during the double-blind phase may be vaccinated with Ad26.COV2.S (single-dose regimen), if allowed by local regulations for
emergency use of vaccines and if the investigator considers that the potential benefits outweigh any potential risks to the mother and fetus (see Section 6.4).

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e. 
Diagnostic molecular RT-PCR test for SARS-CoV-2 infection (from nasal swab) will be performed by a central laboratory. This sample should be collected in all
participants and should not be tested locally.
f. 
Blood sample for humoral immunogenicity and sero-confirmation of SARS-CoV-2 infection. Blood sample should be taken except when the previous sample for
assessment ofhumoral immunogenicity and sero-confirmation of SARS-CoV-2 infection occurred within 5 days of the visit. These results will not be available in
real time, and this cannot be used to inform participants at the time of visit. If the visit is combined with a scheduled visit (Section 1.3.3) that comprises a blood
sample, only the blood sample from the scheduled visit should be collected.
g. 
Whole blood samples will be used for immediate measurement of a platelet count (as part of a complete blood count, if applicable) in a local laboratory or
substitute for local laboratory, depending on local feasibility towards turnaround time of sample processing. Serum samples will be derived from the whole blood
sample and stored for potential future coagulation-related testing in a central laboratory if the participant experiences a suspected AESI (see Section 10.2,
Appendix 2). If a whole blood sample has been taken within 5 days before vaccination and platelet results are available, sample collection does not need to be
performed before vaccination.
h. 
Investigator must check for acute illness or body temperature ≥38.0°C/100.4°F at the time ofvaccination. If any of these events occur within 24 hours prior to the
planned vaccination, the vaccination can be rescheduled as long as this is within the allowed window. If the vaccination visit cannot be rescheduled within the
allowed window or the contraindications to vaccination persist, the sponsor should be contacted for further guidance.
i. 
Participants who initially received either one dose or two doses of placebo will be offered to receive a single dose of Ad26.COV2.S, under the conditions
delineated in Section 6.4. Participants from the Ad26.COV2.S arm will receive their second dose under the conditions delineated in Section 6.4.
j. 
The observation period for participants who will receive vaccination must be at least 15 minutes, except where local regulations require a longer observation period
(eg, Belgium), after vaccination in the study. Participants who will receive vaccination will be allowed to leave the study site after it is documented that the post-
vaccination observation period is complete.
k. 
MAAEs are to be reported for all participants from the moment of the 1st vaccination until 6 months after the last double-blind or open-label vaccination, except for
MAAEs leading to study discontinuation which are to be reported during the entire study. New onset of chronic diseases will be collected as part of the MAAEs.
l. 
All (S)AEs related to study procedures or non-investigational sponsor products will be reported from the time a signed and dated ICF is obtained until the end of
the study/early withdrawal. All other SAEs are to be reported from the moment of vaccination until completion of the participant’s last study-related procedure.
AEs leading to study discontinuation or discontinuation of study vaccination (regardless of the causal relationship) are to be reported from the moment of the 1 st
vaccination until completion of the participant’s last study-related procedure. Applicable from the time of local approval of Protocol Amendment 5 onwards:
Suspected AESIs are to be reported from the moment of vaccination until completion of the participant’s last study-related procedure (see Section 8.3.1). Special
reporting situations, whether serious or non-serious, are to be recorded for each vaccination from the time of vaccination until 28 days post-vaccination (applicable
for both double-blind and open-label). Participants will be reminded once a month to contact the study site in case of an SAE.
m. Refer to Section 6.10 for collection and recording of concomitant therapies associated with SAEs, suspected AESIs, and MAAEs.
n. 
For those who do not need to receive further vaccination at the time of the unblinding visit (see Section 6.4), all activities (except those related to vaccination) need
to be performed to comply with the required reconsent, blood and swab sampling, and safety evaluations.
AE = adverse event; AESI = adverse event of special interest; EUA = Emergency Use Authorization; d = day(s); ICF = informed consent form; MAAE = medically-
attended adverse event; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus-2.

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1.3.5. 
Booster Vaccination Visit
With implementation ofProtocol Amendment 6, all ongoing participants who received only a single Ad26.COV2.S vaccination in the study
will be offered a single booster Ad26.COV2.S vaccination, under the conditions delineated in Section 6.5. Participants who already received
2 vaccinations with Ad26.COV2.S at the 5x1010 vp dose level or any COVID-19 vaccinations outside of the study (including the Janssen
vaccine) at the time of local approval of Protocol Amendment 6 are not eligible to receive a booster vaccination with Ad26.COV2.S.
As of Protocol Amendment 7, no further booster vaccination will be provided unless there is a medical reason or if there is a non-availability
of other vaccines to the participant (and prior to vaccine expiry date at the study site level). The investigator should counsel on possible
vaccination outside of the study.
Visit # 
Booster Vaccination Visita
Visit Timing and Window  
Preferably Vac 1 + 6-12 months
Minimally Vac 1 + 3 months
Informed reconsentb
#
Body temperaturec
#
Pre-vaccination symptomsd
#
Urine pregnancy teste
#
Nasal sample collection for SARS-CoV-2 testingf
#
Blood sample for humoral immunogenicity and SARS-CoV-2 serology, mLg
#10 mL
Clinical lab blood sample (whole blood)h
#7 mL
Vaccinationi

Post-vaccination observation  
j

(S)AE, MAAE and suspected AESI recordingk

Concomitant therapiesl

# procedure to be completed pre-vaccination
a. The Booster Vaccination Visit should occur preferably within 6-12 months after first Ad26.COV2.S vaccination. If this is not possible, the booster vaccination
should not occur earlier than 3 months after first Ad26.COV2.S vaccination. The Booster Vaccination Visit should preferably coincide with the participant’s
next scheduled visit (ie, Visit 7 or Visit 8 for the majority of participants) from the original schedule in Section 1.3.3. If not operationally feasible to coincide
with an existing visit, an unscheduled visit may be planned. If the Booster Vaccination Visit coincides with a scheduled visit, the procedures of the scheduled
visit should be completed as well. However, procedures that would be duplicated should be done only once. All participants will be encouraged to remain in the
study and will be followed for efficacy, safety, and immunogenicity, as originally planned. All participants will be counselled to continue practicing other
public health/preventive measures that were introduced at the start of this pandemic (eg, social distancing, face masks, frequent hand washing), in compliance
with local and national guidelines. After the Booster Vaccination Visit, participants will resume procedures and visits depicted in Schedule of Activities,
Section 1.3.3.
b. Signing of the ICF should be done before any visit-related procedures are performed.
c. Body temperature will be measured preferably via the oral route, or in accordance with the local standard of care.

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d. Investigator must check for acute illness or body temperature ≥38.0°C/100.4°F at the time of vaccination. If any of these events occur within 24 hours prior to
the planned vaccination, the vaccination can be rescheduled as long as this is within the allowed window.
e. For participants of childbearing potential only. Note: Participants who are pregnant and previously received the open-label vaccination may receive the booster
vaccination, if allowed by local regulations for use of the vaccines and if the investigator considers that the potential benefits outweigh any potential risks to the
mother and fetus.
f. 
Up to Protocol Amendment 7, diagnostic molecular RT-PCR test for SARS-CoV-2 infection (from nasal swab) will be performed by a central laboratory. This
sample should be collected in all participants and should not be tested locally.
g. Up to Protocol Amendment 7, blood sample for humoral immunogenicity and sero-confirmation of SARS-CoV-2 infection. Blood sample should be taken
except when the previous sample for assessment of humoral immunogenicity and sero-confirmation of SARS-CoV-2 infection occurred within 5 days of the
visit. These results will not be available in real time, and this cannot be used to inform participants at the time of visit. If the visit is combined with a scheduled
visit (Section 1.3.3) that comprises a blood sample, only the blood sample from the scheduled visit should be collected.
h. Whole blood samples will be used for immediate measurement of a platelet count (as part of a complete blood count, if applicable) in a local laboratory or
substitute for local laboratory, depending on local feasibility towards turnaround time of sample processing. Serum samples will be derived from the whole
blood sample and stored for potential future coagulation-related testing in a central laboratory if the participant experiences a suspected AESI (see
Section 10.2). If a whole blood sample has been taken within 5 days before vaccination and platelet results are available, sample collection does not need to be
performed before vaccination.
i. 
With implementation of Protocol Amendment 6, all ongoing participants who received only a single Ad26.COV2.S vaccination in the study will be offered to
receive a single Ad26.COV2.S booster vaccination, under the conditions delineated in Section 6.5. Participants who already received 2 vaccinations with
Ad26.COV2.S at the 5x1010 vp dose level or any COVID-19 vaccinations outside of the study (including the Janssen vaccine) at the time of local approval of
Protocol Amendment 6 are not eligible to receive a booster vaccination with Ad26.COV2.S.
j. 
The observation period for participants who will receive vaccination must be at least 15 minutes, except where local regulations require a longer observation
period (eg, Belgium), after vaccination in the study. Participants who will receive vaccination will be allowed to leave the study site after it is documented that
the post-vaccination observation period is complete.
k. All (S)AEs related to study procedures or non-investigational sponsor products will be reported from the time a signed and dated ICF is obtained until the end
of the study/early withdrawal. All other SAEs and all AEs leading to study discontinuation or discontinuation of study vaccination are to be reported from the
moment of first vaccination until completion of the participant’s last study-related procedure. Participants will be reminded once a month to contact the study
site in case of an SAE. Special reporting situations, whether serious or non-serious, are to be recorded for each vaccination from the time of vaccination until
28days post-vaccination. MAAEs are to be reported from the moment of the 1st vaccination until 6 months after the last vaccination (including the open-label
vaccination or booster vaccination, whichever comes last), except for MAAEs leading to study discontinuation which are to be reported during the entire study.
New onset of chronic diseases will be collected as part of the MAAEs. Suspected AESIs are to be reported from the moment of vaccination until completion of
the participant’s last study-related procedure or (as of Amendment 7) phone call/study contact (see Section 1.3.7).
l. 
Refer to Section 6.10 for collection and recording of concomitant therapies associated with (S)AEs, MAAEs, and suspected AESIs.
AE = adverse event; AESI = adverse event of special interest; d = day(s); ICF = informed consent form; MAAE = medically-attended adverse event; SAE = serious
adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus-2.

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1.3.6. 
Participants With (Suspected) COVID-19
1.3.6.1. 
Passive Follow-up (As of Amendment 7)
As of Amendment 7, active follow-up of suspected COVID-19 episodes will be replaced by a passive follow-up approach.
New suspected COVID-19 episodes will be participant-reported and may include available laboratory findings from local testing. Site staff
will collect information on the new COVID-19 episodes at scheduled time points and report these as SAEs, AEs, or MAAEs, as applicable.
Participants may also contact the site at any time in between scheduled visits to report a safety concern (eg, hospitalization) or COVID-19
episodes. Concomitant therapies related to these events are to be reported, as well as any confirmatory COVID-19 laboratory information, if
available. As of Protocol Amendment 7, there will be no further central testing for COVID-19 events.
Guidance on (S)AE coding may be provided.
Some participants will have an ongoing COVID-19 episode at time of signing the informed consent of Protocol Amendment 7. Also, under
Protocol Amendment 7, the eCOA will be decommissioned. Hence, participants with an ongoing COVID-19 episode will stop using the eCOA
as ofsite approval of Amendment 7. The outstanding activities planned for the follow-up of COVID-19 episodes will also end on that date for
the participants (eg, no further samples, no MRU completion, no MA-COV completion, no further visit in the context of the COVID-19
follow-up). The eCOA will be stopped based on approval of Protocol Amendment 7 at each study site.
1.3.6.2. 
Active Follow-up (Prior to Amendment 7)
Timing relative to onset of signs and symptoms
COVID
-19
Day 1-2
COVID-19 
Day 3-50 
2-day cycle to be
repeatedc,d,e
COVID
-19
Day 29
(±7 d)f,g
Part 1 
Part 2b
1st day of
cycle
2nd day
of cycle
Location 
Homeh
Site or
Homei,j 
Site or 
Homei,j
Homej
Homej
Site or
Homei,j
Participant to contact study site with any health concerns/participant notifies the site of
becoming aware of a positive RT-PCR test

Site to contact participant if COVID-19 signs or symptoms are recorded in eCOA  

Confirmation of suspected COVID-19 using prespecified criteria 
k 
l
Nasal swab sample (collected by the participant at home)m 
n

Nasal swab sample (collected by qualified study staff) 
o
Saliva sample (collected by the participant)p
 
 


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if needed), if allowed by local regulations. Under these circumstances, the participant will be contacted by the site at least once per week and the participant’s
medical care provider will be notified.
k. In case of COVID-19 like symptoms, based on the information collected through the SIC, the site will reach out to the participant at the latest on COVID-19 Day 2
(the day after the day of symptom onset) to assess whether the reported signs and symptoms qualify as a suspected COVID-19 episode using prespecified criteria
(Section 8.1.1). In case the participant would actively reach out to the site already on COVID-19 Day 1, the site should already make a first assessment on
COVID-19 Day 1 to check whether the reported signs and symptoms qualify as a suspected COVID-19 episode using prespecified criteria (Section 8.1.1). As
several of the prespecified criteria for suspected COVID-19 overlap with vaccine-related reactogenicity, investigators' clinical judgement is required to exclude
vaccine-related events when assessing suspected COVID-19.
l. 
In case of COVID-19 like symptoms, the site will interview the participant to assess whether the reported signs and symptoms still qualify as a suspected
COVID-19 episode using prespecified criteria (Section 8.1.1).
m. A nasal swab should be collected from the participant at home (using available material for home swabs provided by the study staff) as soon as the prespecified
criteria for suspected COVID-19 are met and, in case of COVID-19 like symptoms, preferably on the day of symptom onset or the day thereafter (COVID-19
Day 1-2). The sample collected on COVID-19 Day 1-2 should be transferred to the study site, as arranged by the study site, as soon as possible after collection,
preferably within 24 hours. Nasal swabs should also be collected once every 2 days until 14 days after symptoms onset (COVID-19 Day 15) or until resolution of
the COVID-19 episode, whichever comes last. These samples should be transferred to the study site, as arranged by the study site, within 3 days after collection.
Details are provided in the laboratory manual. If the participant requires assistance, a trained HCP can help the participant to collect the nasal swabs. Depending on
local practice, 2 samples may be collected. For participants with a positive test result for SARS-CoV-2 infection, a study visit will be conducted 28 days after
symptom onset (ie, at the COVID-19 Day 29 visit) to assess the clinical course of the infection. If 2 consecutive nasal swabs negative for SARS-CoV-2 are not
available due to operational reasons (eg, delays in results availability), participants may cease collection of nasal swabs at the COVID-19 Day 29visit, provided
they have 2 consecutive days with no COVID-19-related signs and symptoms. In these cases, participants may be asked to resume sample collection if nasal sample
results—once available—do not present with 2 consecutive negative swabs for SARS-CoV-2 (Section 8.1.2).
n. The nasal swab should be collected and pulse oximetry should be started as soon as possible after it has been confirmed that the prespecified criteria for suspected
COVID-19 (Section 8.1.1) are met.
o. For participants with suspected COVID-19, confirmation of SARS-CoV-2 infection by a central laboratory will be used for the analysis of the case definition. All
nasal swabs will also be tested by a local laboratory for case management.
p. Saliva samples should be collected from the participant (using recipients provided by the study staff). The samples should be transferred to the study site, as
arranged by the study site, within 3 days after collection. Details are provided in the laboratory manual. If the participant requires assistance, a trained HCP can help
the participant to collect the saliva samples.
q. Blood sample for humoral immunity also includes sample for sero-confirmation of SARS-CoV-2 infection (antibody).
r. Participants should complete the (suspected) COVID-19 surveillance (symptom check) in the eCOA. In case of COVID-19 like signs and symptoms, participants
should be encouraged by the site to complete the SIC (Appendix 6)daily, preferably in the evening around the same time each day, starting on the first day they
experience symptoms. Sites should remind the participant to complete the SIC, unless special circumstances occur such as hospitalization or ventilation, in which
case the reason for not completing the SIC should be recorded by site staff in the clinical database. If signs and symptoms are still ongoing on COVID-19 Day 3-5,
collection of SIC will be continued until at least 14 days after symptoms onset unless both COVID-19 Day 1-2 and COVID-19 Day 3-5 nasal swabs are negative.
If either of the swabs are positive or the result is unknown AND the participant is beyond 14 days after onset of symptoms, the SIC can be stopped after 2 days
without signs and symptoms.
If a participant is unable to complete the eCOA, a study staff member or the participant’s caregiver can collect information on the participant’s behalf as detailed in
Section 8.1.2.
Participant should measure body temperature daily (oral route preferred, or in accordance with the local standard of care) and record the highest temperature in the
last 24 hours.

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s. If the participant does not have symptoms at that time, he/she will only need to complete the (suspected) COVID-19 surveillance (symptom check). If symptoms are
ongoing at the time of the COVID-19 Day 29 visit, the investigator can stop the SIC. To close the COVID-19 episode, the investigator should follow-up participants
and document the end of the episode in the eCRF (2 consecutive days without signs and symptoms and 2 negative nasal swab results).
t. 
If allowed by local regulations and if the participant consents, he/she will be interviewed on characteristics related to their current work situation, living situation,
and community interactions (See Appendix 12). These data will be used for risk factor analysis.
u. Includes measurement of vital signs (preferably supine systolic and diastolic blood pressure, heart rate, and respiratory rate [after at least 5 minutes rest] and body
temperature). It is recommended that vital signs are measured before collection of nasal swabs and blood draws.
v. In case of COVID-19 like symptoms, the participant will be asked to measure blood oxygen saturation and pulse rate at home 3 times a day (preferably in the
morning, at lunch time, and in the evening). The results will be recorded by the participant in the eCOA.
w. Data collected as part of the MRU will be recorded in the eCRF. The end of COVID-19 episode will be documented in the eCRF. Any symptom with sequelaea
ongoing at the time of the COVID-19 Day 29 visit, will need to be followed and the end date of the symptom will be documented in the eCRF.
x. The MA-COV form (Appendix 8) will be provided to the participant at the vaccination visit and should be completed by the medical care provider or the study site
personnel during medical visits for COVID-19or COVID-19 complications.
Upon closure of the COVID-19 episode and procedures, all participants will fall back to the default Schedules of Activities, until the end of the study/early withdrawal.
If the participant experiences new signs or symptoms suggesting possible COVID-19 at a later point in time, the participant would restart the COVID-19 procedures
from COVID-19 Day 1 onwards.
COVID-19 = coronavirus disease-2019; eCOA = electronic clinical outcome assessment; eCRF = electronic case report form; ePRO = electronic patient-reported
outcome; MA-COV = medically-attended COVID-19; MRU = medical resource utilization; SARS-CoV-2 = severe acute respiratory syndrome coronavirus-2; SIC =
Symptoms of Infection with Coronavirus-19.
a long-term sequelae of COVID-19 will not be followed until their resolution if not resolved at COVID-19 Day 29.

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1.3.7. 
Participants with a Suspected AESI
The medical management of thrombotic events with thrombocytopenia is different from the
management of isolated thromboembolic diseases. Study site personnel and/or treating physicians
should follow available guidelines for treatment of thrombotic thrombocytopenia (eg, from the
American Society of Hematology2, British Society of Haematology Expert Haematology Panel10,
and the CDC15). The use of heparin may be harmful and alternative treatments may be needed.
Consultation with a hematologist is strongly recommended. Management of the participant should
not be delayed by decision-making of the AESI AssessmentCommittee. In the event of a suspected
thrombotic event, thrombocytopenia, or TTS, laboratory assessments (to be performed locally) are
required to facilitate diagnosis and determine treatment options, including but not limited to
platelet count and anti-PF4 tests.
Additional blood samples should be collected for central laboratory testing as detailed below.
However, results of central laboratory testing may not be available to guide immediate treatment
decisions.
a. Day 1 refers to first awareness of the event, which might be later than the date of onset. Every effort should be
made to report as much information as possible about the event to the sponsor in a reasonable timeframe. The
investigator should contact the sponsor for input on the feasibility of collecting blood samples, including the need
for additional samples based on the nature of the event.
b. Day 29 is to be calculated relative to the actual day of onset of the event. If the event is not resolved on Day 29,
subsequent follow-up assessments can be performed at unscheduled visits as needed until resolution of the event.
If the event is reported to the investigator more than 28 days after the onset of the event, the AESI Day 29 visit
will therefore become redundant and does not need to be performed.
c. Suspected AESIs must be reported to the sponsor within 24 hours of awareness irrespective of seriousness
(ie, serious and non-serious AEs) or causality assessment (see Section 8.3.7).
d. On AESI Day 1 and again on Day 29, whole blood samples will be used for immediate measurement of a platelet
count (as part of a complete blood count, if applicable) in a local laboratory or substitute for local laboratory,
depending on local feasibility towards turnaround time of sample processing. Serum (3.5 mL) and plasma (1.5 mL)
samples will be derived from the whole blood samples (7 mL and 3 mL, respectively) for coagulation-related
testing in a central laboratory (see Section 10.2, Appendix 2). For the follow-up visit, the volume ofblood to be
collected may vary depending on the clinical evaluation of the case. All local laboratory results need to be encoded
in the eCRF, including platelet counts. Low platelet counts are to be recorded as suspected AESI
(thrombocytopenia).
e. Medical information on local case management will be collected. Upon becoming aware of the suspected AESI,
study site personnel should provide information on an ongoing basis. See Section 8.3.7 and Section  10.13,
Appendix 13 for further details.
f. Refer to Section 6.10 for collection and recording of concomitant therapies associated with a suspected AESI.
* Depending on when the suspected AESI occurred, Day 1 and Day 29 visit can occur on the same date (eg, the
investigator becomes aware of the event weeks after the actual date of the AE). Also, for late reported events, the
sponsor may be contacted to confirm the need of the visit.
AESI = adverse event of special interest; CDC = Centers for Disease Control and Prevention; eCRF = electronic case
report form; PF4 = platelet factor 4; TTS = thrombosis with thrombocytopenia syndrome
Timing relative to onset of suspected AESI*
AESI 
Day 1 a 
AESI
Day 29b
Visit Window  
 
±7 d
Site to report suspected AESIc 

Clinical lab blood sample (whole blood), mLd 
15 
15
TTS AESI forme 
---Continuous---
Concomitant therapiesf 
 


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2. 
INTRODUCTION
Ad26.COV2.S  (previously known as Ad26COVS1) is a monovalent vaccine composed of a
recombinant, replication-incompetent adenovirus type 26 (Ad26) vector, constructed to encode the
severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike (S) protein.
Unless clearly specified otherwise, this section presents information available at the time of the
writing of the initial protocol, dated 22 August2020. At that time, the Ad26.COV2.S Investigator’s
Brochure (IB) Edition 1.0 and its Addendum 1 were in place.40,41
Information about the disease, correlates of immunity, and safety issues concerning this new
pandemic-causing virus are rapidly evolving. Therefore, it is critical to recognize that the approach
outlined in this document might or will change as insights and discussions evolve.
For the most comprehensive nonclinical and clinical information regarding Ad26.COV2.S, refer
to the latest version of the IB and its addenda (if applicable) for Ad26.COV2.S.
The term “study vaccine” throughout the protocol, refers to Ad26.COV2.S or placebo as defined
in Section 6.1. The term “sponsor” used throughout this document refers to the entities listed in
the Contact Information page(s), which will be provided as a separate document. The term
“participant” throughout the protocol refers to the common term “subject”.
COVID-19 Vaccine and Considerations
Currently, there are no available vaccines for the prevention of coronavirus disease-2019
(COVID-19). The development of a safe and effective COVID-19 vaccine is considered critical to
contain the current outbreak and help prevent future outbreaks.
Although the quantitative correlate of protection against SARS-CoV-2 infection has not yet been
identified, neutralizing antibody responses against the severe acute respiratory syndrome
coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV)
S protein have been associated with protection against experimental SARS-CoV and MERS-CoV
infection in nonclinical models.23,78 Recent studies suggest that SARS-CoV-2 has several
similarities to SARS-CoV based on the full-length genome phylogenetic analysis and the
putatively similar cell entry mechanism and human cell receptor usage.48,50,79 Therefore, a
neutralizing antibody response against the SARS-CoV-2 S protein may also have a protective
effect.
Adenoviral-vectored Vaccines
Recombinant, replication-incompetent adenoviral vectors are attractive candidates for expression
of foreign genes for a number of reasons. The adenoviral genome is well characterized and
comparatively easy to manipulate. Adenoviruses exhibit broad tropism, infecting a variety of
dividing and non-dividing cells. The adenoviral vaccine (AdVac®) vector platform, developed by
Crucell Holland B.V. (now Janssen Vaccines & Prevention B.V.) allows for high-yield production
of replication-incompetent adenovirus vectors, eg, Ad26, with desired inserts. The adenovirus E1

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region is deleted to render the vector replication-incompetent and create space for transgenes, with
viral replication taking place in cells that complement for the E1 deletion in the virus genome.
Ad26 has been selected as a potential vaccine vector because there is substantial nonclinical and
clinical experience with Ad26-based vaccines that demonstrate their capacity to elicit strong
humoral and cellular immune responses and their acceptable safety profile, irrespective of the
antigen transgene (see also Section 2.3.1).
The immunogenicity profile of adenoviral vectors is illustrated by data obtained following the
immunization of adults with Ad26-vectored human immunodeficiency virus (HIV) vaccines
(Ad26.ENVA.01, Ad26.Mos.HIV, and Ad26.Mos4.HIV), an Ad26-vectored Ebola virus vaccine
(Ad26.ZEBOV), Ad26-vectored respiratory syncytial virus (RSV) vaccines (Ad26.RSV.FA2 and
Ad26.RSV.preF), an Ad26-vectored Zika virus vaccine (Ad26.ZIKV.001), and an Ad26-vectored
malaria vaccine (Ad26.CS.01). Antigen-specific antibody responses are observed in almost all
participants after 1 dose, in both naïve and pre-immune individuals (RSV). These antibodies may
persist for a year or more (RSV) after a single-dose in pre-immune participants. They have
functional properties of neutralization (RSV, Zika), crystallizable fragment (Fc)-mediated
antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis
(HIV, malaria). Furthermore, these data support an immunogenicity profile with emphasis on
T-helper cell type 1 (Th1) responses and demonstrate predominantly interferon gamma (IFN-γ)
and tumor necrosis factor alpha (TNF-α) production in CD4+ and CD8+ T cells.4,42,53
Ad26.COV2.S Candidate Vaccine
The aim of the COVID-19 vaccine clinical development program is to develop a safe and effective
vaccine for the prevention of COVID-19. The candidate vaccine to be assessed in this study is
Ad26.COV2.S, which is a recombinant, replication-incompetent Ad26 encoding a prefusion
stabilized variant of the SARS-CoV-2 S protein. The parental S protein sequence was derived from
a SARS-CoV-2 clinical isolate (Wuhan, 2019; whole genome sequence NC_045512). The
selection of antigen was based on previous work on the SARS-CoV and MERS-CoV candidate
vaccines.23,33,54 The S protein is the major surface protein on coronaviruses and is responsible for
binding to the host cell receptor and mediating the fusion of host and viral membranes, thereby
facilitating virus entry into the cell.81
SARS-CoV-2 Virology and COVID-19 Disease Burden
SARS-CoV-2 is an enveloped, positive-sense, single-stranded ribonucleic acid (RNA)
betacoronavirus.26,74 It was first identified following reports of a cluster of acute respiratory illness
cases in Wuhan, Hubei Province, China in December 2019.49 Early epidemiological investigations
suggested that the majority of early cases were linked to a seafood market, with patients infected
through zoonotic or environmental exposure, followed by the subsequent spread of infection by
human-to-human transmission among close contacts.49 However, there is some controversy about
the initial origin of the virus.27 Genomic sequencing was performed on bronchoalveolar lavage
fluid samples collected from patients with viral pneumonia admitted to hospitals in Wuhan, which
identified a novel RNA virus from the family Coronaviridae.50,74 Phylogenetic analysis of the
complete viral genome revealed that the virus, SARS-CoV-2, is part of the subgenus Sarbecovirus

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of the genus Betacoronavirus, and is most closely related (approximately 88% identity) to a group
of SARS-CoV-like coronaviruses previously sampled from bats in China.50
SARS-CoV-2 has spread rapidly and globally since its emergence. The World Health Organization
(WHO) declared that the outbreak constituted a public health emergency of international concern
on 30 January 2020, and declared the outbreak to be a pandemic on 11 March  2020.71,72 As of
1 June 2020, approximately 6,680,000 cases of COVID-19 and approximately 375,000
COVID-19-related deaths have been reported.43
Symptoms of infection may appear from 2 to 14 days following exposure, with the clinical
manifestations ranging from mild symptoms to severe illness or death.14 Severe clinical
presentations have been reported in as many as 20% to 25% of laboratory-confirmed cases.32 In a
study of 99patients in a single center in Wuhan with SARS-CoV-2 infection confirmed by
real-time reverse-transcriptase polymerase chain reaction (RT-PCR), the most commonly reported
clinical manifestations were fever (83%), cough (82%), shortness of breath (31%), and muscle
aches (11%).22 In chest X-rays and computed tomographic (CT) scans, 75% of patients showed
bilateral pneumonia and 14% of patients showed diffuse mottling and ground-glass opacities. In a
further study of 138patients with novel coronavirus-induced pneumonia in a single center in
Wuhan, common symptoms included fever (98.6%), fatigue (69.6%), and dry cough (59.4%).64
Lymphopenia occurred in 70.3% of patients, and chest CT scans showed bilateral patchy shadows
or ground-glass opacities in the lungs of all patients. Thirty-six patients (26%) were transferred to
the intensive care unit (ICU) because of complications, including acute respiratory distress
syndrome, arrhythmia, and shock. Subsequent United States (US) Centers for Disease Control and
Prevention (CDC) descriptions of COVID-19 clinical case definitions14 and Janssen-sponsored
interviews with COVID-19-experienced clinicians have included signs and symptoms of
respiratory distress such as blue lips, extreme shortness of breath and dyspnea, persistent cough,
deep vein thrombosis (DVT), Kawasaki-like disease, discoloration of feet and toes, chills, shaking
chills, loss of sense of taste and smell, signs of stroke, disorientation, inability to respond or
understand verbal communication, among others.
At present, it appears that individuals aged ≥65 years, especially those with comorbid diseases, are
subject to the highest incidence of morbidity and mortality.35 In contrast, a study of 2,143 children
aged <18 years in China with laboratory-confirmed (34.1%) or suspected (65.9%) COVID-19
indicated that the clinical manifestations of the disease may be less severe in children than adults,
with approximately 94% of cases being asymptomatic, mild, or moderate.29 However, young
children, particularly infants, were susceptible to severe disease, with the highest proportion of
severe and critical cases by age group reported for children aged <1 year (10.6% of cases in this
age group). A study of 149,082 COVID-19 cases reported in the US was consistent with these
findings.18 Only 1.7% of these cases occurred in persons aged <18 years although this age group
accounts for 22% of the US population. Furthermore, relatively few pediatric COVID-19 cases
were hospitalized, indicating that COVID-19 might have a mild course among younger patients.
Hospitalization was most common among pediatric patients aged <1 year and those with
underlying conditions. Recent (April-May 2020) reports describe several cases of multisystem
inflammatory syndrome (MIS) in children with Kawasaki disease-like features (ie, fever,

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laboratory markers of inflammation, severe illness requiring hospitalization, multisystem organ
involvement). Most of these children had tested positive for current or recent SARS-CoV-2
infection or were linked to a COVID-19 case. It is currently unknown if MIS is specific to children
or if it may also occur in adults.13,69
The identification of SARS-CoV-2 follows the emergence of 2 other novel betacoronaviruses
capable of causing severe human disease over the past 18years: SARS-CoV and MERS-CoV,
which have nucleotide sequence identity with SARS-CoV-2 of approximately 79% and 50%,
respectively.50 The first known cases of severe acute respiratory syndrome (SARS) occurred in
Southern China in November 2002.73 The etiological agent, SARS-CoV, is believed to be an
animal virus that crossed the species barrier to humans followed by human-to-human transmission,
leading to SARS cases in >25 countries. The MERS-CoV was isolated from a patient in Saudi
Arabia who died of severe pneumonia and multi-organ failure in June 2012.81 MERS-CoV is
considered to be a zoonotic virus capable of nonsustained human-to-human transmission. Since
2012, sporadic cases and community and health-care-associated clusters of infected individuals
have been reported in the Middle East.
Patients with SARS or MERS present with various clinical features, ranging from asymptomatic
or mild respiratory illness to fulminant severe acute respiratory disease with extrapulmonary
manifestations.21,81 Both diseases have predominantly respiratory manifestations, but
extrapulmonary features may occur in severe cases. By July 2003, the international spread of
SARS-CoV resulted in 8,098 SARS cases and 774 deaths (case- fatality rate: 10%) with substantial
social, economic and health service disruption in some affected countries.21,73 The case-fatality
rate of MERS-CoV infections is estimated to be 35%.21
It is not known if SARS-CoV-2 will remain as a worldwide pandemic. It is also not known if
immunity is acquired after symptomatic or asymptomatic SARS-CoV-2 infection and how long it
might last. Currently, the only preventive measures that have been employed with some success
have been social distancing and quarantine after contact tracing and testing. Test and treat
approaches await an effective proven safe therapy that can be implemented on a mass scale. It is
generally believed that an effective vaccine will be 1 of the most important tools to help control
this highly contagious respiratory virus.
2.1. 
Study Rationale
The sponsor is developing a COVID-19 vaccine based on a human replication-incompetent Ad26
vector encoding the SARS-CoV-2 S protein. The S protein is the major surface protein of
coronaviruses. Different animal models have been used for the evaluation of candidate coronavirus
vaccines against SARS-CoV (2003 outbreak), and the common conclusion that has emerged from
the evaluation of several different vaccines is that the viral S protein is the only significant target
for neutralizing antibodies11,61,77,80 and the only viral protein that can elicit protective immunity in
animal models.6,7,12,60,75 Based on these findings, the S protein was selected as the sponsor’s
candidate vaccine antigen.

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Even though a single-dose regimen in study VAC31518COV1001 showed good immunogenicity
that may already protect against COVID-19, data from other vaccines using the Ad26 platform
suggest that a second vaccination may potentially result in a higher and more durable immune
response, providing justification for the evaluation of a 2-dose regimen in this study. The single
dose regimen will be further evaluated in study VAC31518COV3001.
Vaccine-associated enhanced disease has been described in some animal models for SARS and
MERS in which candidate vaccines induced a Th2 biased immune response,1,8,28,38,39 but proof of
human SARS- or MERS-vaccine-associated enhanced disease does not exist as these candidate
vaccines were never tested for efficacy nor used in outbreak situations. The Ad26 vector was
chosen due to its ability to induce humoral and strong cellular responses with a Th1 immune
phenotype.3,5,25,53,56,57,59,68,70,76 This type 1 polarity of the immune response is thought to minimize
the risk of enhanced disease after SARS-CoV-2 infection.
Study VAC31518COV3009 will include participants ≥18 years of age, with and without
comorbidities that are associated with increased risk of progression to severe COVID-19.
Enrollment of participants in these 2 categories will be initiated in a staggered manner, as described
below.
Stage 1: the study will start by enrolling approximately 1,000 participants in 2 age-dependent
subgroups (≥18 years to <60 years of age and ≥60 years of age) without comorbidities that are
associated with increased risk of progression to severe COVID-19 (including approximately
500 Ad26.COV2.S recipients and approximately 500 placebo recipients), then vaccination will be
paused to allow the Independent Data Monitoring Committee (IDMC) to examine Day 3 safety
data (ie, from Day 1 to Day 3; including safety data from the ongoing studies).
Stage 2: if no safety concerns are identified in Stage 1, enrollment will proceed, expanding
enrollment to participants with or without comorbidities that are associated with increased risk of
progression to severe COVID-19in 2 age-dependent subgroups (≥18 years to <60 years of age and
≥60 years of age)(see Section 1.2 [Figure 1] for a schematic overview of the study and Section 5.2
for the list of relevant comorbidities).
Following Ad26.COV2.S EUA in the US and approval of Protocol amendment 4 by both Health
authority and IEC/IRB, a single dose of Ad26.COV2.S will be offered to enrolled participants who
initially received placebo, resulting in de facto unblinding of participants and investigators. Prior
to the unblinding visit, participants may be unblinded upon their request to receive a different
authorized/licensed COVID-19vaccine. Since the study is expected to still be enrolling at the time
of EUA, participants who received 1 dose or 2 doses of placebo will receive a single dose of
Ad26.COV2.S as their next dose, and participants yet to be enrolled will be randomized (1:1) to
either a single-dose or a 2-dose schedule of Ad26.COV2.S. Participants from the Ad26.COV2.S
arm will receive the second vaccination, if applicable (Section 6.4). All participants will be
encouraged to remain in the study and will be followed for efficacy, safety, and immunogenicity,
as originally planned. This will allow assessment of the level of efficacy and duration of protection
of a 2-dose schedule of Ad26.COV2.S compared to the single-dose schedule, as well as a direct

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comparison of the immunogenicity of the 2 schedules, whereby the single dose is introduced at
different time points.
The total sample size for the study (Stages 1 and 2) will be approximately 30,000 participants. It
is intended that a minimum of approximately 30% of recruited participants will be ≥60 years of
age and approximately 20% of recruited participants will be ≥18 to <40 years of age. This sample
size range is determined based on an estimated annualized COVID-19 incidence of 1% to 4% at
study start and the number of COVID-19 cases needed to reach the requirements for efficacy
evaluation within the targeted time frames. The actual sample size for the study, approximately
30,000 participants, will be selected at the operational cut-off date before initiation of the study,
based on estimated incidence rates for the targeted study region and population at that time.
Enrollment may be stopped if the primary endpoint is reached.
This sample size takes into consideration the uncertainty of the epidemiological situation in
combination with the ability to provide a high probability (approximately 90%) to reach a time to
signal within 15 months of the last study for a vaccine with an assumed 65% vaccine efficacy (VE)
or higher. Efforts will be made to ensure good representation in terms of race, ethnicity, and
gender. Details on the possible blinded sample-size reassessment will be described in the Statistical
Analysis Plan (SAP). Refer to Section 9.2.1 for details about the sample size determination.
With implementation of Protocol Amendment 6, all ongoing eligible participants who received
only a single vaccination with Ad26.COV2.S in the study will be offered a single booster dose of
Ad26.COV2.S vaccine. Participants who already received 2 vaccinations with Ad26.COV2.S at
the 5x1010 virus particles (vp) dose level or any COVID-19 vaccinations outside of the study
(including the Janssen vaccine) at the time of local approval of Protocol Amendment 6 are not
eligible to receive a booster vaccination with Ad26.COV2.S. All participants (whether they
consent to the booster vaccination or not) will be encouraged to remain in the study and will be
monitored for safety, immunogenicity, and efficacy according to their original schedule.
A single dose of Ad26.COV2.S vaccine is immunogenic and highly efficacious against severe
COVID-19 disease and COVID-19 related hospitalization and death. Furthermore, while
protection against variants of concern (such as the Beta and Mu variants in study COV3001 and
the Delta variant in the Sisonke study37)remains high against serious disease, hospitalization, and
death, this protection is lower against, eg, the Gamma variant compared to the reference Wuhan
strain. Protection against severe/critical disease caused by different variants of concern (such as
Gamma, Lambda and Mu variants) was shown to be reduced in the final analysis of study
COV3001 compared to the reference Wuhan strain and the Alpha variant, for example. Giving a
second dose of Ad26.COV2.S results in marked increases of immune responses and those higher
immune responses correlate with better protection against COVID-19, as shown in the primary
analysis of study COV3009.44 Some national vaccination recommendation bodies (eg, CDC20)
have recently advised to give a booster vaccination. Therefore, this amendment will permit
boosting of all eligible ongoing participants in this study who received only a single vaccination
with Ad26.COV2.S in the study. As the Janssen vaccine is approved as a single dose vaccine,
participants who received two doses of Ad26COV2.S are considered to already have received the
booster dose. Given that the sponsor has no safety information on mixed schedule vaccinations,

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participants that received a COVID-19 vaccination outside of the study will not be offered the
booster dose in this study.
Following EUA approval, Ad26.COV2.S EUA, conditional licensure, or approval in any country
of COVID-19 vaccines, all participants were gradually unblinded and a single dose of
Ad26.COV2.S was offered to enrolled participants who initially received placebo. Also, the
epidemic continued, and new variants of concern emerged, national recommendations introduced
booster vaccination. The primary analysis of the study that described the double-blind phase has
been completed and the primary objective has been met. Further efficacy evaluations of the
open-label data have limitations, due to the unblinding and the loss of the placebo group, due to
the loss of randomization, as many participants in the placebo groups in the studies did not cross
over to Ad26.COV2.S (eg, because they received another vaccine), and the participants’
knowledge of the number of doses received or the timing since vaccination, which could have led
to behavioral changes impacting the results. Operational challenges have impacted the feasibility
of a strict follow-up of any COVID-19 episode and active surveillance cannot be sustained.
Because of these reasons, the protocol has been amended to reduce the need for on-site visits and
to change the requirements for COVID-19 episode reporting by applying a passive surveillance
approach. Participants in the Immunogenicity Subset will continue with the on-site study visits.
There are no changes to follow-up of safety endpoints, including the reporting of adverse events
of special interest (AESIs). Two analyses are planned for the study: a first analysis will be
conducted for the open-label phase of the study (using the initially designed “active” follow-up of
COVID-19 events) and a second end-of-study analysis is planned (using passive follow-up of
COVID-19 events).
2.2. 
Background
Nonclinical Pharmacology
Nonclinical studies were performed to test the immunogenicity of different vaccine candidates,
leading to the selection of the current vaccine for this development program. In addition, VE of
Ad26.COV2-S has been shown in Syrian hamsters and NHP. Details are provided in the IB.40,41
Nonclinical Safety
Biodistribution
To assess distribution, persistence, and clearance of the Ad26 viral vector platform, intramuscular
(IM) biodistribution studies have been conducted in rabbits using an Ad26-based HIV vaccine,
Ad26.ENVA.01, and an Ad26-based RSV vaccine, Ad26.RSV.preF. In the available
biodistribution studies, the Ad26 vector did not widely distribute following IM administration in
rabbits. Ad26 vector deoxyribonucleic acid (DNA) was primarily detected at the site of injection,
draining lymph nodes and (to a lesser extent) the spleen. Clearance of the Ad26 vector from the
tissues was observed. Both Ad26 vectors showed a comparable biodistribution despite carrying
different antigen transgenes. These data further indicate that the Ad26 vector does not replicate
and/or persist in the tissues following IM injection. These platform data are considered sufficient

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to inform on the biodistribution profile of Ad26.COV2.S  for which the same Ad26 vector
backbone is used.
Toxicology
The sponsor has significant nonclinical experience with Ad26-vectored vaccines using various
transgenes encoding HIV, RSV, Ebola virus, filovirus, human papilloma virus, Zika, influenza
(universal flu [Uniflu]), and malaria antigens. To date, more than 10 Good Laboratory Practice
(GLP) combined repeated dose toxicology and local tolerance studies have been performed in
rabbits (and 1 study in rats), testing the nonclinical safety of various homologous and heterologous
regimens with Ad26-based vaccines at full human doses up to 1.2×1011  vp. No adverse effects
have been observed in these studies. The vaccine-related effects observed were similar across
studies, considered to be reflective of a physiological response to the vaccines administered, and
seem to be independent of the antigen transgene. Overall, there were no safety signals detected in
any of the available GLP toxicology studies with Ad26-based vaccines up to the highest dose
tested (1.2×1011 vp). In a combined embryo-fetal and pre- and postnatal development GLP study
in female rabbits with another Ad26-based vaccine (Ad26.ZEBOV, encoding an Ebola virus
antigen), there was no maternal or developmental toxicity observed following maternal exposure
during the premating and gestation period. A repeated dose and local tolerance GLP study, and a
combined embryo-fetal and pre- and postnatal development GLP study with Ad26.COV2.S  are
planned to run in parallel with study VAC31518COV1001.
Clinical Studies
At the time of initial protocol writing, no clinical data with the Ad26.COV2.S  vaccine were
available.
Several clinical studies with Ad26.COV2.S will be ongoing at the time of initiation of study
VAC31518COV3009.
The FIH  study  VAC31518COV1001 is a randomized, double-blind, placebo-controlled,
Phase 1/2a multicenter study in adults aged ≥18 to ≤55 years and aged ≥65 years. The safety,
reactogenicity, and immunogenicity of Ad26.COV2.S will be evaluated at 2 dose levels (5×1010
vp and 1×1011 vp), administered IM as a single-dose or 2-dose schedule, with a single booster
vaccination administered in 1 cohort.
The safety, reactogenicity, and immunogenicity will be evaluated in a cohort of adults aged ≥18to
≤55 years (Cohort 1a). Safety, reactogenicity, and immunogenicity will also be evaluated in an
expanded cohort in this age group  (Cohort 2). In addition, safety, reactogenicity, and
immunogenicity will be evaluated in a cohort of adults aged ≥65 years (Cohort 3). Overall, a target
of1,045 adult participants in these 2 age groups will be randomly assigned in this study.
As of 10 September 2020, a single injection of Ad26.COV2.S has been administered to 805 adult
participants, aged 18 and older in the FIH study VAC31518COV1001.

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At the time of protocol Amendment 1 writing, initial immunogenicity and safety data (28 days
post-Dose 1 data from Cohort 1a [participants aged ≥18 to ≤55 years] and available data from
Cohort 3 [participants aged ≥65 years]) from study VAC31518COV1001 became available to
demonstrate that a single dose of Ad26.COV2.S at 5×1010 vp and 1×1011 vp induces an immune
response that meets prespecified minimum criteria and has an acceptable safety profile. These data
supported the sponsor’s decision to proceed with Ad26.COV2.S at a dose level of 5×1010 vp in its
Phase 3 studies.
Refer to the latest IB and its addenda (if applicable) for a high level description of the additional
ongoing studies with Ad26.COV2.S.41
Clinical Safety Experience With Ad26-based Vaccines
As described above, replication-incompetent Ad26 is being used as a vector in the development of
vaccine candidates against diseases such as malaria, RSV, HIV, Ebola virus, Zika virus, and
filovirus.
As of 01 July  2020, Ad26-based vaccines had been administered to approximately  90,000
participants in ongoing and completed studies, including more than 76,000 participants in an
ongoing 
Ebola 
vaccine 
study 
in 
the 
Democratic 
Republic 
of the 
Congo
(VAC52150EBL3008/DRC-EB-001) and an ongoing immunization campaign  in  Rwanda
(UMURINZI Ebola Vaccine Program campaign).
The sponsor’s clinical AdVac® safety database report (V5.0, dated 10 April 2020, cut-off date
20 December 2019) describes integrated safety data from 26 completed clinical studies using
Ad26-based vaccines for which the database was locked for final analysis. In these 26 studies,
4,224 adult participants were vaccinated with an Ad26-based vaccine and 938adult participants
received a placebo. A total of 6,004 Ad26-based vaccine doses were administered to adults. Most
adult participants (3,557 out of 4,224; 84.2%) received Ad26-based vaccine at a dose level of
5×1010 vp, while 284 adult participants (6.7%) received Ad26-based vaccine at the 1×1011 vp dose
level (the highest dose level tested).
As of 01 July  2020, more than 85,000 participants were enrolled in ongoing studies and the
ongoing immunization campaign in Rwanda (UMURINZI Ebola Vaccine Program campaign).
However, their safety data were not included in the AdVac® safety database report V5.0 because
the studies were still blinded, the studies were unblinded but their analysis took place after the
AdVac® safety database report cut-off date, or the study data were not integrated in the Ad26-based
vaccine database used for the report.
Overall, the Ad26-based vaccines were well tolerated irrespective of the antigen transgene, without
significant safety issues identified to date. See Section 2.3.1 for a summary of data from the
AdVac® safety database report.

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Ad26-based Vaccines in Adults Aged 60 Years and Older
In the RSV vaccine clinical development program, Ad26.RSV.preF has been evaluated in studies
in participants aged ≥60 years, including the Phase 1 studies VAC18193RSV1003 and
VAC18193RSV1005, 
Phase 
1/2a 
study 
VAC18193RSV1004, 
Phase 
2a 
study
VAC18193RSV2003, and Phase 2b study VAC18193RSV2001. Up to a cut-off date of
24 April 2020, 
approximately 
3,700 participants 
aged 
≥60 years 
have 
received 
an
Ad26.RSV.preF-based regimen in completed and ongoing studies. An acceptable safety and
reactogenicity  profile in participants aged ≥60 years has been reported for the
Ad26.RSV.preF-based regimens assessed in these studies, and no safety concerns have been raised
to date.
Th1/Th2 Profile of Ad26-based Vaccines in Clinical Studies
In the 1960s, a formalin-inactivated RSV vaccine was associated with enhanced respiratory disease
(ERD) in young children, characterized by an increased rate of RSV-mediated, severe lower
respiratory tract infection in the vaccinated individuals compared with the control group.24,34,45,46
Although the mechanisms for ERD are not fully understood, it is thought that FI-RSV may have:
1) failed to induce adequate neutralizing antibody titers; 2) led to an overproduction of binding
antibodies promoting immune complex deposition and hypersensitivity reactions; 3) failed to
induce adequate numbers of memory CD8+ T cells important for viral clearance; and 4) induced
a Th2-skewed type T-cell response.55 Vaccine-induced ERD has also been described for
SARS-CoV and MERS-CoV in animal models,41 but proof of human SARS-CoV or MERS-CoV
vaccine-associated enhanced disease does not exist as these candidate vaccines were never tested
for efficacy nor used in outbreak situations. For SARS and MERS, the mechanism of enhanced
disease observed in mice has been associated with a Th2-mediated eosinophilic infiltration in the
lung, which is similar to the ERD effects observed after RSV infection of mice immunized with
FI RSV. Similar to RSV vaccines, enhanced disease has been shown for whole-inactivated SARS-
CoV vaccines, as well as subunit vaccines inducing a Th2-type immune response, which can be
rescued by formulating vaccines in Th1-skewing adjuvants. In addition to a Th1-biased immune
response, also induction of a high proportion of neutralizing antibodies compared with virus
binding antibodies is desirable to prevent predisposition to enhanced disease as observed for RSV
vaccines. While vaccine-associated enhanced disease was observed in nonclinical studies with
experimental SARS and MERS vaccines, it is not a given that the same risk applies to COVID-19
vaccines. To the sponsor’s knowledge, antibody-related COVID-19 disease enhancement has not
been observed in nonclinical models yet. Antibodies against the receptor-binding domain of
SARS-CoV-2 were shown not to enhance in vitro infectivity. Repeated SARS-CoV-2 challenge
of NHP or NHP studies with Th2 biasing COVID-19 vaccines that would be expected to
predispose to enhanced disease did not show any signs of enhanced disease. In addition, disease
enhancement was not observed in NHP immunized with ChAdOx1 encoding SARS-CoV-2 S
protein prior to challenge with SARS-CoV-2.41
The immunogenicity profile of adenoviral vectors, with particular emphasis on Th1 responses, is
illustrated by data obtained from immunization of adults with Ad26-vectored HIV vaccines
(Ad26.ENVA.01 and Ad26.Mos.HIV) and Ad26-vectored Ebola vaccine (Ad26.ZEBOV). These
data show predominantly IFN-γ and TNF-α production in CD4+ and CD8+ T cells.3,4,5 In the RSV

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vaccine clinical development program, Ad26.RSV.preF is being evaluated in healthy
RSV-seropositive toddlers aged 12 to 24 months (Phase 1/2a study VAC18194RSV2001). Safety
data from the PA at 28 days after the second study vaccination revealed no safety concerns
following Ad26.RSV.preF dosing at 5×1010 vp or a placebo. The immunogenicity of a single
immunization with Ad26.RSV.preF in RSV-seropositive toddlers aged 12 to 24 months, including
favorable Th1 bias, was confirmed. In a further study of Ad26.RSV.preF in RSV-seronegative
toddlers aged 12 to 24 months (Phase 1/2a study VAC18194RSV2002), initial safety data have
not revealed concerns after Ad26.RSV.preF dosing.
2.3. 
Benefit-Risk Assessment
More detailed information about the known and expected benefits and risks of Ad26.COV2.S may
be found in the IB.41
2.3.1 Risks Related to Study Participation
The following potential risks of Ad26.COV2.S  will be monitored during the study and are
specified in the protocol.
Risks Related to Ad26.COV2.S
No clinical data with Ad26.COV2.S  are available at the time of finalization of the initial
VAC31518COV3009protocol.
For emerging clinical data and the most comprehensive nonclinical information regarding
Ad26.COV2.S, refer to the latest version of the IB and its addenda (if applicable).41
Sites should advise participants that side effects include fever as well as injection site pain,
headache, fatigue, myalgia, and nausea per the current ICF; however, the occurrence of fever
appears to be more common in younger adults and can be severe. This is based on information
from study VAC31518COV1001 that became available at the time of protocol Amendment 1
writing.
Anaphylaxis is considered an important identified risk for Ad26.COV2.S. Individuals should be
observed by a healthcare provider after vaccination per protocol requirements. Refer to the latest
version of the IB and its addenda (if applicable) for further details.
Thrombosis in combination with thrombocytopenia (thrombosis with thrombocytopenia syndrome
[TTS]), in some cases accompanied by bleeding, has been observed very rarely following
vaccination with Ad26.COV2.S. Reports include severe cases of venous thrombosis at unusual
sites such as cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis and arterial
thrombosis, in combination with thrombocytopenia. These cases occurred approximately
1-2 weeks following vaccination, mostly in women under 60 years of age. Thrombosis in
combination with thrombocytopenia can be fatal. The exact physiology of TTS is unclear. TTS is
considered an important identified risk for Ad26.COV2.S. Participants should be instructed to seek
immediate medical attention if they develop symptoms such as shortness of breath, chest pain, leg
swelling, persistent abdominal pain, severe or persistent headaches, blurred vision, and skin

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bruising and/or petechiae beyond the site of vaccination. The medical management of thrombosis
with thrombocytopenia is different from the management of isolated thromboembolic diseases.
Study site personnel and/or treating physicians should follow available guidelines for treatment of
thrombotic thrombocytopenia (e.g. from the American Society of Hematology2, British Society of
Haematology Expert Haematology Panel10, and the CDC15). The use of heparin may be harmful
and alternative treatments may be needed. Consultation with a hematologist is strongly
recommended. Management of the participant should not be delayed by decision-making of the
AESI Assessment Committee. Refer to the latest version of the IB and its addenda (if applicable)
for further details. Due to the possibility of the occurrence of TTS after vaccination with
Ad26.COV2.S, additional reporting and data collection procedures have been included in the study
for thrombotic events, thrombocytopenia, and TTS (see Section 8.3.7 and Section 8.3.7.1), which
may facilitate diagnosis and clinical management of the event.
More detailed information about the known and expected benefits and risks of Ad26.COV2.S may
be found in the IB.41
Risks Related to Ad26.COV2.S Administration after Previous Vaccination Ad26.COV2.S
Preliminary safety data of an Ad26.COV2.S booster (5×1010 vp, 2.5×1010 vp, or 1×1010 vp)
administered ≥6 months post-primary single-dose Ad26.COV2.S (5×1010 vp) vaccination are
available from 244 participants (dose-level blinded data). The data indicate that the safety and
reactogenicity of a second Ad26.COV2.S dose is acceptable and in line with the safety and
reactogenicity observed after the first Ad26.COV2.S dose. There is no indication of increased
reactogenicity upon administration of a second dose of Ad26.COV2.S and no safety concerns have
been observed.
In addition, the primary analysis of this study COV3009 indicated that the safety profile of the
Ad26.COV2.S vaccine remained consistent and was generally well-tolerated when administered
as a second dose according to the study schedule (vaccinations at Day 1 and Day 57).44
Risks Related to Adenoviral-vectored Vaccines
The clinical AdVac® safety database (report version 5.0, dated 10 April 2020, cut-off date
20 December 2019) contains pooled safety data from 26 Janssen-sponsored clinical studies with
Ad26 vaccine candidates: Ad26.ZEBOV (Ebola; 10 studies), Ad26.ENVA.01, Ad26.Mos.HIV
and Ad26.Mos4.HIV (HIV; 8 studies), Ad26.CS.01 (malaria; 1 study), Ad26.RSV.FA2 and
Ad26.RSV.preF (RSV; 6 studies), and Ad26.Filo (filovirus; 1 study). In these studies, 4,224 adult
participants and 650 children received at least 1 vaccination with an Ad26-based vaccine. The
AdVac® safety database report includes data only from studies for which the database has been
locked for the final analysis; therefore, of the studies including an Ad26.RSV.preF-based regimen
mentioned in Section 2.2, only data for approximately 230 participants aged ≥60 years from
studies VAC18193RSV1003, VAC18193RSV1005, and VAC18193RSV2003 were included.
Overall, the Ad26-based vaccines were well tolerated, without significant safety issues identified.

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The majority of solicited local and systemic AEs were of mild or moderate severity and usually
started within 1 to 2 days after vaccination. Most of the events resolved within 1 to 3 days.
In adults, the most frequently reported solicited local AE was injection site pain (56.9% of
Ad26 participants, compared with 22.5% of placebo participants). All other solicited local AEs
were experienced by less than 25% of adult participants. The most frequently experienced solicited
local AE in children was injection site pain, reported in 13.9% of children aged 1-3 years, 29.8%
of children aged 4 to 11 years, and 24.8% of children aged 12 to 17 years after vaccination with
an Ad26-based vaccine. For placebo, these percentages were 29.2% in children aged 4 to 11 years
and 14.3% in children aged 12 to 17 years. No children aged 1 to 3 years have received placebo.
Severe injection site pain was experienced by 1.0% of adult Ad26 participants and 0.8% of children
aged 4 to 11 years. No children in the other 2 age groups and no placebo participants experienced
severe injection site pain.
There was a trend toward an increase in the frequency of some local AEs with an increase in Ad26
dose, ie, injection site pain (18.7% of participants at the 0.8×1010 vp dose level, 38.7% of
participants at the 2×1010 vp dose level, 52.0% of participants at the 5×1010 vp dose level, and
77.1% of participants at the 1×1011 vp dose level), and to a lesser extent injection site swelling
(6.7%, 2.7%, 9.3%, and 17.6%, respectively). Injection site warmth was not collected at the
0.8×1010 vp and the 2×1010 vp dose level. The frequency of injection site warmth at the 5×1010 vp
and the 1×1011 vp dose level was 19.5%, and 26.7%, respectively. This trend needs to be
interpreted with caution since the participants in the lower dose groups (0.8×1010 vp and 2×1010 vp
dose level) were all from a single study (VAC52150EBL3002), and the majority of the participants
in the highest dose group (1×1011 vp dose level) were also from a single study
(VAC18193RSV2003).
The most frequently reported solicited systemic AEs (ie, reported in more than 30% of
participants) for adult Ad26 participants were malaise (53.8%), fatigue (48.3%), headache
(45.7%), and myalgia (38.3%), all of which were more frequent for Ad26 participants compared
with placebo (36.4%, 30.7%, 30.0%, and 17.7% of placebo participants, respectively). Most of
these events were considered related to the study vaccine. Pyrexia (9.9%) and vaccine-related
pyrexia (9.0%) were also reported more frequently after administration of an Ad26-based vaccine
compared with placebo (3.5% and 2.9%, respectively).
Solicited systemic AEs reported in ≥10% of children aged 1 to 3 years were decreased appetite
(13.9%), decreased activity (13.2%), pyrexia (11.1%), and irritability (10.4%). The most
frequently reported solicited systemic AEs in children aged 4 to 11 years (reported in ≥15% of
Ad26 participants) were headache (23.6%; no data are available for the placebo group in this age
group), and decreased activity (18.5%) and irritability (17.6%), which were both reported in
4.2% (N 1) of placebo participants. The most frequently reported solicited systemic AEs in
children aged 12 to 17 years (reported in ≥15% of Ad26 participants) were headache (34.6%) and
fatigue (24.0%), compared to 33.3% and 19.0% of placebo participants, respectively. Most of the
frequently experienced solicited systemic AEs in children were considered related to the study
vaccine.

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The majority of solicited systemic AEs were of mild or moderate severity. For adults, 6.5% of
Ad26 participants and 2.0% of placebo participants reported severe solicited systemic AEs, mostly
malaise and fatigue. Other severe solicited systemic AEs were reported in less than 3% of adult
Ad26 participants.
There was a trend toward an increase in the frequency of solicited systemic AEs with an increase
in Ad26 dose (35.3% at the 0.8×1010 vp dose level, 49.3% at the 2×1010 vp dose level, 64.5% at
the 5×1010 vp dose level, and 70.4% at the 1×1011 vp dose level). The frequency of severe solicited
systemic AEs also tended to increase with higher Ad26 dose, ie, 1.3% of participants at the
0.8×1010 vp and the 2×1010 vp dose level, 5.3% of participants at the 5×1010 vp dose level, and
14.4% of participants at the 1×1011 vp dose level. This trend needs to be interpreted with caution
since the participants in the lower dose groups (0.8×1010 vp and 2×1010 vp dose level) were all
from a single study (VAC52150EBL3002), and the majority of the participants in the highest dose
group (1×1011 vp dose level) were also from a single study (VAC18193RSV2003).
The most frequently reported unsolicited AE in adult Ad26 participants was upper respiratory tract
infection (5.3% vs. 7.0% in adult placebo participants). The most frequently reported unsolicited
AEs considered related to the vaccine were neutropenia (1.0% of adult Ad26 participants vs. 0.5%
of adult placebo participants) and dizziness (0.7% vs. 0.2%, respectively).
For Ad26, the most frequently reported unsolicited AE in children was malaria,a reported in 36.8%
of children aged 1 to 3 years, in 19.0% of children aged 4 to 11 years, and in 10.6% of children
aged 12 to 17 years. One child in the 12 to 17 years group (4.8%) experienced malaria after placebo
vaccination. There were no other children in the placebo groups who experienced malaria. The
most frequently reported related unsolicited AE was hypernatremia (1.6% of children aged 4 to 11
years [vs. 4.2% with placebo] and 2.4% of children aged 12 to 17 years [vs. 4.8% with placebo]).
No AEs in children aged 1 to 3 years were considered related to the vaccine.
General Risks Related to Vaccination
In general, IM injection may cause local itching, warmth, pain, tenderness, erythema/redness,
induration, swelling, arm discomfort, or bruising of the skin. Participants may exhibit general signs
and symptoms associated with IM injection of a vaccine and/or placebo, including fever, chills,
rash, myalgia, nausea/vomiting, headache, dizziness, arthralgia, general itching, and fatigue. These
side effects will be monitored, but are generally short-term. Instructions regarding use of
antipyretic medication can be found in Section 6.10.
Syncope can occur in association with administration of injectable vaccines. Syncope can be
accompanied by falls. Procedures should be in place to avoid falling injury. If syncope develops,
participants should be observed until the symptoms resolve. Fear of injection might lead to fainting
and fast breathing.
aThis was expected as the pediatric studies were conducted in malaria-endemic regions. The imbalance in the
frequency of malaria between Ad26 participants and placebo participants can largely be explained by the fact that the
active control group of study VAC52150EBL3001 was not included in the pooling.

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Participants may have an allergic reaction to the vaccination. An allergic reaction may cause a
rash, urticaria, or even anaphylaxis (see above risks related to Ad26.COV2.S). Severe reactions
are rare. Participants with a known or suspected allergy, or history of anaphylaxis or other serious
adverse reactions to vaccines or their excipients (including specifically the excipients of the study
vaccine), will be excluded from the study.
After each vaccination, participants will remain at the study site for close observation by study
staffto monitor for the development of any acute reactions. The first 1,000 participants will remain
under observation at the study site for at least 30 minutes after each vaccination to monitor for the
development of acute reactions. If at the time of the Day 3 safety review of the initial
1,000 participants no acute reactions have been observed, the observation period at the study site
may be reduced to at least 15 minutes, except where local regulations require a longer observation
period (eg, Belgium), after each vaccination for the remaining participants in the study. Necessary
emergency equipment and medications must be available in the study site to treat severe allergic
reactions.
Pregnancy and Birth Control
The effect of the study vaccine on a fetus or on nursing baby is unknown.
Given the limited number of incident pregnancies in the clinical studies with Ad26-based vaccines
in the AdVac® safety database report (HIV vaccine: 20 pregnancies in participants and 10 in
partners of participants; Ebola vaccine: 32 pregnancies in participants and 13 in partners of
participants), it is not possible at present to draw firm conclusions on the safety of the vaccines
when administered around the time of conception or prior to the initiation of the pregnancies. There
is currently no concerning pattern of AEs in the pregnancies initiated around the time of
vaccination or after exposure to the Ad26-based vaccines in the Janssen vaccines clinical
development programs.
Participants of childbearing potential will be required to agree to practicing an acceptable effective
method of contraception and agree to remain on such a method of contraception from providing
consent until 3 months after receiving the last dose of the study vaccine (see Section 5.1). Use of
condoms is not considered as an acceptable contraceptive barrier method due to the failure rate of
female and male condoms.19 Participants who are pregnant at screening will be excluded from the
study. Participants who become pregnant during the study and received Ad26.COV2.S will not
receive further vaccination. However, participants who became pregnant during the study and
received placebo during the double-blind phase, may be vaccinated with Ad26.COV2.S
(single-dose regimen, open-label dose) if allowed by local regulations for emergency use of
vaccines and if the investigator considers that the potential benefits outweigh any potential risks
to the mother and fetus (see Section 6.4). Participants will remain in the study and will continue to
undergo all procedures for surveillance and follow-up of COVID-19 and all safety follow-up as
outlined in the protocol for all participants. Likewise, pregnant participants who previously
received the open-label vaccination may receive the booster vaccination  if allowed by local
regulations for use of vaccines and if the investigator considers that the potential benefits outweigh
any potential risks to the mother and fetus (see Section 6.5).

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Participants who are breastfeeding are allowed to participate in the study.
Risks from Blood Draws
Blood draws may cause pain, tenderness, bruising, bleeding, dizziness, vasovagal response,
syncope, and rarely, infection at the site where the blood is taken.
Risks from Collection of Nasal Swab Samples
Collection of a nasal swab sample may cause a nosebleed.
Participants are asked to perform the nasal swab samples themselves at home or to seek assistance
from a trained health care professional (HCP). Assistance with the collection of nasal swab
samples bears the risk of potentially infecting the assistant.
Theoretical Risk of Enhanced Disease
Vaccine-associated enhanced disease has been described for SARS-CoV and MERS-CoV in some
animal models1,8,28,38,39, and is associated with non-neutralizing antibodies and a Th2-skewed
immune response. In contrast, the Ad26-based vaccines have been shown to induce a clear
Th1-skewed immune response and generate potent neutralizing antibody responses in both humans
and animal models (see Section 2.2). Participants in the present study will be informed of the
theoretical risk of disease enhancement in the informed consent form (ICF). Initially, this study
will include healthy adults aged ≥18 to <60 years of age and healthy elderly ≥60 years of age
(Stage 1). As a risk mitigation strategy, all enrolled participants will be intensively monitored (up
to Amendment 7) during the conduct of the study to rapidly diagnose COVID-19 and refer for
treatment, ifapplicable. In case ofany new symptoms or health concerns that could be related to
infection with SARS-CoV-2, participants will be evaluated for acquisition of molecularly
confirmed COVID-19 and severity will be assessed using the case definitions specified in
Section 8.1.3 by the investigator. COVID-19 cases will be assessed by the Clinical Severity
Adjudication Committee (see Section 8.1.3.6), as part of the primary and secondary endpoints (see
Section 3). All participants will be monitored for safety, including enhanced disease and SAEs
until the last study visit and including MAAEs up to 6 months after the last Ad26.COV2.S dose.
In addition, as detailed in Section 9.8, the statistical support group (SSG)will monitor the number
and severity of molecularly confirmed COVID-19 cases in the Ad26.COV2.S and placebo groups
to identify an imbalance between groups if it occurs. The SSG will inform the IDMC as soon as
an imbalance between groups is detected. A prespecified threshold (imbalance above a certain
percentage and/or number of cases) that will trigger notification of the IDMC will be described in
the SAP.
Unknown Risks
There may be other risks that are not known. If any significant new risks are identified, the
investigators and participants will be informed.
2.3.2 Benefits of Study Participation
Participants may benefit from clinical testing and physical examination.

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The efficacy, immunogenicity and safety data generated to date suggest a favorable benefit-risk
profile for Ad26.COV2.S in the proposed indication, ie, active immunization to prevent
COVID-19 caused by SARS-CoV-2 in adults ≥18 years of age. The overall benefit and risk balance
for individual participants is ongoing.
Preliminary  immunogenicity and safety data for a Ad26.COV2.S booster dose (5×1010 vp) at
≥6 months post-primary single-dose Ad26.COV2.S administration and efficacy data for a 2nd dose
of Ad26.COV2.S 2-3 months post-primary single-dose Ad26.COV2.S administration  support a
favorable benefit-risk profile in participants who received a single dose of Ad26.COV2.S.
2.3.3 Benefit-Risk Assessment of Study Participation
Based on the available data and proposed safety measures, the overall benefit-risk assessment for
this clinical study is considered acceptable for the following reasons:
 
Only participants who meet all inclusion criteria and none of the exclusion criteria (specified
in Section 5) will be allowed to participate in this study. The selection criteria include adequate
provisions to minimize the risk and protect the well-being of participants in the study.
 
Safety will be closely monitored throughout the study:
 
In general, safety evaluations will be performed at scheduled visits during the study, as
indicated in the Schedules of Activities.
 
The first 1,000 participants will remain under observation at the study site for at least
30 minutes after each vaccination to monitor for the development of acute reactions. If at
the time of the Day 3 safety review of the initial 1,000 participants no acute reactions
have been observed, the observation period at the study site may be reduced to at least
15 minutes, except where local regulations require a longer observation period
(eg, Belgium), after each vaccination for the remaining participants in the study.
Necessary emergency equipment and medications must be available in the study site to
treat severe allergic reactions. Participants in the Safety Subset will use an e-Diary to
document solicited signs and symptoms. Details are provided in Section 8.3.
 
The investigator or the designee will document unsolicited AEs for participants in the
Safety Subset, and SAEs and medically-attended adverse events (MAAEs) for all
participants as indicated in Section 8.3 and Appendix 4.
 
As of Protocol Amendment 7, the investigator or the designee will document COVID-19
(S)AEs.
 
From the time of local approval of Protocol Amendment 5 onwards, TTS is considered
to be an adverse event of special interest (AESI) (Section 8.3.7). Suspected AESIs
(thrombotic events and thrombocytopenia [defined as platelet count below 150,000/µL9])
must be reported to the sponsor within 24 hours of awareness. Suspected AESIs will be
followed up as described in the Schedule of Activities in Section 1.3.7.
 
Any clinically significant abnormalities (including those persisting at the end of the
study/early withdrawal) will be followed by the investigator until resolution or until
clinically stable.

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An IDMC will be established to monitor safety data on an ongoing basis to ensure the
continuing safety of the participants enrolled in this study. This committee will review
interim unblinded data. The IDMC responsibilities, authorities, and procedures will be
documented in the IDMC Charter. Additional ad hoc review may be performed further to
the occurrence of any SAE leading to a study pausing situation as outlined in
Section 6.11, or at request of the sponsor’s medical monitor or designee. During the
open-label phase, the IDMC will continue to monitor safety  and efficacy  in case of
concerns.
 
Several safety measures are included in this protocol to minimize the potential risk to
participants, including the following:
 
The study will use a staggered enrollment strategy to mitigate the risks for participants at
increased risk of progression to severe COVID-19:
o 
In Stage 1, the study will initially enroll participants based on  acceptable Day 29
post-Dose 1 immunogenicity and safety data from Cohorts 1a and 3 of study
VAC31518COV1001 (see details in the IB40,41). In this stage, approximately
1,000 participants without comorbidities that are associated with increased risk of
progression to severe COVID-19 will be enrolled (including approximately
500 Ad26.COV2.S recipients and approximately 500 placebo recipients).
o 
In Stage 2, after a vaccination pause in Stage 1 to allow the IDMC to examine Day 3
safety data (ie, from Day 1 to Day 3; including safety data from the ongoing studies)
and if no safety concerns are identified, enrollment will proceed, also including
participants with and without comorbidities that are associated with increased risk of
progression to severe COVID-19 in 2 age-dependent subgroups (≥18 years to
<60 years of age and ≥60 years of age). See Section 1.2 (Figure 1) for a schematic
overview of the study and Section 5.2 for the list of relevant comorbidities.
 
Up to Amendment 7: Participants will be intensively monitored in this study to rapidly
diagnose COVID-19, and refer for treatment, if applicable. This will mitigate the
theoretical potential risk for vaccine-associated enhanced disease when immunized
individuals are infected with the virus. The induction of neutralizing antibody and the
Th1 response induced by this vaccine in animals also mitigates this risk.
 
There are prespecified rules for participants in Stage 1 that if met would result in pausing
of further vaccinations (see Section 6.11), preventing exposure of new participants to
study vaccine until the IDMC reviews all safety data (see Committees Structure in
Appendix 3 [Section 10.3.6]).
 
Study vaccinations will be discontinued in participants for the reasons included in
Section 7.
 
Contraindications to vaccination are included in Section 5.5.
 
After the Ad26.COV2.S EUA in the US and approval of Protocol Amendment 4 by the
local Health Authority and the IEC/IRB, the study will be conducted in the open-label
fashion. Participants who initially received placebo will be offered to receive a single
dose of Ad26.COV2.S  (open-label vaccination) under the conditions delineated in
Section 6.4 and will continue to be monitored for safety as mentioned in Section 8.3. At
the unblinding visit, all participants will be counselled about the importance of continuing

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other public health measures to limit the spread of disease including social distancing,
wearing a mask, and hand washing (Section 8.8). After local approval of Protocol
Amendment 6, eligible participants who received a single Ad26.COV2.S vaccination in
this study will be offered to receive a single Ad26.COV2.S booster vaccination, under
the conditions delineated in Section 6.5 and will continue to be monitored for safety as
mentioned in Section 8.3. With the implementation of Protocol Amendment 7, active
follow-up of new  (suspected) COVID-19 episodes will be replaced by a passive
surveillance approach and on-site visits will be replaced by safety assessments via phone
call visits (except for participants in the Immunogenicity Subset).
3. 
OBJECTIVES AND ENDPOINTS
1. Double-blind Phase
The objectives and endpoints for the double-blind phase are:
Objectives 
Endpoints
Primary
To demonstrate the efficacy of Ad26.COV2.S  in the 
prevention of molecularly confirmeda, moderate to 
severe/critical COVID-19b, as compared to placebo, in 
SARS-CoV-2 seronegative adults 
First occurrence of molecularly confirmeda,
moderate to severe/critical COVID-19b,
with onset at least 14 days after the second
vaccination (Day 71).
Secondaryf
(The method used to perform hypothesis testing preserving the family-wise error rate [FWER] will be
specified in the Statistical Analysis Plan [SAP])
Efficacy
To demonstrate the efficacy of Ad26.COV2.S  in the 
prevention of molecularly confirmeda, moderate to 
severe/critical COVID-19b, as compared to placebo, in 
adults regardless of their serostatus 
 First 
occurrence 
of 
molecularly
confirmeda, moderate to severe/critical
COVID-19b, with onset 1 day after the 1st
vaccination
 First 
occurrence 
of 
molecularly
confirmeda, moderate to severe/critical
COVID-19b, with onset 14 days after the
second vaccination (Day 71)
To evaluate the efficacy of Ad26.COV2.S in the prevention
of molecularly confirmeda, moderate to severe/critical
COVID-19b as compared to placebo
 
First 
occurrence 
of 
molecularly
confirmeda, moderate to severe/critical
COVID-19b with onset 1 day after the 1st
vaccination
 
First 
occurrence 
of 
molecularly
confirmeda, moderate to severe/critical
COVID-19b with onset 14 days after the
1st vaccination (Day 15)
 
First 
occurrence 
of 
molecularly
confirmeda, moderate to severe/critical
COVID-19b with onset 28 days after the
1st vaccination (Day 29).

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Objectives 
Endpoints
To assess the effect of Ad26.COV2.S  on COVID-19
requiring medical intervention (based on objective criteria)
compared to placebo
First occurrence of COVID-19 requiring
medical intervention (such as a composite
endpoint of hospitalization, ICU admission,
mechanical ventilation, and ECMO, linked
to objective measures such as decreased
oxygenation, X-ray or CT findings) and
linked to any molecularly confirmeda,
COVID-19b,c at least 14 days after the
second vaccination (Day 71)
To assess the effect of Ad26.COV2.S  on SARS-CoV-2
viral RNA load compared to placebo for moderate to
severe/critical COVID-19b
Assessment of the SARS-CoV-2 viral load
by quantitative RT-PCR, in participants
with molecularly confirmeda, moderate to
severe/critical COVID-19b by serial viral
load measurements during the course of a
COVID-19 episode, at least 14 days after the
second vaccination (Day 71)
To assess the effect of Ad26.COV2.S  on molecularly
confirmeda, mild COVID-19c
First occurrence of molecularly confirmeda,
mild COVID-19c, at least 14 days after the
second vaccination (Day 71)
To assess the effect of Ad26.COV2.S on COVID-19 as
defined by the US FDA harmonized case definitiond
First occurrence of molecularly confirmeda
COVID-19d at least 14 days after the second
vaccination (Day 71)
To assess the effect of Ad26.COV2.S on all molecularly
confirmeda symptomatic COVID-19b,c, as compared to
placebo
Burden of disease (BOD) endpoint (see
Section 9.4.2) derived from the first
occurrence of molecularly confirmeda
symptomatic COVID-19b,c (meeting the
mild, moderate or severe/critical COVID-19
case definition) with onset at least 14 days
after the second vaccination (Day 71)
To assess the effect of Ad26.COV2.S on occurrence of
confirmed asymptomatic or undetected infections with
SARS-CoV-2, as compared to placeboe
 
Serologic conversion between baseline
and other blood samples before
unblinding visit using an enzyme-
linked immunosorbent assay (ELISA)
and/or SARS-CoV-2 immunoglobulin
assay that is dependent on the SARS-
CoV-2 nucleocapsid (N) protein
 
Asymptomatic infection detected by
RT-PCR
To assess the efficacy of Ad26.COV2.S in the prevention
of SARS-CoV-2 infection (both symptomatic and
asymptomatic infections combined, that are serologically
and/or molecularly confirmeda), as compared to placebo
First occurrence of SARS-CoV-2 infection
(serologically 
and/or 
molecularly
confirmeda) with onset at least 14 days after
the second vaccination (Day 71)
Safety
To evaluate safety in terms of SAEs and AESIs (during the
entire study), MAAEs (until 6 months after the last double-
Occurrence and relationship of SAEs and
AESIs (during the entire study), MAAEs
(until 6 months after the last double-blind

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Objectives 
Endpoints
blind vaccination), and MAAEs leading to study
discontinuation (during the entire study) for all participants
vaccination), and MAAEs leading to study
discontinuation (during the entire study) for
all participants
In a subset of participants, to evaluate the safety and
reactogenicity in terms of solicited local and systemic AEs
during 7 days after each vaccination, and in terms of
unsolicited AEs during 28 days after each vaccination
Occurrence, 
intensity, 
duration 
and
relationship of solicited local and systemic
AEs during 7 days following each
vaccination and of unsolicited AEs during
28days following each vaccination
Immunogenicity
In a subset of participants, to evaluate the immunogenicity
of Ad26.COV2.S, as compared to placebo
Analysis of antibodies binding to the
SARS-CoV-2 S protein by ELISA.
Exploratory
To assess the effect of Ad26.COV2.S on SARS-CoV-2
viral RNA load compared to placebo for mild COVID-19c
Assessment of the SARS-CoV-2 viral load
by quantitative RT-PCR, in participants
with molecularly confirmeda, mild COVID-
19c by serial viral load measurements during
the course of a COVID-19 episode
To assess the effect of Ad26.COV2.S on health care
utilization (such as hospitalization, ICU admission,
ventilator use) linked to any molecularly confirmeda
COVID-19, as compared to placebo
Health 
care 
utilization 
(such 
as
hospitalization, ICU admission, ventilator
use) linked to any molecularly confirmeda
COVID-19 at least 14 days after the second
vaccination (Day 71)
To assess the efficacy of Ad26.COV2.S in the prevention
of SARS-CoV-2 
infection 
in 
participants 
with
comorbidities associated with increased risk of progression
to severe COVID-19, as compared to placebo
First occurrence of SARS-COV-2 infection
(serologically 
and/or 
molecularly
confirmeda) 
in 
participants 
with
comorbidities associated with increased risk
of progression to severe COVID-19 with
onset at least 14 days after the second
vaccination (Day 71)
To explore the effect of Ad26.COV2.S on other potential
complications of COVID-19 (linked to any respiratory
disease and linked to any molecularly confirmeda COVID-
19) not previously described, as compared to placebo
First occurrence of potential complications
of COVID-19 linked to any respiratory
disease and linked to any molecularly
confirmeda COVID-19, with onset at least
14 days after the second vaccination (Day
71)
To explore the effect of Ad26.COV2.S on all-cause
mortality, as compared to placebo
Deaths occurring at least 14 days after the
second vaccination (Day 71)
To evaluate the immune response in participants with
COVID-19 in relation to risk of development of COVID-
19, protection induced by Ad26.COV2.S, and risk of
accelerated disease
Assessment of the correlation  of humoral
immune responses with emphasis on
neutralizing, 
binding 
and 
functional
antibodies, with the risk of COVID-19 and
protection induced by the study vaccine
In a subset of participants to further assess the humoral
immune response to Ad26.COV2.S, as compared to
placebo
Humoral immunogenicity endpoints:
 
Functional and molecular antibody
characterization including, but not
limited to avidity, Fc-mediated viral
clearance, 
Fc 
characteristics, 
Ig
subclass, 
IgG 
isotype, 
antibody

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Objectives 
Endpoints
glycosylation, and assessment of
antibody repertoire
 
Original and/or emerging SARS-CoV-
2 lineage neutralization as measured by
virus neutralization assay (VNA; wild-
type 
virus 
and/or 
pseudovirion
expressing SARS-CoV-2 S protein)
 
Adenovirus neutralization as measured
by VNA
 
Analysis of antibodies to the receptor-
binding domain (RBD) of the SARS-
CoV-2 S protein
 
Passive transfer: analysis of immune
mediators correlating with protection
against experimental SARS-CoV-2
challenge in a suitable animal model.
To explore changes in the SARS-CoV-2 genome 
Development of SARS-CoV-2 variants
To examine efficacy for moderate/severe and severe 
disease as well as medical utilization or death in the 
vaccine and placebo groups for variant strains that have 
been identified or if there are cases associated with a 
combination of variants.
Occurrence of moderate/severe or severe
COVID-19, medical utilization, or death for
each of the circulating viral variants,
identified by S-gene sequencing
To evaluate patient-reported outcomes (PROs) in relation  
to the presence of SARS-CoV-2 infection and the presence, 
severity and duration of COVID-19 signs and symptoms in
participants who received Ad26.COV2.S, as compared to
placebo
 
Presence, severity and duration of
COVID-19 signs and Symptoms;
 
Confirmation 
of 
SARS-CoV-2
infection by molecular testing
To assess the difference in severity of cases in participants 
who received Ad26.COV2.S as compared to placebo 
Reduction in severity of COVID-19 signs
and Symptoms
To assess the impact of pre-existing humoral immunity 
against coronaviruses other than SARS-CoV-2 at baseline 
on Ad26.COV2.S vaccine immunogenicity  
Analysis 
of 
antibodies 
binding 
to
coronaviruses other than SARS-CoV-2 by
ELISA
To assess the incidence of co-infection of SARS-CoV-2 
and other respiratory pathogens and to assess the effect of 
the vaccine during such co-infections as well as to estimate 
the incidence of other respiratory pathogens during the 
study period. 
Analysis of broad respiratory pathogens
panel in the nasal swabs collected during a
confirmed COVID-19 episode and in a
subset of nasal swab samples from
participants with a symptomatic infection.
In US participants, To increase the information on prior 
medical history (electronic health records, claims, 
laboratory data from other care settings) in order to further 
evaluate its potential effect on the response to 
immunization and the impact of immunization on efficacy 
and duration of efficacy as well as AEs that may occur 
during and after completion of the study. 
Utilization of tokenization and matching
procedures for exploratory analysis of
participant’s medical data prior to, during,
and following participation in the study
(real-world 
data). 
Analysis 
will 
be
performed to relate real-world data to
vaccine immune responses, efficacy and

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Objectives 
Endpoints
duration of protection, and AEs (see
Section 4.1 and Section 8.7).
a Molecularly confirmed COVID-19 is defined as a positive SARS-CoV-2 viral RNA result by a central laboratory
using a RT-PCR-based or other molecular diagnostic test .
b Per case definition for moderate to severe/critical COVID-19 (see Section 8.1.3.1) as determined by the Clinical
Severity Adjudication Committee (See Section 8.1.3.6).
c Per case definition for mild COVID-19 (see Section 8.1.3.2)as determined by the Clinical Severity Adjudication
Committee (See Section 8.1.3.6).
d Per case definition for COVID-19 according to the US FDA harmonized case definition (see Section 8.1.3.3)
e Per case definition for asymptomatic or undetected COVID-19 (see Section 8.1.3.4) as determined by the Clinical
Severity Adjudication Committee (See Section 8.1.3.6).
f All secondary efficacy endpoint analyses will occur in the PP analysis set, in seronegative participants unless
otherwise indicated in the statistical analysis plan (SAP).
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
Based on the changes in the objectives and endpoints, the SAP for the double-blind phase will be
amended and will be provided to the authorities prior to the primary analysis of efficacy of the
two-dose schedule versus placebo in the double-blind phase.
HYPOTHESES
The double-blind phase of the study is designed to test the primary hypothesis of VE in the
per-protocol (PP)population: H0: VE ≤30% versus H1: VE >30% and will be evaluated at a 2.5%
one-sided significance level.
The primary endpoint will evaluate the first occurrence of molecularly confirmed, moderate to
severe/critical COVID-19 according to the case definition (Section 8.1.3.1), with onset at least
14 days after the second vaccination with Ad26.COV2.S versus placebo, in the PP population
including all events with and without comorbidities.
If the primary endpoint of the double-blind phase hypothesis testing is successful, secondary
objectives will be evaluated against a null hypothesis employing a lower limit VE>0%. The
method to perform hypothesis testing of primary and secondary objectives preserving the FWER
will be specified in the SAP. The FWER will be controlled at 2.5% 1-sided significance level.
Details are described in the Section 9.

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2. Open-label Phase
Figure 2: 
Schema of Cohorts Throughout the VAC31518COV3009 Study:
With Protocol Amendment 4, an unblinding visit was introduced at which participants who were
initially assigned to the placebo arm in the double-blind phase, and consent, receive a single dose
of Ad26.COV2.S vaccine (open-label vaccination). Following the unblinding, the study is
conducted in an open-label fashion. After the study pause, the unblinding visit was scheduled as
soon as reasonably practicable and preferably no later than 2 months following local approvals of
Protocol Amendment 5 were received.
With Protocol Amendment 6, the open-label phase of the study is extended to include an open
label booster vaccination with a single dose of Ad26.COV2.S.
With Protocol Amendment 7, requirements for COVID-19 episode reporting are changed, ie, a
passive surveillance approach is adopted, defined as following up on  new COVID-19 episodes
during scheduled phone calls with the participants.
2.1 Open-label Active Surveillance Phase
Participants will enter the open-label active phase on the day that the participant received the
open-label vaccination, received a vaccine outside of the study, or is unblinded until the day that
the participant consented to Protocol Amendment 7 or the site stops the electronic clinical outcome
assessment (eCOA) (whichever comes first).
The open-label phase will include 3 main study cohorts, based on the vaccination schedules
received during the open-label phase:
 Two-dose schedule cohort: participants who received the 2 doses of the Ad26.COV2.S
vaccine according to initial design of the study on Day 1 and Day 57 (Visit 1 and Visit 4),
regardless whether this was before or after unblinding.
 One-dose schedule cohort: participants who received a single dose of the Ad26.COV2.S
vaccine in the context of the open-label vaccination (eg, placebo participants receiving
Ad26COV2.S vaccine during cross-over vaccination) or participants who only received
one dose of Ad26COV2.S vaccine during the double-blind phase of the study. These
participants remain in this cohort until they receive the booster vaccination in the context

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of Protocol Amendment 6. Participants who will not receive a booster dose will continue
in this cohort.
 Booster dose schedule cohort: participants who, during the course of the study, have
received only a single dose of the Ad26.COV2.S vaccine and received a booster
vaccination under Amendment 6, preferably within 6 to 12 months after the initial
vaccination, with a minimum of 3 months after the initial vaccination with Ad26.COV2.S.
Data from participants who received a COVID-19 vaccination outside of the study will be
described separately (other dose cohort).
The main objective of the open-label active phase of the study is to describe COVID-19 outcomes,
safety, and immunogenicity in the different study cohorts. All analyses are descriptive, efficacy
evaluations may be done if feasible, ie, if pre-specified criteria are met, as described in the SAP.
Up to the implementation of Protocol Amendment 7, suspected COVID-19 cases are monitored
through active surveillance (see Section 1.3.6.2).
The list of objectives and endpoints of the open-label active surveillance phase are defined below.
Objectives 
Endpoints
Secondary
The secondary safety objective of the double-blind 
phase (see secondary double-blind objectives) 
The secondary safety endpoint of the double-
blind phase (see secondary double-blind
endpoints)
Exploratory
To evaluate symptomatic molecularly confirmeda 
coronavirus disease-2019 (COVID-19)b in the different 
study cohorts.
Incidence of symptomatic COVID-19 cases
starting at 28days after last vaccination
To evaluate molecularly confirmeda severe/critical 
COVID-19b in the different study cohorts. 
Incidence of severe/critical COVID-19 cases
starting at 28days after last vaccination
To evaluate molecularly confirmeda COVID-19 cases 
that required medical intervention (based on objective 
criteria) in the different study cohorts. 
Incidence of COVID-19 cases requiring
medical intervention, starting at 28 days after
last vaccination
To evaluate COVID-19 related death in the different 
study cohorts. 
Incidence of COVID-19 related deaths starting
at 28days after last vaccination
To describe the severity of molecularly confirmeda 
breakthrough infections 
The severity of COVID-19 cases may be
evaluated by the severity, number, and
duration  of symptoms of COVID-19 cases,
ratio of severe/critical COVID-19 cases and
ratio of long COVID-19 cases (duration of
more than 28 days)
In a subset of participants, to evaluate the 
immunogenicity ofAd26.COV2.S  
Analysis of antibodies binding to the
SARS-CoV-2 S protein by ELISA

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Objectives 
Endpoints
In a subset of participants, to further evaluate the
immunogenicity of Ad26.COV2.S
 
Immune response to Ad26.COV2.S as
compared to Functional and molecular
antibody 
placebo 
characterization
including, but not limited to avidity,
Fc-mediated 
viral 
clearance, 
Fc
characteristics, Ig subclass, IgG isotype,
antibody glycosylation, and assessment
of antibody repertoire
 
Original and/or emerging SARS-CoV-2
lineage neutralization as measured by
virus neutralization assay (VNA; wt virus
and/or 
pseudovirion 
expressing
SARS-CoV-2 S protein)
 
Adenovirus neutralization as measured
by VNA
 
Analysis of antibodies binding to the
receptor-binding domain (RBD) of the
SARS-CoV-2 S protein
To estimate potential correlate of risk/efficacy in
relation to the primary endpoint of the main study and
serious disease, hospitalization, and death based on
immune responses in breakthrough cases compared to
non-infected participants.
 
Analysis of binding antibody titer
measured by S-ELISA and/or MSD
assay, as available for participants having
COVID-19 compared to non-infected
participants. and/or MSD assay
 
Analysis of SARS-CoV-2 neutralizing
antibody titers measured by psVNA or
wild-type VNA, as available for
participants having COVID-19 compared
to non-infected participants.
An attempt to describe the duration of protection
following booster vaccination with Ad26.COV2.S for
the primary and key secondary endpoints of the double
blind phase will be made as outlined in the SAP
Incidence 
over 
time 
of symptomatic
COVID-19 
cases, 
severe 
COVID-19,
COVID-19 
cases 
requiring 
medical
intervention, and COVID-19 related deaths
starting 28 days after vaccination
a Molecularly confirmed COVID-19 is defined as a positive SARS-CoV-2 viral RNA result by a central laboratory
using a RT-PCR-based or other molecular diagnostic test.
b Per case definition for mild, moderate or severe/critical COVID-19 or determined by the Clinical Severity
Adjudication Committee (see below).
2.2 Open-label Passive Follow-up Phase
With the implementation of Protocol Amendment 7, the active follow-up of suspected COVID-19
episodes is replaced by a passive follow-up. Participants will enter this phase on the day of
consenting to Amendment 7 (or with the stop of the eCOA at each study site, whichever comes
first) until end of study.
In the passive follow-up phase, the same cohorts as from the open-label active phase are included,
and all data will be descriptively presented by cohort depending on the vaccination schedule

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received during the follow-up phase. Since COVID-19 reporting changed from an active approach
to a passive approach, the evaluations will be limited. Efficacy evaluations may be performed if
feasible and will be described in the SAP as applicable.
Passive follow-up of COVID-19 consists of recording of new COVID-19 episodes as SAEs, AEs,
or MAAEs. The information of these AEs is collected during the scheduled phone calls with the
participants.
The list of objectives and endpoints of the passive follow-up phase is provided below.
Objectives 
Endpoints
Secondary
the secondary safety objective of the double-blind 
phase (see secondary double-blind objectives) 
The secondary safety endpoint of the double-blind
phase (see secondary double-blind endpoints)
during the entire follow-up period
Exploratory
To evaluate COVID-19a in terms of (S)AEs 
MAAEs, hospitalizations and fatal AE linked to
COVID-19 in the different study cohorts
 
SAEs and AEs linked to COVID-19
 
MAAEs linked to COVID-19
 
AEs linked to COVID-19 that require
hospitalization
 
Fatal AEs linked to COVID-19b
In a subset of participants, to evaluate the 
immunogenicity of Ad26.COV2.S  in the different 
study cohorts
 
Analysis of antibodies binding to the
SARS-CoV-2 S protein by ELISA
 
Analysis 
of SARS-CoV-2 
neutralizing
antibody titers as measured by psVNA and/or
wtVNA
If feasible, to estimate a correlate of immunity 
(correlate of risk) in relation to the primary 
endpoint of the main study and serious disease, 
hospitalization, and death based on available 
immune responses in the different study cohorts 
 
Analysis of binding antibody titer measured
by S-ELISA and/or MSD assay, as available,
for participants having COVID-19 compared
to non-infected participants and/or MSD
assay
 
Analysis 
of SARS-CoV-2 
neutralizing
antibody titers measured by psVNA or
wtVNA, as available, for participants having
COVID-19 
compared 
to 
non-infected
participants
a Refer to Section 8.3 for the safety follow-up and COVID-19 reporting requirements as of Protocol Amendment 7.
b Fatal AEs linked to COVID-19 as determined by the Clinical Severity Adjudication Committee.
4. 
STUDY DESIGN
4.1. 
Overall Design
This is a multicenter, randomized, double-blind, placebo-controlled, Phase 3, pivotal efficacy and
safety studyin adults ≥18 years of age. The efficacy, safety, and immunogenicity of Ad26.COV2.S

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will be evaluated in participants living in, or going to, locations with high risk for acquisition of
SARS-CoV-2 infection after administration of 2 doses of study vaccine.
Initial immunogenicity and safety data (28 days post-Dose 1 data from Cohort 1a and available
data from Cohort 3) from study VAC31518COV1001 have demonstrated that a single dose of
Ad26.COV2.S at 5×1010 vp and 1×1011  vp induces an immune response that meets prespecified
minimum criteria and has an acceptable safety profile. The sponsor has therefore decided to
proceed with the Ad26.COV2.S at a dose level of 5×1010 vp in its Phase 3 studies. Even though a
single-dose regimen in study VAC31518COV1001 showed good immunogenicity that may
already protect against COVID-19, data from other vaccines using the Ad26 platform suggest that
a second vaccination may potentially result in an increased and more durable immune response,
providing justification for the evaluation of a 2-dose regimen in this study. The single dose regimen
will be further evaluated in study VAC31518COV3001.
The study will consist of a screening phase of up to 28 days, a 60-week study period (including
the administration of 2 doses of study vaccine [1 dose on Day 1 and 1 dose on Day 57] or 1 dose
of study vaccine [on Day 1 or at unblinding visit in case of the open-label vaccination], after
randomization, and administration of a booster vaccination), and a long-term follow-up period of
1 additional year. The duration of individual participation, including screening, will be maximum
2 years and 3 months. Consenting for the open-label and/or booster vaccination will not prolong
the study duration for an individual participant. If a participant is unable to complete the study, but
has not withdrawn consent, an early exit visit will be conducted. The end-of-study is considered
as the completion of the last visit for the last participant in the study (see Section 4.4).
Participants will be randomized in parallel in a 1:1 ratio in the double-blind phase to receive
Ad26.COV2.S or placebo intramuscularly (IM) as shown in Table 1. Ad26.COV2.S will be
administered at a dose level of 5×1010 vp.
Following Ad26.COV2.S  EUA  in the US for the single dose schedule, based on the
VAC31518COV3001 primary analysis results, all participants from countries where Protocol
Amendment 4 is approved by Health Authority and IEC/IRB will be unblinded at the on-site or
remote unblinding visit. All participants will be asked to continue to be followed in this study in
line with the Schedule of Activities in Section 1.3.3. After the study pause, the unblinding of all
participants and vaccination of placebo recipients may be conducted as soon as reasonably
practicable and preferably no later than 2 months after local approvals of Amendment 5 have been
received. Investigators will be encouraged to follow local health authority guidelines on
prioritization of immunization. If a scheduled study visit is planned within 2 months of the local
approval of Protocol Amendment 5, the unblinding visit may be combined with this planned study
visit. Every effort should be made to combine the unblinding visit with a scheduled visit;
otherwise, it must be done as an unscheduled visit. In the event that the unblinding takes place at
a scheduled visit, procedures that would be duplicated should be done only once.
Participants from the placebo arm enrolled during the double-blind phase will be offered to
receive a single dose of Ad26.COV2.S. vaccine (open-label vaccination), unless they met certain
vaccination discontinuation rules during the double-blind phase of the study (refer to Section 6.4).

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Participants from the Ad26.COV2.S arm enrolled during the double-blind phase will
continue in the same arm to receive their second dose, if applicable (refer to Section 6.4).
Newly enrolled participants in the open-label phase under Amendment 4 will be randomized in
a 1:1 ratio to receive either 1 dose or 2 doses of Ad26.COV2.S vaccine. After the study pause, the
unblinding visit was scheduled as soon as reasonably practicable and preferably no later than
2 months following local approvals of Protocol Amendment 5 were received.
With implementation of Protocol Amendment 6, all ongoing participants who received only a
single vaccination with Ad26.COV2.S in the study will be offered a single booster dose of
Ad26.COV2.S vaccine (5×1010 vp) (see Table 2) under the conditions delineated in Section 6.5.
Participants who already received 2 vaccinations with Ad26.COV2.S at the 5x1010 vp dose level
or any COVID-19 vaccinations outside of the study (including the Janssen vaccine) at the time of
local approval of Protocol Amendment 6 are not eligible to receive a booster vaccination with
Ad26.COV2.S. The booster vaccination will be administered in the open-label phase of the study,
preferably within 6 to 12 months after the participant’s first Ad26.COV2.S vaccination in the
study. If this is not possible, the booster vaccination should not occur earlier than 3 months after
the participant’s first Ad26.COV2.S vaccination. The Booster Vaccination Visit should preferably
coincide with the participant’s next scheduled visit (ie, Visit 7 or Visit 8 for the majority of
participants) from the original SoA in Section 1.3.3. If not operationally feasible to coincide with
an existing visit, an unscheduled visit may be planned. After the booster vaccination visit,
participants will continue procedures and visits as in the original SoA. All participants (whether
they consent to the booster vaccination or not) will be encouraged to remain in the study and will
be monitored for safety, immunogenicity, and efficacy according to their original schedule.
With Amendment 7, active follow-up ofsuspected COVID-19 episodes will be replaced by passive
follow-up (ie, follow-up phone call visits by the site instead of on-site study visits to document
new COVID‑19 events as SAEs, AEs, or MAAEs, and to record concomitant therapies associated
with COVID-19). The assay methodology should be mentioned. During these calls, the protocol-
required safety information (eg, [S]AEs, AESIs, MAAEs 6 months after the last vaccination) is
also collected. In between the scheduled phone calls, participants who experienced a (S)AE,
MAAE or AESI are encouraged to contact the study site.
In the future, participants might be invited for a rollover/follow-up study.
Table 1: 
Vaccination Schedule VAC31518COV3009 - Double-blind Phase
Group  
N 
Day 1 
Day 57
1 
Approx. 15,000 
Ad26.COV2.S (5×1010 vp) 
Ad26.COV2.S (5×1010 vp)
2 
Approx. 15,000 
Placebo 
Placebo
N  number of participants; NA  Not applicable; vp  virus particles.
Note: It is intended that a minimum of approximately 30% of recruited participants will be ≥60 years of age and approximately
20% of recruited participants will be ≥18 to <40 years of age.

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Table 2: 
Vaccination Schedule VAC31518COV3009 - Open-label Phase
Group  N* 
Day 1 
Day 57 
Unscheduled 
Unblinding Visit**/ 
Day 1 for newly 
enrolled 
participants*** 
Booster Vaccination
Preferably  Vac 1 +
6-12 months
Minimally Vac 1 +
3 months*****
1 
Approx. 
15,000 
Ad26.COV2.S 
(5×1010 vp) 
Ad26.COV2.S
(5×1010vp) 
Ad26.COV2.S
(5×1010 vp)
2 
Approx. 
15,000 
Placebo*** 
Placebo****
Ad26.COV2.S 
(5×1010 vp)
N  number of participants; vp  virus particles.
Note: It is intended that a minimum of approximately 30% of recruited participants will be ≥60 years of age and approximately
20% of recruited participants will be ≥18 to <40 years of age.
* It is possible that there might be over enrollment of participants in this study.
** All participants will be unblinded (informed whether they received placebo or Ad26.COV2.S) at the on site or remote
unblinding visit following EUA in the US and approval of Protocol Amendment 4 by the local Health Authority and the
IEC/IRB, and the study will continue as an open label study. Participants who were in the placebo arm will be offered to
receive a single dose of Ad26.COV2.S 5×1010 vp. After the study pause, the unblinding visit should be scheduled as soon as
reasonably practicable and preferably no later than 2 months following local approvals of Protocol Amendment 5 have been
received. The unblinding visit may be combined with the next planned study visit, if appropriate.
*** The newly enrolled participants will be randomized to Group 1 (to receive two doses of Ad26.COV2.S) or to Group 2 (to
receive one dose of Ad26.COV2.S on Day 1 instead of 2 doses of placebo. (There will be no administration of placebo on
Day 57).
**** Vaccination at Day 57 is not applicable for participants who were unblinded after the placebo vaccination at Day 1 and
prior to receiving the second placebo vaccination.
*****Following implementation of Protocol Amendment 6, all ongoing eligible participants who received only 1 Ad26.COV2.S
vaccination in the study will be offered 1 Ad26.COV2.S booster vaccination. Participants who already received 2 vaccinations
with Ad26.COV2.S at the 5x1010 vp dose level or any COVID 19 vaccinations outside of the study (including the Janssen
vaccine) at the time of local approval of Protocol Amendment 6 are not eligible to receive a booster vaccination with
Ad26.COV2.S.
A staggered enrollment strategy will be used in the double-blind phase:
 
Stage 1: Initially, approximately 1,000 participants without comorbidities that are associated
with increased risk of progression to severe COVID-19 (including approximately
500 Ad26.COV2.S recipients and approximately 500 placebo recipients) will be enrolled).
 
Stage 2: After a vaccination pause in Stage 1, to allow the IDMC to examine Day 3 safety
data (ie, from Day 1 to Day 3; including safety data from the ongoing studies)and if no safety
concerns are identified enrollment will proceed, expanding enrollment to include participants
with and without comorbidities that are associated with increased risk of progression to severe
COVID-19 in 2 age-dependent subgroups (≥18 years to <60 years of age and ≥60 years of
age). See Section 1.2 (Figure 1)for a schematic overview of the study and Section 5.2 for the
list of relevant comorbidities.
Overall, a target ofapproximately 30,000 adult participants (≥18to <60 years of age and ≥60 years
of age, with and without relevant comorbidities)will be randomly assigned in this study, under the
assumption that the annualized incidence of moderate to severe/critical COVID-19 (meeting the
COVID-19 case definition for the primary endpoint) will be approximately 1% to 4% at the start
of the study. Every effort will be made to identify regions of high SARS-CoV-2 activity and
populations within these regions with high risk of exposure to the virus will be enrolled.
Recruitment for high incidence populations will also take into account age. Per stage, participants
will be enrolled in 2 subgroups (≥18 to <60 years of age and ≥60 years of age).

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This sample size takes into consideration the uncertainty of the epidemiological situation in
combination with the ability to provide a high probability (approximately 90%) to reach a time to
signal within 15 months of the last study for a vaccine with an assumed 65% VE or higher. Efforts
will be made to ensure good representation in terms of race, ethnicity, and gender.
Of the total sample size, a minimum of approximately 30% of recruited participants will be ≥60
years of age and approximately 20% of recruited participants will be <40 years of age. Efforts will
be made to ensure good representation in terms of race, ethnicity, and gender. Refer to
Section 9.2.1 for details about the sample size determination.
The overall recruitment target is of approximately 30,000 participants. Up to 10% of additional
participants may be recruited to partially compensate for increased fraction unblinded prior to
unblinding visit and/or increased seroprevalence rates and/or drop-outs.
All participants will be actively and passively followed for acute molecularly confirmed,
symptomatic COVID-19, regardless of severity. Molecularly confirmed COVID-19 is defined as
a positive SARS-CoV-2 viral RNA result by a central laboratory using a RT-PCR-based or other
molecular diagnostic test. With Amendment 7, new COVID-19 episodes will be monitored
through passive follow-up.
For any case definition to be considered for classification of COVID-19 there needs to be at least
one SARS-CoV-2 positive RT-PCR or molecular test result from any available respiratory tract
sample (eg, nasal swab sample, sputum sample, throat swab sample, saliva sample) that is
confirmed by the central laboratory. It is possible that not all samples can be confirmed at the time
of the analysis. Hence a sensitivity analysis may be performed using all RT-PCR or molecular test
result, regardless of the confirmation by the central laboratory.
The primary objective will be evaluated in real-time manner through sequential testing of
accumulating primary endpoints through the SSG and IDMC. As soon as a decision is reached,
the Sponsor Committee will be alerted who can initiate internal decision procedures to trigger
health authority interactions based on the outcome of the study. The study team will remain blinded
until the database for primary analysis is locked. Further details are described in Section 9.4.1.
Key efficacy assessments include the (suspected) COVID-19 surveillance (symptom check),
recording of COVID-19-related hospitalizations and complications, and the laboratory
confirmation of SARS-CoV-2 infection by a molecular assay  (based on RT-PCR) and by
anti-SARS-CoV-2 serology (see Section 8.1.2). Immunogenicity assessments, and especially
assessments of the humoral immune responses with emphasis on neutralizing and binding
antibodies will also be performed (see Section 8.1.4).
Key safety assessments will include the monitoring of solicited and unsolicited AEs (in the Safety
Subset only), and the collection of SAEs, MAAEs, and AESIs in all participants (see Section 8.3).

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Up to Amendment 7, the viral load of SARS-CoV-2 will be assessed in confirmed COVID-19
cases (see Section 8.4). Medical resource utilization (MRU)following vaccination will be recorded
for all participants with molecularly confirmed, symptomatic COVID-19 (see Section 8.5).
Additional characteristics related to current work situation, living situation, and community
interactions will be collected for risk factor analyses, if allowed per local regulations. Participants
who consent to this will be interviewed on these aspects prior to vaccination on Day 1 and, at other
timepoints, on changes compared to Day 1 (See Appendix 12). In the US, for consenting
participants, medical data (electronic health records, claims, laboratory data from other settings)
from 5 years prior to study enrollment until 5 years after study completion may be accessed
utilizing tokenization and matching procedures (see sections 4.2 and 8.7). These data together with
prior medical history data collected at study entry may be used for exploratory analyses to enhance
our understanding of the potential impact of prior medical history on the response to immunization
and the impact of immunization on efficacy and duration of efficacy as well as adverse events that
may occur during and after completion of the study. Concomitant therapies associated with
COVID-19 are also to be reported as of Amendment 7.
As of Amendment 7, participants will continue to be required to report safety events, such as SAEs,
AESIs, MAAEs. The active follow-up of new suspected COVID-19 episodes will be replaced by
passive follow-up, defined as follow-up phone call visits by the site instead of on-site study visits
to document COVID-19 events as SAEs, AEs, or MAAEs.
The first 1,000 participants will remain under observation at the study site for at least 30 minutes
after each vaccination to monitor for the development of acute reactions. If at the time of the Day 3
safety review of the initial 1,000 participants no acute reactions have been observed, the
observation period at the study site may be reduced to at least 15 minutes, except where local
regulations require a longer observation period (eg, Belgium), after each vaccination for the
remaining participants in the study. After each vaccination, for participants in the Safety Subset,
solicited local (at injection site) and systemic AEs, unsolicited AEs, SAEs, and concomitant
therapies will be documented by study-site personnel following this observation period.
Participants in the Safety Subset will also record solicited signs and symptoms in an e-Diary for
7 days post-vaccination. The reporting periods of unsolicited AEs, MAAEs, SAEs, and special
reporting situations are detailed in Section 8.3. Reporting periods for concomitant therapy are
outlined in Section 6.10. Solicited and unsolicited AEs collected as part of Safety Subset will be
collected in the electronic case report form (eCRF)up to the unblinding visit.
All participants will be monitored for safety, including enhanced disease and SAEs until the last
study visit and including MAAEs up to 6 months after the last Ad26.COV2.S dose. As of Protocol
Amendment 7, COVID-19 events will be followed through a passive follow-up approach and sites
are instructed to report these events as (S)AE or MAAEs. The approach for the analysis of this
long-term follow-up cohort for safety and VE will be provided in detail in the analytic plan.
Participants in the Immunogenicity Subset will be followed-up for long-term immunogenicity. Up
to Amendment 7, participants will also be monitored for complications potentially associated with
COVID-19(such as but not limited to hyperinflammatory syndrome, pneumonia, neurological or

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vascular complications, severe pneumonia, severe neurological or vascular events, acute
respiratory distress syndrome, renal complications, sepsis, septic shock, death)71, and for MRU
(such as rates of ICU admission, ventilator use).
Up to Amendment 7, until completion of Visit 8, each participant will be asked at least twice a
week, through the electronic clinical outcome assessment (eCOA), if they have experienced any
new symptoms or health concerns that could be related to infection with SARS-CoV-2. As of
completion of Visit 8, until the end of the 2-yearfollow-up period, the frequency of this (suspected)
COVID-19 surveillance (symptom check)through the eCOA will decrease to once every 2 weeks.
Every effort will be made to document the status of all participants that are lost to follow-up due
to not completing the eCOA and for whom hospitalization has not been recorded. As from
Amendment 7, the eCOA will be decommissioned (passive follow-up approach). The eCOA will
be stopped based on approval of Amendment 7 at each study site.
Enrolled participants will be counselled on SARS-COV-2 infection prevention each time that they
have a contact with site staff, in line with local guidelines.
At the time of study entry, each participant will need to indicate to the study site, in case they
would get infected with SARS-CoV-2, the identity and location of their routine medical care
physician and/or facility and the identity and location of where they would obtain emergency care
and hospitalization if necessary. If this information is not available, a plan for where such care
could be obtained should be developed. If a participant should have COVID-19 and their
symptoms deteriorate, they will be instructed to go to the HCP or hospital that has been identified
in advance.
Up to Amendment 7, all participants with COVID-19-like signs or symptoms meeting the
prespecified criteria for suspected COVID-19(see Section 8.1.1) and all participants with at least
one positive RT-PCR test for SARS-CoV-2 on COVID-19 Day 1-2 and Day 3-5 visits should
undertake the COVID-19 procedures (see Section 8.1.2 and Section 1.3) until 14 days after
symptom onset (COVID-19 Day 15) or until resolution of the COVID-19 episode, whichever
comes last. However, participants with COVID-19-like signs or symptoms meeting the
prespecified criteria for suspected COVID-19 should stop the COVID-19 procedures as soon as it
is confirmed that both nasal swabs collected on COVID-19 Day 1-2 and Day 3-5 are negative for
SARS-CoV-2. Resolution of the COVID-19 episode is defined as having 2 consecutive SARS-
CoV-2 negative nasal swabs and 2 consecutive days with no COVID-19-related signs or
symptoms. At the time of resolution of the COVID-19 episode, the collected information will be
applied against the clinical case definition (Sections 8.1.3.1, 8.1.3.2, and 8.1.3.3).
As of Amendment 7, active follow-up of suspected COVID-19 episodes will be replaced by
passive follow-up (see Section 8.1.2.1).
Site staff and participants will not be blinded as to the outcome of the molecular test results from
the local (hospital) laboratory and the baseline molecular test results from a central laboratory.
Their routine health care professional (HCP) can obtain external diagnostics, including RT-PCR
or other molecularly confirmed viral tests, as medically needed.

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The occurrence of molecularly confirmed COVID-19, all complications associated with
COVID-19, and concomitant therapies associated with COVID-19 will be captured in the
electronic case report form (eCRF) for the duration of the study. Up to Amendment 7, every effort
will be made to capture medical information from any medical visits (eg, visits to the primary care
providers, emergency department/urgent care clinic visits, etc.) related to COVID-19 or its
complications via the medically-attended COVID-19 form (MA-COV form) (see Appendix 8). As
of Amendment 7, the MA-COV and the MRU forms are no longer to be completed.
All necessary precautions (as per local regulation) should be taken to protect medical staff and
other contacts of participants who are suspected to have COVID-19 until proven negative by
molecular techniques or who are positive until they are no longer positive. In the event of a
confirmed SARS-CoV-2 infection, the participant and the participant’s medical care provider
and/or local health authorities (if required) will be notified, and the participant will be asked to
adhere to the appropriate measures and restrictions as defined by local regulations.
Additional study procedures and assessments for immunogenicity and safety (reactogenicity and
unsolicited AE) will be performed in subsets of participants (see Section 8.1.4 and Section 8.3).
An IDMC will be commissioned for this study. Refer to Section 9.8 and Appendix 3 for more
details.
A diagram of the study design is provided in Section 1.2.
4.2. 
Scientific Rationale for Study Design
Vector Selection
The rationale behind the selection of the Ad26 vector is described in Section 2.
Dose Selection
The rationale behind the selection of the dose is described in Section 4.3.
Blinding, Control, Study Phase/Periods, Vaccine Groups
A placebo control will be used to establish the frequency and magnitude of changes in clinical and
immunological endpoints that may occur in the absence of active vaccine.
Randomization will be used to minimize bias in the assignment of participants to vaccine groups,
to increase the likelihood that known and unknown participant attributes (eg, demographic and
baseline characteristics) are evenly balanced across vaccine groups, and to enhance the validity of
statistical comparisons across vaccine groups. Blinded study vaccine will be used to reduce
potential bias during data collection and evaluation of study endpoints.
Blinding will be guaranteed by the preparation of the study vaccine by an unblinded pharmacist or
other qualified study-site personnel with primary responsibility for study vaccine preparation and
dispensing, and by the administration of vaccine in a masked syringe by a blinded study vaccine
administrator. Participants will be randomly assigned to 1 of the groups based on a computer-

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generated randomization schedule prepared before the study by or under the supervision of the
sponsor and using the interactive web response system (IWRS)(see also Section 6.3).
After implementation of Protocol Amendment 4, all enrolled participants will be invited for an
on-site unblinding visit and will be unblinded at that visit (unblinding may also occur remotely)to
enter the open-label phase of the study. All participants will be reconsented and requested to
provide a blood sample and a nasal swab. The statistical analysis of data from the point of
unblinding is outlined in Section 9.
Medical Resource Utilization Data Collection (Up to Amendment 7)
Prophylaxis of COVID-19with Ad26.COV2.S may reduce the need for and duration of supportive
care (eg, hospitalization, oxygen supplementation). The study will evaluate the impact of
Ad26.COV2.S versus placebo on the development and clinical course of COVID-19.
Participant Medical Information Prior to, During and After the Study (Real-world Data)
(For US Participants Only)
Real-world data plays a critical role in improving understanding of factors that may influence
response to immunization and the effectiveness and safety of a vaccine product during and after
completion of the study. This may be important in gaining insight in terms of duration of efficacy
and incidence of adverse events after study completion. This may be especially important in the
event that efficacy of Ad26.COV2.S or another vaccine is shown and follow-up in a randomized
manner is compromised.
To allow the linking of participant records from different sources, ie, data collected as part of the
study as specified in the Schedules of Activities and longitudinal real-world data (from 5 years
prior to enrollment in the study until 5 years after study completion) such as electronic health
record, claims, and laboratory data from other care settings, without compromising the
participant’s confidentiality, tokenization and matching procedures will be utilized for US
participants only. The tokenization process starts with each data provider generating a token
behind the firewall via a proprietary software. Personal information such as names and dates of
birth from study participants are removed from real-world data sources and replaced with
encrypted, one-way, hashed identifiers, and then further encrypted using asymmetric keys in
compliance with Health Insurance Portability and Accountability Act (HIPAA).62 This encrypted
anonymized information is sent for matching to the anonymized participant master index. While
it is not possible to reverse the hash, source-specific tokens can be decrypted and re-encrypted so
that records can be linked across sources. The result of the process is a unique anonymized
identifier for each participant, which can be used to link participant records across sources (real-
world data and study data).
4.2.1. 
Study-specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during
the study, participants will be given any new information that may affect their decision to continue
participation. They will be told that their consent to participate in the study is voluntary and may be
withdrawn at any time with no reason given and without penalty or loss of benefits to which they

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would otherwise be entitled. Only participants who are fully able to understand the risks, benefits,
and potential AEs of the study, and provide their consent voluntarily will be enrolled.
The primary ethical concern is that this study will be performed in adult participants who will
receive no direct benefit from participation in the study, except for participant reimbursement for
the time and inconveniences that may arise from participation in the study. See Section 2.3 for
details on potential and known benefits and risks, and for the safety measures taken to minimize
risk to participants.
Another ethical concern is the use of placebo vaccine and maintaining the study blind during the
double-blind phase of the study while the active study vaccine may prevent a serious disease. The
study design, with continuous evaluation of efficacy, addresses that concern as much as possible.
The sponsor will offer the active study vaccine to placebo recipients with the implementation of
Protocol Amendment 4. See Section 6.8for details. In addition, with implementation of Protocol
Amendment 6, the sponsor will offer a single Ad26.COV2.S booster vaccination under the
conditions as delineated in Section 6.5.
The total blood volume to be collected is considered to be an acceptable amount of blood to be
collected over this time period from the population in this study based upon the US Department of
Health and Human Services Office for Human Research Protections, and US Food and Drug
Administration (FDA) guidelines of 550 mL in any 8-week period.64,65
In US only, for participants who consent to the optional collection of real-world medical data, the
sponsor is committed to protect their data and privacy. Tokenization and matching procedures will
be utilized to allow for those participant’s medical data to be obtained without violation of
participant confidentiality (See Section 4.2). Participants will be informed that consent to this part
of the study is completely optional and that they can withdraw their consent at any given time. In
case of withdrawal of consent, the sponsor will remove the token generated and any associated
linked real-world data. Participation in or withdrawal from this optional part of the study will not
affect the participation in the main study.
4.3. 
Justification for Dose
The dose level of Ad26.COV2.S  to be assessed in the present study (5×1010 vp) is based on
experience with other Ad26-vectored vaccines administered to adults in clinical studies including
Ad26.ZEBOV (Ebola virus program); Ad26.ENVA.01, Ad26.Mos.HIV, and Ad26.Mos4.HIV
(HIV program); Ad26.CS.01 (malaria program); Ad26.RSV.FA2 and Ad26.RSV.preF (RSV
program); and Ad26.ZIKV.001 (Zika virus program). Studies with Ad26.RSV.preF also
included participants aged ≥60 years. The dose level of 5×1010 vp is the most extensively tested
dose to date and has shown to be well tolerated and immunogenic in these vaccine programs.
Safety data from studies with other Ad26-based vaccines are summarized in Section 2.3.1.
The same dose level is also being assessed in study VAC31518COV1001. Initial immunogenicity
and safety data (28 days post dose 1 from Cohort 1a) from study VAC31518COV1001 has
demonstrated that a single dose with the 5×1010 vp and 1×1011  vp Ad26.COV2.S dose levels is
immunogenic (according to the study’s prespecified criteria) and safe in adults ≥18-≤55 year of

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age. The sponsor has therefore decided to proceed with Ad26.COV2.S at a dose level of 5×1010
vp in the Phase 3 studies. Even though a single-dose regimen in study VAC31518COV1001
showed good immunogenicity that may already protect against COVID-19, data from other
vaccines using the Ad26 platform suggest that a second vaccination may potentially result in a
higher and more durable immune response, providing justification for the evaluation of a 2-dose
regimen in this study. The single dose regimen will be further evaluated in study
VAC31518COV3001.
Non-human primates immunized with a single-dose of Ad26.COV2.S (Study 20-14, dose level
titration study) showed robust protection after intranasal and intratracheal challenge with SARS-
CoV-2. Ad26.COV2.S at 5×1010 vp provided complete protection in the lung in 5 of 5 animals,
and in 5 of 6 animals in the upper respiratory tract. All control animals showed substantial viral
load in both the lower and upper respiratory tract.
The 5×1010 vp  dose level will be assessed to determine whether Ad26.COV2.S  has a similar
immunogenicity profile to that observed with other Ad26-based vaccines.
4.4. 
End-of-study Definition
End-of-study Definition
The end-of-study is considered as the completion of the last visit for the last participant in the
study. The final data from each participating study site will be sent to the sponsor (or designee)
after completion of the final participant visit at that study site, in the time frame specified in the
Clinical Trial Agreement.
All participants should have their last study contact visit completed by 30 June 2023. The
investigator (like for any lost to follow-up) should make 3 attempts to reach the participant for the
last call, whereafter the participant is considered to have finished participation in the study. The
last study visit window is based on Visit 4. Due to the study pause or other reasons, Visit 4 may
have occurred late for a number of participants. Nevertheless , the last study visit should occur by
30 June 2023 at the latest, even if that visit is out of window for the participant.
Study Completion Definition
A participant will be considered to have completed the study if he or she has completed the
assessments at Visit 10. Participants who prematurely discontinue study participation for any
reason before completion of these assessments will not be considered to have completed the study.
5. 
STUDY POPULATION
Screening for eligible participants will be performed within ≤28days before randomization and 1st
administration of the study vaccine, or on the day of the 1st vaccination. Refer to Section 5.4 for
conditions under which the repeat of any screening procedures are allowed.
The inclusion and exclusion criteria for enrolling participants in this study are described below.
Some inclusion and exclusion criteria only apply to a particular stage (1 or 2), as indicated below.

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See Section 4.1 for more details about enrollment in the different stages. If there is a question about
these criteria, the investigator must consult with the appropriate sponsor representative and resolve
any issues before enrolling a participant in the study. Waivers are not allowed.
Once enrolled, participants who received placebo during the double-blind phase will be eligible to
receive a single dose of vaccination with Ad26.COV2.S (open-label dose) in the open-label phase
if they agree and consent to receive the active vaccine and meet the criteria described in
Section 6.4. Eligibility criteria to receive the booster vaccination are described in Section 6.5.
Following approval of Protocol Amendment 4 and start of the open-label phase, newly enrolled
participants must meet the stage 2 criteria in Sections 5.1 and 5.2.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2.
5.1. 
Inclusion Criteriafor the Double-blind Phase and for Newly Enrolled
Participants in the Open-label Phasea
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. Participants must provide consent indicating that he or she understands the purpose,
procedures and potential risks and benefits of the study, and is willing to participate in the
study.
2. Participant is willing and able to adhere to the prohibitions and restrictions specified in this
protocol.
3. Criterion modified per Amendment 2
3.1 Criterion modified per Amendment 6
3.2 Participant is ≥18to <60 years or ≥60 years of age on the day of signing the ICF. Vaccine
administration/recruitment in each age group may change per country based on national
recommendation. The investigator should contact the sponsor prior to any change to vaccine
administration/recruitment.
4. Criterion modified per Amendment 1:
4.1 Criterion modified per Amendment 2:
4.2 Criterion modified per Amendment 3:
4.3 Stage 1: In the investigator’s clinical judgement, participant must be either in good or
stable health, including a BMI <30 kg/m2.
Participants may have underlying illnesses (not associated with increased risk of
progression to severe COVID-19b,17 as specified in Exclusion Criterion 14), as long as
a Eligibility criteria for the open-label and the booster vaccination are described in Section 6.4 and Section 6.5,
respectively.
bPer US CDC (Appendix 11). In this study, former or current smoking/vaping and mild hypertension (according to
the Toxicity Grading Scale in Section 10.9) will not be considered as a comorbidity. In addition, for this study
gestational diabetes was deleted from the list since it is not applicable as pregnant women are not allowed to
participate in the study.

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their symptoms and signs are stable and well-controlled. If participants are on medication
for a condition  not part of the comorbidities listed in Exclusion Criterion 14, the
medication dose cannot have been increased within  12 weeks preceding the 1st
vaccination and expected to remain stable for the duration of the study. Participants will
be included on the basis of relevant medical history and BMI at screening.
As of Stage 2:In the investigator’s clinical judgement, participant may have a stable and
well-controlled comorbidity including comorbidities associated with an increased risk of
progression to severe COVID-19 as specified in Exclusion Criterion 14 (eg,
stable/well-controlled HIV  infection)*. If participants are on medication for a
comorbidity (including comorbidities associated with an increased risk of progression to
severe COVID-19), the medication dose cannot have been increased within  12 weeks
preceding the 1st vaccination and must be expected to remain stable for the duration of
the studya. Participants will be included on the basis of relevant medical history and BMI
at screening.
*Stable/well-controlled HIV infection includes:
a. CD4 cell count ≥300 cells/µL within 6 months prior to screening.
b. HIV viral load <50 copies/mL within 6 months prior to screening.
c. Participant must be on a stable anti-retroviral treatment (ART) for 6 months (unless the
change is due to tolerability, in which case the regimen can be for only the previous
3 months; changes in formulation are allowed; nationwide guidelines that require
transition from one ART regimen to another are allowed) and the participant must be
willing to continue his/her ART throughout the study as directed by his/her local
physician.
Note: Participants with ongoing and progressive comorbidities associated with HIV
infection will be excluded but comorbidities associated with HIV infection that have been
clinically stable for the past 6 months are not an exclusion criterion.
Laboratory methods for confirming a diagnosis of HIV infection are: Any evidence
(historic or current) from medical records, such as ELISA with confirmation with Western
Blot orRT-PCR, or of a detectable viral load (country specific regulatory approved tests).
A laboratory result within 6 months of screening does not need to be repeated.
If a potential participant does not have HIV viral load and CD4 cell count data in his/her
medical records from the last 6 months, they will be instructed to go to their local health
care provider and obtain the necessary data for potential entry into the study.
5. Contraceptive (birth control) use should be consistent with local regulations regarding the
acceptable methods of contraception for those participating in clinical studies.
Before randomization, participants must be either (as defined in Appendix 5):
a. Not of childbearing potential
b. Of childbearing potential and practicing an acceptable effective method of
contraception and agrees to remain on such a method of contraception from providing
consent until 3 months after the last dose of study vaccine. Use of hormonal
a No longer applicable as of Amendment 7.

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contraception should start at least 28 days before the 1st administration of study
vaccine. The investigator should evaluate the potential for contraceptive method
failure (eg, noncompliance, recently initiated) in relationship to the 1st vaccination.
Acceptable effective methodsa for this study include:
1. hormonal contraception:
i. 
combined (estrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation (oral, intravaginal, or transdermal)
ii. 
progestogen-only hormonal contraception associated with inhibition of
ovulation (oral, injectable, or implantable)
2. intrauterine device;
3. intrauterine hormone-releasing system;
4. bilateral tubal occlusion/ligation procedure;
5. vasectomized partner (the vasectomized partner should be the sole partner for
that participant);
6. sexual abstinence*.
*Sexual abstinence is considered an effective method only if defined as refraining from
heterosexual intercourse from providing  consent until 3 months after the last dose of study
vaccine. The reliability of sexual abstinence needs to be evaluated in relation to the duration of
the study and the preferred and usual lifestyle of the participant.
6. All participants of childbearing potential must:
a. Have a negative highly sensitive urine pregnancy test at screening
b. Have a negative highly sensitive urine pregnancy test on the day of and prior to each
study vaccine administration.
7. Participant agrees to not donate bone marrow, blood, and blood products from the first study
vaccine administration until 3 months after the last dose of the study vaccine.
8. Must be willing to provide verifiable identification, has means to be contacted and to contact
the investigator during the study.
9. Must be able to read, understand, and complete questionnaires in the eCOA (ie, the COVID-19
signs and symptoms surveillance question, the e-Diary, and the electronic patient-reported
outcomes (ePROs)[see Appendix 1 for definition of terms])b.
a Use of condoms is not considered as an acceptable contraceptive barrier method due to the failure rate of female and
male condoms.19
b Participants with visual impairment are eligible for study participation and may have caregiver assistance in
completing the eCOA questionnaires

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5.2. 
Exclusion Criteriafor the Double-blind Phase and for Newly Enrolled
Participants in the Open-label Phasea
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
1. Participant has a clinically significant acute illness (this does not include minor illnesses such
as diarrhea or mild upper respiratory tract infection) or temperature ≥38.0ºC (100.4°F) within
24 hours prior to the planned 1st dose of study vaccine; randomization at a later date is
permitted at the discretion of the investigator and after consultation with the sponsor.
2. Participant has a known or suspected allergy or history of anaphylaxis or other serious adverse
reactions to vaccines or their excipients (including specifically the excipients of the study
vaccine; refer to the IB).
3. Criterion modified per Amendment 2:
3.1 Criterion modified per Amendment 4:
3.2 Participant has abnormal function of the immune system resulting from:
a. Clinical conditions (eg, autoimmune disease or potential immune mediated disease or
known or suspected immunodeficiency, or patient on hemodialysis) expected to have an
impact on the immune response of the study vaccine. Participants with clinical conditions
stable under non-immunomodulator treatment (eg, autoimmune thyroiditis, autoimmune
inflammatory rheumatic disease such as rheumatoid arthritis) may be enrolled at the
discretion of the investigator. Non-immunomodulator treatment is allowed as well as
steroids at a non-immunosuppressive dose or route of administrationb.
b. Chronic or recurrent use of systemic corticosteroids within 6 months before
administration of the 1st dose of study vaccine and duringa the study. A substantially
immunosuppressive steroid dose is considered to be ≥2 weeks of daily receipt of 20 mg
of prednisone or equivalent.
Note: Ocular, topical, inhaled, or injectable corticosteroids for local use are allowed.
c. Administration of antineoplastic and immunomodulating agents or radiotherapy within
6 months before administration of the 1st dose of study vaccine and during the studya.
Note: Non-immunomodulating monoclonal antibodies (after discussion with Sponsor
study physician) are allowed.
4. Criterion modified per Amendment 3:
4.1 
Participant received treatment with Ig in the 3 months or exogenous blood products
(autologous blood transfusion are not exclusionary) in the 4 months before the planned
administration of the 1st dose of study vaccine or has any plans to receive such treatment
during the studya.
5. Participant received or plans to receive:
a Eligibility criteria for the open-label and the booster vaccination are described in Section 6.4 and Section 6.5,
respectively.
b No longer applicable as of first date of Protocol Amendment 7.

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a. Licensed live attenuated vaccines
within 28 days before or after planned administration
of the 1st or subsequent study vaccinations.
b. Other licensed (not live) vaccines within 14 days before or after planned administration
of the 1st or subsequent study vaccinations.
6. Participant previously received a coronavirus vaccine.
7. Criterion modified per Amendment 1:
7.1 Criteria modified per Amendment 2:
7.2 Participant received an investigational drug within 30 days (including investigational
drugs for prophylaxis of COVID-19) or used an invasive investigational medical device
within 30 days or received investigational Ig or investigational monoclonal antibodies
within 3 months, or received convalescent serum for COVID-19 treatment within 4
months or received an investigational vaccine (including investigational Adenoviral-
vectored vaccines) within 6 months before the planned administration of the 1st dose of
study vaccine or is currently enrolled or plans to participate in another investigational
study during the course of this studya. See also Section 6.10.
Note: Participation in an observational clinical study is allowed at the investigator’s
discretion; please notify the sponsor (or medical monitor) of this decision.
Efforts will be made to ensure inclusion of participants who have not been previously
enrolled in coronavirus studies and to prevent participants from subsequently enrolling
in other coronavirus studies during their participation in this study.
The use of any coronavirus vaccine (licensed or investigational) other than Ad26.COV2.S
is disallowed at any time prior to vaccination (see also Exclusion Criterion 6)and during
the study, except under the conditions described in Section 6.8a.
8. Participant is pregnant or planning to become pregnant within 3 months after the last dose of
study vaccine.
9. Participant has a history of an underlying clinically significant acute or chronic medical
condition or physical examination findings for which, in the opinion of the investigator,
participation would not be in the best interest of the participant (eg, compromise the well-
being) or that could prevent, limit, or confound the protocol-specified assessmentsa.
10. Participant has a contraindication to IM injections and blood draws, eg, bleeding disorders.
11. Participant has had major psychiatric illness, which in the investigator’s opinion would
compromise the participant’s safety or compliance with the study procedures.
12. Participant cannot communicate reliably with the investigator.
13. Participant who, in the opinion of the investigator, is unlikely to adhere to the requirements of
the study, or is unlikely to complete the full course of vaccination and observation.
a No longer applicable as of first date of Protocol Amendment 7.

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14. Criterion modified per Amendment 1:
14.1 Criteria modified per Amendment 2:
14.2 Stage 1a:
 Participants with comorbidities that are or might be associated with an increased risk
of progression to severe COVID-19a,17, ie, participants with moderate-to-severe
asthma; chronic lung diseases such as chronic obstructive pulmonary disease (COPD)
(including emphysema and chronic bronchitis), idiopathic pulmonary fibrosis and
cystic fibrosis; diabetes (including type 1 ortype 2); serious heart conditions, including
heart failure, coronary artery disease, congenital heart disease, cardiomyopathies, and
pulmonary hypertension; moderate to severe high blood pressure; obesity (body mass
index [BMI] ≥30 kg/m2); chronic liver disease, including cirrhosis; sickle cell disease;
thalassemia; cerebrovascular disease; neurologic conditions (eg, dementia); end stage
renal disease; organ transplantation; cancer; HIV infection and other
immunodeficiencies; hepatitis B infection; sleep apnea; and participants who live in
nursing homes or long-term care facilities.
 Participants with a history of or current Parkinson’s disease; seizures; ischemic
strokes; intracranial hemorrhage; encephalopathy and meningoencephalitis.
15. Stage 1: Participant has a history of malignancy within 1 year before screening (exceptions
are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or
other malignancies with minimal risk of recurrence).
16. Criterion modified per Amendment 2:
16.1 
Participant has a history of acute polyneuropathy (eg, Guillain-Barré syndrome).
17. Criterion modified per Amendment 2:
17.1 
Participant had surgery requiring hospitalization (defined as inpatient stay for
longer than 24 hours or overnight stay), within 12 weeks before 1st vaccination, or will not
have fully recovered from surgery requiring hospitalization, or has surgery requiring
hospitalization planned during the time the participant is expected to participate in the study
or within 6 months after the last study vaccine administrationb.
18. Stage 1:Participant has chronic active hepatitis B or hepatitis C infection per medical history.
Note: Investigators should ensure that all study enrollment criteria have been met prior to the 1st
dose of study vaccine. If a participant’s clinical status changes (including any available laboratory
results or receipt of additional medical records) after screening but before the 1st dose of study
vaccine is given such that he or she no longer meets all eligibility criteria, then the participant
should be excluded from participation in the study. Section 5.4 describes options for retesting. The
aPer US CDC (Appendix 11). In this study, former or current smoking/vaping and mild hypertension (according to the
Toxicity Grading Scale in Section 10.9will not be considered as a comorbidity. Gestational diabetes was deleted
from the list since it is not applicable as pregnant women are not allowed to participate in the study.
b No longer applicable as of first date of Protocol Amendment 7.

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required documentation to support meeting the enrollment criteria is described under Source
Documents in Appendix 3.
In areas where seroprevalence is predicted to be high, a screening serologic test for past or current
infection with SARS-CoV-2 may be performed (in a local laboratory) at the discretion of the
sponsor to restrict the proportion of seropositive participants in the study.
5.3. 
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle considerations
during the course of the study to be eligible for participation:
1. 
Refer to Section 6.10 for details regarding prohibited and restricted therapy during the
study.
2. 
Agree to follow all requirements that must be met during the study as noted in the
inclusion and exclusion criteria (eg, contraceptive requirements).
3. 
Agree to follow requirements for the electronic completion of the COVID-19signs and
symptoms surveillance question in the eCOA.
5.4. 
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy
identification of each participant during and after the study, however, without referring to direct
communication with participants. This document will be reviewed by the sponsor study-site
contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed
by the investigator in the study file. To ensure participant confidentiality, no copy will be made.
All reports and communications relating to the study will identify participants by participant
identification and age at initial informed consent. In cases where the participant is not randomized
into the study, the date seen and age at initial informed consent will be used.
In cases where a participant does not meet the criteria for participation in this study (screen failure),
the main reason for non-eligibility is to be documented in the eCRF.
An individual who does not meet the criteria for participation in Stage 1, but does meet the criteria
for participation in Stage 2, will not be considered a screening failure and can be enrolled in the
appropriate stage, if enrollment occurs within the 28-day Screening window.
An individual who does not meet the criteria for participation in this study (screen failure) or
individuals for whom the 28-day screening window is exceeded may be rescreened on 1 occasion
only.

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All participants who are rescreened will be assigned a new participant number, undergo the
informed consent process, and then restart a new screening phase.
5.5. 
Criteria for Temporarily Delaying Administration of Study Vaccination
The following events constitute a temporary contraindication to study vaccination:
 
Clinically significant acute illness at the time of vaccination. This does not include minor
illnesses, such as diarrhea or mild upper respiratory tract infection.
 
Fever (body temperature ≥38.0°C/100.4°F) within 24 hours prior to the planned time of
vaccination.
 
An illness which in the judgement of the investigator may interfere with reactogenicity/Day
0-7 safety assessments.
If any of these events occur at the scheduled time for the 1st vaccination, randomization at a later
date within the screening window is permitted at the discretion of the investigator and after
consultation with the sponsor. If randomization cannot occur within the screening window,
rescreening is required. If any of these events occur at the scheduled time for the second
vaccination, the vaccination can be rescheduled, as long as this is in agreement with the allowed
windows (see Visit Windows in the Schedules of Activities).
If the second vaccination visit cannot be rescheduled within the allowed window or the
contraindications to vaccination persist, the sponsor should be contacted for further guidance.
For randomized participants who could not be vaccinated on the day of randomization for any
reason, vaccination can be administered on another day provided that vaccination occurs within
the 28-day screening visit window. Baseline procedures (Visit 2) should be performed on the day
ofvaccination. Participants who cannot be dosed within the 28-day screening window should be
discontinued from the study and should not be rescreened.
If any of the above listed events occur at the scheduled time for the booster vaccination, the Booster
Vaccination Visit can be delayed within the preferred visit window. In addition, a urine pregnancy
test (for participants of childbearing potential, according to the local guidelines) will be required
for the Booster Visit for participants who will be vaccinated at this visit. Participants who are
pregnant at the Booster Visit may receive booster vaccination with Ad26.COV2.S, if allowed by
local regulations, and if the investigator considers that the potential benefits outweigh the potential
risks to the mother and fetus (see Section 6.5).
As of Amendment 7, no further booster doses will be administered, except if there was a medical
reason that prevented a participant to receive the Ad26.COV2.S vaccine prior to acceptance of
Amendment 7 or if there is a non-availability of other vaccines to the participant. The investigator
should inform participants on the availability of other COVID-19 vaccines.

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6. 
STUDY VACCINATION AND CONCOMITANT THERAPY
6.1. 
Study Vaccines Administered
Ad26.COV2.S  will be supplied at a concentration of 1×1011 vp/mL in single-use vials, with an
extractable volume of 0.5 mL, and dosed at 5×1010 vp. Placebo is 0.9% NaCl.
For blinding purposes during the double-blind phase, all participants will receive a vaccination at
Day 1 and Day 57 (see Schedules of Activities), using the same volume (ie, 0.5 mL).
In the open-label phase, all newly randomized participants will receive either 1 dose (Day 1) or 2
doses (Day 1 and Day 57) of Ad26.COV2.S (see Section 1.3.3), using the same dose level and the
same volume (ie, 5×1010 vp per 0.5 mL). For participants already enrolled, upon unblinding of the
study vaccine allocation, participants in the placebo arm will receive a single dose of
Ad26.COV2.S  at the unblinding visita (Section 1.3.4), under the conditions delineated in
Section 6.4. Participants in the active arm who have not yet received their second vaccination at
the time of unblinding, will receive the second vaccination at Day 57 in an open-label fashion, if
applicable (See Section 6.4). Eligible consenting participants will receive a 1-dose booster
vaccination of Ad26.COV2.S (5×1010 vp  per 0.5 mL) at the Booster Vaccination Visit (see
Section 1.3.5 and Section 6.5).
For information on vaccination windows, see Visit Windows in the Schedules of Activities. If a
participant cannot be vaccinated within the allowed window (eg, if the window is missed due to a
study pause [see Section 6.11]), the decision regarding vaccination will be assessed on a
case-by-case basis, upon discussion between sponsor and investigator.
Study vaccine will be administered by IM injection into the deltoid muscle, preferably of the
non-dominant arm. If an injection cannot be given in the deltoids due to a medical or other
contraindication (for example, tattooed upper arms rendering it difficult to assess site
reactogenicity), use alternative locations such as the hip, thigh or buttocks (to be avoided in
overweight participants). In all circumstances, IM injections in other locations than the upper arm
are not considered protocol deviations.
Study vaccine administration must be captured in the source documents and the eCRF.
Ad26.COV2.S will be manufactured and provided under the responsibility of the sponsor. Refer
to the IB for a list of excipients.41
Refer to the study site investigational product and procedures manual (SIPPM) and the
Investigational Product Preparation Instructions (IPPI) for additional guidance on study vaccine
administration.
a If a scheduled study visit is planned within 2 months of the local approvals of Amendment 5, the unblinding visit
may be combined with the scheduled study visit and procedures that would be duplicated should be done only
once.

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Description of Interventions
Group Name 
Group 1 (including Group 1 unblinded 
participants and newly randomized 
participants assigned 2 doses**) 
Group 2 
Group 2 unblinded participants*and
newly randomized participants
assigned 1 dose**, Booster
Vaccination***
Intervention Name 
Ad26.COV2.S (1×1011 vp/mL) (2 doses) 
Placebo: 0.9% Sodium Chloride (2 
doses) 
Ad26.COV2.S (1×1011 vp/mL) (single
dose)
Type 
Biologic/vaccine (2 doses) 
Placebo (2 doses) 
Biologic/vaccine (single dose)
Dose Formulation 
Single-use vials, with an extractable 
volume of 0.5 mL 
Single-use vials, with an extractable 
volume of 0.5 mL 
Single-use vials, with an extractable
volume of 0.5 mL
Unit Dose Strength(s) 
Ad26.COV2.S at a concentration of 
1×1011 vp/mL (2 doses) 
0.9% Sodium Chloride (2 doses) 
Ad26.COV2.S at a concentration of
1×1011 vp/mL (single dose)
Dosage Level(s) 
Day 1 and Day 57: Ad26.COV2.S (5×1010 
vp) 
Day 1 and Day 57: Placebo 
Day 1 or unblinding visit, Booster
Vaccination Visit: Ad26.COV2.S
(5×1010 vp)
Route of Administration 
IM injection  
IM injection  
IM injection
Use 
Experimental 
Placebo-comparator 
Experimental
Investigational Medicinal 
Product (IMP)
Yes 
Yes 
Yes
Non-Investigational 
Medicinal Product/Auxiliary
Medicinal Product
(NIMP/AxMP)
No 
No 
No
Sourcing 
Provided centrally by the sponsor 
Provided centrally by the sponsor 
Provided centrally by the sponsor
Packaging and Labeling 
The study vaccines will be packaged and labeled according to good manufacturing practices and local regulations. The study
vaccines will not be packed in individual participant kits, 1 kit will be used by multiple participants. Each kit will contain single-
use vials.
Not in child resistant packaging
IM = intramuscular; vp = virus particles
*who are eligible per criteria in Section 6.4
**who are eligible per criteria in Sections 5.1 and 5.2.
***who are eligible per criteria in Section 6.5

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6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study vaccine must be stored in a secured location with no access for unauthorized personnel
and at controlled temperatures as indicated on the clinical labels. If study vaccine is exposed to
temperatures outside the specified temperature range, all relevant data will be sent to the sponsor
to determine if the affected supplies can be used or will be replaced. The affected study vaccine
must be quarantined and not used until further instruction from the sponsor is received.
Refer to the study SIPPM and the IPPI for additional guidance on study vaccine preparation,
handling, and storage.
In the double-blind phase, an unblinded study-site pharmacist, or other qualified individual, who
will have no other study function following vaccination, will prepare the appropriate vials and
syringes, labeled with the participant’s identification number, and provide the syringes for the
study vaccine in a blinded manner to the blinded vaccine administrator (a trained and qualified
study nurse, medical doctor, otherwise qualified healthcare professional) who will perform the
injection.
In the open-label phase, vaccination will be performed by a trained and qualified study nurse,
medical doctor, otherwise qualified HCP.
Accountability
The investigator is responsible for ensuring that all study vaccine received at the site is inventoried
and accounted for throughout the study. The study vaccine administered to the participant must be
documented on the vaccine accountability form. All study vaccine will be stored and disposed of
according to the sponsor’s instructions. Study-site personnel must not combine contents of the
study vaccine containers.
Study vaccine must be handled in strict accordance with the protocol and the container label and
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate
environmental conditions. Unused study vaccine must be available for verification by the
sponsor’s unblinded site monitor during on-site monitoring visits. The return to the sponsor of
unused study vaccine will be documented on the vaccine accountability form. When the study site
is an authorized destruction unit and study vaccine supplies are destroyed on-site, this must also
be documented on the vaccine accountability form.
Potentially hazardous materials containing hazardous liquids, such as needles and syringes should
be disposed of immediately in a safe manner and therefore will not be retained for vaccine
accountability purposes.
Study vaccine should be dispensed under the supervision of the investigator or a qualified member
of the study-site personnel, or by a hospital/clinic pharmacist. Study vaccine will be administered
only to participants participating in the study. Returned study vaccine must not be dispensed again,
even to the same participant. Study vaccine may not be relabeled or reassigned for use by other

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participants. The investigator agrees neither to dispense the study vaccine from, nor store it at, any
site other than the study sites agreed upon with the sponsor. Further guidance and information for
the final disposition of unused study vaccine are provided in the SIPPM.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Participants will be randomly assigned
to 1 of 2 vaccination groups (active vaccine [Group 1] versus placebo [Group 2]). This will be
based on a computer-generated randomization schedule prepared before the study by or under the
supervision of the sponsor. The randomization will be balanced by using randomly permuted
blocks and will be stratified by vaccination unit (eg, site, mobile unit), age group (≥18to <60 years
of age versus ≥60 years of age), and absence/presence of comorbidities that are or might be
associated with an increased risk of progression to severe COVID-19 as described in Exclusion
Criterion 14.
The IWRS will assign a unique intervention code, which will dictate the intervention assignment
for the participant. The requestor must use his or her own user identification and personal
identification number when contacting the IWRS and will then give the relevant participant details
to uniquely identify the participant.
Following implementation of Amendment 4, IWRS will still assign newly enrolled participants to
receive vaccine or placebo. The system will not be updated, and participants assigned to receive
placebo will receive a single dose of Ad26.COV2.S on Day 1.
Blinding (Applicable for Double-blind Phase)
Blinding will be guaranteed by the preparation of the study vaccine by an unblinded pharmacist or
other qualified study-site personnel with primary responsibility for study vaccine preparation and
dispensing, and by the administration of vaccine in a masked syringe by a blinded study vaccine
administrator. Participants will be randomly assigned to 1 of the groups based on a computer-
generated randomization schedule prepared before the study by or under the supervision of the
sponsor and using the IWRS.
The investigator will not be provided with randomization codes. The codes will be maintained
within the IWRS, which has the functionality to allow the investigator to break the blind for an
individual participant.
Data that may potentially unblind the study vaccine assignment (ie, immunogenicity data, study
vaccine accountability data, study vaccine allocation, or other specific laboratory data) will be
handled with special care to ensure that the integrity of the blind is maintained and the potential
for bias is minimized. This can include making special provisions, such as segregating the data in
question from view by the investigators, clinical team, or others as appropriate until the time of
database lock and unblinding.

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Under normal circumstances, the blind should not be broken until all participants have attended
the unblinding visit. Note that key personnel of the sponsor will be unblinded at the time of primary
analysis. Sites and participants will remain blinded until participants have completed their
unblinding visit, whenever applicable. Details will be provided in the IDMC Charter. The
investigator may in an emergency determine the identity of the intervention  by contacting the
IWRS. While the responsibility to break the intervention  code in emergency situations resides
solely with the investigator, it is recommended that the investigator contact the sponsor or its
designee if possible, to discuss the particular situation, before breaking the blind. Telephone
contact with the sponsor or its designee will be available 24 hours per day, 7 days per week. In the
event the blind is broken, the sponsor must be informed as soon as possible. The date, time, and
reason for the unblinding must be documented in  the IWRS  and in the source document. The
documentation received from the IWRS indicating the code break must be retained with the
participant’s source documents in a secure manner.
Participants who have had their intervention assignment unblinded should continue to return for
scheduled evaluations (please refer also to section 6.4).
In general, randomization codes will be disclosed fully only after the unblinding visit in the
open-label phase.
Participants may be unblinded upon their request to receive a different authorized/licensed
COVID-19 vaccine. Investigators may receive requests to unblind study participants who become
eligible to receive another authorized/licensed COVID-19 vaccine outside of the study if/when
these become available. In these cases, the investigator will discuss with the participant available
options and ramifications, including whetherthey are eligible to receive the Ad26.COV2.S vaccine
in the study during the unblinding study visit. The reason for the unblinding request should be
documented. The name and date(s) of administration of the other COVID-19 vaccine should be
recorded (see Section 6.10).
If it is determined that the participant received the Ad26.COV2.S vaccine (and not placebo), the
participant will be informed that there are no data on the safety of receiving two different
COVID-19 vaccines and no further study vaccination would be permitted in the event he/she
chooses to receive the vaccine outside the study. Unblinded participants, whether in the vaccine or
control group, will be asked to continue to be followed in this study in line with the Schedules of
Activities. Safety, efficacy, and immunogenicity evaluations will be identical for all participants,
including participants that are unblinded to obtain an authorized/licensed COVID-19 vaccine and
who remain in the study. All data will be analyzed separately from the point of unblinding for
safety, efficacy and immunogenicity, as described in the Statistical Analysis Plan.
Participants who opt for enrollment in an Expanded Access Program or a Phase 3b study
(eg, Sisonke/TOGETHER in South Africa) may be unblinded upon their request and will be
encouraged to continue in the VAC31518COV3009 study. Study investigators should query
participants to elicit and document such participation in other studies in the VAC31518COV3009
eCRF including the vaccination.

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Once Protocol Amendment 4 is approved, participants who were previously unblinded (under
previous amendments) because they were offered another approved/licensed vaccine will follow
the procedures detailed in Section 6.4 and Section 8.8.
6.4. 
Unblinding and Open-label Phase
Following Ad26.COV2.S EUA  in the US  for the single dose schedule, based on the
VAC31518COV3001 primary analysis results, all enrolled participants from countries where
Amendment 4 is approved by the Health Authority and IEC/IRB will be unblinded at the on-site
or remote unblinding visit.
Before the actual participant unblinding, all of the previously available data should be complete
and accurate in the participant’s eCRF.
Participants from the placebo arm enrolled during the double-blind phase:
Participants will be offered to receive a single dose of Ad26.COV2.S  vaccine, except for
participants who met any of the following vaccination discontinuation criteria between vaccination
1 and vaccination 2 under previous amendments:
 
received a COVID-19vaccine outside of the study or,
 
withdrew consent to receive further study vaccination or,
 
received any experimental medication (including experimental vaccines other than the study
vaccine) or,
 
previously experienced TTS or heparin-induced thrombocytopenia (HIT)
 
previously experienced capillary leak syndrome (CLS)
Participants who discontinued study vaccination due to an AE may receive a single dose of
Ad26.COV2.S vaccine at the investigator’s discretion.
Participants who are pregnant may be vaccinated with Ad26.COV2.S  (single-dose regimen), if
allowed by local regulations for emergency use of vaccines and if the investigator considers that
the potential benefits outweigh any potential risks to the mother and fetus.
Participants who use systemic corticosteroids (chronic or recurrent use) or received antineoplastic
and immunomodulating agents or radiotherapy may receive a single dose of Ad26.COV2.S if
allowed by local regulations and after being made aware that the safety and efficacy data in
participants using/receiving these medications/treatments is limited.
Participants who were already unblinded for any reason (eg, accidentally or offered another
licensed/authorized COVID-19 vaccination) may receive a single dose of Ad26.COV2.S vaccine
at the investigator’s discretion, provided that they did not receive a COVID-19 vaccine and did
not meet any of the criteria mentioned above.
Participants who may have missed visits after vaccination on Day 1 and subsequently request the
active vaccine may be offered single dose of the Ad26.COV2.S vaccine at the discretion of the
investigator.

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Participants who have become infected with SARS-CoV-2 may receive a single dose of
Ad26.COV2.S vaccine if they have recovered from the acute illness and at least 1 month has passed
since recovery, based on the investigator’s judgement, and after being made aware that the safety
and efficacy data on vaccinating a previously infected individual is limited. These participants will
follow the Schedule of Activities from Section 1.3.4 and will resume Schedule of Activities 0
afterwards.
Participants eligible to receive a single dose of Ad26.COV2.S will follow the procedures detailed
in Section 8.8 and the Schedule of Activities (Section 1.3.4) and will resume the Schedule of
Activities from Section 1.3.3.
Participants from the Ad26.COV2.S arm enrolled during the double-blind phase:
Depending on the participant status at time of unblinding visit, participants may or may not have
received their second dose:
 
Those who had already received their 2 doses at time of unblinding visit will follow the
Schedule of Activities from Section 1.3.4 for unblinding visit and will resume Schedule of
Activities from Section 1.3.3 afterwards but will not be vaccinated.
 
If the participant has not yet received the second dose at the time of the unblinding visit, the
second dose will be administered as planned, at Visit 4 (Day 57) (Schedule of Activities 1.3.3)
 
Participants who met vaccination discontinuation rules between vaccination 1 and vaccination
2 applicable during the double-blind phase (Section 7.1) will not receive a second dose of
Ad26.COV2.S except participants who have become infected with SARS-CoV-2 who may
receive their second dose of Ad26.COV2.S vaccine if they have recovered from the acute
illness and at least 1 month has passed since recovery, based on the investigator's judgement.
They will also have to be made aware that the safety and efficacy data on vaccinating a
previously infected individual is limited. These participants will follow the Schedule of
Activities from Section 1.3.4 (at which the vaccination 2 may occur) and will resume Schedule
of Activities from Section 1.3.3 afterwards).
Participants initially enrolled in the Ad26.COV2.S group during the double-blind phase who are
not eligible to receive a second vaccination will be assured they received the dose level that was
submitted for EUA or conditional approval (single-dose schedule of 5x1010 vp Ad26.COV2.S).
Participants newly enrolled in the study (under Amendment 4)
Participants will be randomized to receive either 1 or 2 doses of Ad26.COV2.S and will follow the
Schedule of Activities in Section 1.3.3.
6.5. 
Booster Vaccination
With implementation of Protocol Amendment 6, all ongoing participants who received only a
single vaccination with Ad26.COV2.S in the study will be offered a single booster dose of
Ad26.COV2.S vaccine (5×1010 vp), as indicated in the SoA in Section 1.3.5. Participants who
already received 2 vaccinations with Ad26.COV2.S at the 5x1010 vp dose level or any COVID-19
vaccinations outside of the study (including the Janssen vaccine) at the time of local approval of

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Protocol Amendment 6 are not eligible to receive a booster vaccination with Ad26.COV2.S. The
booster vaccination will be administered in the open-label phase of the study, preferably within
6 to 12 months after the participant’s first Ad26.COV2.S vaccination in the study. If this is not
possible, the booster vaccination should not occur earlier than 3 months after the participant’s first
Ad26.COV2.S vaccination  The Booster Vaccination Visit should preferably coincide with the
participant’s next scheduled visit (ie, Visit 7 or Visit 8 for the majority of participants) from the
original SoA in Section 1.3.3 and should not occur after the expiry date of the Ad26.COV2.S vials
available at the site. If not operationally feasible to coincide with an existing visit, an unscheduled
visit may be planned. After the Booster Vaccination Visit, participants will continue procedures
and visits as in the original SoA. All participants (whether they consent to the booster vaccination
or not) will be encouraged to remain in the study and will be monitored for safety, immunogenicity,
and efficacy according to their original schedule.
Participants may be offered the single booster dose of Ad26.COV2.S vaccine under the following
special conditions:
 
Participants, who had met vaccination discontinuation criteria under previous amendments,
will be offered a single booster dose of Ad26.COV2.S vaccine at the discretion of the
investigator, except the following participants, who:
 
withdrew consent from the study or,
 
received any COVID-19-related experimental medication (including any experimental
vaccines other than the study vaccine) or,
 
previously experienced TTS or heparin-induced thrombocytopenia (HIT) or,
 
previously experienced CLS or,
 
are planning to receive another COVID-19 vaccine within the 3 months after the booster
vaccination.
 
Participants who are pregnant may receive booster vaccination with Ad26.COV2.S, if allowed
by local regulations and if the investigator considers that the potential benefits outweigh the
potential risks to the mother and fetus.
 
Participants who use systemic corticosteroids (chronic or recurrent use) or received
antineoplastic and immunomodulating agents or radiotherapy may receive booster vaccination
with Ad26.COV2.S if allowed by local regulations and after being made aware that the safety
and efficacy data in patients using/receiving these medications/treatments in combination with
Ad26.COV2.S is limited.
 
Participants who have become infected with SARS-CoV-2 during the study may receive
booster vaccination with  Ad26.COV2.S vaccine, even if they received steroid treatment,
convalescent plasma, or monoclonal antibody treatment, after they have recovered from the
acute illness and at least 1 month has passed. Such participants should be made aware that the
safety and efficacy data on vaccinating a previously infected individual is limited.

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 
Vaccination should be deferred in case of any other illness, until the person has recovered
from the acute illness (see Section 5.5).
Investigators will be encouraged to follow health authority guidelines on prioritization of
immunization when feasible. Investigators are encouraged to consider current local public health
guidance for determining the scheduling priority of participants when feasible, eg, participants
with comorbidities and/or of specific age groups can be scheduled prior to participants without
comorbidities if this is in line with local guidance. Based on operational considerations, the
investigators at their discretion may prioritize those participants who had their priming regimen at
a more distant time prior to the booster vaccination.
All participants will be counselled to continue practicing other public health/preventative measures
that were introduced at the start of this pandemic (eg, social distancing, face masks, frequent hand
washing), in compliance with local and national guidelines. Participants who receive booster
vaccination with Ad26.COV2.S. will continue to follow the Schedule of Activities in
Section 1.3.3.
As of Amendment 7, no further booster doses will be administered, except if there was a medical
reason that prevented a participant to receive the Ad26.COV2.S vaccine prior to acceptance of
Amendment 7 or if there is a non-availability of other vaccines to the participant, but no later than
vaccine expiry date at the study site. The investigator should inform participants on the availability
of other COVID-19 vaccines.
6.6. 
Study Vaccine Compliance
Study vaccines will be administered intramuscularly by a study vaccine administrator a trained
and qualified study nurse, medical doctor, otherwise qualified HCP. The date and time of each
study vaccine administration and the location used will be recorded in the eCRF.
6.7. 
Dose Modification
Dose modification is not applicable in this study.
6.8. 
Continued Access to Study Vaccine After the End of the Study
Participants who opt for enrollment in an Expanded Access Program or a Phase 3b study
(eg, Sisonke/TOGETHER in South Africa) may  be unblinded upon their request and will be
encouraged to continue in the VAC31518COV3009 study. Study investigators should query
participants to elicit and document such participation in other studies in the VAC31518COV3009
eCRF, including the vaccination.
Following EUA in the US and approval of Protocol Amendment 4 by the local Health Authority
and the IEC/IRB, participants who received placebo will be offered the Ad26.COV2.S study
vaccine at no cost, as described in Section 6.4 and refer to Section 8.8 for more details. Upon
implementation of Protocol Amendment 6, a single dose booster Ad26.COV2.S vaccination will
be offered at no cost to eligible participants as described in Section 6.5 and detailed in Section 8.9.

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All data will be analyzed separately from the point of unblinding for safety, efficacy and
immunogenicity (under the conditions outlined in Section 6.3), as described in the SAP.
6.9. 
Treatment of Overdose
For this study, any dose of Ad26.COV2.S greater than the assigned dose will be considered an
overdose. The sponsor does not recommend specific treatment for an overdose.
In the event of a known overdose, the investigator should:
 
Contact the medical monitor immediately.
 
Closely monitor the participant for AE/SAE/MAAE (ie, the participant will remain at the
study site for at least 1 hour and will be closely monitored for allergic or other reactions by
study staff. Follow-up telephone calls 12 hours and 24 hours post-dose will be made).
 
Document the quantity of the excess dose in the source document.
 
Report as a special reporting situation.
6.10. Prestudy and Concomitant Therapy
Prestudy therapies are only to be recorded for participants with relevant comorbidities and
participants aged ≥60 years. For these participants, all prestudy therapies (excluding vitamins,
herbal supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture,
special diets, and exercise regimens)administered up to 30 days before the 1st vaccination must be
recorded at screening. Prestudy therapies linked to inclusion and exclusion criteria (eg, flu vaccine)
should be recorded.
For all participants, concomitant therapies associated with an SAE, or suspected AESI meeting the
criteria outlined in Section 10.4.1 and Section 8.3.7, respectively, will be collected and recorded
in the eCRF from the moment of 1st vaccination (or from the time of local approval of Protocol
Amendment 5 for suspected AESIs) through the end of the study. Concomitant therapies
associated with MAAEs will be collected and recorded in the eCRF from the moment of 1st
vaccination until 6 months after the last vaccination  (including the open-label vaccination or
booster vaccination, whichever comes last). Concomitant therapies associated with MAAEs
leading to study discontinuation will be recorded in the eCRF during the entire study.
For all participants, concomitant therapies associated with COVID-19 will be captured in the eCRF
for the duration of the study. This will still be applicable after implementation of Amendment 7.
Hence, under Amendment 7, concomitant medication in case of COVID-19 (S)AEs and
COVID-19 MAAEs need to be recorded, as well as any confirmatory laboratory result, if available
(eg, positive COVID-19 PCR results, positive nasal swab). The assay methodology should be
mentioned.
For participants in the Safety Subset, concomitant therapies associated with unsolicited AEs will
be collected and recorded in the eCRF from the time of 1st vaccination through 28 days after the
last vaccination. Concomitant therapies associated with solicited AEs will be collected by the
participants and recorded in the eCRF from the time of each vaccination through 7 days after each

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vaccination. If the solicited signs and symptoms are not resolved by 7 days post-vaccination, the
concomitant therapies associated with these solicited AEs will be collected by the participants and
recorded in the eCRF until Day 29 post-vaccination or until they are resolved, whichever comes
first.
Antipyretics are recommended post-vaccination for symptom relief as needed. Prophylactic
antipyretic use is not encouraged; however, in some instances, it could be considered for
participants with special circumstances and/or comorbidities.
Participants may not have received an investigational drug within 30 days (including
investigational drugs for prophylaxis of COVID-19) or used an invasive investigational medical
device within 30 days or received investigational Ig or investigational monoclonal antibodies
within 3 months, or received convalescent serum for COVID-19 treatment within 4 months or
received an investigational vaccine (including investigational Adenoviral-vectored vaccines)
within 6 months before the planned administration of the 1st dose of the study vaccine. During the
study, the use of investigational vaccines other than the study vaccine is not allowed, and the use
of investigational drugs is only allowed if medically indicated. Treatment with investigational
COVID-19 drugs after diagnosis of a COVID-19 case is allowed during the follow-up period and
needs to be recorded in the COVID-19 episode description.
Licensed live attenuated vaccines should be given at least 28 days before or at least 28 days after
a study vaccination. Other licensed (not live) vaccines (eg, influenza, tetanus, hepatitis A,
hepatitis B, rabies) should be given more than 14 days before (or more than 14 days after, as per
Exclusion Criterion 6) administration of any dose of the study vaccine in order to avoid potential
confusion of adverse reactions and potential immune interference. The use of any coronavirus
vaccine (licensed or investigational) other than Ad26.COV2.S is disallowed at any time prior to
vaccination and during the study except under the conditions described in Sections 6.3 and 6.8. If
a vaccine is indicated in a post-exposure setting (eg, rabies or tetanus), it must take priority over
the study vaccine. Receipt of any COVID-19 vaccine (outside the study) at any timepoint during
the study must be recorded. The name and date(s) of administration of the COVID-19 vaccine
should be recorded in the eCRF.
Chronic or recurrent use of systemic corticosteroidsa at immunosuppressive dose and
administration of antineoplastic and immunomodulating agents or radiotherapy are prohibited
during the study and within 6 months before the planned administration of the 1st dose of the study
vaccine. If any of these agents are indicated in a disease setting, these must take priority over the
study vaccine.
Refer to Section 5.2 for further details of prohibited therapy.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered. The participant should remain in the study but receive
a Note: Ocular, topical, inhaled, or injectable corticosteroids for local use are allowed.

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no further study vaccination. Depending on the time of the occurrence, any participant who
receives a prohibited concomitant therapy will not be included in the immunogenicity analyses.
6.11. Study Vaccination Pausing Rules for Stage 1
The sponsor (including designated sponsor teams) and/or Sponsor Committee as well as the
investigator(s)will monitor safety in a blinded manner. Adverse events that may lead to the study
vaccination pausing rules (applicable to Stage 1 only)are described below and will be assessed by
the designated sponsor team/committee to confirm that the study pause is warranted.
The occurrence of any of the following events in Stage 1 will lead to a pause in further study
vaccination:
1. 
Death of a participant, considered related to study vaccine or if the causal relationship
to the study vaccine cannot be excluded; OR
2. 
One or more participants experience an SAE (solicited or unsolicited) that is
determined to be related to study vaccine; OR
3. 
One or more participants experience anaphylaxis or generalized urticaria, clearly not
attributable to other causes than vaccination with study vaccine.
To enable prompt response to a situation that could trigger pausing rules, the investigator should
notify the sponsor’s medical monitor or designee (AND fax or email the SAE form to Global
Medical Safety Operations, if applicable), immediately and no later than 24 hours after becoming
aware of any related SAE AND update the eCRF with relevant information on the same day the
SAE information is collected (see also Section 8.3.1). Based on the pausing criteria, the sponsor’s
medical monitor or designee then decides whether a study pause is warranted and informs the
IDMC of the decision. All sites will be notified immediately in the event of a study pause. The
sponsor’s medical monitor or designee is responsible for the immediate notification of IDMC
members and coordination of an IDMC meeting in the event of a study pause.
The IDMC will review unblinded data and will make recommendations regarding the continuation
of the study to the sponsor study team. Resumption of vaccinations will start only upon receipt of
written recommendations by the IDMC. The clinical site(s) will be allowed to resume activities
upon receipt of a written notification from the sponsor. The formal recommendation from the
IDMC will be forwarded by the investigator to the IRB/IEC and by the sponsor to the relevant
health authorities, according to local standards and regulations. Refer to Section 10.3.6,
Committees Structure in Appendix 3.
Vaccinations for an individual participant may be suspended for safety concerns other than those
described in the pausing criteria, at the discretion of the investigator if he/she feels the participant’s
safety may be threatened. The sponsor’s medical monitor or designee or the investigator(s) (upon
consultation with the sponsor’s medical monitor or designee) may initiate IDMC review for any
single event or combination of multiple events which, in their professional opinion, could
jeopardize the safety of the participants or the reliability of the data.

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Vaccinations for the study may be suspended for safety concerns other than those described above,
or before pausing rules are met, if, in the judgement of the IDMC, participant safety may be
threatened.
7. 
DISCONTINUATION  OF STUDY VACCINATION  AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Vaccination
Study vaccinations in the double-blind phase will be withheld for the reasons listed below. These
participants must not receive any further doses of study vaccine but should remain on study for
follow-up with assessments of safety, efficacy, and immunogenicity as indicated in the Schedules
of Activities. Additional unscheduled visits may be performed for safety/reactogenicity reasons, if
needed. In case of questions, the investigator is encouraged to contact the sponsor.
 
Any related AE, worsening of health status or intercurrent illnesses that, in the opinion of the
investigator, requires discontinuation from study vaccine
 
The participant becomes pregnant
 
Unblinding on the participant level that, in the opinion of the sponsor, would compromise the
integrity of the data
 
Unblinding requested by a study participant in order to receive an authorized/licensed
COVID-19 vaccine prior to general unblinding at the time of EUA in the US for the single-
dose schedule of Ad26.COV2.S
 
Anaphylactic reaction following vaccination, not attributable to causes other than vaccination
 
SAE or other potentially life-threatening (Grade 4) event that is determined to be related to
study vaccine
 
Chronic or recurrent use of systemic corticosteroids and administration of antineoplastic and
immunomodulating agents or radiotherapy
 
Participant received any experimental medication (including experimental vaccines other than
the study vaccine) or received a COVID-19 vaccine or treatment
 
Withdrawal of consent to receive further study vaccination
 
Participant has a molecularly confirmed SARS-CoV-2 infection based on samples collected
within the study (see Section 8.1.2)
 
Participant previously experienced TTS or HIT.
During the open-label phase, study vaccinations for newly enrolled participants (under Protocol
Amendment 4) and participants enrolled under Protocol Amendments 1, 2 or 3 who have not yet
received their second dose of Ad26.COV2.S will be withheld for the reasons listed below. These
participants must not receive any further doses of study vaccine but should remain on study for
follow-up with assessments of safety, efficacy, and immunogenicity as indicated in the Schedules
of Activities. Additional unscheduled visits may be performed for safety/reactogenicity reasons, if
needed. In case of questions, the investigator is encouraged to contact the sponsor.

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 
Any related AE, worsening of health status or intercurrent illnesses that, in the opinion of the
investigator, requires discontinuation from study vaccine
 
The participant becomes pregnant
 
Anaphylactic reaction following vaccination, not attributable to causes other than vaccination
 
SAE or other potentially life-threatening (Grade 4) event that is determined to be related to
study vaccine
 
Chronic or recurrent use of systemic corticosteroids and administration of antineoplastic and
immunomodulating agents or radiotherapy
 
Participant received any experimental medication (including experimental vaccines other than
the study vaccine) or received a COVID-19 vaccine or treatment
 
Withdrawal of consent to receive further study vaccination
 
Participant previously experienced TTS or HIT
 
Participant previously experienced CLS.
Note: Participants who are pregnant and previously received placebo during the double-blind
phase may be vaccinated with Ad26.COV2.S  (single-dose regimen), if allowed by local
regulations for emergency use of the vaccines and if the investigator considers that the potential
benefits outweigh any potential risks to the mother and fetus (See section 6.4). Likewise, pregnant
participants who previously received the open-label vaccination may receive the booster
vaccination if allowed by local regulations for use of vaccines and if the investigator considers that
the potential benefits outweigh any potential risks to the mother and fetus (see Section 6.5).
7.2. 
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:
 
Lost to follow-up
 
Withdrawal of consent from the study
 
Death
 
Repeated failure to comply with protocol requirements
When a participant withdraws before study  completion, the reason for withdrawal is to be
documented in the eCRF and in the source document. If the reason for withdrawal from the study
is withdrawal ofconsent then no additional assessments are allowed.
Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of
consent. Alternate follow-up mechanisms that the participant agreed to when signing the consent
form apply as local regulations permit.

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7.2.1. 
Withdrawal From the Use of Research Samples
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent for use of samples for research (refer to Long-Term
Retention of Samples for Additional Future Research in Section 10.3.5 in Appendix 3). In such a
case, samples will be destroyed after they are no longer needed for the clinical study. Details of
the sample retention for research are presented in the main ICF.
7.3. 
Lost to Follow-up
To reduce the chances of a participant being deemed lost to follow-up, prior to randomization
attempts should be made to obtain contact information from each participant, eg, home, work, and
mobile telephone numbers and email addresses for both the participant as well as appropriate
family members.
A participant will be considered lost to follow-up if he or she repeatedly fails to return for
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed
lost to follow-up until all reasonable efforts made by the study-site personnel to contact the
participant are deemed futile. The following actions must be taken if a participant fails to return to
the study site for a required study visit:
 
The study-site personnel must attempt to contact the participant to reschedule the missed study
visit or phone call visit as soon as possible, to counsel the participant on the importance of
maintaining the assigned visit schedule, to ascertain whether the participant wishes to or
should continue in the study.
 
Before a participant is deemed lost to follow-up, the investigator or designee must make every
reasonable effort to regain contact with the participant (where possible, 3 telephone calls,
e-mails, fax, and, if necessary, a certified letter to the participant’s last known mailing address,
or local equivalent methods). Locator agencies may also be used as local regulations permit.
These contact attempts should be documented in the participant’s medical records.
 
Should the participant continue to be unreachable, they will be considered to have withdrawn
from the study.
Should a study site close, eg, for operational, financial, or other reasons, and the investigator cannot
reach the participant to inform them, their contact information will be transferred to another study
site.
8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedules of Activities summarize the frequency and timing of all measurements applicable
to this study.
Up to Amendment 7, all participants will be provided access to an eCOA digital tool. This eCOA
will be used to collect COVID-19 signs and symptoms surveillance info for all participants, ePRO
(Symptoms of infection with Coronavirus-19 [SIC], including body temperature, and pulse

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oximetry results)for all participants at baseline and in case of COVID-19-like signs and symptoms,
and e-Diary data on  7-day reactogenicity (solicited signs and symptoms, including body
temperature) in the Safety Subset. All eCOA assessments should be conducted/completed before
any tests, procedures, or other consultations to prevent influencing participant responses. Refer to
the PRO completion guidelines for instructions on the administration of ePROs. The baseline SIC
must be completed prior to the first vaccine administration.
As of Amendment 7, the number of on-site visits for participants who are not part of the
Immunogenicity Subset is reduced. For these participants, any outstanding on-site visits will be
replaced by phone call visits. No further booster vaccination will be provided in the protocol. In
addition, requirements for COVID-19 episodes reporting are changed (ie, a passive follow-up
approach is adopted, defined as safety follow-up phone call visits by the site instead of on-site
study visits to document COVID-19 events as SAEs, AEs, or MAAEs until end of study). All
participants will be reconsented at an unscheduled visit and as per local informed consent process
guidelines.
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures
be performed in the following sequence: vital signs before blood draws. If needed, assessments
may be performed on another day within the applicable visit window. Actual dates and times of
assessments will be recorded in the source document, the eCRF, or the sample requisition form.
Up to Amendment 7, all participants will be provided a thermometer to measure body temperature
ifthey experience COVID-19-like signs and symptoms. Participants in the Safety Subset will be
provided a ruler (to measure local injection site reactions) and a participant e-Diary in the eCOA
digital tool to record body temperature and solicited local (at injection site) and systemic signs and
symptoms. The e-Diary includes instructions on how to capture the data and grading scales to
assess severity of the signs and symptoms post-vaccination (reactogenicity). The study staff is
responsible for providing appropriate training to the participant to avoid missing or incorrect data.
The e-Diary will be reviewed by the study personnel at visits indicated in the Schedules of
Activities. If the e-Diary review is missed, the diary will be reviewed during the following visit.
All participants will also be provided with a kit to collect nasal swabs samples and recipients to
collect saliva (see Section 8.1.2).
The total blood volume to be collected over the course of the study from each participant will be
up to a maximum of161.0 mL. This includes the situations in which the open-label vaccination
(see Section 1.3.4) or the booster vaccination (see Section 1.3.5) would not coincide with an
existing visit of the SoA of Section 1.3.3, and approximately 17 mL of blood might need to be
collected at both visits. Additional blood samples (up to 30 mL) will be collected from participants
that experience COVID-19-like signs and symptoms meeting prespecified criteria for suspected
COVID-19. As of Protocol Amendment 7, this additional blood sample will not be collected
anymore. For participants who experience a suspected AESI, an additional 30 mL of blood may
be collected. Refer to the Schedules of Activities for the total blood volume (serum and, as
applicable, whole blood samples) to be collected at each visit, over the complete course of the

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study, and in the event of a suspected COVID-19 episode. Repeat or unscheduled samples may be
taken for safety reasons or for technical issues with the samples.
If allowed by local regulation, study visits may take place at the participant’s home or other
location in the event of ongoing SARS-CoV-2 transmission in the area of the participant.
If possible and allowed per local regulation, visits, except screening and vaccination visits, can be
performed by a phone call or a telemedicine contact provided that assessments requiring a face-to-
face interaction between the participant and a trained health care professional (including but not
limited to blood sampling) are performed by a Site staff member or a designee at the participant’s
home or other location, whichever is applicable. Conversely, in case of home visit, assessments
that cannot be delegated to a designee must be performed by an appropriate Site staff member via
a phone call or telemedicine.
Visit Windows
Visit windows are provided in the Schedules of Activities. The participant should be encouraged
to come on the exact day planned and use the visit window only if absolutely necessary.
If a vaccination window is missed due to a study pause (see Section 6.11), efforts will be made to
still vaccinate the participant as soon as possible after the pause has been lifted, even if out of
window. The timings of the post-vaccination visits will be determined relative to the actual day of
the corresponding vaccination. If a participant misses a vaccination, the post-vaccination visits
will be calculated from the imputative vaccination date according to protocol.
Screening
The study will consist of a screening phase of up to 28 days. Screening may also be performed
prior to randomization on the day of vaccination. In that case, Visits 1 and 2 will coincide on
Day 1. Screening must be completed and all eligibility criteria must be fulfilled prior to
randomization and 1st vaccination.
Screening may be conducted in part via a sponsor- and IRB/IEC-pre-approved non-study-specific
screening consent process, but only if the relevant pre-screening tests are identical to the per-
protocol screening tests and are within 28 days prior to the 1st vaccination. However, no study-
specific procedures, other than these pre-approved pre-screening assessments, will be performed
until the participant has signed the study-specific ICF. The study-specific ICF date will be
collected for the study database. The non-study-specific ICF will be considered source data.
Long-term follow-up
Up to Protocol Amendment 7, until completion of Visit 8, each participant will be asked at least
twice a week, through the eCOA, if they have experienced any new symptoms or health concerns
that could be related to infection with SARS-CoV-2. As of completion of Visit 8, until the end of
the 2-year follow-up period, the frequency of this (suspected) COVID-19 surveillance (symptom
check) through the eCOA will decrease to once every 2 weeks. All participants will be monitored
for safety, including enhanced disease and SAEs until the last study visit and including MAAEs

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up to 6 months after the last Ad26.COV2.S dose. Sites should monitor participant compliance with
(suspected) COVID-19 surveillance (symptom check) and SIC completion on a daily basis and
reach out to a participant if the participant fails to complete the surveillance question upon any of
these reminders. Every effort will be made to document the status of all participants that are lost
to follow-up due to not completing the eCOA and for whom hospitalization has not been recorded.
The questionnaire will be accessible on the eCOA platform in between scheduled reminders and
participants will be encouraged to answer the surveillance question in the eCOA as soon as
possible after the onset of COVID-19-like symptoms. Procedures to be followed in case of
(suspected) COVID-19 are outlined in Section 8.1.2. As of Amendment 7, active follow-up of
suspected COVID-19 episodes will be replaced by a passive surveillance and eCOA will be
stopped.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory
requisition form. Refer to the Schedules of Activities for the timing and frequency of all sample
collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples
must be under the specified, and where applicable, controlled temperature conditions as indicated
in the laboratory manual.
Study-Specific Materials
The investigator will be provided with the following supplies:
 
IB for Ad26.COV2.S
 
Thermometer
 
Ruler (to measure diameter of any erythema and swelling)
 
A pulse oximeter
 
Pharmacy manual/SIPPM
 
IPPI
 
IWRS Manual
 
Sample ICF
 
Laboratory manual and laboratory supplies
 
Nasal swab kits, saliva recipients, and participant instructions
 
eCOA platform access and participant instructions. Participants may use their own eDevice
using an application if their device (smartphone or tablet) is compatible, or a web  portal.
Provisioned devices will be available on a limited basis.
 
Tablet for eConsent, if applicable
 
Contact information page(s)

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 
eCRF completion guidelines
As of Protocol Amendment 7, the sponsor will no longer be providing lab kits for COVID-19
testing.
8.1. 
Efficacy and Immunogenicity Assessments
No generally accepted immunological correlate of protection has been demonstrated for
SARS-CoV-2 to date.
8.1.1. 
Prespecified Criteria for Suspected COVID-19 Prior to Amendment 7
The criteria for suspected COVID-19 (ie, the triggers to proceed with home-collection of the nasal
swabs on COVID-19 Day 1-2 and to proceed with the COVID-19 Day 3-5 visit) are prespecified
as follows:
 
A positive RT-PCR result for SARS-CoV-2, through a private or public laboratory
independent of the study, whether symptomatic or asymptomatic
OR
 
New onset or worsening of any 1 of the symptoms listed below, which lasts for at least 24
hours, not otherwise explained:
 
Headache
 
Malaise (appetite loss, generally unwell, fatigue, physical weakness)
 
Myalgia (muscle pain)
 
Chest congestion
 
Cough
 
Runny nose
 
Shortness of breath or difficulty breathing (resting or on exertion)
 
Sore throat
 
Wheezing
 
Eye irritation or discharge
 
Chills
 
Fever (≥38.0°C or ≥100.4°F)
 
Pulse oximetry value ≤95%, which is a decrease from baseline
 
Heart rate ≥90 beats/minute at rest, which is an increase from baseline
 
Gastrointestinal symptoms (diarrhea, vomiting, nausea, abdominal pain)
 
Neurologic symptoms (numbness, difficulty forming or understanding speech)
 
Red or bruised looking toes
 
Skin rash

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Taste loss or new/changing sense of smell
 
Symptoms of blood clots: pain/cramping, swelling or redness in your legs/calves
 
Confusion
 
Bluish lips or face
 
Clinical suspicion/judgement by investigator of symptoms suggestive for COVID-19
As several of the prespecified criteria for suspected COVID-19 overlap with vaccine-related
reactogenicity, investigators' clinical judgement is required to exclude vaccine-related events when
assessing suspected COVID-19.
8.1.2. 
Procedures in the Event of (Suspected) COVID-19
8.1.2.1. 
Passive Follow-up (As of Amendment 7)
As of Amendment 7, active follow-up of suspected COVID-19 episodes will be replaced by a
passive follow-up approach. For COVID-19 events that are ongoing at the time of informed
consent:
a. Participant will be instructed to stop using the eCOA.
b. Any outstanding activities planned for the follow-up of COVID-19 events will end.
c. No further sampling for participants and no Day 1-2, Day 3-5, and Day 29 visit will be
performed.
d. MRU and MA-COV forms are no longer to be completed.
The eCOA will be stopped based on approval of Amendment 7 at each study site. From that point
onwards, active participants are no longer able to use eCOA.
For new suspected COVID-19 episodes no samples will be collected in the context of the study.
Site staff will collect information on new COVID-19 episodes at scheduled time points and report
these as SAEs, AEs, or MAAEs, as applicable. Participants may also contact the site at any time
in between scheduled visits to report a safety concern (eg, hospitalization) or COVID-19 episodes.
Concomitant medications for each COVID-19 episode are to be reported into the eCRF as well as
any laboratory confirmation of COVID-19, if available. As of Protocol Amendment 7, there will
be no further central testing for COVID-19 events.
8.1.2.2. 
Active Follow-up (Up to Amendment 7)
Procedures to be performed in the event a participant experiences signs or symptoms suggesting
possible COVID-19 or a participant became aware of a positive RT-PCR test result for
SARS-CoV-2 outside the study context, whether symptomatic or asymptomatic, are detailed in the
Schedules of Activities. A high-level schematic overview is presented in Figure 3.

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Figure 3: 
Decision Tree for COVID-19 Procedures
COVID-19 = coronavirus disease-2019; eCOA = electronic clinical outcome assessment; PCR= polymerase chain reaction; SARS-CoV-2 = severe acute respiratory
syndrome coronavirus-2; SIC = Symptoms of Infection with Coronavirus-19.

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If signs and symptoms are still ongoing on COVID-19 Day 3-5, collection of SIC will be continued until at least 14 days after onset unless both COVID-19 Day 1-2 and
COVID-19 Day 3-5 nasal swabs are negative. If either of the swabs is positive or the result is unknown AND the participant is beyond 14 days after onset of symptoms,
the SIC can be stopped after 2 days without signs and symptoms.
For participants with a positive test result for SARS-CoV-2 infection, a study visit will be conducted 28 days after symptom onset (ie, at the COVID-19 Day 29 visit) to
assess the clinical course of the infection.
If 2 consecutive nasal swabs negative for SARS-CoV-2 are not available due to operational reasons (eg, delays in results availability), participants may cease collection
of nasal swabs and saliva samples at the COVID-19 Day 29visit, provided they have 2 consecutive days with no COVID-19-related signs and symptoms. In these cases,
participants may be asked to resume sample collection if nasal sample results—once available—do not present with 2 consecutive negative swabs for SARS-CoV-2. For
more details regarding closure of the episode, refer to “Closure of the COVID-19 episode” section.

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For all medical visits for COVID-19 or COVID-19 complications, including those resulting in
hospitalization, a standard list of questions will be provided (MA-COV form [Appendix 8]), with
the aim to collect additional information on any other diagnostics (eg, chest X-rays, spirometry,
pulmonary function tests) or interventions during the clinical course of COVID-19. The MA-COV
form will be provided to the participant at the first vaccination visit and should be completed by
the medical care provider or the study site personnel during medical visits for COVID-19 or
COVID-19 complications. All nasal swabs should be tested locally, and remainders of each sample
sent to a central laboratory.
Note: if for any reason a site visit per the procedures described below is not feasible, a member of
the study staff or designee can visit the participant at home (or at the hospital or other location, if
needed), if allowed by local regulations.
Day 1-2 procedures in case of signs and symptoms
If a participant records in the eCOA or informs the site that he/she experienced any signs or
symptoms suggesting possible COVID-19, this will be considered COVID-19 Day 1 (day of onset
of signs and symptoms). The participant will be asked to complete the ePROs (ie, the SIC
[Appendix 6], including body temperature)in the eCOA.
Notes:
 
The SIC questionnaire asks the participant if he/she had any of the prespecified signs or
symptoms (see Appendix 6) during the past 24 hours, and (when applicable) to rate the
severity. The SIC questionnaire takes approximately 5 minutes to complete.
 
The participant should record the highest temperature in the last 24 hours in the SIC.
 
The participant should record at least 1 of the 3 pulse oximetry readings in the last 24 hours
in the eCOA.
 
If a participant is unable to complete the SIC in the eCOA, a study staff member can collect
information on the participant’s symptoms and body temperature, by contacting the
participant by telephone (or visit the participant at home), reading the questions aloud to the
participant and entering the participant’s responses on the participant’s behalf. If the
participant requires assistance, the participant’s caregiver can help the participant to complete
the SIC in the eCOA by reading the questions aloud to the participant and recording the
participant’s responses in the eCOA using the caregiver’s unique identifier and PIN on the
participant’s behalf. Procedures for caregivers to collect and report the participant’s responses
to the eCOA questions will be detailed in instructions for caregiver assessment of COVID-19
episodes. Details are provided in the PRO completion guidelines.
 
If a participant is unable to complete the SIC in eCOA, the reason for missing the SIC
completion should be recorded in the eCRF.
Based on the information collected through the SIC, the site will reach out to the participant at the
latest on COVID-19 Day 2 (the day after the day of symptom onset) to assess whether the reported
signs and symptoms qualify as a suspected COVID-19 episode using prespecified criteria
(Section 8.1.1). As several of the prespecified criteria for suspected COVID-19 overlap with
vaccine-related reactogenicity, investigators' clinical judgement is required to exclude vaccine-

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related events when assessing suspected COVID-19. Ifthe participant would actively reach out to
the site already on COVID-19 Day 1, the site should already make a first assessment on COVID-19
Day 1 to check whether the reported signs and symptoms qualify as a suspected COVID-19
episode using prespecified criteria (Section 8.1.1). As soon as the prespecified criteria for
suspected COVID-19 are met (COVID-19 Day 1-2), the participant will be asked to undertake the
COVID-19 procedures. In particular:
 
The participant will be asked to continue to complete the ePROs in the eCOA, as specified
above for COVID-19 Day 1:
 
SIC (including body temperature): every day, preferably in the evening around the same
time each day.
 
Blood oxygen saturation and pulse rate using a pulse oximeter 3 times a day, preferably
in the morning, at lunch time, and in the evening.
Note: the ePROs do not have to be completed if special circumstances occur, such as
hospitalization or ventilation, in which case the reason for not completing the ePROs
should be recorded by site staff in the eCRF.
 
The participant will be asked to collect a nasal swab at home on COVID-19 Day 1-2, as soon
as possible after it has been confirmed that the prespecified criteria for suspected COVID-19
are met. If the participant requires assistance, a trained HCP can help the participant to collect
the nasal swab. The study site should arrange transfer of the nasal swab to the study site as
soon as possible after collection, preferably within 24 hours. The COVID-19 Day 1-2 nasal
swab can also be collected at the study site (or hospital or other location, if needed), if
preferred by the participant.
Day 1-2 procedures in case of a positive RT-PCR test outside the study context
If a participant becomes aware of a positive RT-PCR test for SARS-CoV-2, he/she should contact
the site as soon as possible. The day the participant became aware of the positive PCR test will be
considered COVID-19 Day 1. Regardless of whether the participant is symptomatic or
asymptomatic, he/she will be asked to:
 
Complete the (suspected) COVID-19 surveillance (symptom check) in the eCOA. In case of
COVID-like signs and symptoms, they will need to complete the SIC (Appendix 6, including
body temperature) in the eCOA.
 
Collect a nasal swab at home on COVID-19 Day 1-2, as described for the participants with
signs and symptoms (see above).
These precautionary measures are to ensure that site staff who come into physical contact with a
participant deemed to be a COVID-19 case undertake the proper safety procedures such as wearing
of personal protective equipment.
Day 3-5 procedures for all participants who have met the prespecified criteria for
(suspected) COVID-19
The participant will be asked to come to the site on COVID-19 Day 3-5 (between 2 and 4 days
after symptom onset/becoming aware of a positive RT-PCR test).

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 
If a site visit is not feasible, a member of the study staff or designee could visit the participant
at home (or at the hospital or other location, if needed), if allowed by local regulations. The
study staff or designee visiting participants at home will use personal protective equipment
according to local regulations. The COVID-19 Day 3-5 assessments may also be performed
by a trained HCP, if allowed per local regulations.
 
During Part 1 of the COVID-19 Day 3-5 visit, if the participant has experienced COVID-19
like signs and symptoms, the site will interview the participant to assess whether the reported
signs and symptoms still qualify as a suspected COVID-19 episode using prespecified criteria
(Section 8.1.1). In addition, for all participants, a qualified member of the study site will
measure vital signs (body temperature, blood pressure, heart rate, and respiratory rate) and
pulse oximetry. A targeted physical examination will be performed based on the judgement
of the investigator. A nasal swab will be collected for detection of SARS-CoV-2 by a qualified
member of the study site.
 
If the signs and symptoms still meet the prespecified criteria for suspected COVID-19 on
COVID-19 Day 3-5 or if the nasal sample collected at Day 1-2 or Day 3-5 visits is positive
for SARS-CoV-2 (tested by RT-PCR), the following assessments and procedures are to be
performed during Part 2 of the COVID-19 Day 3-5 visit: a blood sample for sero-
confirmation of SARS-CoV-2 infection will be collected by a qualified member of the study
site. A saliva sample will be taken by the participant during the study visit. The MRU
questionnaire will be completed based on a clinical interview (Appendix 7). The medical
history and description of COVID-19 episode will be collected by interview with the
participant.
If signs and symptoms are still ongoing on COVID-19 Day 3-5, collection of SIC will continue
as specified in the next section (Closure of the COVID-19 episode).
 
If allowed by local regulations and if the participant consents, he/she will be interviewed on
characteristics related to their current work situation, living situation, and community
interactions (See Appendix 12). These data will be used for risk factor analysis.
 
If the signs and symptoms no longer meet the prespecified criteria for suspected COVID-19
on COVID-19 Day 3-5 and no result from nasal swabs collected on Day 1-2 or Day 3-5 visits
is available, the participant will not undertake any further COVID-19 procedures. He/she will
fall back to the default Schedules of Activities, until the end of the study/early withdrawal.
Procedures during the 2-day cycles
If a participant has signs and symptoms that meet the prespecified criteria for suspected COVID-19
(Section 8.1.1) at COVID-19 Day 3-5 visit or has at least one positive sample for SARS-CoV-2
collected on COVID-19 Day 1-2 or Day 3-5 visits, he or she will be asked to undertake the
COVID-19 procedures, in particular:
 
All participants will be asked to collect a nasal swab and a saliva sample at home once every
2 days (daily alternating between nasal swabs and saliva samples).
If the participant requires assistance, a trained HCP can help the participant to collect the nasal
swabs and/or saliva samples. The study site should arrange transfer of the nasal swabs and
saliva samples to the study site within 3 days after collection. Details are provided in the
laboratory manual.

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 
In case of signs and symptoms: The participant will be reminded to further complete the
ePROs in the eCOA as described for COVID Day 1-2.
 
In case the nasal swabs collected on Day 1-2 or Day 3-5 visits are tested positive for SARS-
CoV-2 and the participant is asymptomatic: the participant will be reminded to further
complete (suspected) COVID-19 surveillance (symptom check).
 
If, on COVID-19 Day 3-5, the participant stopped the COVID-19 procedures and returned to
default Schedules of Activities, due to lack of signs and symptoms and unavailability of results
from nasal swabs collected on Day 1-2 and Day 3-5 visits, the participant will be contacted as
soon as at least one of these samples is found to be positive for SARS-CoV-2 presence. The
participant will be asked to resume COVID-19 procedures, until 14 days after symptom onset
(COVID-19 Day 15) or until resolution of the COVID-19 episode, whichever comes last.
Note:
 Participants should be encouraged by the site to collect nasal swabs and saliva samples
as indicated in the Schedules of Activities. If the participant is unable or unwilling to
collect all samples as requested, the participant should still complete the other
COVID-19 assessments, including the visit at COVID-19 Day 29.
Day 29 procedures
If a participant has at least 1 SARS-CoV-2 positive nasal swab collected on COVID-19 Day 1-2
or Day 3-5 visits, then he or she will be asked to return to the site on COVID-19 Day 29 (±7 days)
where a blood sample will be drawn for sero-confirmation of SARS-CoV-2 infection (antibody).
A qualified member of the study site will measure vital signs (body temperature, blood pressure,
heart rate, and respiratory rate) and pulse oximetry. A targeted physical examination will be
performed based on the judgement of the investigator. The MRU questionnaire MUST be
completed for all participants who have met the prespecified criteria for (suspected) COVID-19
and will be based on a clinical interview (Appendix 7). The medical history and description of
COVID-19 episode will be collected by interview with the participant. If the participant is still
symptomatic, he/she will complete the SIC (Appendix 6) in the eCOA. Asymptomatic participants
will complete the (suspected) COVID-19 surveillance (symptom check).
Note: COVID-19 Day 29 should still be performed even if the nasal swabs results are still
pending. The COVID-19 Day 29 assessments may also be performed by a trained HCP at the
participant’s home, if allowed per local regulations.
Note: if symptoms are ongoing at the time of the COVID-19 Day 29 visit, the investigator can stop
the SIC. To close the COVID-19 episode, please refer to next section.
This visit can be combined with a regular study visit if within the applicable visit windows.
Closure of the COVID-19 episode
The participant should continue the COVID-19 procedures until any of the following occurs, based
on molecular test results:

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 
If both nasal swabs (collected on COVID-19 Day 1-2 and COVID-19 Day 3-5) are negative
for SARS-CoV-2, the participant will not undertake any further COVID-19 procedures and
will fall back to the default Schedules of Activities, until the end of the study/early withdrawal.
 
If the participant has at least 1 SARS-CoV-2 positive nasal swab collected on COVID-19 Day
1-2 or Day 3-5 visits, thenthe participant will be asked to undertake the COVID-19 procedures
(2-day cycles) until 14 days after symptom onset (COVID-19 Day 15) or until resolution of
the COVID-19 episode, whichever comes lasta. Resolution of the COVID-19 episode is
defined as having 2 consecutive SARS-CoV-2 negative nasal swabs and 2 consecutive days
with no COVID-19-related signs or symptoms. Once past COVID-19 Day 15, participants
should stop the collection of nasal swabs and saliva samples as soon as 2 consecutive nasal
swabs are SARS-CoV-2 negative, but (if still symptomatic at that time) should continue
completing the ePROs (including SIC, body temperature, and pulse oximetry) in the eCOA
until 2 consecutive days with no COVID-19-related signs or symptoms.
Note: for participants who have signs and symptoms present at baseline (assessed
pre-vaccination), only signs and symptoms that are associated with COVID-19 and that
developed during the COVID-19 episode are to be taken into account.
 
If signs and symptoms are still ongoing on COVID-19 Day 3-5, collection of SIC will be
continued until at least 14 days after onset unless both COVID-19 Day 1-2 and COVID-19
Day 3-5 nasal swabs are negative. If either of the swabs is positive or the result is unknown
AND the participant is beyond 14 days after onset of symptoms, the SIC can be stopped after
2 days without signs and symptoms.
 
For participants with a positive test result for SARS-CoV-2 infection, a study visit will be
conducted 28 days after symptom onset (ie, at the COVID-19 Day 29 visit) to assess the
clinical course of the infection.
 
If 2 consecutive nasal swabs negative for SARS-CoV-2 are not available due to operational
reasons (eg, delays in results availability), participants may cease collection of nasal swabs
and saliva samples at the COVID-19 Day 29visit, provided they have 2 consecutive days with
no COVID-19-related signs and symptoms. In these cases, participants may be asked to
resume sample collection if nasal sample results
once available
do not present with 2
consecutive negative swabs for SARS-CoV-2
Upon closure of the COVID-19 episode and procedures, all participants will fall back to the default
Schedules of Activities, until the end of the study/early withdrawal.
Note: if symptoms are ongoing at the time of the COVID-19 Day 29 visit, the investigator can stop
the SIC. To close the COVID-19 episode, the investigator should follow-up participants and
document the end of the episode in the eCRF (2 consecutive days without signs and symptoms and
2 negative nasal swab results). Any symptom with sequelaeb ongoing at the time of the COVID-19
Day 29 visit, will need to be followed and the end date of the symptom will be documented in the
eCRF.
All confirmed COVID-19 episodes will be communicated to the respective participant and to other
authorities according to local regulations.
a long-term sequelae of COVID-19 will not be followed until their resolution if not resolved at COVID-19 Day 29.
b long-term sequelae of COVID-19 will not be followed until their resolution if not resolved at COVID-19 Day 29.

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If the participant experiences new signs or symptoms suggesting possible COVID-19 at a later
point in time, the participant would restart the COVID-19 procedures from COVID-19 Day 1
onwards.
With regards to the ePRO (ie, the SIC, including body temperature):
 
The ePRO instrument will be provided in the local language in accordance with local
guidelines.
 
The ePRO instrument must be available for regulators and for IRB/ERC submissions,
therefore the ePRO instrument or screen shots need to be attached to the protocol or provided
in a companion manual with the instruments that will be submitted with the protocol.
 
The ePRO and AE data will not be reconciled with 1 another.
8.1.3. 
Efficacy Assessments
Up to Amendment 7, identification and molecular confirmation of SARS-CoV-2 infection and
symptomatic COVID-19 will be performed throughout the study as described in Section 8.1.2. Up
to Amendment 7, the ePRO to evaluate VE parameters will be the SIC. See Section 8.1.3.1 for
Case Definition of Moderate to Severe/Critical COVID-19and Section 8.1.3.2 for Case Definition
of Mild COVID-19. Molecular confirmation of SARS-CoV-2 infection by acentral laboratory will
be used for the analysis of the case definition. As of Amendment 7, no identification or molecular
confirmation of SARS-CoV-2 infection and symptomatic COVID-19 will be done via central
testing.
COVID-19 cases will be assessed independently by a Clinical Severity Adjudication Committee
(see Section 8.1.3.6). Classification of severity will be based on the highest degree of severity
during the observation period (see Sections 8.1.3.1, 8.1.3.2, and 8.1.3.4) and on the Committee's
clinical judgement.
Up to Amendment 7, the occurrence of COVID-19-related hospitalization and COVID-19-related
complications (such as but not limited to hyperinflammatory syndrome, pneumonia, neurological
or vascular complications, severe pneumonia, severe neurological or vascular events, acute
respiratory distress syndrome, renal complications, sepsis, septic shock, death)71 will be monitored
throughout the study.
As a secondary objective, VE in the prevention of asymptomatic SARS-CoV-2 infection and mild
COVID-19 will be analyzed. For samples collected prior to implementation of Amendment 7: an
immunologic test for SARS-CoV-2 seroconversion (ELISA and/or SARS-CoV-2 immunoglobulin
assay) based on SARS-CoV-2 N protein, may be performed to identify cases of asymptomatic
infection. This assay will be performed on samples obtained at Day 1 (before the 1st vaccination)
and 14 days, 6 months, and 1 year after the second vaccination (see Section 8.1.3.5). Additionally,
this assay will be performed on blood samples obtained (prior to Amendment 7)at the unblinding
visit (before open-label vaccination) and at the Booster Vaccination Visit (before booster
vaccination).

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8.1.3.1. 
Case Definition for Moderate to Severe/Critical COVID-19
For the primary -endpoint (see Section 3), all moderate and severe/critical COVID-19 cases will
be considered.
Case Definition for Moderate COVID-19
 
A SARS-CoV-2 positive RT-PCR or molecular test result from any available respiratory tract
sample (eg, nasal swab sample, sputum sample, throat swab sample, saliva sample) or other
sample
AND at any time during the course of observationa:
Any 1 of the following new or worsening
signs or symptoms:
OR
Any 2 of the following new or worsening
signs or symptoms:
 
Respiratory rate ≥20 breaths/minute
 
Abnormal saturation of oxygen
(SpO2) but still >93% on room air at
sea level*
 
Clinical or radiologic evidence of
pneumonia
 
Radiologic evidence of deep vein
thrombosis (DVT)
 
Shortness of breath or difficulty
breathing 
 
Fever (≥38.0°C or ≥100.4°F)
 
Heart rate ≥90 beats/minute
 
Shaking chills or rigors
 
Sore throat
 
Cough
 
Malaise as evidenced by 1 or more of
the following**:
- Loss ofappetite
- Generally unwell
- Fatigue
- Physical weakness
 
Headache
 
Muscle pain (myalgia)
 
Gastrointestinal symptoms (diarrhea,
vomiting, nausea, abdominal pain)**
 
New or changing olfactory or taste
disorders
 
Red or bruised looking feet or toes
* SpO2 criteria will be adjusted according to
altitude, per the investigator judgement.
** Having 2 or more elements of a symptom (eg,
vomiting and diarrhea or fatigue and loss of
appetite) is counted only as 1 symptom for the case
definition. To meet the case definition, a
participant would need to have at least 2 different
symptoms.
Case Definition for Severe/Critical COVID-19
a Participants will be asked to undertake the COVID-19 procedures until 14 days after symptom onset (COVID-19
Day 15) or until resolution of the COVID-19 episode, whichever comes last (see Section 8.1.2).

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 
A SARS-CoV-2 positive RT-PCR or molecular test result from any available respiratory tract
sample (eg, nasal swab sample, sputum sample, throat swab sample, saliva sample) or other
sample
AND any 1 of the following at any time during the course of observationa:
 
Clinical signs at rest indicative of severe systemic illness (respiratory rate ≥30 breaths/minute,
heart rate ≥125 beats/minute, oxygen saturation (SpO2)≤93% on room air at sea level*, or
partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2)<300 mmHg)
* SpO2 criteria will be adjusted according to altitude per the investigator judgement.
 
Respiratory failure (defined as needing high-flow oxygen, non-invasive ventilation,
mechanical ventilation, or extracorporeal membrane oxygenation [ECMO])
 
Evidence of shock (defined as systolic blood pressure <90 mmHg, diastolic blood pressure
<60 mmHg, or requiring vasopressors)
 
Significant acute renal, hepatic, or neurologic dysfunction
 
Admission to the ICU
 
Death
8.1.3.2. 
Case Definition for Mild COVID-19
 
A SARS-CoV-2 positive RT-PCR or molecular test result from any available respiratory tract
sample (eg, nasal swab sample, sputum sample, throat swab sample, saliva sample) or other
sample;
AND at any time during the course of observationa:
 
One of the following symptoms: fever (≥38.0C or ≥100.4°F), sore throat, malaise (loss of
appetite, generally unwell, fatigue, physical weakness), headache, muscle pain  (myalgia),
gastrointestinal symptoms, cough, chest congestion, runny nose, wheezing, skin rash, eye
irritation or discharge, chills, new or changing olfactory or taste disorders, red or bruised
looking feet or toes, or shaking chills or rigors.
A case is considered mild when it meets the above case definition but not the moderate to
severe/critical definition in Section 8.1.3.1.
8.1.3.3. 
US FDA Harmonized Case Definition for COVID-19
If a participant presents with symptoms as those listed by the US FDA harmonized case definition14
(see Appendix 10), the investigator (or designated medically trained clinician) should assess if
these are suggestive of COVID-19:
 
A SARS-CoV-2 positive RT-PCR or molecular test result from any available respiratory tract
sample (eg, nasal swab sample, sputum sample, throat swab sample, saliva sample) or other
sample; AND
a Participants will be asked to undertake the COVID-19 procedures until 14 days after symptom onset (COVID-19
Day 15) or until resolution of the COVID-19 episode, whichever comes last (see Section 8.1.2).

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 
COVID-19 symptoms consistent with those defined by the US  FDA harmonized case
definition14 at the time of finalization of this protocol: fever or chills, cough, shortness of
breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or
smell, sore throat, congestion or runny nose, nausea or vomiting, diarrhea.
8.1.3.4. 
Case Definition for Asymptomatic or Undetected COVID-19
If a participant does not fulfil the criteria for suspected COVID-19 based on signs and symptoms
(see Section 8.1.1), which would classify them as mild or moderate to severe/critical by the
protocol definitions mentioned above (Section 8.1.3.1 and Section 8.1.3.2).
AND
 
has a SARS-CoV-2 positive RT-PCR or molecular test result from any available respiratory
tract sample (eg, nasal swab sample, sputum sample, throat swab sample, saliva sample) or
other sample
OR
 
develops a positive serology (non-S protein) test
Then, the participant will be considered to have experienced asymptomatic or undetected
COVID-19.
A molecularly confirmed positive RT-PCR for SARS-CoV-2 will need to be captured in the eCRF.
As of Amendment 7, severity assessment by the CSAC may still be performed and will be based
on the data collected through the passive follow-up (eg, hospitalization reported in the context of
SAEs). The scope of the severity review may change and will be described in the charter.
8.1.3.5. 
SARS-CoV-2 Seroconversion Assessment
For samples collected prior to implementation of Amendment 7, an  immunologic test for
SARS-CoV-2 seroconversion (ELISA and/or SARS-CoV-2 immunoglobulin assay) based on
SARS-CoV-2 N protein, maybe performed to identify cases of asymptomatic infection on samples
obtained at Day 1 (before the 1st vaccination) and 14 days, 6 months, and 1 year after the second
vaccination (see Section 8.1.4)and at the unblinding visit and at the Booster Vaccination Visit.
8.1.3.6. 
Clinical Severity Adjudication Committee
The Clinical Severity Adjudication Committee will be utilized for adjudication of the severity of
COVID-19 cases taking into account all available relevant information at the time of adjudication.
As of Amendment 7, Clinical Severity Adjudication Committee may review all cases based on
available data from the passive follow-up (eg, limited to COVID-19AE/SAE data, CIOMS forms,
local laboratory results). The Clinical Severity Adjudication Committee's decisions will be
considered the definitive classification of the case. The role of the Committee and adjudication
process will be provided in the committee's charter and more details regarding the impact on the
analysis will be provided in the SAP. The case review including severity assessments after
implementation of Amendment 7 may change and will be reflected in the charter of the committee.

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8.1.4. 
Immunogenicity Assessments
Up to Protocol Amendment 7, blood will be collected from all non-Immunogenicity  Subset
participants for humoral immunogenicity assessments at Day 1 (before the 1st vaccination),
14 days, 6 months and 1 year after the second vaccination.
In the double-blind phase, for a total of approximately 400 participants in the Immunogenicity
Subset, blood will be collected for analysis of humoral immune responses before each vaccination,
28 days after the 1st vaccination and 14 days , 6 months, 1 year, 18 months, and 2 years after the
second vaccination.
For a total of approximately 400 participants in the new Immunogenicity Subset, blood will be
collected for analysis of humoral immune responses at baseline and at Day 71, Week 32, and Week
60 after the first vaccination.
All participants in the Immunogenicity Subset will be enrolled from Study Stage 2. Participants in
the Immunogenicity Subset in the double-blind phase and in the open-label phase (referred to as
Subset "B") will be divided into 4 groups as presented in Table 3 and Table 4, respectively.
Table 3: 
Sample Size and Distribution of the Immunogenicity Subset Between Active and Placebo
Groups
Study Vaccine 
Subset 1a 
Subset 1b 
Subset 2a 
Subset 2b
5×1010 vp/5×1010 vp 
50 
50 
50 
50
Placebo/placebo 
50 
50 
50 
50
Total 
100 
100 
100 
100
vp  virus particles
Subset 1a: healthy participants ≥18 years to <60 years of age without relevant comorbidities, enrolled during Stage 2.
Subset 1b: healthy participants ≥60 years of age without relevant comorbidities, enrolled during Stage 2.
Subset 2a: participants ≥18 to <60 years of age with relevant comorbidities, enrolled during Stage 2.
Subset 2b: participants ≥60 years of age with relevant comorbidities, enrolled during Stage 2
Table 4: 
Sample Size and Distribution of the Immunogenicity Subset B for the Open-label Phase
Study Vaccine 
Subset B1a  
Subset B1b 
Subset B2a  
Subset B2b
5×1010 vp, 5×1010 vp 
50 
50 
50 
50
5×1010 vp 
50 
50 
50 
50
Total 
100 
100 
100 
100
vp  virus particles
Subset B1a: healthy participants ≥18 years to <60 years of age without relevant comorbidities.
Subset B1b: healthy participants ≥60 years of age without relevant comorbidities.
Subset B2a: participants ≥18 to <60 years of age with relevant comorbidities.
Subset B2b: participants ≥60 years of age with relevant comorbidities.
All enrolled participants will have a blood sample taken at the time of the unblinding visit (before
open-label vaccination) and at the Booster Vaccination Visit (before booster vaccination) for
analysis of immune responses, regardless of whether they were part of the Immunogenicity Subset
in the double-blind phase.

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Up to Amendment 7, during a COVID-19 episode, blood will be collected on COVID-19 Day 3-5
and on COVID-19 Day 29for immunogenicity assessments, including the assays summarized in
Table 5. As from Amendment 7, active follow-up will no longer be pursued and blood sampling
for this purpose will no longer be performed.
Table 5: 
Immunogenicity Assays
Humoral Assays 
Purpose
Supportive of Secondary Objectives
SARS-CoV-2 binding antibodies 
to S protein (ELISA)
Analysis of antibodies binding to SARS-CoV-2 S protein
SARS-CoV-2 seroconversion 
based on antibodies to N protein
(ELISA and/or SARS-CoV-2
immunoglobulin assay)
Analysis of antibodies binding to SARS-CoV-2 N protein
Supportive of Exploratory Objectives
SARS-CoV-2 neutralization 
(VNA) 
Analysis of neutralizing antibodies to the wild-type or variant
virus, and/or pseudovirion expressing S protein
SARS-CoV-2 binding antibodies 
to S protein (MSD) 
Analysis of antibodies binding to SARS-CoV-2 S protein
(different than the assays supportive of the secondary
objectives) and the receptor-binding domain (RBD) of
SARS-CoV-2 S protein
Functional and molecular 
antibody characterization 
Analysis of antibody characteristics including, but not limited
to, avidity, Fc-mediated viral clearance, Fc characteristics, Ig
subclass, IgG isotype, antibody glycosylation, and assessment
of antibody repertoire
Adenovirus neutralization (VNA) Adenovirus neutralization assay to evaluate neutralizing
antibody responses against the Ad26 vector
Binding antibodies to other 
coronaviruses (MSD) 
Analysis of antibodies binding to coronaviruses other than
SARS-CoV-2
Ad26  adenovirus type 26; ELISA  enzyme linked immunosorbent assay; Fc  crystallizable fragment; Ig(G) 
immunoglobulin (G); MSD  Meso Scale Discovery; N
nucleocapsid; RBD  receptor binding domain; S  spike; SARS
CoV 2  severe acute respiratory syndrome coronavirus 2; VNA  virus neutralization assay.
In areas where seroprevalence is predicted to be high, a screening serologic test for past or current
infection with SARS-CoV-2 may be performed (in a local laboratory) at the discretion of the
sponsor to restrict the proportion of seropositive participants in the study.
For samples collected prior to implementation of Amendment 7, a serologic test for past or current
infection with SARS-CoV-2 may be performed for all participants at Day 1 (before the
1st vaccination) and 14 days and 6 months after the second vaccination. All participants in the
open-label phase will have 1 blood sample taken at the unblinding visit (before open-label
vaccination) and at the Booster Vaccination Visit (before booster vaccination), except when the
previous blood sampling for the serologic test occurred within 5 days of the visit.a Samples for the
a The unblinding visit and the Booster Vaccination Visit may be combined with the scheduled study visit and
procedures that would be duplicated should be done only once. If a blood draw is planned in the scheduled visit
no additional blood draw is needed.

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serologic tests will be sent to a central laboratory for testing.a Participants who test positive will
be informed of the result by the study staff.
8.2. 
Safety Assessments
Details regarding the IDMC are provided in Section 9.8and in Appendix 3.
Adverse events will be reported and followed by the investigator as specified in Section 8.3 and
Appendix 4.
Any clinically relevant changes occurring during the study must be recorded on the AE section of
the eCRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be
followed by the investigator until resolution or until a clinically stable condition is reached.
The study will include the following evaluations of safety and reactogenicity according to the
timepoints provided in the Schedules of Activities.
As of Amendment 7, active follow-up of new suspected COVID-19 episodes will be replaced by
a passive follow-up approach.
The Sponsor/Sponsor committee will monitor safety in a blinded manner (see Section 6.11).
8.2.1. 
Physical Examinations (Up to Amendment 7)
Height and body weight will be assessed at screening. To obtain the actual body weight,
participants must be weighed lightly clothed. The height should be measured without footwear.
A targeted physical examination will be performed during a COVID-19 episode by the investigator
or designated medically trained clinician  (or a trained HCP  or home health care nurse under
supervision of the investigator, if allowed per local regulations). Any clinically relevant
abnormalities or changes in severity observed during the review of body systems should be
documented in the eCRF.
8.2.2. 
Vital Signs
At all on-site visits, body temperature (oral route preferred, or in accordance with the local standard
of care) will be assessed.
Participants in the Safety Subset will utilize an e-Diary to record body temperature measurements
from the time of vaccination until 7 days after each vaccination in the eCOA (see Section 8).
a Vaccination with Ad26.COV2.S may interfere with some serologic assays utilized at local community health
clinics/commercial laboratories, by seeking and identifying the spike protein in the vaccine and rendering a false
positive result. For this reason, participants will be encouraged to not seek testing outside the study. If a participant
requires testing outside of the protocol-mandated testing schedule, the site will guide them on the appropriate assay
that identifies the viral nucleocapsid protein (and not the spike protein).

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Up to Amendment 7, all participants with COVID-19 signs and symptoms should measure body
temperature daily (oral route preferred, or in accordance with the local standard of care) and record
the highest temperature in the last 24 hours each day in the ePRO in the eCOA, for the duration of
follow-up of COVID-19 episodes (as defined in Section 8.1.2).
Up to Amendment 7, vital signs will be measured during a COVID-19 episode by a qualified
member of the study site. This includes measurement of, preferably, supine systolic and diastolic
blood pressure, heart rate, respiratory rate, oxygen saturation, and body temperature. It is
recommended that vital signs are measured before collection of nasal swabs and blood draws.
Blood pressure and pulse/heart rate measurements will be assessed in a supine position (preferably)
with a completely automated device. Manual techniques will only be used if an automated device
is not available.
Blood pressure and pulse/heart rate measurements should be performed before blood draws and
preceded by at least 5 minutes of rest in a quiet setting without distractions (eg, television, cell
phones).
Under special circumstances such as high altitude, the investigator should assess baseline
respiratory rate and other vital signs, as appropriate.
Any vital signs measurements taken at home that may trigger the severe/critical case definition
will be confirmed as soon as possible by qualified medical staff and participants will be referred
for care, if needed.
8.2.3. 
Pregnancy Testing
A urine pregnancy test for participants of childbearing potential will be performed at screening
and before any vaccination either in double-blind phase or in open-label phase of the study.
Additional serum or urine pregnancy tests may be performed for participants of childbearing
potential, as determined necessary by the investigator or required by local regulation, to establish
the absence of pregnancy at any time during the participation in the study.
8.2.4. 
Clinical Laboratory Assessments
Blood samples for clinical laboratory assessments (as detailed in Section 10.2, Appendix 2) will
be collected as described in the Schedules of Activities in Section 1.3. In case of a thrombotic
event thrombocytopenia, or TTS, every effort should be made to collect local hospital/laboratory
test results obtained by the treating physician to allow rapid diagnosis and treatment. This
information should be reported through the TTS AESI form (see Section 10.13, Appendix 13)
electronically per instructions in the eCRF completion guidelines. In addition, every effort should
be made to collect blood samples from the participant for a platelet count (local laboratory  or
substitute for local laboratory) and other applicable testing (central laboratory) (see the Schedule
of Activities in Section 1.3.7 and Section 10.2, Appendix 2). All local laboratory results need to
be encoded in the eCRF, including platelet counts. Low platelet counts are to be recorded as

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suspected AESI (thrombocytopenia). The Investigator will review the laboratory test results to
assist the investigation of the AESI.
See Section 8.3.7.1 for details on laboratory test details to be reported for an AE of
thrombocytopenia.
8.3. 
Adverse Events, Serious Adverse Events, Medically-attended Adverse
Events, Adverse Events of Special Interest, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including AEs, SAEs,
MAAEs, suspected AESIs, and product quality complaints (PQCs), from clinical studies are
crucial for the protection of participants, investigators, and the sponsor, and are mandated by
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in
accordance with those procedures.
AEs will be reported by the participant (or, when appropriate, by a caregiver or surrogate) during
the reporting periods detailed below.
Further details on AEs, SAEs, MAAEs, suspected AESIs, and PQCs can be found in Appendix 4.
8.3.1. 
Time Period and Frequency for Collecting Adverse Event,
Medically-attended Adverse Event, Adverse Event of Special Interest,
and Serious Adverse Event Information
All Adverse Events
For all participants (throughout the study regardless of any protocol amendment):
 
(S)AEs that are related to study procedures or that are related to non-investigational sponsor
products will be reported from the time a signed and dated ICF is obtained until the end of the
study/early withdrawal.
 
Clinically relevant medical events not meeting the above criteria and occurring between first
signing of the ICF and moment of 1st vaccination will be collected on the Medical History
eCRF page as pre-existing conditions.
 
All SAEs and all AEs leading to study discontinuation or discontinuation of study vaccination
(regardless of the causal relationship) are to be reported from the moment of 1st vaccination
until completion of the participant’s last study-related procedure, which may include contact
for safety follow-up. The sponsor will evaluate any safety information that is spontaneously
reported by an investigator beyond the time frame specified in the protocol.
 
MAAEs are defined as AEs with medically-attended visits including hospital, emergency
room, urgent care clinic, or other visits to or from medical personnel for any reason. Routine
study visits will not be considered medically-attended visits. New onset of chronic diseases
will be collected as part of the MAAEs. MAAEs are to be reported for all participants from
the moment of 1st vaccination until 6 months after the last vaccination (including the open-

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label vaccination or booster vaccination, whichever comes last), except for MAAEs leading
to study discontinuation which are to be reported during the entire study.
 
Special reporting situations, whether serious or non-serious, will be recorded for each
vaccination from the time of vaccination until 28 days post-vaccination.
 
All AEs will be followed until resolution or until clinically stable.
As of Amendment 7, for all participants:
 
A passive follow-up approach is adopted, defined as follow-up phone call visits by the site
instead of on-site study visits to document new COVID-19 events as SAEs, AEs, or MAAEs.
Participants may also contact the site at any time in between scheduled visits to report a safety
concern (eg, hospitalization) or COVID-19 episodes.
 
Concomitant medications for these events should be reported.
 
If a COVID-19 confirmatory laboratory or assay read-out is available, this should be reported
in the eCRF (self-reported or as part of CIOMS form)together with the method of the test.
 
COVID-19 events ongoing at time of informed consent do not need to be reported as AEs,
SAE, or MAAEs, only new onset of COVID-19 events need to be reported.
For participants in the Safety Subset (applicable to double-blind phase only):
 
Solicited AEs, collected through an e-Diary, will be recorded for each vaccination from the
time of vaccination until 7 days post-vaccination. If these solicited signs and symptoms are
not resolved by that time, the participant will continue to complete the e-Diary until Day 29
post-vaccination or until they are resolved, whichever comes first.
 
All other unsolicited AEs, whether serious or non-serious, will be recorded for each
vaccination from the time of vaccination until 28 days post-vaccination. Unsolicited AEs with
the onset date outside the timeframe defined above (>28 days after previous study
vaccination), which are ongoing on the day of the subsequent vaccination, should be recorded
as such.
After the unblinding visit, participants in the Safety Subset will stop the collection of solicited AEs
and will not continue in the Safety Subset for any subsequent vaccination. Newly enrolled
participants in the open-label phase will not participate in the Safety Subset.
Adverse Events of Special Interest
From the time of local approval of Protocol Amendment 5 onwards, TTS is considered to be an
AESI. Suspected AESIs (thrombotic events and thrombocytopenia [defined as platelet count below
150,000/µL9]) will be recorded from the moment of vaccination until the end of the study/early
withdrawal (see Section 8.3.7). An AESI Assessment Committee with appropriate expertise will
be established to evaluate each suspected AESI and determine whether it is a case of TTS.
Serious Adverse Events
All SAEs, as well as PQCs, occurring during the study must be reported to the appropriate sponsor
contact person by study-site personnel within 24 hours of their knowledge of the event.

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SAEs, including those spontaneously reported to the investigator before the end of the study, must
be reported using an SAE form. The sponsor will evaluate any safety information that is
spontaneously reported by an investigator beyond the time frame specified in the protocol.
Up to Amendment 7, participants will be reminded once a month to contact the study site in case
of an SAE. As from Amendment 7, this is replaced by the passive follow-up approach.
All participants will be monitored for safety, including enhanced disease and SAEs until the last
study visit and including MAAEs up to 6 months after the last Ad26.COV2.S dose.
Information regarding SAEs will be transmitted to the sponsor using the SAE Form and Safety
Report Form of the eCRF, which must be completed and reviewed by a physician from the study
site and transmitted to the sponsor within 24 hours. The initial and follow-up reports of an SAE
should be transmitted electronically or by facsimile (fax). Telephone reporting should be the
exception and the reporter should be asked to complete the appropriate form(s) first.

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Overview of Safety Reporting
Figure 4: 
Diagram of Safety Reporting in the Study
(a) Please refer to Section 10.4.4.
(b)AEs related to study procedures which are procedures-related interventions (eg, blood drawn for immunogenicity sampling) that may result in an AE (eg, bruise).
(c) Suspected adverse event of special interest (AESI) that needs to be reported to the sponsor within 24 hours
*open-label vaccination can occur prior to Vac 2.

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8.3.2. 
Method of Detecting Adverse Events, Medically-attended Adverse
Events, Adverse Events of Special Interest, and Serious Adverse
Events
Care will be taken not to introduce bias when detecting AEs, MAAEs, suspected AESIs, or SAEs.
Open-ended and nonleading verbal questioning of the participant is the preferred method to inquire
about AE occurrence.
Solicited and unsolicited AEs collected as part of Safety subset will be collected in the eCRF up
to the unblinding visit.
Solicited Adverse Events
Solicited AEs are used to assess the reactogenicity of the study vaccine and are predefined local
(at injection site) and systemic events for which the participant is specifically questioned, and
which are noted by participants in their e-Diary.
The first 1,000 participants will remain under observation at the study site for at least 30 minutes
after each vaccination to monitor for the development of acute reactions. If at the time of the Day 3
safety review of the initial 1,000 participants no acute reactions have been observed, the
observation period at the study site may be reduced to at least 15 minutes, except where local
regulations require a longer observation period (eg, Belgium), after each vaccination for the
remaining participants in the study.
In addition, after each vaccination, participants in the Safety Subset will record solicited signs and
symptoms in an e-Diary from time of vaccination until 7 days post-vaccination. If these solicited
signs and symptoms are not resolved by that time, the participant will continue to complete the
e-Diary until Day 29 post-vaccination or until they are resolved, whichever comes first.
Participants in the Safety Subset will be provided with an e-Diary and instructions on how to
complete the diary (see Overview in Section 8). Electronic diary information will be transferred
from the e-Diary source to the sponsor. After review and verbal discussion of the initial e-Diary
entries with the participant, the investigator will complete his/her own assessment in the relevant
sections of the eCRF/eCOA. Once a solicited sign or symptom from an e-Diary is considered to
be of severity Grade 1 or above, it will be recorded as a solicited AE in the eCRF.
Solicited Injection Site (Local) Adverse Events
Participants will be asked to note in the e-Diary occurrences of injection site pain/tenderness,
erythema, and swelling at the study vaccine injection site daily for 7 days after each vaccination
(day of vaccination and the subsequent 7 days). The extent (largest diameter) of any erythema and
swelling should be measured (using the ruler supplied) and recorded daily. The case definitions
for solicited injection site events can be found in the references.36,47
Solicited Systemic Adverse Events
Participants will be instructed on how to record daily temperature using a thermometer provided
for home use. Participants should record the temperature in the e-Diary in the evening of the day
of each vaccination, and then daily for the next 7 days approximately at the same time each day.

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If more than 1 measurement is made on any given day, the highest temperature of that day will be
recorded in the e-Diary.
Fever is defined as endogenous elevation of body temperature ≥38.0°C or ≥100.4°F, as recorded
in at least 1 measurement.51
Participants will also be instructed on how to note signs and symptoms in the e-Diary on a daily
basis for 7 days after each vaccination (day of vaccination and the subsequent 7 days), for the
following events: fatigue, headache, nausea, myalgia.
Unsolicited Adverse Events
Unsolicited AEs are all AEs for which the participant is not specifically questioned.
Medically-attended Adverse Events
MAAEs are AEs with medically-attended visits including hospital, emergency room, urgent care
clinic, or other visits to or from medical personnel for any reason. New onset of chronic diseases
will be collected as part of the MAAEs. Routine study visits will not be considered medically-
attended visits.
For details about AESIs, refer to Section 8.3.7.
8.3.3. 
Follow-up of Adverse Events, Medically-attended Adverse Events,
Adverse Events of Special Interest, and Serious Adverse Events
The investigator is obligated to perform or arrange for the conduct of supplemental measurements
and evaluations as medically indicated to elucidate the nature and causality of the AE, MAAE,
suspected AESI, SAE, or PQC as fully as possible. This may include laboratory tests or
investigations, histopathological examinations, or consultation with other HCPs.
AEs, including pregnancy, will be followed by the investigator as specified in Appendix 4.
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities.
The sponsor will also report to the investigator (and the head of the investigational institute where
required) all suspected unexpected serious adverse reactions (SUSARs). The investigator (or
sponsor where required) must report SUSARs to the appropriate IEC/IRB that approved the
protocol unless otherwise required and documented by the IEC/IRB. A SUSAR will be reported to
regulatory authorities unblinded. Participating investigators and IEC/IRB will receive a blinded
SUSAR summary, unless otherwise specified.
8.3.5. 
Pregnancy
All initial reports of pregnancy in participants or partners of male participants must be reported to
the sponsor by the study-site personnel within 24 hours of their knowledge of the event using the
appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and

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must be reported using an SAE reporting form. Any participant who becomes pregnant during the
study must be promptly withdrawn from study vaccinations but will remain in the study and will
continue to undergo all procedures for surveillance and follow-up of COVID-19 and all safety
follow-up as outlined in the protocol for all participants. Note that participants who are pregnant
and previously received placebo during the double-blind phase may be vaccinated with
Ad26.COV2.S  (single-dose regimen), if allowed by local regulations for emergency use of the
vaccines and if the investigator considers that the potential benefits outweigh any potential risks
to the mother and fetus (See section 6.4). Likewise, pregnant participants who previously received
the open-label vaccination may receive the booster vaccination if allowed by local regulations for
use of vaccines and if the investigator considers that the potential benefits outweigh any potential
risks to the mother and fetus (see Section 6.5).
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
infant will be required.
8.3.6. 
Disease-related Events and Disease-related Outcomes Not Qualifying
as Adverse Events or Serious Adverse Events
(S)AEs caused by molecularly confirmed SARS-CoV-2 infection will be removed at the analysis
level from the (S)AE listings and tables and presented separately.
All events that meet the definition of an SAE will be reported as SAEs, regardless of whether they
are protocol-specific assessments.
8.3.7. 
Adverse Events of Special Interest
Adverse events of special interest (AESIs) are significant AEs that are judged to be of special
interest because of clinical importance, known or suspected class effects, or based on nonclinical
signals. Adverse events of special interest will be carefully monitored during the study by the
sponsor.
AESIs must be reported to the sponsor within 24 hours of awareness irrespective of seriousness
(ie, serious and non-serious AEs) or causality following the procedure described above for SAEs.
Specific requirements for the AESI are described below.
8.3.7.1. 
Thrombosis with Thrombocytopenia Syndrome
As described in Section 2.3.1, Risks Related to Study Participation, TTS has been observed very
rarely following vaccination with Ad26.COV2.S and is considered to be an AESI in this study.
TTS is a syndrome characterized by a combination of both a thrombotic event and
thrombocytopenia.2,9
Because this syndrome is rare and not completely understood, all cases of thrombosis and/or
thrombocytopenia will be considered a suspected case of TTS until further adjudication can be
performed. An AESI Assessment Committee with appropriate expertise will be established to
evaluate each suspected AESI and determine whether it is a case of TTS. The investigator shall be

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responsible for reporting any suspected AESI of TTS using the SAE form and the form detailed in
Section 10.13, Appendix 13. A suspected TTS case is defined as:
 
Thrombotic events: suspected deep vessel venous or arterial thrombotic events as detailed in
Section 10.14, Appendix 14
 
Thrombocytopenia, defined as platelet count below 150,000/µL9 as per the Brighton
Collaboration.
Symptoms, signs, or conditions suggestive of a thrombotic event should be recorded and reported
as a suspected AESI even if the final or definitive diagnosis has not yet been determined, and
alternative diagnoses have not yet been eliminated or shown to be less likely. Follow-up
information and final diagnoses, if applicable, should be submitted to the sponsor as soon as they
become available.
In the event of thrombocytopenia, study site personnel should report the absolute value for the
platelet count and the reference range for the laboratory test used.
For either a thrombotic event or thrombocytopenia, testing for anti-PF4 should be performed at
the local laboratory or substitute local laboratory; repeat testing may be requested for confirmation
upon sponsor discretion.
Suspected AESIs will require enhanced data collection and evaluation (see Section 1.3.7). Every
effort should be made to report as much information as possible about the AESI to the sponsor in
a reasonable timeframe.
If an event meets the criteria for an SAE (Section 10.4.1), it should be reported using the same
process as for other SAEs.
The form detailed in Section 10.13, Appendix 13 is intended as a guide for assessment of the
AESIs to facilitate diagnosis and determine treatment options. If the investigator is not the treating
physician, every effort should be made to collect the information requested in the form from the
treating physician and enter the available information in the eCRF.The sponsor will also attempt
to collect information from any thrombotic event / thrombocytopenia / TTS reported prior to
Protocol Amendment 5.
8.4. 
Virology Assessments
Nasal swabs will be used to detect and/or quantify SARS-CoV-2. Exploratory quantification of
the SARS-CoV-2 viral load in saliva samples may also be performed.
Gene sequencing may be performed to detect changes in the S gene and potentially also other parts
of the viral genome, if a sample is available.
Up to Amendment 7, nasal swabs collected during a confirmed COVID-19 episode may also be
tested at a central laboratory for the presence of other respiratory pathogens using a broad
respiratory pathogens panel.

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All confirmed COVID-19 episodes will be communicated to the respective participant and to other
authorities according to local regulations.
Participants, with stable/well-controlled HIV infection, will be encouraged to have HIV RNA viral
load and CD4 cell count assessed at least twice a year and to provide these data for inclusion in
the eCRF.
8.5. 
Medical Resource Utilization
As of Amendment 7, this is no longer applicable.
Medical resource utilization data over the last 3 months, associated with medical encounters, will
be collected by interview with the participant and recorded in the eCRF by the investigator and
study-site personnel at baseline (for all participants, concerning MRU within the last 3 months
before 1st vaccination), and on COVID-19 Day 3-5 and COVID-19 Day 29 (for all participants
during a COVID-19 episode; which is defined to be resolved after having 2 consecutive SARS-
CoV-2 negative nasal swabs and 2 consecutive days with no COVID-19-related signs or
symptoms; see Section 8.1.2])(Appendix 7).
Medical resource utilization data will also be collected through the MA-COV form (Appendix 8).
This form will be provided to the participant at the 1st vaccination visit and should be completed
by the medical care provider or the study site personnel during medical visits for COVID-19 or
COVID-19 complications. Protocol-mandated procedures, tests, and encounters are excluded. The
data collected may be used to conduct exploratory economic analyses and will include:
 
Number and duration of medical care encounters, including selected procedures (inpatient and
outpatient)
 
Duration and type of mechanical ventilation and ECMO use
 
Duration of hospitalization (total days length of stay, including duration by wards; eg, ICU)
 
Number and character of diagnostic and therapeutic tests and procedures
 
Outpatient medical encounters and treatments (including physician or emergency room visits,
tests and procedures, and medications)
8.6. 
Risk Factor Assessment
As of Amendment 7, this is no longer applicable.
If allowed by local regulations and if the participant consents, he/she will be interviewed on
characteristics related to his/her current work situation, living situation, and community
interactions (See Appendix 12) prior to vaccination on Day 1 and at other timepoints, on changes
compared to Day 1. These characteristics can potentially be useful to identify the risk of individual
participants in acquiring COVID-19 and will be used in several analyses including correlate
analysis.

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Risk factor data initially collected at screening from the participants, prior to implementation of
the Protocol Amendment 2 will also be used for the planned risk-factor analysis.
8.7. 
Participant Medical Information Prior to, During and After the Study (Real-
world Data)
In the US, for consenting participants, medical data from 5 years prior to study enrollment until
5 years after study completion, such as electronic health records, claims and laboratory data from
other care settings, may be accessed utilizing tokenization and matching procedures. These data
together with data collected as part of the study as specified in the Schedules of Activities, may be
used to conduct exploratory analyses to enhance our understanding of the impact of prior medical
history on the response to immunization and the impact of immunization on efficacy and duration
of efficacy as well as adverse events that may occur during and after completion of the study (see
Section 9.4.4). The utilization of tokenization and matching procedures allows for the medical data
to be obtained without violation of participant confidentiality (Sections 4.2 and 4.2.1). The
real-world medical data, which are not collected as part of the study, will not be part of the clinical
study database.
8.8. 
Assessment and Procedures After Emergency Use Authorization and
Implementation of Protocol Amendment 4
Following Ad26.COV2.S EUA  in the US for the single dose schedule based on the
VAC31518COV3001 study interim results, all participants from countries where Protocol
Amendment 4 is approved by the local Health Authority and IEC/IRB will be unblinded. The study
will then be conducted in an open-label fashion. Before the actual participant unblinding, all of the
previously available data should be complete and accurate in the participant’s eCRF.
All participants that have not discontinued prematurely from the study will have an unblinding
visit at which they will be reconsented (Schedule of Activities 1.3.4). This visit is also applicable
for participants who were already unblinded during the double-blind phase of the study. If
applicable, participants will receive a single dose of Ad26.COV2.S (refer to Section 6.4  for
participants enrolled in the study during the double-blind phase). At this visit, body temperature,
a blood sample, and a nasal swab will be collected from all participants.a The nasal sample will
not be tested locally and will be sent to a central laboratory. A urine pregnancy test (for participants
of childbearing potential) will be collected from participants who will be vaccinated with a single
dose of Ad26.COV2.S at this visit. If the participant receives a single dose of Ad26.COV2.S at
this visit, the above-mentioned procedures will be performed before vaccination.
After vaccination, participants should remain under observation at the study site for at least
15 minutes, except where local regulations require a longer observation period (eg, Belgium), for
the presence of any acute reactions after vaccination and will be followed for safety as per
a The unblinding visit may be combined with the scheduled study visit and procedures that would be duplicated should
be done only once. If a blood draw is planned in the scheduled visit no additional blood draw is needed.

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Section 8.3. After the unblinding visit, all participants will resume the Schedule of Activities from
Section 1.3.3.
The unblinding visit can be done at an already scheduled or an unscheduled visit. Preferably, if a
scheduled study visit (Schedule of Activities 1.3.3)is planned within 2 months after the receipt of
Amendment 5 local approvals, this unblinding visit may be combined with the planned study visit.
If the unblindingvisit is combined with a scheduledvisit, the procedures of the planned visit should
be completed as well with the exception of solicited symptoms collection in the Safety subset (See
Section 8.3). If a blood sample is already planned for the scheduled visit, the blood sample of the
unblinding visit does not need to be collected.
Participants initially enrolled in the Ad26.COV2.S group during the double-blind phase who will
not receive a second vaccination (refer to Section 6.4) will be assured they received the dose level
that was submitted for EUA (single-dose schedule of 5x1010 vp Ad26.COV2.S), and will be asked
to continue to be followed in this study in line with the Schedule of Activities Section 1.3.3.
Investigators will be encouraged to follow health authority guidelines on prioritization of
immunization. Investigators are encouraged to consider current local public health guidance for
determining the scheduling priority of participants. For example, participants with comorbidities
and/or of specific age groups can be scheduled prior to participants without comorbidities if this
is in line with local guidance. This should be done in a blinded way, ensuring that participants who
were not previously unblinded for other reasons are not unblinded until the unblinding visit. All
participants will be counselled to continue practicing other public health/preventive measures that
were introduced at the start of this pandemic (eg, social distancing, face masks, frequent hand
washing), in compliance with local and national guidelines.
8.9. 
Assessment and Procedures for Booster Vaccination and Follow-up After
Implementation of Protocol Amendment 6
As of Protocol Amendment 7:
No further booster doses will be administered after implementation of Protocol Amendment 7,
except if there is a medical reason or if there is a non-availability of other vaccines to the
participant. The investigator should inform participants on the availability of other COVID-19
vaccines.
Up to Protocol Amendment 7:
With implementation of Protocol Amendment 6, all ongoing participants who received only a
single vaccination with Ad26.COV2.S in the study will be offered a single booster dose of
Ad26.COV2.S vaccine under the conditions delineated in Section 6.5. Participants who already
received 2 vaccinations with Ad26.COV2.S at the 5x1010 vp dose level or any COVID-19
vaccinations outside of the study (including the Janssen vaccine) at the time of local approval of
Protocol Amendment 6 are not eligible to receive a booster vaccination with Ad26.COV2.S.
Eligible participants who consent to receive the booster vaccination will follow the schedule as
presented in Section 1.3.5. The following assessments will be performed before booster

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vaccination: measurement of body temperature, check of pre-vaccination symptoms (see
Section 5.5), a urine pregnancy test (women of childbearing potential only), a nasal sample
collection for SARS-CoV-2 testing, a blood sample for humoral immunogenicity and SARS-
CoV-2 serology, and a clinical lab blood samplea (for platelet count, as part of a complete blood
count, if applicable). After receiving the booster vaccination, participants should remain under
observation at the study site for at least 15 minutes, except where local regulations require a longer
observation period (eg, Belgium), for the presence of any acute reactions after vaccination and will
be followed for safety as per Section 8.3. Concomitant therapies will be recorded as per
Section 6.10.
The booster vaccination will be administered in the open-label phase of the study, preferably
within 6 to 12 months after the participant’s first Ad26.COV2.S vaccination in the study. If this is
not possible, the booster vaccination should not occur earlier than 3 months after the participant’s
first Ad26.COV2.S vaccination. The Booster Vaccination Visit should preferably coincide with
the participant’s next scheduled visit (ie, Visit 7 or Visit 8 for the majority of participants) from
the original SoA in Section 1.3.3. If not operationally feasible to coincide with an existing visit,
an unscheduled visit may be planned. If the Booster Vaccination Visit coincides with a scheduled
visit, the procedures of the scheduled visit should be completed as well. However, procedures that
would be duplicated should be done only once. If a whole blood sample has been taken within
5 days before vaccination and platelet results are available, sample collection does not need to be
performed before vaccination.
After the Booster Vaccination Visit, participants will continue procedures and visits as in the
original SoA. All participants (whether they consent to the booster vaccination or not) will be
encouraged to remain in the study and will be monitored for safety, immunogenicity, and efficacy
according to their original schedule.
Investigators will be encouraged to follow health authority guidelines on prioritization of
immunization. Investigators are encouraged to consider current local public health guidance for
determining the scheduling priority of participants. For example, participants with comorbidities
and/or of specific age groups can be scheduled prior to participants without comorbidities if this
is in line with local guidance. All participants will be counselled to continue practicing other public
health/preventive measures that were introduced at the start of this pandemic (eg, social distancing,
face masks, frequent hand washing), in compliance with local and national guidelines.
a Whole blood samples will be used for immediate measurement of a platelet count (as part of a complete blood count
if applicable) in a local laboratory or substitute for local laboratory, depending on local feasibility towards
turnaround time of sample processing. Serum samples will be derived from the whole blood sample and stored for
potential future coagulation-related testing in a central laboratory if the participant experiences a suspected AESI
(see Section 10.2, Appendix 2).

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9. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the SAP.
Sections 9.2 to 9.6 are applicable to the double-blind phase of the study. Considerations for the
analysis of the open-label active phase and the open-label passive follow-up phase (introduced
with Amendment 4 to Amendment 7) of the study are described in Section 9.7; details will be
provided in a separate SAP.
9.1. 
Statistical Hypotheses
Refer to Section 3 for the statistical hypotheses.
The study will have 3 timepoints for analysis:
1. The primary efficacy analysis of the double-blind phase is planned to be performed when all
participants have reached the open-label phase/been unblinded. Depending on the operational
implementation of unblinding visits, as well as the stage of the pandemic, the analysis may be
conducted when  a minimum of 90% of the study population have reached the open-label
phase/been unblinded.
After the primary analysis, additional analyses to support health authority interactions may be
planned, if deemed appropriate.
During the open-label phase, 2 analyses can be performed:
2. The open-label active phase analysis
3. An end-of-study analysis is planned 1 year after a minimum of 90% of the enrolled study
population have reached Visit 8 or discontinued earlier and will be conducted upon
completion of the last active participant visit. Depending on the timing of approval of
Amendment 7 across study sites, the open-label active phase analysis may be combined with
the end-of-study analysis. All boosted participants will have at least 6 months safety
follow-up.
Additional analyses may be conducted to support health authority interactions and/or based on
public health demand in case of emerging variants.
9.2. 
Sample Size Determination
9.2.1. 
Efficacy (Total Sample Size)
For the double-blind phase, the sample size is determined using the following assumptions:
 
a VE for molecularly confirmed, moderate to severe/critical SARS-CoV-2 infection of 65%.
 
type 1 error rate α 2.5% to evaluate VE of the vaccine regimen.
 
a randomization ratio of 1:1 for active versus placebo

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Events are defined as first occurrence of molecularly confirmed, moderate to severe/critical
COVID-19 according to the case definition in Section 8.1.3.1 in the PP population at least 14 days
after the second vaccination with study vaccine (Day 71).
Under the assumptions above, a total of 104 events will provide approximately 90% power to
reject the null hypothesis of H0: VE≤30%, according to the primary endpoint case definition of
moderate to severe/critical COVID-19(Section 8.1.3.1).
If the primary hypothesis testing is successful, secondary objectives will be evaluated against a
null hypothesis employing a lower limit VE>0%. The method to perform hypothesis testing of
primary and secondary objectives preserving the FWER will be specified in the SAP. The FWER
will be controlled at 2.5%.
Sample Size Justification
Based on the variations in seroprevalence, degree of social distancing and use of personal
protective equipment, it is not feasible to estimate the incidence rates that can be attained at the
time of the start of this study. It is also unknown which local regulations (eg, potential lockdowns)
will be in effect at that time.
The sample size is approximately 15,000/group (approximately 30,000 in total) and is determined
based on estimated annualized incidence rate ofmoderate to severe/critical COVID-19 of 1% to
4% at the start of the study.
Assuming 2 months of recruitment and 10% seroprevalence, the selected sample size will have a
high probability (approximately 90%) to have reached an efficacy signal within 15 months after
first participant vaccinated for an assumed VE≥65% under an assumed incidence of 1.4% in Month
1-3, and waning of incidence thereafter, eg, 50% reduction at Month 4 (0.70% annualized)
followed by further reduction to 0.58%.
With higher incidences at the start of the study, the timelines to efficacy will shorten.
The operating characteristics of the study design, statistical methods, study monitoring rules and
efficacy evaluations specified in this protocol with the chosen event and sample sizes will be
described in a separate modeling and simulation report and will be added to the SAP before the
first participant is vaccinated. The SAP will be amended before primary analysis of the
double-blind phase. Upon implementation of Protocol Amendment 6, the SAP will be amended
before the next scheduled analysis.
To maximize power for the secondary objectives and evaluations in subgroups, any interim testing
was abandoned, and a single analysis planned at the end of the double-blind phase.
The overall recruitment target is approximately 30,000 participants. Up to 10% of additional
participants may be recruited to partially compensate for increased fraction unblinded prior to
unblinding visit and/or increased seroprevalence rates and/or drop-outs.

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9.2.2. 
Immunogenicity Subset
All participants included in the Immunogenicity Subset (N 400) will be added randomly during
Stage 2 of the double-blind phase of the study. Healthy adults and elderlywill be assigned to subset
1a and 1b respectively, while adults and elderly with comorbidities will be assigned to subset 2a
and 2b respectively, with approximately 100 participants per group as displayed in Table 3.
A sample size of 400 participants, distributed as described in Table 3, is estimated to be sufficient
to allow robust description of immune responses to Ad26.COV2.S vaccine. These numbers are
expected to provide a solid understanding of the magnitude and kinetics of the humoral response
induced by the Ad26.COV2.S vaccine.
9.2.3. 
Immunogenicity Correlates (Correlates Subset)
Correlates will be assessed in a subset where immune responses and/or transcriptome
modifications are measured in all vaccine recipients who experience a SARS-CoV-2 event, and in
random samples of vaccine recipients who have not been infected, in a 1:5 ratio. The goal of this
case control study is to assess correlates of risk of SARS-CoV-2 infection (and potential other
secondary endpoints) in the vaccine group by comparing vaccine-induced immune responses and
transcriptome modifications associated with COVID-19. Also, placebo participants will be
included in this subset (placebo infected, seropositive [based on N-protein] non-infected and
seronegative non-infected), if feasible.
Correlates will also be investigated via a case-cohort design, including measurement of
immunological markers in a random subcohort augmented by infected and symptomatic cases.
Placebo controls will be matched with cases from the same stage (comorbidities), age, and other
co-factors as deemed appropriate. These will be detailed in the Correlates SAP.
9.2.4. 
Safety (Safety Subset)
While mild to moderate reactogenicity (local injection site and systemic reactions) are expected,
AEs that preclude further vaccine administration (if applicable) are not anticipated.
Unsolicited AEs will be captured for a period of 28 days after each vaccination. Solicited and
unsolicited AEs will be captured in the Safety Subset, ie, approximately 6,000 participants (~3,000
from the active group, ~3,000 from the placebo group; and including at least 2,000 from the older
age group [≥60 years of age] if feasible).
AESIs (from Protocol Amendment 5), and SAEs will be captured in all participants and throughout
the study. MAAEs (including new onset of chronic diseases) will be captured in all participants
until 6 months after the last double-blind or open-label vaccination  (including the open-label
vaccination or booster vaccination, whichever comes last), except for MAAEs leading to study
discontinuation, which are to be reported during the entire study. Based on a sample size of
approximately 30,000 participants, and approximately 15,000 in the active vaccination group, for
SAEs, the observation of 0 events in the database would be associated with 95% confidence that

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the true rate is less than 0.01%. Table 6 shows the probabilities of observing at least 1 event
(solicited, unsolicited, or SAE) in 1 of the groups at given true AE rates.
Table 6: 
Probability of Observing at Least 1 Adverse Event or Serious Adverse Event at a Given True
Adverse Event Rate in the Active Group (With a Total Sample Size of Approximately 30,000
Participants)
True AE  
Rate 
Probability of Observing at Least 1 Adverse Event in the Active Group in N Participants
Solicited/Unsolicited AEs 
N=3,000 
SAEs
N=15,000
0.01% 
26% 
78%
0.1% 
95%  
100%
≥0.5%  
100%  
100%
AE  adverse event; N
number of participants receiving study vaccine (Ad26.COV2.S or placebo); SAE  serious adverse
events
The aim is to recruit up to 6,000 participants in the Safety Subset. At the time of writing the
Protocol Amendment 4, the target recruitment has not been completed yet. Every effort will be
made to reach the target of 6,000 participants, but the final number of participants recruited in the
Safety Subset may be less due to unblinding of the participants. After an individual participant has
been unblinded, he/she is no longer considered as part of the Safety Subset and no further
solicited/unsolicited symptoms that are specific to the Safety Subset will be collected. All other
safety reporting requirements applicable for all participants will be maintained (Section 8.3.1).
As of Amendment 7, a passive follow-up approach is adopted: follow-up visits or phone calls by
the site at scheduled time points to collect information on any protocol-required safety assessment
(see Section 8.3.1).
In addition, SAEs, AEs, and MAAEs related to COVID-19 need to be reported together with the
concomitant medications related to these events until study end. Any confirmatory COVID-19
laboratory information should be reported in the eCRF.
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:
Full Analysis Set (FAS): All randomized participants with at least 1 documented study vaccine
administration, regardless of the occurrence of protocol deviations and serostatus at enrollment.
Analyses of safety will be performed on the FAS. Vaccine efficacy analyses can be repeated using
the FAS.
Safety Subset: subset of the FAS for the analysis of solicited and unsolicited AEs.

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Per-protocol Efficacy (PP) populationa: Participants in the FAS who receive 2 doses of study
vaccine and who are seronegative at the time of 1st vaccination and at Day 71, and who have no
other major protocol deviations that were judged to possibly impact the efficacy of the vaccine
before unblinding. The PA of VE will be based on the PP population. In the double-blind phase,
the PP will be the main analysis population for efficacy analyses.
Per-protocol Immunogenicity (PPI) populationa: All randomized participants who receive
2 doses of study vaccine in the double-blind phase, including those who are part of the
Immunogenicity Subset and for whom immunogenicity data are available, excluding participants
with major protocol deviations expected to impact the immunogenicity outcomes. In addition, for
participants who experience a SARS-CoV-2 event (molecularly confirmed), samples taken after
the event and samples taken outside protocol windows will not be taken into account in the
assessment of the immunogenicity. The PPI population is the primary immunogenicity population.
For key tables, sensitivity immunogenicity analyses will also be performed on the FAS, including
participants who are part of the Immunogenicity Subset for whom immunogenicity measures are
available. Excluded samples might be taken into account as well in the sensitivity analysis.
Analyses of vaccine immunogenicity and immune correlates of risk will be based on PPI.
The populations for the open-label active and open-label passive follow-up phase are described in
the SAP.
The list of major protocol deviations to be excluded from the efficacy for the double-blind analysis
and/or immunogenicity analyses will be specified in the SAP and/or this list will be reported into
protocol deviation dataset of the clinical database before database lock and unblinding.
9.3. 
Participant Information
For all participants, descriptive statistics of demographic (eg, gender, age, height, weight, BMI,
race, and other baseline characteristics) will be provided by vaccination group. Additional
characteristics related to current work situation, living situation, and community interactions will
be collected for risk factor analysis, if allowed per local regulations. Risk factor data initially
collected at screening from the participants, prior to implementation of the Protocol Amendment
2 will also be used for the planned risk-factor analysis. See also Section 9.4.3.
9.4. 
Efficacy Analyses
The SAP  for the primary analysis was finalized prior to database lock and it includes a more
technical and detailed description of the statistical analyses described in this section. This section
is a summary of the planned statistical analyses of the most important endpoints including primary
and key secondary endpoints.
a If a participant would be vaccinated out of window due to a study pause or any other reason, this will not by default
be a reason for excluding this participant from the PP and PPI population. A sensitivity analysis might also be
performed. Further details will be described in the SAP. This analysis set will only be applied to the double-blind
phase.

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9.4.1. 
Primary Endpoint Evaluation for the Double-blind Phase
The double-blind phase of the study is designed to test the primary hypothesis of VE in the PP
population: H0: VE ≤30% versus H1: VE >30% and will be evaluated at a 2.5% 1-sided
significance level.
The primary endpoint will evaluate the first occurrence of molecularly confirmed, moderate to
severe/critical COVID-19 according to the case definition in Section 8.1.3.1, with onset at least
14 days after the second vaccination  (Day 71) with Ad26.COV2.S versus placebo, in the PP
population, including all events from both age groups, with and without comorbidities.
Participants included in the seronegative analysis set are those participants with a negative SARS-
CoV-2 serology test result at baseline.
The unblinding visit marks for a participant the end of the double-blind phase, and the start of the
open-label phase. For a given participant, all data up to the unblinding visit will be incorporated
in the analysis of the double-blind phase.
The minimum criteria that may trigger the primary analysis before at least 90% of participants are
unblinded is if the prespecified harm boundaries have been crossed.
A successful primary efficacy conclusion will require establishing the hypothesis H1: VE>30%
for the primary endpoint.
Exact Poisson regression will be used to estimate the VE and associated CI taking into account the
follow-up time. To evaluate the primary null hypothesis: H0: VE ≤30% versus H1: VE >30% for
the primary endpoint, 95% 2-sided confidence interval based on Poisson regression model will be
used.
The decision rules for harm are detailed in Section 9.4.1.1.
For any case definition to be considered for classification of COVID-19 cases, there needs to be
at least one SARS-CoV-2 positive RT-PCR or molecular test result from any available respiratory
tract sample (eg, nasal swab sample, sputum sample, throat swab sample, saliva sample) that is
confirmed by the central laboratory. It is possible that not all samples can be confirmed at the time
of the analysis. Hence, a sensitivity analysis may be performed using all RT-PCR or molecular
test result, regardless of the confirmation by the central laboratory.
The primary efficacy analysis will pool data across populations (with and without comorbidities)
to evaluate the primary and secondary objectives. In addition, these will be supplemented with a
subgroup analysis for age and comorbidities employing a descriptive summary including 95%
confidence intervals to describe the VE in each subpopulation.
In addition, to assess potential time-effects of VE, the Kaplan-Meier method will be used to plot
the estimated cumulative incidence rates over time for the vaccine and placebo groups. This

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method will be used to estimate cumulative VE over time, defined as [(1 minus
ratio (vaccine/placebo) of cumulative incidence by time t)×100%].
Furthermore, VE will be evaluated in seronegative participants, counting primary endpoints since
onset after the first vaccination.
Of note, the data may be pooled with data of other ongoing efficacy studies in support of health
authorities' interactions.
9.4.1.1. 
Study Monitoring
Table 7: 
Specification of Sequential Statistical Analyses
Parameter 
Population  
Hypothesis 
Statistical Method 
Criterion 
Monitoring Plan
Potential
Harma of
Symptomatic
Cases
FAS  
H0: VE ≥0%  
vs. 
H1: VE <0%  
Exact 1 sided
binomial test of the 
fraction of infections 
assigned to who 
receive the vaccine.
Constant p value cut  
off controlling 
⍺at 5%  
After every event
starting from the 12th
event b
Potential 
Harma of
Severe Cases 
FAS  
H0: VE ≥0%  
vs. 
H1: VE <0%  
Exact 1 sided
binomial test of the 
fraction of infections 
assigned to who 
receive the vaccine.
Unadjusted p value ⍺
at 5%
After every event
starting from the 5th
event
CI  confidence interval; FAS  full analysis set; PP  per protocol; VE  vaccine efficacy.
a Harm in the form of an increased rate of symptomatic COVID 19 events due to vaccination (which meet the mild, moderate or
severe/critical case definition).
b Monitoring stops when the primary efficacy analysis is triggered.
c The monitoring can only start as soon as the conditions outlined in Section 9.4.1 are met.
The boundary of potential harm will be monitored by an SSG. Once a boundary has been crossed,
the SSG will inform the IDMC and an IDMC meeting will be organized. The statistical details of
the decision rules and the frequency of evaluation and operational implementation will be fully
detailed in the SAP and IDMC Charter.
9.4.2. 
Secondary Endpoints for the Double-blind Phase
All secondary endpoint analyses for the double-blind phase will occur in the PP analysis set, in
seronegative participants unless otherwise indicated.
To evaluate the effect of the vaccine against symptomatic molecularly confirmed COVID-19,
including mild infections, a BOD endpoint will be evaluated based on the first occurrence of
molecularly confirmed COVID-19, including mild, moderate and severe/critical case definitions
in Sections 8.1.3.1 and 8.1.3.2, with onset at least 14 days after the second vaccination (Day 71)
with Ad26.COV2.S versus placebo, in the PP population, including all events across age groups,
with and without comorbidities. In this study, the BOD endpoint is defined as taking the value 1
for mild and moderate disease and the value 2 for severe disease (implicitly assigning a value of 0
for no disease [not infected or asymptomatic infection]). By assigning higher weight to severe
infections, the BOD endpoint aims at providing higher statistical power for differentiating from
placebo vaccines with increased protection against severe infections (but potentially lower VE
against milder infections). The BOD evaluates the severity-adjusted VE against preventing

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symptomatic incidence. The hypothesis to evaluate the VE against symptomatic infection will be
based on this method. In addition, the VE against each severity category according to the case
definition (severe, moderate, mild) will be summarized separately. Statistical significance for the
BOD endpoint will be tested using H0:VE≤0 at a one-sided α 2.5% according to multiplicity
adjusted strategy. Details on the calculation of VE for the BOD endpoint and its associated
confidence interval (for testing) and hypothesis testing will be foreseen in the SAP.
At the time of the primary analysis VE against any infection will be evaluated. At the time of the
primary analysis, available N-ELISA measurements will be incorporated to evaluate VE against
any infection, including asymptomatic infection. A participant will be defined as having any
infection whether he/she had either a symptomatic infection (mild, moderate or severe according
to the case definition) or an asymptomatic infection (as defined in Section 8.1.3.4). When all
participants had 6 months of follow-up, the available N-ELISA measurements will be used to
evaluate VE against asymptomatic/undetected infections only. Poisson regression will be used to
estimate the VE and associated 95% confidence interval in seronegative participants in the PP
analysis set for each of both analyses.
Among participants with SARS-CoV-2 infection, the effect of the study vaccine on the viral load
levels at and after diagnosis as well as on the duration of SARS-CoV-2 viral load positivity will
be evaluated.
The effect of the vaccine will be evaluated against molecularly confirmed COVID-19 infections
requiring medical intervention once sufficient events are available. Medical interventions are
evaluated as a composite endpoint of hospitalization, ICU admission, mechanical ventilation and
ECMO, linked to objective measures such as decreased oxygenation, X-ray or CT findings.
Poisson regression will be used to estimate the VE and the associated 95% confidence interval in
seronegative participants in the PP analysis set.
All VE evaluations will be repeated regardless of their serostatus.
The statistical analysis for secondary endpoints, multiple testing strategy to evaluate the secondary
objectives and the timing of the hypothesis testing will be detailed in the SAP.
See also Section 9.4.1.
9.4.3. 
Exploratory Endpoints
Exploratory endpoint analyses will be detailed in the SAP.
If appropriate, subgroup or covariate-adjusted analyses may be performed. These
subgroups/covariates may include baseline demographics and other characteristics.

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9.4.4. 
Other Analyses
Participant Medical Information Prior to, During and After the Study (Real-world Data, in
US Participants Only)
The exploratory analyses that may be conducted using the real-world data will be detailed in a
SAP and results may, partially, be reported separately from the VAC31518 Clinical Study
Report(s).
Medical Resource Utilization Analyses
Medical resource utilization will be descriptively summarized by intervention group.
9.5. 
Immunogenicity Analyses
For the double-blind phase, no formal statistical testing of the immunogenicity data is planned. All
immunogenicity analyses will be performed on the PPI set. Key tables might be repeated for the
FAS (including samples that are excluded from the PPI analysis). For the open-label phase and
passive follow-up phase, no statistical testing of the immunogenicity data is planned. All details
regarding the analysis and will be described in the SAP.
9.5.1. 
Immunogenicity Subset
No formal hypothesis on immunogenicity will be tested. Descriptive statistics (eg, geometric mean
and 95% confidence interval for the neutralization assay and ELISA) will be calculated for
continuous immunologic parameters at all timepoints. Geometric mean fold rises from baseline
and corresponding 95% confidence intervals might additionally be calculated. Baseline is
considered as the last available assessment before vaccination. Graphical representations of
immunologic parameters will be made as applicable.
The impact of baseline factors on the humoral responses will be explored graphically or via
descriptive statistics. In addition, in a subset of 400 participants (the Immunogenicity  Subset;
~200 from the active group, ~200 from the placebo group), humoral immunogenicity samples are
taken on more occasions.
9.5.2. 
Correlates of Risk
If VE is demonstrated, correlates of risk will be explored. Details with appropriate methods will
then be provided in a separate analysis plan.
9.6. 
Safety Analysis
No formal statistical testing of safety data is planned. Safety data according to the vaccination
received and based on the FAS will be analyzed descriptively. The analysis of solicited and
unsolicited AEs will be restricted to a subset of the FAS (ie, the Safety Subset).
For SAEs, AESIs, and MAAEs the full FAS is considered. New onset of chronic diseases will be
collected as part of the MAAEs.

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Subanalyses (descriptive) will be performed on participants with stable/well-controlled HIV
infection to evaluate the effect of the vaccine on HIV RNA viral load and CD4 cell count.
Safety endpoints following the open-label vaccination and following the booster vaccination will
be descriptively summarized. Pooled safety analyses with other studies may also be performed.
Adverse Events (Solicited and Unsolicited) (Double-blind Phase)
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the
Medical Dictionary for Regulatory Activities (MedDRA). All Reported AEs with onset during the
active vaccination phase (ie, AEs occurring after vaccination up to 28 days after each vaccination),
and all SAEs/MAAEs/AESIs will be included in the analysis. (S)AEs caused by molecularly
confirmed SARS-CoV-2 infection will be removed at the analysis level from the (S)AE listings
and tables and presented separately. For each AE, the percentage of participants who experience
at least 1 occurrence of the given event will be summarized by study vaccine group.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue the study due to an AE or who experience a severe AE, an
AESI, or an SAE.
Solicited local (at injection site) and systemic AEs will be summarized descriptively. The number
and percentages of participants with at least 1 solicited local (at injection site) or systemic AE will
be presented. Solicited AEs shown in the tables and listings will be based on the overall assessment
of the investigator. The overall frequencies by vaccine group as well as frequencies according to
severity and duration will be described for solicited AEs. Frequencies of unsolicited AEs,
separately for all and vaccination-related only, will be presented by System Organ Class and
preferred term, while those of solicited AEs will be presented only by preferred term.
Clinical Laboratory Tests
Laboratory data (abnormal or graded, when available) will be listed and/or tabulated by participant
and time point.
Vital Signs
For all participants, weight and height (and BMI) at baseline will be summarized using descriptive
statistics. Temperature will be measured at each scheduled timepoint and summarized using
descriptive statistics. Other vital signs may be measured at the discretion of the investigator. Vital
signs abnormalities will be listed.
For COVID-19 cases, temperature will be summarized over time from start of symptoms, using
descriptive statistics and/or graphically. For systolic and diastolic blood pressure, heart rate,
respiratory rate, oxygen saturation, and pulse oximetry, values and the percentage of participants
with values beyond clinically relevant limits will be summarized at each scheduled timepoint.
Descriptive statistics will be calculated for changes between COVID-19 Day 29 and COVID-19
Day 3-5.

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Physical Examinations
For all participants, physical examinations can be performed at the discretion of the investigator.
Physical examination abnormal findings will be listed.
For COVID-19 cases, physical examination findings and the percentage of participants with values
beyond clinically relevant limits will be summarized at each scheduled timepoint. Descriptive
statistics will be calculated for changes between COVID-19 Day 29 and COVID-19 Day 3-5, if
available.
9.7. 
Analyses of the Open-label Phase
Safety, immunogenicity, and efficacy endpoints following the open-label and/or booster
vaccination will be descriptively summarized by the different cohorts (as specified in Section 3)
for the different phases (ie, for the active follow-up phase and the passive follow-up phase).
Additional analyses may be conducted to support health authority interactions and/or based on
public health demand in case of emerging variants.
The statistical methodology, definition of cases for evaluation on the regimen for evaluation as
well as data to be included in the data base will be defined in the SAP.
For definitions of the main groups for analysis in the open-label phase, see Section 3.
9.7.1. 
Immunogenicity Analyses
For the open-label phase, no formal statistical testing of the immunogenicity data is planned.
9.7.2. 
Immunogenicity Correlates (Correlates Subset)
Correlates for participants who received a booster dose may be explored, similar to the methods
as described in Section 9.5 for the double-blind phase.
9.7.3. 
Safety Analyses
Safety endpoints following the open-label vaccination and following the booster vaccination for
both the open-label active phase and the open-label passive follow-up phase will be descriptively
summarized. Pooled safety analyses with other studies may also be performed.
9.7.4. 
Efficacy Analyses
For the analysis of efficacy in the open-label active phase, follow-up time will be expressed on a
calendar time scale, and defined as time since a predefined calendar date, eg, study start or time
period to start evaluation, to adjust for changing incidence over time.
The analysis will be conducted according to the regimen as received (see Section 3 for the main
study cohorts).
Follow-up time (a participant at risk for an event) will begin on the date of administration of the
first dose of the vaccine regimen under evaluation, expressed on a calendar time scale as time since

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study start/predefined calendar date. Follow-up time and events occurring within 14 days since
(last) vaccination may be ignored.
If deemed feasible, efficacy of the booster vaccination may be explored by comparing efficacy
data after boosting to data in the absence of booster, on the same primary regimen. Feasibility will
be assessed based on data availability as well as adjustments for potential confounding (including,
but not limited to age, country and/or site, presence of co-morbidities). Additional factors may be
added and prespecified in the SAP.
Efficacy data of the open-label active phase may be compared following a homologous vaccination
schedule (Ad26 COV2.S) versus a heterologous vaccination schedule. The duration of protection
of the booster vaccinations may be summarized (as early booster versus late booster vaccination).
All details will be described in the SAP.
9.8. 
Interim Analysis and Committees
The primary analysis of the double-blind phase will be performed after at least 90% of participants
are unblinded at the and have moved from the double-blind phase to the open-label phase.
In addition to the current objectives and endpoints outlined for the double-blind analyses, the
sponsor may conduct a preliminary and descriptive assessment of efficacy to assess the impact of
the vaccine on possible emerging variants that may arise in the current epidemic situation. This
analysis, if needed, will be performed by the independent statistical group that is supporting the
IDMC of the trial (SSG). The sponsor personal directly involved in the oversight and conduct of
the trial will be kept blinded. The results can only be shared with the Sponsor Committee and
regulatory authorities upon request.
The study will be formally monitored by an IDMC. In general, the IDMC will monitor safety data
on a regular basis to ensure the continuing safety of the participants. Enrollment will not be paused
during these safety reviews, except after Stage 1 (approximately 1,000 participants). The IDMC
will review unblinded data. The IDMC responsibilities, authorities, and procedures will be
documented in the IDMC Charter.
Continuous monitoring for vaccine-associated enhanced disease will be performed through the
SSG who will look at each of the diagnosed FAS COVID-19 events. Vaccine harm monitoring
will be performed for severe/critical COVID-19/death endpoint based on the FAS. As these events
will be monitored in real-time, and, after each confirmed respective case, the SSG will assess if a
stopping boundary is reached. Specifically, monitoring for a higher rate of severe/critical disease
or death in the vaccine group compared to the placebo group starts at the 5th  event and at each
additional event until the harm boundary is reached or until the primary analysis is triggered. If
the stopping boundary is met, then the SSG immediately informs the Chair of the IDMC through
secure communication procedures. At this point the IDMC  will convene and provide a
recommendation to the Sponsor Committee. As such, the potential harm monitoring is in real-time,
resulting in the earliest indication of harm possible as soon as data come in; for more details , see
Section 9.4.1 and 9.4.1.1

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The monitoring rules will be detailed in the IDMC charter, with the statistical details in the SAP.
The SAP will describe the planned analyses in greater detail.
9.9. 
Analyses for cohort unblinded due to administration of an
authorized/licensed COVID-19 vaccine
Investigators may receive requests to unblind study participants who become eligible to receive
another authorized/licensed COVID-19 vaccine outside of the study  if/when these become
available. In these cases, the investigator will discuss with the participant available options and
ramifications, including whether they are eligible to receive the Ad26.COV2.S vaccine in the study
during the unblinding study visit. If the participant is eligible for an authorized/licensed vaccine
according to local immunization guidelines or recommendation and if the participant wishes to
proceed with the unblinding to receive another authorized/licensed COVID-19 vaccine outside of
the study, the investigator will follow the unblinding procedures. The reason for the unblinding
request should be documented.
When unblinding, if it is determined that the participant received the Ad26.COV2.S vaccine (and
not placebo), the participant will be informed that there are no data on the safety of receiving
2 different COVID-19 vaccines. Unblinded participants will be asked to continue to be followed
in this study in line with the Schedules of Activities. Safety, efficacy and immunogenicity
evaluations will be identical for all participants, if applicable and feasible, including participants
that are unblinded to obtain an authorized/licensed COVID-19 vaccine and who remain in the
study, including participants in the safety subset, if applicable and feasible. All data will be
analyzed separately from the point of unblinding for safety, efficacy and immunogenicity, as
described in the Statistical Analysis Plan.

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations
Ad26 
adenovirus type 26
AdVac® 
adenoviral vaccine
AE 
adverse event
AESI 
adverse event of special interest
ART  
anti-retroviral treatment
BIDMC  
Beth Israel Deaconess Medical Center
BMI 
body mass index
BOD 
burden of disease
CDC  
Centers for Disease Control and Prevention
CEC  
clinical evaluation committee
CLS  
capillary leak syndrome
COPD  
chronic obstructive pulmonary disease
COVID-19 
coronavirus disease-2019
CT  
computed tomographic
DNA  
deoxyribonucleic acid
DSMB  
Data Safety Monitoring Board
DVT  
deep vein thrombosis
ECMO  
extracorporeal membrane oxygenation
eCOA  
electronic clinical outcome assessment
eCRF  
electronic case report form
eDC  
electronic data capture
ePRO  
electronic patient-reported outcomes
ELISA  
enzyme-linked immunosorbent assay
ERD  
enhanced respiratory disease
EUA  
Emergency Use Authorization
FAS  
Full Analysis Set
FC 
crystallizable fragment
FDA  
Food and Drug Administration
FIH  
first-in-human
FiO2 
fraction of inspired oxygen
FOIA  
Freedom of Information Act
FWER  
family-wise error rate
GCP  
Good Clinical Practice
GLP  
Good Laboratory Practice
HCP  
health care professional
HIPAA  
Health Insurance Portability and Accountability Act
HIT  
heparin-induced thrombocytopenia
HIV  
human immunodeficiency virus
IB  
Investigator’s Brochure
ICF  
informed consent form
ICH  
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use
ICMJE  
International Committee of Medical Journal Editors
ICU  
intensive care unit
IDMC  
independent Data Monitoring Committee
IEC  
Independent Ethics Committee
IFN-γ 
interferon gamma
Ig 
immunoglobulin
IM  
intramuscular(ly)
IPPI 
Investigational Product Preparation Instructions
IRB  
Institutional Review Board
IWRS  
interactive web response system
MAAE  
medically-attended adverse event
MA-COV  
medically-attended COVID-19

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MedDRA  
Medical Dictionary for Regulatory Activities
MERS  
Middle East respiratory syndrome
MERS-CoV  
Middle East respiratory syndrome coronavirus
MIS  
multisystem inflammatory syndrome
MRU  
medical resource utilization
N 
nucleocapsid
NHP  
non-human primate
PA 
primary analysis
PaO2 
partial pressure of oxygen
PP 
Per-protocol (efficacy)
PPI 
Per-protocol Immunogenicity
PQC  
product quality complaint
RBD  
receptor-binding domain
RNA  
ribonucleic acid
RSV  
respiratory syncytial virus
RT-PCR  
reverse-transcriptase polymerase chain reaction
S 
spike
SAE  
serious adverse event
SAP  
Statistical Analysis Plan
SARS  
severe acute respiratory syndrome
SARS-CoV(-2) 
severe acute respiratory syndrome coronavirus(-2)
SIC  
Symptoms of Infection with Coronavirus-19
SIPPM  
site investigational product and procedures manual
SpO2 
oxygen saturation
SSG  
statistical support group
SUSAR  
suspected unexpected serious adverse reaction
Th(1/2) 
T-helper cell (type 1/2)
TNE  
target number of events
TNF-α 
tumor necrosis factor alpha
TTS  
thrombosis with thrombocytopenia syndrome
US  
United States
VE  
vaccine efficacy
VNA  
virus neutralization assay
vp 
virus particles
WHO  
World Health Organization
Definitions of Terms
COVID-19 
COVID-19 is the disease caused by the virus SARS-CoV-2. COVID-19 refers to SARS-
CoV-2 infection with symptoms, and can range from mild to severe disease, the latter
including pneumonia, severe acute respiratory syndrome, multi-organ failure, and death.66,67
eCOA  
An umbrella term encompassing different types of outcomes assessments, in particular, the
COVID-19 signs and symptoms surveillance question, the ePRO and the e-Diary.
ePRO  
The electronic technology used to collect the patient-reported outcome data. PROs are
reports that come directly from the participant without interpretation by clinician or anyone
else. This includes the SIC questionnaire (Symptoms of Infection with Coronavirus-19)and
the recording of pulse oximetry results.
e-Diary  
The electronic technology used to record solicited signs and symptoms by the participants
in the Safety Subset.
Electronic source 
system  
Contains data traditionally maintained in a hospital or clinic record to document medical
care or data recorded in a CRF as determined by the protocol. Data in this system may be
considered source documentation.
Open-label 
unblinding visit 
Timepoint at which participants who initially received placebo will be administered a single
dose of the Ad26.COV2.S vaccine (only upon EUA, conditional licensure or approval in any
country) (ie, open-label vaccination).

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10.3. Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
10.3.1. 
Regulatory and Ethical Considerations
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current International Council for Harmonisation (ICH) guidelines on Good Clinical
Practice (GCP), and applicable regulatory and country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing,
conducting, recording, and reporting studies that involve the participation of human participants.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study participants are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or
when the relevant competent authority has raised any grounds for non-acceptance, except when
necessary to eliminate immediate hazards to the participants, in which case the amendment must
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable,
the investigator or other physician in attendance will contact the appropriate sponsor representative
listed in the Contact Information page(s), which will be provided as a separate document. Except
in emergency situations, this contact should be made before implementing any departure from the
protocol. In all cases, contact with the sponsor must be made as soon as possible to discuss the
situation and agree on an appropriate course of action. The data recorded in the eCRF and source
documents will reflect any departure from the protocol, and the source documents will describe
this departure and the circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country, if applicable. A study may not be initiated until all local regulatory
requirements are met.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study vaccine to the
study site:

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 
Protocol and amendment(s), if any, signed and dated by the principal investigator
 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if
applicable, participant compensation programs. This approval must clearly identify the
specific protocol by title and number and must be signed (or sealed, where appropriate per
local regulations) by the chairman or authorized designee.
 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their
function, with a statement that it is organized and operates according to GCP and the
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a
member of the study-site personnel is a member of the IEC/IRB, documentation must be
obtained to state that this person did not participate in the deliberations or in the vote/opinion
of the study.
 
Regulatory authority approval or notification, if applicable
 
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable
 
Documentation of investigator qualifications (eg, curriculum vitae)
 
Completed investigator financial disclosure form from the principal investigator, where
required
 
Signed and dated Clinical Trial Agreement, which includes the financial agreement
 
Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first
participant:
 
Completed investigator financial disclosure forms from all subinvestigators
 
Documentation of subinvestigator qualifications (eg, curriculum vitae)
 
Name and address of any local laboratory conducting tests for the study, and a dated copy of
current laboratory normal ranges for these tests, if applicable
 
Local laboratory documentation demonstrating competence and test reliability
(eg, accreditation/license), if applicable
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB
with current and complete copies of the following documents (as required by local regulations):
 
Final protocol and amendments
 
Sponsor-approved ICF (and any other written materials to be provided to the participants)
 
IB (or equivalent information) and amendments/addenda
 
Sponsor-approved participant recruiting materials

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 
Information on compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
Investigator’s curriculum vitae or equivalent information (unless not required, as documented
by the IEC/IRB)
 
Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for participants
 
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol,
amendments (if any, excluding the ones that are purely administrative, with no consequences for
participants, data or study conduct, unless required locally), the ICF, applicable recruiting
materials, and participant compensation programs, and the sponsor has received a copy of this
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents
and updates to the IEC/IRB for their review and approval, where appropriate:
 
Protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct)
 
Revision(s) to ICF and any other written materials to be provided to participants
 
If applicable, new or revised participant recruiting materials approved by the sponsor
 
Revisions to compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
New edition(s) of the IB and amendments/addenda
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually)
 
Reports of AEs that are serious, unlisted/unexpected, and associated with the study vaccine
 
New information that may adversely affect the safety of the participants or the conduct of the
study
 
Deviations from or changes to the protocol to eliminate immediate hazards to the participants
 
Report of deaths of participants under the investigator’s care
 
Notification if a new investigator is responsible for the study at the site
 
Development Safety Update Report and Line Listings, where applicable
 
Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct), the amendment and applicable ICF revisions
must be submitted promptly to the IEC/IRB for review and approval before implementation of the
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At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise help
ensure access to the developed product if the need for the product persists, unless explicitly
addressed as a specific ethical consideration in Section 4.2.1.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
10.3.2. 
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial
information in accordance with local regulations to allow the sponsor to submit complete and
accurate financial certification or disclosure statements to the appropriate regulatory authorities.
Investigators are responsible for providing information on financial interests during the course of
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) for details on financial disclosure.
10.3.3. 
Informed Consent Process
Consent of each participant must be obtained according to local requirements after the nature of
the study has been fully explained. The informed consent(s)must be obtained before performance
of any study-related procedure. Downloading of an application to the participant’s eDevice, to
access materials for enrollment and study information, is not considered a study-related procedure.
The ICF can be signed remotely prior to the Screening Visit.
The ICF(s) that is/are used must be approved by both the sponsor and by the reviewing IEC/IRB
and be in a language that the participant can read and understand. The informed consent should be
in accordance with principles that originated in the Declaration of Helsinki, current ICH and GCP
guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site
personnel must explain to potential participants the aims, methods, reasonably anticipated benefits,
and potential hazards of the study, and any discomfort participation in the study may entail.
Participants will be informed that their participation is voluntary and that they may withdraw
consent to participate at any time. They will be informed that choosing not to participate will not
affect the care the participant will receive. Finally, they will be told that the investigator will
maintain a participant identification register for the purposes of long-term follow-up if needed and
that their records may be accessed by health authorities and authorized sponsor personnel without
violating the confidentiality of the participant, to the extent permitted by the applicable law(s) or
regulations. By signing the ICF the participant is authorizing such access. It also denotes that the

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participant agrees to allow his or her study physician to recontact the participant for the purpose
of obtaining consent for additional safety evaluations, if needed.
The participant will be given sufficient time to read the ICF and the opportunity to ask questions.
After this explanation and before entry into the study, consent should be appropriately recorded
by means of the participant’s personally dated signature. After having obtained the consent, a copy
of the ICF must be given to the participant.
Participants who are rescreened are required to sign a new ICF. All participants enrolled in the
double-blind phase will be reconsented at the unblinding visit before vaccination when entering
into the open-label phase. Eligible participants that want to receive the booster vaccination will
need to reconsent before any procedure of the Booster Vaccination Visit is performed.
As described in Section 8.1.2, a caregiver may assist a participant who is unable to complete the
SIC in the eCOA, by reading the questions aloud and recording the responses in the eCOA on the
participant’s behalf (using the caregiver’s unique identifier and PIN). For this purpose, a caregiver
consent form has been developed. Consent must be obtained according to local requirements and
must be obtained from the caregiver before he or she is allowed to complete the eCOA on behalf
of the participant. After having obtained the caregiver’s consent, a copy of the consent form must
be given to the caregiver. Of note, the caregiver is not intended to be a Legally Authorized
Representative who can provide informed consent for study participation on behalf of the
participant. It is also not the intent that the caregiver collects nasal swabs or other samples from
the participant unless he or she is specifically qualified to perform these tasks and can document
the use of appropriate personal protective equipment during the performance of such tasks.
10.3.4. 
Data Protection
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality
and compliance with applicable data privacy protection laws and regulations. Appropriate
technical and organizational measures to protect the personal data against unauthorized disclosures
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place.
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity
of participants confidential.
The informed consent obtained from the participant includes explicit consent for the processing of
personal data and for the investigator/institution to allow direct access to his or her original medical
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and
regulatory inspection. This consent also addresses the transfer of the data to other entities and to
other countries.

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The participant has the right to request through the investigator access to his or her personal data
and the right to request rectification of any data that are not correct or complete. Reasonable steps
will be taken to respond to such a request, taking into consideration the nature of the request, the
conditions of the study, and the applicable laws and regulations.
Exploratory immunogenicity research is not conducted under standards appropriate for the return
of data to participants. In addition, the sponsor cannot make decisions as to the significance of any
findings resulting from exploratory research. Therefore, exploratory research data will not be
returned to participants or investigators, unless required by law or local regulations. Privacy and
confidentiality of data generated in the future on stored samples will be protected by the same
standards applicable to all other clinical data.
10.3.5. 
Long-term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local regulations)
for additional research. Samples will only be used to understand Ad26.COV2.S, to understand
SARS-CoV-2 infection, to understand differential vaccine responders, and to develop tests/assays
related to Ad26.COV2.S and SARS-CoV-2 infection. The research may begin at any time during
the study or the post-study storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be
labeled with personal identifiers. Participants may withdraw their consent for their samples to be
stored for research (refer to Section 7.2.1).
10.3.6. 
Committees Structure
Independent Data Monitoring Committee
An IDMC will be established to monitor safety data on an ongoing basis to ensure the continuing
safety of the participants enrolled in this study. Enrollment will not be paused during these safety
reviews, except after Stage 1 (approximately 1,000 participants). This committee will consist of at
least 1 medical expert in the relevant therapeutic area and at least 1 statistician; committee
membership responsibilities, authorities, and procedures will be documented in its charter.
Ad hoc review may be performed further to the occurrence of any SAE leading to a study pausing
situation as outlined in Section 6.11, or at request of the sponsor’s medical monitor or designee.
The principal investigator and sponsor’s study responsible physician will inform the IDMC of any
AE of concern.
If the SSG assesses that the stopping boundary is met (see below), the Chair of the IDMC will
immediately be informed through secure communication procedures. At this point, the IDMC will
convene and provide a recommendation to the Sponsor Committee.
In addition, the IDMC will formally monitor the infections in all groups to conclude both non-
efficacy and efficacy. The IDMC will evaluate in an unblinded fashion whether superiority is
established for the primary endpoint or whether non-efficacy is shown (see Section 9.8) based on
a report provided by the SSG, when the prespecified boundaries have been crossed.

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The sponsor designated teams and/or Sponsor Committee reviews all clinical and laboratory safety
data during the course of the study.
Statistical Support Group
The SSG is the statistical support group to the IDMC; they are unblinded and provide the with the
statistical analysis based on unblinded data. As the IDMC, they are independent to the company.
They  will continuously monitor for vaccine-associated enhanced disease by looking at each
diagnosed COVID-19 case in the FAS (and also SARS-CoV-2 infections in participants requiring
hospitalization; and SARS-CoV-2 infections in participants being admitted to the ICU [or
equivalent]; and SARS-CoV-2 infections resulting in death [with death being at least probably
related to COVID-19]). As these infections will be monitored in real-time, and, after each
confirmed respective case, the SSG will assess if a stopping boundary is reached. If the stopping
boundary is met, then the SSG immediately informs the Chair of the IDMC through secure
communication procedures. At this point the IDMC will convene and provide a recommendation
to the Sponsor Committee. As such, the potential harm monitoring is in real-time, resulting in the
earliest indication of harm possible as soon as data come in.
Clinical Severity Adjudication Committee
This committee will consist of independent clinical infectious disease experts and a pulmonologist.
The committee's deliberations per case and conclusions will be documented and will be provided
to the Sponsor. For more details on this committee, refer to Section 8.1.3.6.
The Clinical Severity Adjudication Committee will be utilized for adjudication of cases taking into
account all available relevant information at the time of adjudication. As of Amendment 7, Clinical
Severity Adjudication Committee may review all cases based on available data from the passive
follow-up (eg, limited to COVID-19 AE/SAE data, CIOMS forms, local laboratory results).
Readjudication will occur if new information becomes available. The latest adjudication will
determine the status of the case prior to analysis. The Clinical Severity Adjudication Committee's
decisions will be considered the definitive classification of the case. The case review including
severity assessments after implementation of Amendment 7 may change and will be reflected in
the charter of the committee. More details will be provided in the committee's charter and more
details about the impact on analysis will be provided in SAP.
Sponsor Committee
It is the primary responsibility of the Sponsor Committee to make decisions regarding study
operations and modifications based on monitoring of study vaccine-blinded primary events from
the study.
If any pausing rule is met (Refer to Section 6.11) and if following appropriate safety review, it is
deemed appropriate to restart dosing, the Sponsor must submit a request to restart dosing with
pertinent data to competent authority as a request for a substantial amendment, as required by local
regulations or authority request (e.g MHRA). If needed, this will be followed by a substantial
amendment of the IB and/or protocol.

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The Sponsor Committee responsibilities, authorities, procedures and their interactions with the
IDMC will be documented in the IDMC Charter.
AESI Assessment Committee
An AESI Assessment Committee with appropriate expertise will be established to evaluate each
suspected AESI and determine whether it is a case of TTS (see Section 8.3.7). A Charter will be
developed to describe the roles and responsibilities of the Committee.
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data
All information, including but not limited to information regarding Ad26.COV2.S or the sponsor’s
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior
clinical data, formulation information) supplied by the sponsor to the investigator and not
previously published, and any data generated as a result of this study, are considered confidential
and remain the sole property of the sponsor. The investigator agrees to maintain this information
in confidence and use this information only to accomplish this study and will not use it for other
purposes without the sponsor’s prior written consent.
The investigator understands that the information developed in the study will be used by the
sponsor in connection with the continued development of Ad26.COV2.S, and thus may be
disclosed as required to other clinical investigators or regulatory agencies. To permit the
information derived from the clinical studies to be used, the investigator is obligated to provide
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and
will contain data from all study sites that participated in the study as per-protocol. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the
study will be used to determine a coordinating investigator for the study. Results of analyses
performed after the Clinical Study Report has been issued will be reported in a separate report and
will not require a revision ofthe Clinical Study Report.
Study participant identifiers will not be used in publication of results. Any work created in
connection with performance of the study and contained in the data that can benefit from copyright
protection (except any publication by the investigator as provided for below) shall be the property
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter)
data and information without approval from the investigator. The investigator has the right to
publish study site-specific data after the primary data are published. If an investigator wishes to
publish information from the study, a copy of the manuscript must be provided to the sponsor for
review at least 60 days before submission for publication or presentation. Expedited reviews will
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in
writing, the investigator will withhold such publication for up to an additional 60 days to allow for
filing of a patent application. In the event that issues arise regarding scientific integrity or

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regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will
not mandate modifications to scientific content and does not have the right to suppress information.
For multicenter study designs and sub-study approaches, secondary results generally should not
be published before the primary endpoints of a study have been published. Similarly, investigators
will recognize the integrity of a multicenter study by not submitting for publication data derived
from the individual study site until the combined results from the completed study have been
submitted for publication, within 18months after the study end date, or the sponsor confirms there
will be no multicenter study publication. Authorship of publications resulting from this study will
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which
state that the named authors must have made a significant contribution to the conception or design
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the
work or revised it critically for important intellectual content; and given final approval of the
version to be published; and agreed to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work are appropriately investigated
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law. The disclosure of the final study results will be performed after the end-of-study in order
to ensure the statistical analyses are relevant.
10.3.8. 
Data Quality Assurance
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study-site personnel before the study, and periodic monitoring visits by the sponsor. Written
instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before
the start of the study.
The sponsor will review the eCRF for accuracy and completeness after transmission to the sponsor;
any discrepancies will be resolved with the investigator or designee, as appropriate. After upload
of the data into the study database they will be verified for accuracy and consistency with the data
sources.
Before the actual participant unblinding, all of the previously available data should be complete
and accurate in the participant's eCRF
10.3.9. 
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each participant in electronic
format. All data relating to the study will be recorded in the eCRF or eCOA. All eCRF entries,

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corrections, and alterations must be made by the investigator or authorized study-site personnel.
The investigator must verify that all data entries in the eCRF are accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an
eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any
such worksheets will become part of the participant’s source documents. Data must be entered into
the eCRF in English. The eCRF must be completed as soon as possible after a participant visit and
the forms should be available for review at the next scheduled monitoring visit.
If necessary, queries will be generated in the electronic data capture (eDC) tool. If corrections to
an eCRF are needed after the initial entry into the eCRF, this can be done in either of the following
ways:
 Investigator and study-site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
 Sponsor or sponsor delegate can generate a query for resolution by the investigator and study-
site personnel.
10.3.10. 
Source Documents
At a minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study site as a basis for standard medical care must be available for the following:
participant identification, eligibility(including relevant medical history, including anything related
to footnotes i and j to the Schedules of Activities in Section 1.3.3), and study identification; study
discussion and date of signed informed consent; dates of visits; results of safety and efficacy
parameters as required by the protocol; record of all AEs and follow-up of AEs; concomitant
therapy; study vaccine receipt/dispensing/return records; study vaccine administration
information; and date of study completion and reason for early discontinuation of study vaccine or
withdrawal from the study, if applicable.
The author of an entry in the source documents should be identifiable. Given that PROs are reports
of a patient’s health condition that come directly from the patient, without interpretation by a
clinician or anyone else, the responses to ePRO measures entered by study participants into source
records cannot be overridden by site staff or investigators.
Up to Protocol Amendment 7, participant- and investigator-completed scales and assessments
designated by the sponsor (ie, SIC) will be recordeddirectly into an eDevice and will be considered
source data. The participant’s e-Diary used to collect information regarding solicited signs and
symptoms after vaccination will be considered source data. The documentation of the positive RT-
PCR result that serves as a trigger to start procedures for COVID-19 follow-up, will be considered
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Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines
(or other equivalent document).
An eSource system may be utilized, which contains data traditionally maintained in a hospital or
clinic record to document medical care (eg, electronic source documents) as well as the clinical
study-specific data fields as determined by the protocol. This data is electronically extracted for
use by the sponsor. If eSource is utilized, references made to the CRF in the protocol include the
eSource system but information collected through eSource may not be limited to that found in the
eCRF.
10.3.11. 
Monitoring
The sponsor will use a combination of monitoring techniques (central, remote, or on-site
monitoring)to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary, if allowed per local
regulations. Ifon-site monitoring visits are not possible due to local regulations, restrictions and
guidance, the monitor will conduct site monitoring visits and activities remotely. Additional on-
site monitoring visits may be needed at a later moment in time to catch up on source data review.
Remote source data review of electronic records might be performed if possible and if allowed by
local/national regulations, restrictions and guidance.
The monitor will record dates of the visits in a study site visit log that will be kept at the study site.
The first post-initiation visit will be made as soon as possible after enrollment has begun. At these
visits, the monitor will review the source documents (eg, hospital/clinic/physician’s office medical
records)to ensure adherence to the protocol. The nature and location of all source documents will
be identified to ensure that all sources of original data required to complete the eCRF are known
to the sponsor and study-site personnel and are accessible for review by the sponsor study-site
contact. If electronic records are maintained at the study site, the method of review must be
discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of source
document review and may be needed to ensure that the recorded data are consistent with the
original source data. Findings from this review will be discussed with the study-site personnel.
The sponsor expects that during monitoring visits, the relevant study-site personnel will be
available, the source documents will be accessible, and a suitable environment will be provided
for review of study-related documents. The monitor will meet with the investigator on a regular
basis during the study to provide feedback on the study conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these
remote contacts, study-site personnel will be available to provide an update on the progress of the
study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.

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10.3.12. 
On-Site Audits
Representatives of the sponsor’s clinical quality assurance department may visit the study site at
any time during or after completion of the study to conduct an audit of the study in compliance
with regulatory guidelines and company policy. Remote auditing techniques may also be utilized,
if necessary. These audits will require access to all study records, including (electronic) source
documents as allowed per local regulations, for inspection. Participant privacy must, however, be
respected. The investigator and study-site personnel are responsible for being present and available
for consultation during routinely scheduled study-site audit visits conducted by the sponsor or its
designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part
of a national GCP compliance program or to review the results of this study in support of a
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
10.3.13. 
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF
and all source documents that support the data collected from each participant, as well as all study
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical
Trial, and all study documents as specified by the applicable regulatory requirement(s). The
investigator/institution will take measures to prevent accidental or premature destruction of these
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing applications
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents will be retained for a longer period
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when these documents no
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custody must be transferred to a person who will accept
the responsibility. The sponsor must be notified in writing of the name and address of the new
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator/institution must permit access to such reports.
10.3.14. 
Study and Site Start and Closure
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.

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Study/Site Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been collected
and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not
limited to:
 Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local health authorities, the sponsor’s procedures, or GCP guidelines
 Inadequate recruitment of participants by the investigator
 Discontinuation of further study vaccine development

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10.4. Appendix 4: Adverse Events, Serious Adverse Events, Adverse Events of
Special Interest, Medically-attended Adverse Events, Product Quality
Complaints, and Other Safety Reporting: Definitions and Procedures for
Recording, Evaluating, Follow-up, and Reporting
10.4.1. 
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a
pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have
a causal relationship with the vaccine. An AE can therefore be any unfavorable and unintended
sign (including an abnormal finding), symptom, or disease temporally associated with the use of a
medicinal (investigational or non-investigational) product, whether or not related to that medicinal
(investigational or non-investigational) product. (Definition per ICH).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
For the Safety Subset, any respiratory tract infection will be reported as an AE if it occurs between
the time of any vaccination through the following 28 days. Any respiratory tract infection recorded
as an AE in the eCRF will be excluded from the AE analysis if the molecular test is subsequently
found to be positive for SARS-CoV-2. Respiratory tract infections arising from SARS-CoV-2
infection will not be reported as (S)AEs in the Clinical Study Report but will be tabulated
separately.
As of Protocol Amendment 7, COVID-19 will be reported as SAE, AE, or MAAE.
Note: For time period of sponsor’s AE collection, see All Adverse Events under Section 8.3.1.
Serious Adverse Event
An SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for
Human Use is any untoward medical occurrence that at any dose:
 
Results in death
 
Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe)
 
Requires inpatient hospitalization or prolongation of existing hospitalization
 
Results in persistent or significant disability/incapacity
 
Is a congenital anomaly/birth defect
 
Is a suspected transmission of any infectious agent via a medicinal product
 
Is Medically Important*

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*Medical and scientific judgement should be exercised in deciding whether expedited reporting is
also appropriate in other situations, such as important medical events that may not be immediately
life-threatening or result in death or hospitalization but may jeopardize the participant or may
require intervention to prevent 1 of the other outcomes listed in the definition above. These should
usually be considered serious.
If a serious and unexpected AE occurs for which there is evidence suggesting a causal relationship
between the study vaccine and the event (eg, death from anaphylaxis), the event must be reported
as a SUSAR even if it is a component of the study endpoint (eg, all-cause mortality).
Any respiratory tract infection fulfilling the criteria of an SAE will be reported as such during the
entire study. If the molecular test is positive for SARS-CoV-2, the SAE will be excluded from the
SAE analysis in the Clinical Study Report and will be tabulated separately.
As of Amendment 7, a passive follow-up approach is adopted: follow-up visits or phone calls by
the site at scheduled time points to collect information on any protocol-required safety information
(see Section 8.3.1). In addition, SAEs, AEs, and MAAEs related to COVID-19 need to be reported
together with the concomitant medications related to these events until study end. Any
confirmatory COVID-19 laboratory finding should be reported in the eCRF.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product
reference safety information. For Ad26.COV2.S, the expectedness of an AE will be determined
by whether or not it is listed in the IB.
10.4.2. 
Attribution Definitions
Assessment of Causality
The causal relationship to study vaccine is determined by the investigator. The following selection
should be used to assess all AEs.
Related
There is a reasonable causal relationship between study vaccine administration and the AE.
Not Related
There is not a reasonable causal relationship between study vaccine administration and the AE.
The term “reasonable causal relationship” means there is evidence to support a causal relationship.
By definition, all solicited AEs at the injection site (local) will be considered related to the study
vaccine administration.

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10.4.3. 
Severity Criteria
All AEs and laboratory data will be coded for severity using a modified version of the FDA grading
table, based on version of September 200763, included in Appendix 9.
The AESI definition includes thrombocytopenia, defined as platelet count <150,000/µL as per the
Brighton Collaboration (Section 8.3.7.1).
For the purpose of severity grading, an AE of thrombocytopenia based on platelet counts
>140,000/µL and <150,000 µL should be considered Grade 1.
For AEs not identified in the grading table, the following guidelines will be applied:
Grade 1 
Mild 
Symptoms causing no or minimal interference with usual social
and functional activities
Grade 2 
Moderate 
Symptoms causing greater than minimal interference with usual
social and functional activities
Grade 3 
Severe 
Symptoms causing inability to perform usual social and
functional activities and requires medical intervention
Grade 4 
Potentially 
life- 
threatening 
Symptoms causing inability to perform basic self-care functions
OR medical or operative intervention indicated to prevent
permanent impairment, persistent disability OR ER visit or
hospitalization
For participants in the Safety Subset, the severity of solicited signs and symptoms will be graded
in the e-Diary by the participant based on the severity assessment provided in the diary as well as
assessed by the investigator using the toxicity grading scale in Appendix 9. (Note: severity of the
measured events will be derived from the diameter [for erythema and swelling] and the temperature
measurements [for fever]). See also Section 8.3.2.
10.4.4. 
Special Reporting Situations
Safety events of interest on a sponsor study vaccine in an interventional study that may require
expedited reporting or safety evaluation include, but are not limited to:
 
Known overdose of a sponsor study vaccine
 
Suspected abuse/misuse of a sponsor study vaccine
 
Accidental or occupational exposure to a sponsor study vaccine
 
Medication error, intercepted medication error, or potential medication error involving a
Johnson & Johnson medicinal product (with or without patient exposure to the Johnson &
Johnson medicinal product, eg, product name confusion, product label confusion, intercepted
prescribing or dispensing errors)
Special reporting situations should be recorded in the eCRF. Any special reporting situation that
meets the criteria of an SAE should be recorded on the Safety Report Form of the eCRF.

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10.4.5. 
Procedures
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study vaccine, must be
recorded using medical terminology in the source document and the eCRF. Whenever possible,
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough,
runny nose, sneezing, sore throat, and head congestion should be reported as “upper respiratory
infection”). Investigators must record in the eCRF their opinion concerning the relationship of the
AE to study therapy. All measures required for AE management must be recorded in the source
document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be
provided with a “wallet (study) card” and instructed to carry this card with them for the duration
of the study indicating the following:
 
Study number
 
Statement, in the local language(s), that the participant is participating in a clinical study
 
Investigator’s name and 24-hour contact telephone number
 
Local sponsor’s name and 24-hour contact telephone number (for medical personnel only)
 
Site number
 
Participant number
 
Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon  the
participant’s discontinuation from the study, must be followed until any of the following occurs:
 
The event resolves
 
The event stabilizes
 
The event returns to baseline, if a baseline value/status is available
 
The event can be attributed to agents other than the study vaccine or to factors unrelated to
study conduct
 
It becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE.
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during
participation in the study must be reported as an SAE, except hospitalizations for the following:

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 
Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending
placement in long-term care facility)
 
Surgery or procedure planned before entry into the study (must be documented in the eCRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not be
considered SAEs. Any AE that results in a prolongation of the originally planned
hospitalization is to be reported as a new SAE.
The cause of death of a participant in a study, whether or not the event is expected or associated
with the study vaccine, is considered a SAE.
Information regarding SAEs will be transmitted to the sponsor using a SAE Form and Safety
Report Form of the eCRF, which must be completed and reviewed by a physician from the study
site, and transmitted in a secure manner to the sponsor within 24 hours. The initial and follow-up
reports of an SAE should be transmitted in a secure manner electronically or by facsimile (fax).
Telephone reporting should be the exception and the reporter should be asked to complete the
appropriate form(s) first.
Adverse Events of Special Interest
AESIs will be carefully monitored during the study by the sponsor. Suspected AESIs must be
reported to the sponsor within 24 hours of awareness irrespective of seriousness (ie, serious and
non-serious AEs) or causality assessment, following the procedure described above for SAEs and
will require enhanced data collection.
10.4.6. 
Product Quality Complaint Handling
Definition
A PQC is defined as any suspicion of a product defect related to manufacturing, labeling, or
packaging, ie, any dissatisfaction relative to the identity, quality, durability, reliability, or
performance of a distributed product, including its labeling, drug delivery system, or package
integrity. A PQC may have an impact on the safety and efficacy of the product. In addition, it
includes any technical complaints, defined as any complaint that indicates a potential quality issue
during manufacturing, packaging, release testing, stability monitoring, dose preparation, storage
or distribution of the product or the drug delivery system.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after
being made aware of the event.
A sample of the suspected product should be maintained under the correct storage conditions until
a shipment request is received from the sponsor.

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10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues, PQC, or questions regarding the study are listed in the Contact Information
page(s), which will be provided as a separate document.

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10.5. Appendix 5: Contraceptive Guidance and Collection of Pregnancy
Information
Participants must follow contraceptive measures as outlined in Section 5.1. Pregnancy information
will be collected and reported as noted in Section 8.3.5.
Definition of a Person of Childbearing Potential
A Person of Childbearing Potential
A person  is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
A Person Not of Childbearing Potential
 
premenarchal
A premenarchal state is 1 in which menarche has not yet occurred.
 
postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause.
 
permanently sterile (for the purpose of this study)
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral
oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal person
experiences menarche) or the risk of pregnancy changes (eg, a person who is not heterosexually
active becomes active), a person must begin an acceptable effective method of contraception, as
described throughout the inclusion criteria.

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10.6. Appendix 6: Symptoms of Infection with Coronavirus-19 (SIC)
As of Amendment 7, this is no longer applicable.
The following questions ask about symptoms people with coronavirus-19 infection may
experience. Answer each question carefully by choosing ‘yes’ if you have experienced the
symptom or ‘no’ if you have not experienced the symptom in the last 24 hours. If you
choose ‘yes’, select the rating that best matches your experience.
In the last 24 hours,
have you
experienced…
Please rate the severity of each symptom you experienced.
Feeling generally
unwell (run down)
Yes   No
    If yes, 
How severe was your feeling (generally unwell or run down) in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible
Fatigue (tiredness)
Yes   No
    If yes, 
How severe was your fatigue (tiredness) in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible
Physical weakness
Yes   No
    If yes, 
How severe was your feeling of physical weakness in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible
Cough
Yes   No
    If yes, 
How severe was your cough in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible
Shortness of breath
(difficulty
breathing)
Yes   No
    If yes, 
How severe was your shortness of breath (difficulty breathing) in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible
Sore throat
Yes   No
    If yes, 
How severe was your sore throat in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible
Nasal congestion
(stuffy nose)
Yes   No
    If yes, 
How severe was your nasal congestion (stuffy nose) in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible

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In the last 24 hours,
have you
experienced…
Please rate the severity of each symptom you experienced.
Wheezing
(whistling sound
while breathing)
Yes    No
    If yes, 
How severe was your wheezing (whistling sound while breathing) in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible
Runny nose
Yes   No
    If yes, 
How severe was your runny nose in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible
Sneezing
Yes   No
    If yes, 
How severe was your sneezing in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible
Chest congestion
(mucus in chest)
Yes   No
    If yes, 
How severe was your chest congestion (mucus in chest) in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible
Chest pain/
pressure/tightness
Yes   No
    If yes, 
How severe was your chest pain/pressure/tightness in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible
Muscle aches/pains
Yes   No
    If yes, 
How severe were your muscle aches or pains in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible
Joint aches/pains
Yes   No
    If yes, 
How severe were the aches or pains in your joints in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible

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In the last 24 hours,
have you
experienced…
Please rate the severity of each symptom you experienced.
Headache
Yes   No
    If yes, 
How severe was your headache in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible
Feeling faint
Yes   No
    If yes, 
How severe was your feeling of faintness in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible
Problems thinking
clearly/brain fog
Yes   No
    If yes, 
How severe were your problems thinking clearly/brain fog in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible
Chills
Yes   No
    If yes, 
How severe were your chills in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible
Skin rash
Yes  
No
    If yes, 
How severe was your skin rash in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible
Eye
irritation/discharge
Yes   No
    If yes, 
How severe was your eye irritation/discharge in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible
Diarrhea
Yes   No
    If yes, 
How severe was your diarrheain the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible

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In the last 24 hours,
have you
experienced…
Please rate the severity of each symptom you experienced.
Vomiting
Yes   No
    If yes, 
How severe was your vomiting in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible
Nausea
Yes   No
    If yes, 
How severe was your nauseain the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible
Abdominal/
stomach pain
Yes   No
    If yes, 
How severe was your abdominal/stomach pain in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst possible
Loss of appetite
Yes   No
    If yes, 
How severe was your loss of appetite in the last 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
None 
Worst
possible
What was your highest temperature in the last 24 hours? ____  °C/°F
What method did you use to take your temperature?
oral   armpit    ear   forehead  rectal
In the last 24 hours, have you experienced…
Uncontrollable body shaking/shivering*
Yes   
No
Decreased sense of smell*
Yes   
No
Decreased sense of taste*
Yes   
No
Red or bruised looking feet or toes*
Yes   
No

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*Please rate the severity of your symptoms inthe last 24 hours?
No Symptoms
Mild
Moderate
Severe

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10.7. Appendix 7: MRU Questionnaire
As of Amendment 7, this is no longer applicable since the MRU questionnaire will be discontinued
in view of passive follow-up.
Baseline Version
Participant ID: 
Date (dd-mmm-yyyy): 
1. Medical consultations
In the last 3 months, how many times have you had medical consultations?
No 
Yes 
Type of contact
(personal consultation
/telemedicine)
If yes,
specify the number of
visits
Indicate a reason
for each visit
General Practitioner/Nurse
practitioner
Internal Medicine/Medical
Outpatient Department
Other Specialist (Please
specify):
Other (eg Physiotherapy,
Pharmacist for a consultation
Please specify):
2. Professional home care
Please indicate the need for professional care at home in the last 3 months.
No 
Yes 
Type of contact
(personal consultation
/telemedicine)
If yes,
specify the number of
visits
Indicate a reason
for each type of
professional care
General Practitioner
Nurse/ Nurse practitioner
Internal Medicine/Medical
Outpatient Department
Other Specialist (Please
specify):
Other (eg Physiotherapy,
Pharmacist Please specify:)
Supplemental oxygen

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3. Hospital Services
In the last 3 months, did you visit the hospital?
Yes: 
No: 
No 
Yes 
If yes, 
specify the number 
of visits/admissions 
If yes,
specify the length of
each stay/use (days)
Indicate a reason for
each hospital visit
Emergency Department*
Short-term hospital visit
(<24 hours admission)
Hospitalization in general
ward#
Hospitalization in
intensive/critical care
Mechanical ventilation use
*Please count Emergency Department visits only if the visit did not result in a hospital admission.
#Please capture type of ward and length of stay in each ward.
4. Institutional care admission(s) other than hospital
Yes: 
No: 
Please indicate if there has been any need for admission for care in a long-term facility, in the last 3 months.
No 
Yes 
If yes, 
specify number of 
admissions 
If yes, 
specify the length 
of stay (days) 
Indicate a reason for
each institutional care
admission
Long-term facilities
Rehabilitation facility
Supplemental oxygen

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Version for Confirmed COVID-19 Cases
Participant ID: 
Date (dd-mmm-yyyy): 
1. Medical consultations
Since onset of the confirmed COVID-19 episode, how many times have you had medical consultations?
No Yes 
Type of contact 
(personal 
consultation/ 
telemedicine) 
If yes,
specify the
number of visits
Specify number of
visits related to
COVID-19 or its
complications
Indicate a
reason for each
visit
General Practitioner
Internal
Medicine/Medical
Outpatient Department
Other Specialist (Please
specify):
Other (eg Physiotherapy,
Pharmacist for a
consultation Please
specify:)
2. Professional home care
Please indicate the need for professional care at home since onset of the confirmed COVID-19 episode
No 
Yes
Type of contact 
(personal 
consultation/ 
telemedicine) 
If yes, 
specify the 
number of 
visits 
Specify number of
visits related to
COVID-19 or its
complications
Indicate a
reason for each
type of
professional
care at home
General Practitioner
Nurse/ Nurse
practitioner
Internal
Medicine/Medical
Outpatient Department
Other Specialist
(Please specify):
Other (eg
Physiotherapy,
Pharmacist Please
specify:)
Supplemental oxygen

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3. Hospital Services
Since onset of the confirmed COVID-19 episode, did you visit the hospital?
Yes: 
No: 
No 
Yes
If yes, 
specify number 
of 
visits/admissions 
Specify number
of
visits/admissions
related to
COVID-19 or its
complications
Specify the 
length of each 
stay/use (days) 
Indicate a
reason for each
hospital visit
Emergency Department*
Short-term hospital visit
(<24 hours admission)
Hospitalization in general
ward#
Hospitalization in
intensive/critical care
Mechanical ventilation use
*Please count Emergency Department visits only if the visit did not result in a hospital admission.
#Please capture type of ward and length of stay in each ward.
4. Institutional care admission(s) other than hospital
Please indicate if there has been any need for admission for care in a long-term facility, since onset of the confirmed
COVID-19 episode.
Yes: 
No: 
No 
Yes
If yes,
specify number
of admissions
Specify number
of admissions
related to
COVID-19 or
its
complications
Specify the
length of each
stay (days)
Indicate a
reason for each
institutional
care admission
Long-term facilities
Rehabilitation facility
Supplemental oxygen

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 
Clinical signs at rest indicative of severe systemic illness (respiratory rate ≥30 breaths/minute or heart rate
≥125 beats/minute or SpO2 ≤93% on room air at sea levela, or PaO2/FiO2 <300 mmHg)
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Respiratory failure requiring high-flow oxygen, non-invasive ventilation, mechanical ventilation, or ECMO
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Respiratory rate ≥20 but <30 breaths/minute
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Shortness of breath
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Heart rate ≥90 beats/minute
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Shock (systolic blood pressure <90 mm Hg, or diastolic blood pressure <60 mm Hg or requiring vasopressors)
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Radiologic evidence of DVT
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Significant acute renal or hepatic dysfunction
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
a SpO2 criteria will be adjusted according to altitude per investigator judgement.

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 
Hyperinflammatory Syndrome
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Symptoms or signs of stroke
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Numbness, tingling, or weakness face or limbs
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Difficulty speaking or forming speech
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Difficulty understanding speech
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Feelings of confusion
□    Yes     □   No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Clinical or radiological evidence of pneumonia
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Fever (≥38.0°C or ≥100.4°F)
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Shaking chills or rigors
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________

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 
Cough
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Sore throat
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Malaise
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Headache
□    Yes    □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Myalgia
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Gastrointestinal symptoms
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Chilblains/pernio (red or bruised looking feet or toes)
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________
 
Anosmia (olfactory or taste disorders)
□    Yes     □    No
Severity:  □    Mild 
□    Moderate 
□    Severe
□    Start date: _____________        □    End date: _____________

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10.9. Appendix 9: Toxicity Grading Scale
Adapted from the FDA Guidance document “Toxicity Grading Scale for Healthy Adult and
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” (September 2007)
Local Reaction to 
Injectable Product 
Mild (Grade 1) 
Moderate (Grade 2) Severe (Grade 3) 
Potentially Life
Threatening
(Grade 4)
Pain/Tenderness# 
Aware of symptoms 
but easily tolerated; 
Does not interfere 
with activity; 
Discomfort only to 
touch  
Notable symptoms; 
Requires modification 
in activity or use of 
medications; 
Discomfort with 
movement 
Incapacitating 
symptoms; 
Inability to do work, 
school, or usual 
activities; Use of 
narcotic pain reliever
Hospitalization;
Pain/tenderness
causing inability to
perform basic self-
care function
Erythema# 
25 –50 mm  
51 –100 mm  
>100 mm  
Hospitalization;
Necrosis or
exfoliative dermatitis
Swelling# 
25 –50 mm  
51 –100 mm  
>100 mm  
Hospitalization;
Necrosis
# Revised by the sponsor.
Vital Signs * 
Mild (Grade 1) 
Moderate (Grade 2) Severe (Grade 3) 
Potentially Life
Threatening
(Grade 4)
Fever (°C) ** 
           (°F)** 
38.0 - 38.4 
100.4 - 101.1 
38.5 - 38.9 
101.2 - 102.0 
39.0 - 40.0 
102.1 - 104.0 
>40
>104.0
Tachycardia - beats 
per 
minute
101 –115 
116 –130 
>130 
Hospitalization for
arrhythmia#
Bradycardia - beats 
per 
minute***
50 –54 
45 –49 
<45 
Hospitalization for
arrhythmia#
Hypertension 
(systolic) - mm Hg 
141 –150 
151 –155 
>155 
Hospitalization for
malignant
hypertension#
Hypertension 
(diastolic) - mm Hg 
91 –95 
96 –100 
>100 
Hospitalization for
malignant
hypertension#
Hypotension 
(systolic) –mm Hg 
85 –89 
80 –84 
<80 
Hospitalization for
hypotensive shock#
Respiratory Rate – 
breaths per minute
17 –20 
21 –25 
>25 
Intubation
* Participant should be at rest for all vital sign measurements.
** For oral temperature: no recent hot or cold beverages or smoking.
*** When resting heart rate is between 60 –100 beats per minute. Use clinical judgement when characterizing
bradycardia among some healthy participant populations, for example, conditioned athletes.
# Revised by the sponsor.

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Systemic (General) Mild (Grade 1) 
Moderate (Grade 2) Severe (Grade 3) 
Potentially Life
Threatening
(Grade 4)
Vomiting# 
No interference 
with activity or 1 –2 
episodes/24 hours 
Some interference 
with activity or >2 
episodes/24 hours 
Prevents daily  
activity, requires 
outpatient IV
hydration
Hospitalization;
Hypotensive shock
Nausea# 
Minimal symptoms; 
causes minimal or no 
interference with 
work, school, or self- 
care activities 
Notable symptoms; 
Requires modification 
in activity or use of 
medications; 
Does NOT result in 
loss of work, school, 
or cancellation of 
social activities
Incapacitating 
symptoms; 
Requires bed rest 
and/or results in loss 
of work, school, or
cancellation of social
activities
Hospitalization;
Inability to perform
basic self-care
functions
Diarrhea# 
2 –3 loose stools or 
<400 gms/24 hours 
4 –5 stools or 
400 –800 gms/24 
hours 
6 or more watery  
stools or 
>800 gms/24 hours or 
oral rehydration 
necessary
Hospitalization;
Hypotensive shock
OR IV fluid
replacement indicated
Headache# 
Minimal symptoms;
causes minimal or no
interference with
work, school, or self-
care activities
Notable symptoms; 
Requires modification 
in activity or use of 
medications; 
Does NOT result in 
loss of work, school, 
or cancellation of 
social activities 
Incapacitating
symptoms;
Requires bed rest
and/or results in loss
of work, school, or
cancellation of social
activities;
Use of narcotic pain
reliever
Hospitalization;
Inability to perform
basic self-care
functions
Fatigue# 
Minimal symptoms;
causes minimal or no
interference with
work, school, or self-
care activities
Notable symptoms; 
Requires modification 
in activity or use of 
medications; 
Does NOT result in 
loss of work, school, 
or cancellation of 
social activities 
Incapacitating
symptoms;
Requires bed rest
and/or results in loss
of work, school, or
cancellation of social
activities;
Use of narcotic pain
reliever
Hospitalization;
Inability to perform
basic self-care
functions
Myalgia# 
Minimal symptoms;
causes minimal or no
interference with
work, school, or self-
care activities
Notable symptoms; 
Requires modification 
in activity or use of 
medications; 
Does NOT result in 
loss of work, school, 
or cancellation of 
social activities 
Incapacitating
symptoms;
Requires bed rest
and/or results in loss
of work, school, or
cancellation of social
activities;
Use of narcotic pain
reliever
Hospitalization;
Inability to perform
basic self-care
functions
# Revised by the sponsor.

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Systemic Illness 
Mild (Grade 1) 
Moderate (Grade 2) Severe (Grade 3) 
Potentially Life
Threatening
(Grade 4)
Illness or clinical 
adverse 
event (as defined 
according to 
applicable
regulations)
No interference with  
activity  
Some interference 
with activity not 
requiring medical 
intervention 
Prevents daily  
activity and
requires medical
intervention
Hospitalization#
# Revised by the sponsor.

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10.10. Appendix 10: Symptoms of Coronavirus (US Centers for Disease Control
and Prevention)
The following extract shows symptoms of coronavirus infection as listed on the US CDC website
(https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html) dated 13 May
2020.

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10.11. Appendix 11: Summary of Guidance from CDC Website on Underlying
Medical Conditions That Lead or Might Lead to Increased Risk for Severe
Illness From COVID-19
People of any age with certain underlying medical conditions are at increased risk for severe
illness from COVID-19:
People of any age with the following conditions are at increased risk of severe illness from
COVID-19:
 Cancer
 Chronic kidney disease
 COPD (chronic obstructive pulmonary disease)
 Immunocompromised state (weakened immune system) from solid organ transplant
 Obesity (body mass index [BMI] of 30 or higher)
 Serious heart conditions, such as heart failure, coronary artery disease, or cardiomyopathies
 Sickle cell disease
 Type 2 diabetes mellitus
COVID-19 is a new disease. Currently there are limited data and information about the impact of
underlying medical conditions and whether they increase the risk for severe illness from COVID-
19. Based on what we know at this time, people with the following conditions might be at an
increased risk for severe illness from COVID-19:
 Asthma (moderate to severe)
 Cerebrovascular disease (affects blood vessels and blood supply to the brain)
 Cystic fibrosis
 Hypertension or high blood pressure
 Immunocompromised state (weakened immune system) from blood or bone marrow
transplant, immune deficiencies, HIV, use of corticosteroids, or use of other immune
weakening medicines
 Neurologic conditions, such as dementia
 Liver disease
 Pregnancy
 Pulmonary fibrosis (having damaged or scarred lung tissues)
 Smoking
 Thalassemia (a type of blood disorder)
 Type 1 diabetes mellitus
Source: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-
conditions.html?CDC AA refVal=https%3A%2F%2Fwww.cdc.gov%2 
Fcoronavirus% 2F2019-ncov%2Fneed-
extra-precautions%2Fgroups-at-higher-risk.html. Accessed: 19 July 2020.

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10.12. Appendix 12: Risk Factor Assessment
As of Amendment 7, this is no longer applicable since risk factor assessment will be terminated in
view of passive follow-up.
10.12.1. 
Questionnaire 1
Are you a student?              ☐  Yes 
☐  No
If Yes Are you likely to return to school in person in the near future? 
☐Yes 
☐No 
☐  I don’t know
Are you retired?              ☐  Yes                ☐  No
How often do you go in person to your main workplace (other than work from home)?
☐  0 days/week                     ☐  1 day/week                
☐  2 4 days/week                     ☐  5 or more days/week
Does your main workplace have social distancing measures in place?
☐  Yes           ☐  No         ☐  I don’t know      ☐  Not applicable
Is your main workplace cleaned on a regular basis?
☐  Yes           ☐  No         ☐  I don’t know      ☐  Not applicable
Do people in your main workplace use personal protection equipment (such as masks)?
☐  Yes           ☐  No         ☐  I don’t know      ☐  Not applicable
How do you get to work? (Check all that apply)
☐  Drive own car                         ☐  Carpool                        
☐  Rideshare (Taxi, Uber, Lyft, others)
☐  Bus   
☐  Train / Subway  
☐  Walk / Bike
☐  Frequent Air Travel               ☐  Not applicable
On a typical day, how many people do you interact with in person at work?
☐  No one                                     ☐  Between 1 and 10 people
☐  Between 11 and 30 people  ☐  Between 31 and 50 people
☐  More than 50 people
On a typical day, how many people do you interact with in person outside of work?
☐  No one                                     ☐  Between 1 and 10 people
☐  Between 11 and 30 people  ☐  Between 31 and 50 people
☐  More than 50 people
Living Situation
Do you live in any of the following (choose all that apply):
☐  Single family home                               ☐  Multi family housing (apartment building, condo)
☐  Long term care facility                        ☐  Assisted living facility
☐  Dormitory                                              ☐  RV / Trailer
☐  Single room in a hotel                          ☐  Shelter
☐  Other adult group setting                    ☐  Staying with friends / Couch surfing
☐  No residence                                         ☐Tribal Lands / Reservation
☐  Other
How many people do you live with (other than yourself)?
Total people under 18 years of age
Total people between 18 64 years of age
Total people over 65 years of age
Are any of the people you live with expected to return to school in person in the near future?
☐  Yes       ☐  No     ☐  I don’t know
Community Interactions
In the last 2 weeks, have you attended any gatherings with more than 10 people? (e.g., church, party, concert, wedding, funeral, demonstration
or other event).                   ☐  Yes 
☐  No                         ☐  Not applicable / Don’t want to tell
If yes, approximately how many people were at the largest gathering?
☐  less than 10        ☐  10 20        ☐  21 50        ☐  51 250 
  ☐  More than 250
Was this gathering an indoor or outdoor event?
☐  Indoor       ☐  Outdoor   ☐  Both
How frequently do you have visitors in your residence including people completing work inside?
☐  Daily
☐  Weekly
☐  Monthly
☐  Rarely
☐  Never
☐  N/A
Over the past month, have you been in close contact with anyone that tested positive for COVID 19?
☐  Yes           ☐  No         ☐  I don’t know      ☐Not applicable / Don’t want to tell

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If yes, is this person someone that you live with?
                               ☐  Yes                         ☐  No                            ☐  Not applicable / Don’t want to tell
10.13. Appendix 13: TTS AESI Form
The form below represents the type of information that may be collected in case of a suspected
AESI in order to help adjudicate whether the event is a case of TTS. Additional data may be
requested by the sponsor for investigation of the event.
Adverse Event of Special Interest Questionnaire (AESIQ) for Thromboembolism with
Thrombocytopenia Syndrome
Date of Report: 
[dd-MMM-yyyy]
1. Adverse Event Description
Participant’s clinical signs and symptoms
Leg/Calf Oedema 
Pain in Leg/Calf 
Haemoptysis
Dyspnoea 
Chest Pain/Discomfort 
Syncope
Tachypnoea 
Tachycardia 
Cough
Loss of consciousness 
Headache 
Seizure
Visual impairment 
Weakness 
Impaired speech
Confusional state 
Paresthesia 
Gait disturbance
Other symptoms:
Was patient on VTE prophylaxis? 
No 
Yes, details:

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2. Medical History and Concurrent Conditions
Provide details:
Is the participant overweight or have obesity? 
No 
Yes
    If available, please provide: 
    
       Height 
Weight 
BMI
Does the participant have a sedentary lifestylea? 
No 
Yes – details:
Has the participant been in a sitting position for long 
periods of time prior to the event?
No 
Yes – details:
Is there a current history of smoking (active or passive)? 
No 
Yes – details:
Is there a prior history of smoking (active or passive)? 
No 
Yes – details:
Does the participant have a prior history of:
Cancer 
No 
Yes – details:
Autoimmune disease (i.e., collagen-vascular disease, 
inflammatory bowel disease) or myeloproliferative
disease?
No 
Yes – details:
Clotting disorder or a hypercoagulable state 
No 
Yes – details:
Varicose veins 
No 
Yes – details:
Trauma to the involved leg or pelvis 
No 
Yes – details:
DVT/PE or other VTE  
No 
Yes – details:
Blood transfusion  
No 
Yes – details:
Cardiovascular disease 
No 
Yes – details:
If the participant has experienced a previous thrombotic
event, address the following:
    1.  Date (or estimate) 2.  Provide brief description of the
nature of the event  3.  Provide brief description of the
treatment of the event  4.  Note any residual
manifestations of the event.
 
If the patient has experienced more than one previous
thrombotic event, please list other events.
Was the (female) participant pregnant at the time of 
event?
No 
Yes – details:
Does the participant has any of genetic risk factors:
Dysfibrinogenemia 
Antiphospholipid syndrome  
Factor V Leiden mutation
Protein C or S deficiency  
Elevated factor VIII levels 
Anti-thrombin deficiency
Hyperhomocysteinemia 
Prothrombin gene mutation  
Blood-clotting disorder
Thrombophilia
Does the participant have any acquired risk factors:
Reduced mobility (paralysis, paresis, travel etc.) 
Recent surgery
Indwelling central venous catheters                       
Recent trauma
Recent discontinuation of anticoagulants (e.g., heparin, warfarin, DOACs)
Hormone replacement therapy (including contraceptives)
a Any waking behavior characterized by an energy expenditure less than or equal to 1.5 metabolic equivalents (METs),
while in a sitting, reclining or lying posture

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Phlebitis 
Lupus
Inflammatory bowel disease 
Myeloproliferative disorders
Diabetes mellitus 
Hyperlipidemia
Hypertension                                                                       
Dehydration
Other significant medical co-morbidities or risk factors for DVT, specify:
If yes to any of the above, provide details:
Provide Well’s score, if calculated:
3. Relevant results of diagnostic tests including laboratory tests, imaging, biopsies, etc. (Note
the levels/conclusion, date performed, normal ranges as well as any other details.
Alternatively, attach full reports of the diagnostic tests.)
Diagnostic Test 
Results at baseline or prior 
to use of product (Include 
date and value/details) 
Test results after use of
product (Include date
and value/details)
CBC with smear (microscopic
evaluation)
ESR
Platelet count
Antibodies to platelet factor 4
(PF4)
Fibrinogen levels
Clauss fibrinogen assay
D-Dimer
Clotting Profile (PT, aPTT- prior
to an anticoagulation treatment)
Thrombin time (Bovine) Plasma
Prothrombin
Antithrombin activity
Factor V Leiden
Protein C activity
Protein S activity
C-reactive protein
Homocystein levels
Dilute Russells Viper Venom
Time (DRVVT), Plasma
Activated Protein C Resistance
V (APCRV), Plasma
Thrombophilia interpretation
Anticardiolipin antibodies (IgG
and IgM) or beta-2
glycoproteins antibodies

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Diagnostic Test 
Results at baseline or prior 
to use of product (Include 
date and value/details) 
Test results after use of
product (Include date
and value/details)
Antiphospholipid antibodies
(IgG and IgM)
Lupus anticoagulant
Heparin antibodies
ANA and ANCA
IL6 levels
ADAMTS13 Activity Assay
Ceruloplasmin
Direct Coombs test
Complement C3, C4
MethylenetetraHydrofolate
reductase gene mutation
Prothrombin gene mutation
(G20210A)
Occult blood in stool
COVID-19 test
Troponins
Brain Natriuretic Peptide
Arterial Blood Gases
Chest X-Ray
Electrocardiography
Echocardiography
Duplex Ultrasonography
MRI scan
CT scan
Contrast Venography
Pulmonary Angiography
Ventilation-Perfusion Scanning
Provide details of any additional diagnostic results:

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10.14. Appendix 14: Thrombotic Events to be Reported as Suspected AESIs
At the time of Protocol Amendment 5 writing, the list of thrombotic events to be reported to the
sponsor as suspected AESIs is provided below. Further guidance may become available on
thrombotic events of interest.
 MedDRA PTs for large vessel thrombosis and embolism:
o 
Aortic embolus, aortic thrombosis, aseptic cavernous sinus thrombosis, brain stem
embolism, brain stem thrombosis, carotid arterial embolus, carotid artery thrombosis,
cavernous sinus thrombosis, cerebral artery thrombosis, cerebral venous sinus
thrombosis, cerebral venous thrombosis, superior sagittal sinus thrombosis, transverse
sinus thrombosis, mesenteric artery embolism, mesenteric artery thrombosis, mesenteric
vein thrombosis, splenic artery thrombosis, splenic embolism, splenic thrombosis,
thrombosis mesenteric vessel, visceral venous thrombosis, hepatic artery embolism,
hepatic artery thrombosis, hepatic vein embolism, hepatic vein thrombosis, portal vein
embolism, portal vein thrombosis, portosplenomesenteric venous thrombosis, splenic
vein thrombosis, spontaneous heparin-induced thrombocytopenia syndrome, femoral
artery embolism, iliac artery embolism, jugular vein embolism, jugular vein thrombosis,
subclavian artery embolism, subclavian vein thrombosis, obstetrical pulmonary
embolism, pulmonary artery thrombosis, pulmonary thrombosis, pulmonary venous
thrombosis, renal artery thrombosis, renal embolism, renal vein embolism, renal vein
thrombosis, brachiocephalic vein thrombosis, vena cava embolism, vena cava
thrombosis, truncus coeliacus thrombosis
 MedDRA PTs for more common thrombotic events:
o 
Axillary vein thrombosis, deep vein thrombosis, pulmonary embolism, MedDRA PTs
for acute myocardial infarction*, MedDRA PTs for stroke*
Source: Shimabukuro T. CDC COVID-19 Vaccine Task Force. Thrombosis with thrombocytopenia syndrome (TTS)
following Janssen COVID-19 vaccine. Advisory Committee on Immunization Practices (ACIP). April 23, 2021.
https://www.cdc.gov/vaccines/acip/meetings/slides-2021-04-23.html.
*Vaccine Adverse Event Reporting System (VAERS) Standard Operating Procedures for COVID-19 (as of 29 January
2021) https://www.cdc.gov/vaccinesafety/pdf/VAERS-v2-SOP.pdf

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Status: Approved,  Date:  27 April 2022
10.15. Appendix 15: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents (TOC).
Amendment 6 (15 October 2021)
Overall Rationale for the Amendment: This amendment has been created to offer a 1-dose
booster vaccination with Ad26.COV2.S at the 5x1010 vp dose level to all ongoing participants who
received only a single vaccination with Ad26.COV2.S in the study. Participants who already
received 2 vaccinations with Ad26.COV2.S at the 5x1010 vp dose level or any COVID-19
vaccinations outside of the study (including the Janssen vaccine) at the time of local approval of
Protocol Amendment 6 are not eligible to receive a booster vaccination with Ad26.COV2.S. The
booster vaccination will be administered in the open-label phase of the study, preferably within
6 to 12 months after the participant’s first Ad26.COV2.S vaccination in the study. If this is not
possible, the booster vaccination should not occur earlier than 3 months after the participant’s first
Ad26.COV2.S vaccination. All participants (whether they consent to the booster vaccination or
not) will be encouraged to remain in the study and will be monitored for safety, immunogenicity,
and efficacy according to their original schedule.
Rationale: A single dose of Ad26.COV2.S vaccine is immunogenic and highly efficacious against
severe COVID-19 disease and COVID-19 related hospitalization and death. Furthermore, while
protection against variants of concern (such as the Beta and Mu variants in study COV3001 and
the Delta variant in the Sisonke study) remains high against severe/critical disease, hospitalization,
and death, this protection is lower against, eg, the Gamma variant compared to the reference
Wuhan strain. Protection against severe/critical disease caused by different variants of concern
(such as Gamma, Lambda and Mu variants) was shown to be reduced in the final analysis of study
COV3001 compared to the reference Wuhan strain and the Alpha variant, for example. Giving a
second dose of Ad26.COV2.S results in marked increases of immune responses and those higher
immune responses correlate with better protection against COVID-19, as shown in the primary
analysis of study COV3009. Some national vaccination recommendation bodies (eg, CDC) have
recently advised to give a booster vaccination. Therefore, this amendment will permit boosting of
all eligible ongoing participants in this study who received only a single vaccination with
Ad26.COV2.S in the study. As the Janssen vaccine is approved as a single dose vaccine,
participants who received two doses of Ad26COV2.S are considered to already have received the
booster dose. Given that the sponsor has no safety information on mixed schedule vaccinations,
participants that received a COVID-19 vaccination outside of the study will not be offered the
booster dose in this study.
Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
1.2 Schema 
1.3.1 All Participants 
1.3.2 Open-label Unblinding Visit 
1.3.3 Booster Vaccination  
2.1 Study Rationale 
All ongoing participants who 
received only a single vaccination 
with Ad26.COV2.S in the study
will be offered a booster
vaccination with Ad26.COV2.S at
the same dose level of 5×1010 vp.
Participants who already received
See overall rationale for
amendment.

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Section number 
and Name
Description of Change 
Brief Rationale
2.3.1 Risks Related to Study 
Participation  
2.3.2 Benefits of Study 
Participation  
2.3.3 Benefit-Risk Assessment of 
Study Participation  
3 OBJECTIVES AND 
ENDPOINTS  
4.1 Overall Design  
4.2.1 Study-Specific Ethical Design 
Considerations 
4.4 End-of-study Definition
5 STUDY POPULATION  
5.5 Criteria for Temporarily 
Delaying Administration of Study 
Vaccination  
6.1 Study Vaccines Administered
6.4 Unblinding and Open-label
Phase
6.5 Booster Vaccination
6.8 Continued Access to Study
Vaccine After the End of the Study
6.10 Prestudy and Concomitant 
Therapy  
7.1 Discontinuation of Study  
Vaccination 
8 STUDY ASSESSMENTS AND 
PROCEDURES  
8.1.3 Efficacy Assessments
8.1.3.5 SARS-CoV-2 
Seroconversion Assessment 
8.1.4 Immunogenicity Assessments 
8.3.1 Time Period and Frequency 
for Collecting Adverse Event, 
Medically-attended Adverse Event, 
Adverse Event of Special Interest, 
and Serious Adverse Event 
Information 
8.3.5 Pregnancy  
8.9 Assessment and Procedures for 
Booster Vaccination and Follow-up
After Implementation of Protocol
Amendment 6
9.1 Statistical Hypotheses
9.2.1 Efficacy (Total Sample Size)
9.2.2 Immunogenicity Subset
9.2.4 Safety (Safety Subset)
9.5.3 Analyses for the Open-label
Phase
9.6.1 Immunogenicity Subset
9.7 Safety Analysis
10.1 Appendix 1: Abbreviations
10.2 Appendix 2: Clinical
Laboratory Tests
10.3.3 Informed Consent Process
2 vaccinations with Ad26.COV2.S
at the 5x1010 vp dose level or any
COVID-19 vaccinations outside of
the study (including the Janssen
vaccine) are not eligible to receive a
booster vaccination with
Ad26.COV2.S. Booster vaccination
should preferably be within 6-12
months after first vaccination and
should not occur earlier than 3
months after first vaccination.
The booster vaccination should
preferably coincide with the next
scheduled visit (ie, Visit 7 or Visit 8
for the majority of participants).
Follow-up after the booster
vaccination will be minimally 6
months.
Objectives of the open-label phase
are updated accordingly. The open-
label phase will include 3 study
cohorts (2-dose schedule cohort,
1-dose schedule cohort, and booster
schedule cohort).
Updates to statistical analysis was
made:
- comparison of the 2-dose cohort
with the 1-dose cohort will be
performed when all active
participants have completed their
Visit 8 or discontinued earlier.
- Comparison of the 2-dose cohort
with the booster cohort will be
performed at the time of the end-of-
study analysis.

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Section number 
and Name
Description of Change 
Brief Rationale
6.4 Unblinding and Open-label 
Phase 
7.1 Discontinuation of Study 
Vaccination  
10.1 Appendix 1: Abbreviations 
Capillary leak syndrome (CLS) was 
added to the list of reasons for the 
discontinuation of the 
Ad26.COV2.S vaccine. 
Based on the emerging data
following use of the Ad26.COV2.S
vaccine, CLS has been identified as
a contraindication for the use of
Ad26.COV2.S vaccine.
8.3.1 Time Period and Frequency
for Collecting Adverse Event,
Medically-attended Adverse Event,
Adverse Event of Special Interest,
and Serious Adverse Event
Information
Figure 4 was corrected by adding
AEs and SAEs that are related to
study procedures or that are related
to non-investigational sponsor
products and the corresponding
footnote was corrected: deleted
section of footnote (a) and added
this as new footnote (b).
Correction
5.1 Inclusion Criteria for the
Double-Blind Phase and for Newly
Enrolled Participants in the Open-
Label Phase
5.2 Exclusion Criteria for the
Double-Blind Phase and for Newly
Enrolled Participants in the Open-
Label Phase
Added that the eligibility criteria in
Section 5 are specific for the
double-blind phase and the newly
enrolled 
participants 
in 
the
open-label phase and that eligibility
criteria for open-label and booster
vaccination are described in Section
6.4 and 6.5, respectively.
Clarification on eligibility criteria
for pregnant women throughout the
different phases of the study, on
request of PEI (Paul-Ehrlich-
Institut, Germany)
1.3.5 Participants with a Suspected
AESI
8 STUDY ASSESSMENTS AND
PROCEDURES
The 
volume 
of the 
clinical
laboratory blood sample (whole
blood) taken at AESI Day 1 and Day
29 has been corrected; 15 mL
instead of 12 mL of blood will be
collected at each of the visits.
Correction
10.2 Appendix 2: Clinical
Laboratory Tests
For the clinical evaluation of
suspected AESIs, added that it is
upon discretion of the sponsor that
all or some of the coagulation-
related assays may be conducted on
the stored pre-vaccination sample
and on the AESI samples.
Added that, as part of investigation
of any 
AESI, samples from
appropriate 
controls 
(from
vaccinated participants who did not
experience an AESI) within the
study could be used for coagulation-
related assays.
Clarification

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Section number 
and Name
Description of Change 
Brief Rationale
1.3.4 Participants With (Suspected) 
COVID-19 
8.1.2 Procedures in the Event of 
(Suspected) COVID-19 
Clarification was added that for 
participants with a positive test
result for SARS-CoV-2 infection, a
study visit will be conducted 28 days
after symptom onset (ie, at the
COVID-19 Day 29 visit) to assess
the clinical course of the infection.
Clarification
1.3.5 Participants with a Suspected 
AESI 
Clarification was added that if an 
AESI is reported to the investigator,
more than 28 days after the onset of
the event, the AESI Day 29 visit will
therefore become redundant and
does not need to be performed.
Clarification
1.3.5 Participants with a Suspected
AESI
2.3.1 Risks Related to Study
Participation
The naming ‘Janssen Adjudication
Committee’ was corrected to ‘AESI
Adjudication 
Committee’, 
in
alignment with other places in the
protocol.
Consistency throughout protocol
1.3.5 Participants with a Suspected
AESI
8.2.4 Clinical Laboratory
Assessments
It is clarified that also in the event of
thrombocytopenia, 
laboratory
assessments 
(to be performed
locally) are required to facilitate
diagnosis and determine treatment
options, including but not limited to
platelet count and anti-PF4 tests.
It is clarified that all local laboratory
results need to be encoded in the
electronic case report form (eCRF),
including platelet counts. Low
platelet counts are to be recorded as
suspected 
AESI
(thrombocytopenia).
Clarification
1.1 Synopsis 
11 REFERENCES  
The reference to the Brighton
Collaboration case definition of
thrombotic 
events 
and
thrombocytopenia was updated.
Update
1.3.1 All Participants 
Added a dot in the Early Exit
column of the Schedule of Activities
for recording of MAAEs, (S)AEs
and concomitant therapies, for
consistency with Section 8.3.1
Correction
5.1 Inclusion Criteria for the 
Double-Blind Phase and for Newly 
Enrolled Participants in the Open- 
Label Phase 
Participant is ≥18 to <60 years or
≥60 years of age on the day of
signing the ICF. Vaccine allocation
in each age group may be different
Age limit for individuals that
receive the authorized
Ad26.COV2.S vaccine varies

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Section number 
and Name
Description of Change 
Brief Rationale
per country based on national 
recommendation 
amongst countries based on
national recommendations.
Throughout the protocol 
Minor errors and inconsistencies
were 
corrected, 
and 
minor
clarifications were added throughout
the protocol.
Correction of minor errors and
inconsistencies. Addition of minor
clarifications.
Amendment 5 (6 May 2021)
Overall Rationale for the Amendment: This amendment has been created to include additional
safety measures due to reports of adverse events following use of the Ad26.COV2.S vaccine under
emergency use authorization in the US, suggesting an increased risk of thrombosis combined with
thrombocytopenia. Based on this, thrombosis with thrombocytopenia syndrome (TTS), which is a
very rare event, will be followed in this protocol as adverse event of special interest (AESI) that
needs to be reported to the sponsor within 24 hours of awareness. In addition, the protocol has
been adjusted to align with the latest vaccine risk language.
Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
1.3.1 All Participants 
1.3.2 Open-label Unblinding Visit 
1.3.5 Participants with a Suspected 
AESI 
2.3.1 Risks Related to Study 
Participation  
2.3.3 Benefit-Risk Assessment of 
Study Participation  
3 OBJECTIVES AND 
ENDPOINTS  
4.1 Overall Design  
6.4 Unblinding and Open-label 
Phase 
6.10 Prestudy and Concomitant
Therapy
7.1 Discontinuation of Study
Vaccination
8 STUDY ASSESSMENTS AND
PROCEDURES
8.2.4 Clinical Laboratory
Assessments
8.3 Adverse Events, Serious
Adverse Events, Medically-
attended Adverse Events, Adverse
Events of Special Interest, and
Other Safety Reporting
8.3.1 Time Period and Frequency
for Collecting Adverse Event,
Medically-attended Adverse Event,
Adverse Event of Special Interest,
TTS will be considered an AESI. 
Follow-up assessments will be 
performed in the event of a 
suspected AESI. In addition, blood 
samples will be collected for a 
baseline assessments of platelet 
count and storage for future 
coagulation-related testing. 
Emerging data following use of the
Ad26.COV2.S vaccine under
emergency use authorization in the
US suggest an increased risk of
thrombosis combined with
thrombocytopenia, with onset of
symptoms approximately 1-2 weeks
after vaccination. Therefore,
additional reporting and data
collection procedures are
implemented to follow-up
thrombotic events and
thrombocytopenia and identify
cases of TTS.

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Section number 
and Name
Description of Change 
Brief Rationale
and Serious Adverse Event
Information
8.3.2 Method of Detecting Adverse
Events, Medically-attended
Adverse Events, Adverse Events of
Special Interest, and Serious
Adverse Events
8.3.3 Follow-up of Adverse Events,
Medically-attended Adverse
Events, Adverse Events of Special
Interest, and Serious Adverse
Events
8.3.7 Adverse Events of Special
Interest
8.3.7.1 Thrombosis with
Thrombocytopenia Syndrome
9.2.4 Safety (Safety Subset)
9.7 Safety Analysis
10.2 Appendix 2: Clinical
Laboratory Tests
10.3.6 Committees Structure
10.4 Appendix 4: Adverse Events,
Serious Adverse Events, Adverse
Events of Special Interest,
Medically-attended Adverse
Events, Product Quality
Complaints, and Other Safety
Reporting: Definitions and
Procedures for Recording,
Evaluating, Follow-up, and
Reporting
10.4.5 Procedures
10.13 Appendix 13: TTS AESI
Form
10.14 Appendix 14: Thrombotic
Events to be Reported as Suspected
AESIs
1.1 Synopsis 
1.3.2 Open-label Unblinding Visit 
4.1 Overall Design  
4.2 Scientific Rationale for Study 
Design  
6.4 Unblinding and Open-label 
Phase 
8.1.4 Immunogenicity Assessments
10.2 Appendix 2: Clinical
Laboratory Tests
A blood sample for humoral 
immunogenicity and sero- 
confirmation of SARS-CoV-2
infection should be taken at the
unblinding visit except when the
previous sample was taken within 5
days of the visit.
To decrease the blood sampling
burden for participants.
1.3.1 All Participants 
The Day 57 visit will be a phone 
call visit except for participants 
who will be vaccinated on this day
or who are part of the
immunogenicity subset.
To decrease the visit burden for
participants.

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Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
1.3.2 Open-label Unblinding Visit 
4.1 Overall Design  
6.1 Study Vaccines Administered 
6.4 Unblinding and Open-label 
Phase 
8.8 Assessment and Procedures 
After Emergency Use 
Authorization and Implementation
of Protocol Amendment 4
10.3.3 Informed Consent Process
The schedule for the unblinding 
visit was updated to clarify the 
procedures to be performed when 
vaccination takes place at a later 
date than unblinding. 
Although it is recommended that
the unblinding and vaccination
occur at the same time, due to the
study vaccination pause, there may
be a delay between the date of
unblinding and date of vaccination
of some participants in the open-
label phase.
2.3.1 Risks Related to Study 
Participation  
Side effects were updated to 
include injection site pain and 
nausea. It has been clarified that 
anaphylaxis is considered an
important identified risk.
To align with the vaccine’s risk
language. Added anaphylaxis as
identified risk.
6.1 Study Vaccines Administered 
Placebo is now correctly classified 
as an Investigational Medicinal
Product instead of a Non-
Investigational Medicinal Product.
Correction of an error
1.3.1 All Participants 
1.3.2 Open-label Unblinding Visit 
2.3.1 Risks Related to Study 
Participation  
6.4 Unblinding and Open-label 
Phase 
7.1 Discontinuation of Study 
Vaccination  
8.3.5 Pregnancy  
It has been further clarified that 
participants who become pregnant
during the open-label phase and
previously received placebo during
the double-blind phase may be
vaccinated with Ad26.COV2.S
(single-dose regimen), if the
investigator considers that the
potential benefits outweigh the
potential risks.
For clarification purposes.
8.3.1 Time Period and Frequency 
for Collecting Adverse Event, 
Medically-attended Adverse Event,
Adverse Event of Special Interest,
and Serious Adverse Event
Information
A diagram on the safety reporting 
process is added for clarity. 
Additional clarification per health
authority request.
Throughout the protocol 
Minor grammatical, formatting and 
spelling changes or clarifications 
were made.
Minor errors and unclarities were
noted.

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Status: Approved,  Date:  27 April 2022
Amendment 4 (12 March 2021)
Overall Rationale for the Amendment: The main purpose of this amendment is to outline the
procedures to be followed after Ad26.COV2.S Emergency Use Authorization (EUA) in the United
States (US) and approval of Protocol Amendment 4 by the local Health Authority and the
Independent Ethics Committee/Institutional Review Board (IEC/IRB). A single dose of
Ad26.COV2.S vaccine will be offered to enrolled participants who initially received placebo,
resulting in de facto unblinding of all participants and investigators. In addition, the study design
has been updated to replace the 2-dose placebo arm with a 1-dose active vaccination arm to allow
assessment of the level of efficacy and duration of protection of a 2-dose schedule of
Ad26.COV2.S compared to the 1-dose schedule, as well as a direct comparison of the
immunogenicity of the 2 schedules, whereby the single dose is introduced at different time points.
All participants will be encouraged to remain in the study and continue to be followed for
efficacy/effectiveness, safety and immunogenicity.
The changes made to the clinical protocol of study VAC31518COV3009 are listed below,
including the rationale of each change and a list of all applicable sections.

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Status: Approved,  Date:  27 April 2022
Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
1.2 Schema 
1.3.2 Open-label Unblinding Visit 
(added) 
2.1 Study Rationale (added) 
2.3.3 Benefit-Risk Assessment of 
Study Participation 
4.1 Overall Design4.2 Scientific 
Rationale for Study Design  
5.5 Criteria for Temporarily 
Delaying Administration of Study 
Vaccination 
6.1 Study Vaccines Administered 
6.2 Preparation/Handling/Storage/ 
Accountability 
6.3 Measures to Minimize Bias: 
Randomization and Blinding 
6.4 Unblinding and Open-label 
phase (added) 
6.7 Continued Access to Study 
Vaccine After the End of the Study
8.1.3 Efficacy Assessments
8.1.4 Immunogenicity Assessments
8.3.1 Time Period and Frequency
for Collecting Adverse Event,
Medically-attended Adverse Event,
and Serious Adverse Event
Information
8.3.2 Method of Detecting Adverse
Events, Medically-attended
Adverse Events, and Serious
Adverse Events
8.8Assessment and Procedures
After Emergency Use
Authorization and Implementation
of Protocol Amendment 4
9.5.1 Primary Endpoint Evaluation
9.9Analyses for cohort unblinded
due to administration of an
authorized/licensed COVID-19
vaccine (Double-blind Phase)
10.2 Appendix 2: Clinical
Laboratory tests
10.3.3 Informed Consent Process
10.3.8Data Quality Assurance
An unblinding visit will be 
introduced for all participants who 
have already received 
Ad26.COV2.S or placebo. At the 
unblinding visit, participants who 
initially received placebo will be 
offered a single dose of
Ad26.COV2.S vaccine. Upon 
unblinding, all participants will 
enter the open-label phase of the 
study.
Before the actual participant 
unblinding, all of the previously 
available data should be complete 
and accurate in the participant’s 
eCRF. 
Relevant sections were updated 
regarding the open-label phase.
As 1 dose of the vaccine is highly
efficacious against severe disease,
hospitalization, and death, it is
considered ethical to offer 1 dose of
the active vaccine to the placebo
controls in this study.
Investigators will be encouraged to
follow health authority guidelines
on prioritization of immunization.
All participants will be counselled
to continue practicing other public
health/preventive measures that
were introduced at the start of this
pandemic (eg, social distancing,
face masks, frequent hand
washing), in compliance with local
and national guidelines.

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Status: Approved,  Date:  27 April 2022
Section number 
and Name
Description of Change 
Brief Rationale
Schedule of Activities 
1.3.1 All participants 
1.3.2 Open-label Unblinding Visit 
(added) 
8.1.2 Procedures in the Event of 
(Suspected) COVID-19 
8.1.3 Efficacy Assessments 
8.1.4 Immunogenicity Assessments 
8.3.2 Pregnancy Testing 
8.8Assessment and Procedures 
After Emergency Use 
Authorization and Implementation 
of Protocol Amendment 4 
10.2 Appendix 2: Clinical 
Laboratory Test 
The unblinding visit should be 
scheduled as soon as reasonably 
practicable and preferably no later 
than 2 months following EUA in 
the US and approval of Protocol 
Amendment 4 by the local Health 
Authority and the Independent 
Ethics Committee/Institutional 
Review Board (IEC/IRB). At the
unblinding visit, participants will 
have a blood draw, nasal swab, 
body temperature and urine 
pregnancy test (for participants of 
childbearing potential who will 
receive vaccination). 
A Schedule of Activities 1.3.2 was 
added for the unscheduled
unblinding visit, which can be 
combined with the next scheduled 
visit, if possible, without 
duplicating any procedures. 
The unblinding visit will be
scheduled to inform all participants
about their study vaccine allocation
as well as to offer placebo recipients
Ad26.COV2.S after EUA in the US
and 
approval 
of 
Protocol
Amendment 4 by the local Health
Authority and the IEC/IRB.
Taking blood samples and nasal
swabs from all participants will
allow the comparison of efficacy
and immunogenicity results in a
placebo-controlled manner up to the
point of the unblinding visits, as well
as having a new baseline read-out
for the remainder of the study.
The additional pregnancy test is to
rule 
out 
pregnancy 
prior 
to
vaccinating 
any participant 
at
unblinding visit. Participants who
are 
pregnant 
and 
previously
received placebo during the double-
blind phase may be vaccinated, if
allowed by local regulations for
emergency use of the vaccine.
1.1 Synopsis 
1.2 Schema 
4.1 Overall Design  
4.2 Scientific Rationale for Study 
Design  
5.5 Criteria for Temporarily
Delaying Administration of Study 
Vaccination  
6.1 Study Vaccines Administered 
6.3 Measures to Minimize Bias:
Randomization and Blinding
6.4 Unblinding and Open-label
phase (added)
9.3 Populations for Analysis
A single-dose active vaccination 
regimen was introduced in the 
study to replace the 2-dose placebo 
regimen. 
Newly enrolled participants will be 
randomized 1:1 to the 1- or 2-dose 
regimen.
To ensure the direct comparison of
the immunogenicity of the 2
Ad26.COV2.S dosing schedules
(1 dose vs. 2 dose) in the open-label
phase of the study.
To ensure completion of target
sample size.

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Status: Approved,  Date:  27 April 2022
Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
3 OBJECTIVES AND 
ENDPOINTS  
9.8 Interim Analysis and 
Committees 
For double-blind phase, following 
changes were made: 
 
One 
secondary 
efficacy 
endpoint was added. 
 
The 
endpoints 
for
asymptomatic infection were 
clarified regarding timepoints
at which serologic conversion
will be evaluated.
 
Two 
new 
exploratory 
endpoints were added to gather 
more information regarding
the efficacy against variants.
This change will allow for formal
testing and reporting of the
secondary endpoint counting cases
from 28 days post-vaccination as an
additional condition for success.
Clarification
To gather information regarding
efficacy against variants.
1.1 Synopsis 
3 Objectives and Endpoints 
4.1 Overall Design  
6.3 Measures to Minimize Bias: 
Randomization and Blinding 
6.4 Unblinding and Open-label
phase (added) 
9.1 Statistical Hypotheses 
9.2.1 Efficacy (Total Sample Size) 
9.2.2 Immunogenicity Subset 
9.3 Populations for Analysis Sets 
9.5.1 Primary Endpoint Evaluation 
for the Double-Blind Phase  
9.5.2 Secondary Endpoints for the 
Double-blind Phase 
9.5.3 Analyses for the Open-label
Phase 
9.6 Immunogenicity Analyses 
9.8Interim Analysis and 
Committees 
Objectives were added for the 
open-label phase of the study. 
All data will be analyzed separately 
from the point of unblinding.
Text was added to indicate that the
SAP for the open-label part,
including the detailed objectives,
and endpoints, and inferential
analyses, will be provided to
regulatory authorities prior to the
primary analysis of efficacy of the
2-dose schedule versus placebo in
the double-blind phase.
Text was added to clarify that a
superiority evaluation will be done
for the primary objective of the
open-label phase using a null
hypothesis of relative VE=0%. An
interim analysis may be performed
using group sequential
methodology. All details regarding
the analysis will be specified in the
SAP.
Text was added to indicate that the
final analysis of the open-label
phase will occur when all active
participants have completed Visit 8
or discontinued earlier.
Immunogenicity analyses for the
open-label phase were added.
The study design changed from
double-blind placebo-controlled to
open-label 1-dose versus 2-dose
regimen.

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Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
4.1 Overall Design  
9.5.1 Primary Endpoint Evaluation 
for Double-blind Phase 
Added text to clarify that for any 
case definition to be considered for
classification of COVID-19 cases,
there needs to be at least one SARS-
CoV-2 
positive 
RT-PCR 
or
molecular test result from any
available respiratory tract sample
(eg, nasal swab sample, sputum
sample, throat swab sample, saliva
sample) that is confirmed by the
central laboratory. If there will be
delay in availability of the results, a
sensitivity 
analysis 
may 
be
performed using all RT-PCR or
molecular test result, regardless of
the confirmation by the central
laboratory.
Clarification
1.1 Synopsis 
2.3.1 Risks Related to Study 
Participation  
3 Objectives and Endpoints 
8.1.3 Efficacy Assessments 
8.1.3.1 Case Definition for 
Moderate to Severe/Critical 
COVID-19 
8.1.3.6 Clinical Severity 
Adjudication Committee 
10.3.6 Committees Structure 
The Clinical Evaluation Committee 
is replaced by the Clinical Severity 
Adjudication Committee. Text 
related to Clinical Severity 
Adjudication Committee was 
updated. 
Deletion of the exploratory
endpoint relating to evaluation of
the occurrence, severity, and
duration of COVID-19 episodes by
Clinical Evaluation Committee.
To align with study
VAC31518COV3001, the Clinical
Evaluation Committee is replaced
by the Clinical Severity
Adjudication Committee which will
evaluate and adjudicate COVID-19
cases.
6.3 Measures to Minimize Bias: 
Randomization and Blinding 
6.4 Unblinding and Open-label 
Phase (added) 
6.7 Continued Access to Study 
Vaccine After the End of the Study  
Additional changes made to allow 
unblinding and simultaneous 
participation in an Expanded 
Access Program or a phase 3B 
study (eg, Sisonke/TOGETHER in 
South Africa).
To allow participants in an
Expanded Access Program or Phase
3B study for Ad26.COV2.S, to
continue to be followed in
VAC31518COV3009.
1.3.2 Open-label Unblinding Visit 
(added) 
8.2.3 Pregnancy Testing 
8.8Assessment and Procedures 
After Emergency Use 
Authorization and Implementation 
of Protocol Amendment 4 
10.2 Appendix 2: Clinical 
Laboratory Test 
Added an additional urine 
pregnancy test for participants of 
childbearing potential who will 
receive active vaccination at the
time of unblinding visit.
Participants who are pregnant and
previously received placebo during
the double-blind phase may be
vaccinated, if allowed by local
regulations for emergency use of
the vaccine.
To rule out pregnancy prior to
vaccinating any participant at
unblinding visit.
1.3 Schedule of Activities 
5.2 Exclusion Criteria 
6.4 Unblinding and Open-label 
Phase (added) 
Exclusion criterion 3 has been 
modified to allow 
 
injectable corticosteroids for 
local use. 
 
non-immunomodulating 
monoclonal antibodies 
These therapies will also be allowed 
during the open-label phase.
Clarification that injectable
corticosteroids for local use are
allowed as they are not systemic
corticosteroids
Clarification that non-
immunomodulating monoclonal
antibodies are allowed.

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Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
1.3.1 All Participants 
1.3.2 Open-label Unblinding Visit 
(added)
2.3.1 Risks Related to Study
Participation
2.3.3 Benefit-Risk Assessment of
Study Participation
4.1 Overall Design
8.3.2 Method of Detecting Adverse
Events, Medically-attended
Adverse Events, and Serious
Adverse Events
8.8Assessment and Procedures
After Emergency Use
Authorization and Implementation
of Protocol Amendment 4
Changes previously implemented in 
a local amendment are now 
included in the global amendment. 
To align the Global version of the
protocol with a local protocol
version.
1.3 Schedule of Activities
8STUDY ASSESSMENTS AND
PROCEDURES
Note was added that the baseline
SIC should be completed prior to
the first vaccine administration and
further if a participant is unable to
complete the SIC, the reason for
missing should be recorded in the
eCRF.
If the baseline SIC is not
completed, no eCOA scales will be
triggered.
1.3 Schedule of Activities
8STUDY ASSESSMENTS AND
PROCEDURES
Clarifications have been added to
the "Closure of the COVID-19
episode" regarding collection of
nasal swabs, saliva samples and
SIC.
Clarification
6.3 Measures to Minimize Bias:
Randomization and Blinding
6.4 Unblinding and Open-label
Phase
7.1 Discontinuation of Study
Vaccination
Wording was added to differentiate
between the general unblinding
after EUA in the US and approval
of Protocol Amendment 4 by the
local Health Authority and IEC/IRB
of Ad26.COV2.S and the
unblinding requested previously by
participants in order to receive a
licensed COVID-19 vaccine.
Clarification and alignment.
6.9Prestudy and Concomitant
Therapy
It was added that receipt of any
COVID-19 vaccination (outside the
study) should be recorded at any
timepoint during the study.
Clarification and alignment.
1.3 Schedule of Activities
6.9Prestudy and Concomitant
Therapy
Clarification has been added that
prestudy therapies linked to
inclusion and exclusion criteria (eg,
flu vaccine) should be recorded.
Clarification.

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Section number 
and Name
Description of Change 
Brief Rationale
1.3 Schedule of Activities 
Window period of Visit 7 was 
modified to Day -106 to Day +28. 
Visit Timing references were
changed from Vaccination 2 to
Visit 4 and Visit day/week
references were also changed from
Vaccination 2 to Day 57.
Text was added to the schedule of
activities 1.3.1 to accommodate the
changes for participants who will
be administered a single-dose in the
open-label phase.
To unblind a majority of the
participants at a scheduled visit and
enable the unblinding as soon as
possible.
To clarify the timing of visits in the
open-label phase of the study.
1.1 Synopsis 
1.3 Schedule of Activities 
4.1 Overall Design 
8 Study Assessments and 
Procedures 
Updated the twice weekly eCOA 
assessments to occur until 
completion of Visit 8 (triggering of
final analysis of the open-label
phase).
To ensure that all participants have
1 year of eCOA assessments.
5.1 Inclusion Criteria 
It was clarified in inclusion 
criterion 9 that participants with
visual impairment are eligible and
may have caregiver assistance in
completing the eCOA
questionnaires.
Clarification

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Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
4.1 Overall Design 
9.1Statistical Hypotheses 
9.2.1 Efficacy (Total Sample Size)
9.2.4 Safety (Safety Subset)
9.5 Efficacy Analyses
9.5.1 Primary Endpoint Evaluation 
for the Double-blind Phase 
9.5.1.1 Study Monitoring 
9.6 Immunogenicity Analyses 
9.6.1 Immunogenicity Subset 
9.8Interim Analysis and 
Committees 
10.1 Appendix 1: Abbreviations 
The assumptions for sample size 
were modified to delete reference to 
target number of events (TNE). 
The sequential probability ratio test
(SPRT) was removed.
Target enrollment was updated to
“approximately” 30,000 and text
was added that up to 10% of
additional participants may be
recruited to partially compensate
for increased fraction unblinded
prior to unblinding visit and/or
increased seroprevalence rates
and/or drop-outs.
Text was added/deleted to indicate
that interim testing would not be
conducted on double-blind data,
and that the primary analysis of the
double-blind data would occur
when at least 90% of participants
have reached the unblinding visit.
Monitoring for non-efficacy and
efficacy was removed from the
double-blind phase.
Text was added to clarify that every
effort will be made to reach a target
of 6,000 participants in the safety
subset before unblinding.
A 1-dose vs 2-dose immunogenicity
assessment was added.
To update the analysis as
appropriate for the change to an
open-label design.
9.8Interim Analysis and 
Committees 
The role ofthe IDMC was 
modified. 
To clarify that IDMC will oversee
safety and perform harm
monitoring during double-blind and
open-label phase. Also, to clarify
that IDMC will no longer perform
efficacy monitoring, as the analysis
of the double-blind phase is no
longer event driven but will occur
when at least 90% of the
participants have completed their
unblinding visit.
10.2 Appendix 12: Risk Factor 
Assessment 
Updated the assessment form to 
change any references to 2020 to 
“the near future.”
Deletion of Questionnaire 2.
To extend the data collection
period, as the study is still ongoing.
Questionnaire 2 is not applicable;
the baseline version is repeated at
post-baseline timepoints.

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Section number 
and Name
Description of Change 
Brief Rationale
Throughout the protocol 
Minor errors and inconsistencies 
were corrected, and minor 
clarifications were added 
throughout the protocol. 
Reference to “double-blind”/ 
“double-blind phase” and “open- 
label”/ “open-label phase” were 
made as applicable.
“PCR” was clarified to “RT-PCR,”
where applicable.
Correction of minor errors and
inconsistencies. Minor
clarifications are made. Alignment
across sections in the protocol
Ensure clarity where timing or
procedures are specific to one phase
of the study.
Amendment 3 (18 December 2020)
Overall Rationale for the Amendment: The main purpose of this amendment is to outline the
procedures to be followed in the event that an investigator receives a request to unblind study
participants who may become eligible to receive an authorized/licensed COVID-19 vaccine
if/when these become available. The purpose is to ensure (1) that the participants are informed that
there is no data on the safety of receiving two different COVID-19 vaccines, (2) that in the event
the participant is unblinded, no further study vaccination will be permitted, (3) that unblinded
participants will continue to be followed in this study in line with the Schedules of Activities, and
that safety, efficacy, and immunogenicity evaluations will continue to be performed, although the
data will be analyzed separately from the point of unblinding.
The changes made to the clinical protocol of study VAC31518COV3009 are listed below,
including the rationale of each change and a list of all applicable sections.
Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
6.3 Measures to Minimize Bias:
Randomization and Blinding
6.6 Continued Access to Study
Vaccine After the End of the Study
7.1 Discontinuation of Study
vaccination
9.9 Analyses for cohort unblinded
due to administration of an
authorized/licensed COVID-19
vaccine.
Clarification of procedures for
unblinding of study participants
who may become eligible to receive
an authorized/licensed COVID-19
vaccine during the course of the
study.
To ensure that if participants
become eligible to receive an
authorized/licensed COVID-19
vaccine, they are aware of the
potential options and ramifications,
including the lack of safety data of
the authorized/licensed vaccine in
participants that have received a
1-dose or 2-dose Ad26.COV2.S
vaccine, and that no further study
vaccination will be permitted; that
unblinded participants will continue
to be followed throughout the study
for safety, efficacy and
immunogenicity assessments,
although the data will be analyzed
separately from the point of
unblinding.
7.1 Discontinuation of Study
vaccination
Clarification that study vaccination
will be discontinued in participants
with molecularly confirmed
Clarification

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Section number 
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Description of Change 
Brief Rationale
SARS-CoV-2 infection, regardless
of symptomatic or asymptomatic.
1.1 Synopsis 
3 OBJECTIVES AND 
ENDPOINTS  
8.1.4 Immunogenicity Assessments
psVNA was removed from the 
protocol. 
wtVNA will be used to support the
exploratory immunogenicity 
endpoint. 
Due to lack of sensitivity of the
evaluated psVNA, the assay has
been removed from the protocol
wtVNA is currently only qualified
and not validated and can therefore
not be used to support a secondary
immunogenicity endpoint unless
validated.
5.1 Inclusion Criteria 
Inclusion criterion 4 was updated to 
include a timeframe for criteria a
and b for stable/well-controlled
HIV infection. In addition, it was
clarified that participants with
stable/well-controlled HIV
infection that are on stable ART are
included if nationwide guidelines
require transition from one ART
regimen to another, within a period
of less than 6 months
Clarification
5.2 Exclusion Criteria 
Exclusion criterion 4 updated for 
clarification.
Clarification
Throughout the protocol 
Minor errors and inconsistencies 
were corrected, and minor 
clarifications were added 
throughout the protocol.
Correction of minor errors and
inconsistencies. Minor
clarifications are made.
Amendment 2 (27 November 2020)
Overall Rationale for the Amendment: The amendment is written to clarify that all participants
that have a reverse-transcriptase polymerase chain reaction (RT-PCR) positive finding for
SARS-CoV-2 from any source, even if asymptomatic, will be followed until there are two
consecutive negative PCRs. In addition, text in relation to biomarker evaluation of RNAseq
analyses (PAXgene tube) is deleted, and based on Health Authority request, text in exclusion
criterion #7 was corrected and text regarding United Kingdom (UK) specific self-swabbing test
was deleted. Finally, text was added to introduce the utilization of tokenization and matching
procedures, for United States (US) participants only, to obtain participant's medical data 5 years
prior to enrollment of the participant until 5 years after study completion from consenting
participants.
The changes made to the clinical protocol of study VAC31518COV3009 are listed below,
including the rationale of each change and a list of all applicable sections.
Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
1.3.2 Participants With (Suspected) 
COVID-19 
4.1 Overall Design  
Clarified that all participants that 
have a RT-PCR positive finding for 
SARS-CoV-2 from outside the 
study, even if asymptomatic, will
To ensure safety of staff and other
persons coming in contact with the
infected participant.

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Section number 
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Description of Change 
Brief Rationale
8 Study Assessments and 
Procedures and associated 
subsections
10.3.10 Source Documents
be followed until there are two
consecutive negative PCRs.
1.1 Synopsis 
1.3.1 All Participants 
1.3.2 Participants With (Suspected) 
COVID-19 
3 Objectives and Endpoints 
4.1 Overall Design  
4.2 Scientific Rationale for Study
Design
6.3 Measures to Minimize Bias:
Randomization and Blinding
8 Study Assessments and
Procedures and associated
subsections
9.5.4 Other Analyses
10.2 Appendix 2: Clinical
Laboratory Tests
10.3.4 Data Protection
Text in relation to the evaluation of 
biomarker RNAseq analyses 
(PAXgene tube) is deleted and 
subsequently, the total amount of 
blood drawn from the participants 
has been adjusted.
Deletion. Collection of biomarker
data from participants in Study
VAC31518COV3001 is deemed
sufficient, hereby the assessment
was taken out from this study.
1.1 Synopsis 
2.1 Study Rationale 
2.3.3 Benefit-Risk Assessment of 
Study Participation  
4.1 Overall Design  
8.1.4 Immunogenicity Assessments
9.2.2 Immunogenicity Subset
It has been clarified that Stage 2 
will enroll participants with and
without comorbidities and
immunogenicity subset will be
enrolled in Stage 2 only.
Clarification
5.2 Exclusion Criteria 
6.8 Prestudy and Concomitant 
Therapy  
7.1 Discontinuation of Study 
Vaccination  
The specification of ‘(>10 days)’ 
when referring to the chronic use of 
systemic corticosteroids has been 
removed from the exclusion 
criterion 3 and aligned throughout. 
To remove ambiguity as within the
same exclusion criterion 3 b
substantial immunosuppressive
steroid dose is defined as ≥2 weeks
of daily receipt of 20 mg of
prednisone or equivalent
6.9 Study Vaccination Pausing 
Rules for Stage 1 
10.3.6 Committees Structure 
Text was added to clarify that if 
there will be any study pause, the
Sponsor will submit a request to
restart the study with pertinent data
to the Health Authorities as a
request for a substantial
amendment, as required by the local
regulations.
Upon Health Authority feedback
1.3.1 All Participants 
1.3.2 Participants With (Suspected) 
COVID-19 
8.1.2 Procedures in the Event of 
(Suspected) COVID-19 
8.5 Medical Resource Utilization 
10.8 Appendix 8: 
Medically-attended COVID-19 
(MA-COV) Form  
The MA-COV form has been 
updated to also capture additional 
individual signs and symptoms, 
including clinical or radiological 
evidence of pneumonia, 
hyperinflammatory syndrome, and
if the oxygen saturation for a
participant is considered clinically
abnormal but >93% (corrected for
altitude).
In addition, some clarifications
were added to the form and it is
clarified that the form may also be
To ensure collection of all
necessary information in order to
determine the severity of COVID-
19 per the case definitions and
clarification purposes.

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Section number 
and Name
Description of Change 
Brief Rationale
completed by the study site
personnel.
1.1 Synopsis 
5.1 Inclusion Criteria 
5.2 Exclusion Criteria 
Gestational diabetes has been 
removed from the list of 
comorbidities (or risk factors) that 
might be associated with increased 
risk of progression to severe 
COVID-19.
Gestational diabetes is not
applicable in the current study
VAC31518COV3009 as pregnant
women are not allowed to
participate in the study.
1.1 Synopsis 
1.3.1 All Participants 
1.3.2 Participants With (Suspected) 
COVID-19 
4.1 Overall Design  
8.1.2 Procedures in the Event of 
(Suspected) COVID-19 
8.6 Risk Factor Assessment 
9.4 Participant Information  
10.12 Appendix 12: Risk Factor 
Assessment 
It is clarified that, besides being 
interviewed on characteristics 
related to current work situation, 
living situation, and community 
interactions, as specified in
Appendix 12, prior to vaccination
on Day 1, they will be asked about
any changes related to these
characteristics at Day 71 post-
vaccination 1 followed by 6 months
and 1 year post-vaccination 2, and
at COVID-19 Day 3-5. In addition,
it was also clarified that the risk
factor data initially collected at
screening from the participants,
before the implementation of this
amendment will also be used for the
planned risk factor analysis.
Clarification on when participants
will be interviewed on additional
characteristics that will be used for
risk factor analysis.
5.2 Exclusion Criteria 
Chronic kidney disease has been 
removed and participant on 
hemodialysis has been added to the 
examples of clinical conditions 
expected to have an impact on the
immune response of the study
vaccine.
There is evidence that hemodialysis
has a negative impact on the
immune response elicited by the
vaccination.
5.2 Exclusion Criteria 
6.8 Prestudy and Concomitant 
Therapy  
Exclusion criterion 7 and text for 
Prestudy therapy was updated to 
remove remdesivir and to clarify 
that the use of investigational
Immunoglobulin (Ig),
investigational monoclonal
antibodies or convalescent serum
are not allowed during the study.
Upon Health Authority feedback
and alignment across
Ad26.COV2.S study protocols
2.3.1 Risks Related to Study 
Participation  
10.4.4 Special Reporting Situations 
It is stated more clearly that 
breastfeeding women are allowed to 
participate in the study. In
alignment with this, exposure to a
sponsor study vaccine from
breastfeeding has been removed
from the list of special reporting
situations.
Breastfeeding is allowed in the
current study VAC31518COV3009.
1.1 Synopsis 
1.3.1 All Participants 
3 Objectives and Endpoints 
4.1 Overall Design
8 Study Assessments and
Procedures
Text was deleted related to UK- 
specific self-swabbing test as these 
will not be performed.
Upon National Institute for Health
Research (NIHR), UK feedback

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Section number 
and Name
Description of Change 
Brief Rationale
8.1.3 Efficacy Assessments and
related subsections
10.2 Clinical Laboratory Tests
1.1 Synopsis 
5.2 Exclusion Criteria 
Clarification has been added that 
the history of Parkinson’s disease,
seizures, ischemic strokes,
intercranial hemorrhage
encephalopathy,
meningoencephalitis is
exclusionary from Stage 1.
Clarification.
5.2 Exclusion Criteria 
It is clarified that participants with 
Guillain-Barré syndrome
(Exclusion criterion 16) and
participants requiring
hospitalization as indicated in
exclusion criterion 17 are excluded
from the study altogether and not
only in Stage 1 of the study.
Correction
5.1 Inclusion Criteria 
Clarifications have been made to 
the inclusion criterion 4, indicating
that Stage 1 participants can have a
condition that is stable and well-
controlled except the ones listed in
exclusion criterion 14 which are
associated with increased risk of
progression to severe COVID-19.
In addition, medication dose for
allowed stable conditions (in all
stages of the study) cannot have
been increased within 12 weeks
prior to vaccination.
Clarification
5.4 Screen Failures 
It has been clarified that 
participants can be rescreened once, 
also when they meet all in- and 
exclusion criteria but the 28-day 
screening period was exceeded. 
To allow participants who were
found eligible to be enrolled in the
study but were not randomized
within the 28-day screening
window to still participate in the
study.
1.1 Synopsis 
2.1 Study Rationale 
4.1 Overall Study Design  
9.8 Interim Analyses and 
Committees 
10.3.6 Committees Structure 
Reference to a possible sample size 
adjustment has been deleted and 
sample size considerations has been 
added. 
Correction: per the
VAC31518COV3009 Amendment
1, the sample size of approximately
30,000 participants was selected
based on available epidemiology
data at the time of Amendment 1
writing.
1.3.1 All Participants 
It is clarified that the diagnostic 
molecular RT-PCR test for SARS-
CoV-2 infection (from nasal swab
taken at baseline) will be performed
at a central laboratory on a
retrospective basis. These baseline
results are not available in real
time, and thus cannot be used to
inform participants at time of
enrollment.
Clarification

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Section number 
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Brief Rationale
1.1 Synopsis 
3 Objectives and Endpoints 
4.1 Overall Design  
It is clarified that molecularly 
confirmed COVID-19 is defined as 
a positive SARS-CoV-2 viral RNA 
result by a central laboratory  
using a PCR-based or other 
molecular diagnostic test. 
For clarification purposes and to
align information included in
Section 8.1.3 which states that
molecular confirmation of SARS-
CoV-2 infection by a central
laboratory will be used for the
analysis of the case definition.
10.3.10 Source Documents 
It has been clarified that source 
documents for any relevant medical 
history and prestudy therapies 
determining eligibility (ie, as
specified in the footnotes to the
Schedule of Activities) of the
participants needs to be collected
To ensure that all necessary
information to properly assess
SAEs (relatedness) is collected.
1.1 Synopsis 
5.2 Exclusion Criteria 
The list of comorbidities (or risk 
factors) that are or might be
associated with an increased risk of
progression to severe COVID-19
has been corrected from
‘uncontrolled human
immunodeficiency virus (HIV)
infection’ to ‘HIV infection’
Correction
1.1 Synopsis 
8.1.3.1 Case Definition for 
Moderate to Severe/Critical 
COVID-19 
10.8 Appendix 8:
Medically-attended COVID-19
(MA-COV) Form
It has been clarified that the 
adjustment according to altitude for
the SpO2 criteria is per the
investigator judgement.
Clarification
8.3.6 Disease-related Events and 
Disease-related Outcomes Not 
Qualifying as Adverse Events or 
Serious Adverse Events 
It has been clarified that (S)AEs 
caused by molecularly confirmed 
SARS-CoV-2 infection will be
removed at the analysis level from
the (S)AE listings and tables and
presented separately.
Alignment across different sections
of the protocol.
1.1 Synopsis 
8.1.4 Immunogenicity Assessments 
The list of immunoassays used in 
support of exploratory endpoints
has been completed
Addition of missing assay.
1.1 Synopsis 
1.3.1 All Participants 
1.3.2 Participants With (Suspected) 
COVID-19 
4.1 Overall Design  
8 Study Assessments and 
Procedures and associated 
subsections 
Term "COVID-19 signs and 
symptoms surveillance" is changed
to "(Suspected) COVID-19
surveillance (symptom check)" and
additional clarification is provided
by adding this to the procedures
followed for participants with
(suspected) COVID-19.
Clarification
1.1 Synopsis 
1.3.1 All Participants 
3 OBJECTIVES AND 
ENDPOINTS  
4.1 Overall Design  
4.2 Scientific Rationale for Study 
Design  
4.2.1 Study-Specific Ethical Design 
Considerations 
Addition of the utilization of 
tokenization and matching 
procedures to obtain medical data 5 
years prior to enrollment of the 
participant until 5 years after the 
participant completed the study 
from consenting participants in the 
US. 
Participant medical data (electronic
health records, claims, laboratory
data from other care settings) prior
to, during and following
participation in the study (real-
world data) is important to obtain in
order to better understand the
impact of prior medical history on
the response to immunization and

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Section number 
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Brief Rationale
8.7 Participant Medical Information 
Prior to, During and After the Study 
(Real-world Data) 
9.5.4 Other Analyses 
10.1 Appendix 1: Abbreviations 
11 REFERENCES  
the impact of immunization on
efficacy and duration of efficacy as
well as adverse events that may
occur during and after completion
of the study. The technique
proposed to obtain this data, ie,
tokenization and matching
procedures, allows for such data to
be obtained without violation of
participant confidentiality. This
collection of real-world data will
only be conducted for consenting
participants from the US where this
technique is feasible
1.1 Synopsis 
8Study Assessments and 
Procedures 
9.3 Populations for Analysis Sets 
Clarified that when the study pause 
has been lifted, efforts will be made 
to still vaccinate a participant if the 
vaccination window is missed due
to the study pause. Clarified that
these participants will not be
excluded from the per protocol
efficacy (PP) and per protocol
immunogenicity (PPI) population
by default for this reason.
Mitigation in case of study pause:
Clarification on out of window
vaccination.
1.1 Synopsis 
1.3.1 All Participants 
6.8 Prestudy and Concomitant 
Therapy  
8.3.1 Time Period and Frequency 
for Collecting Adverse Event, 
Medically-attended Adverse Event, 
and Serious Adverse Event 
Information 
8.3.2 Method of Detecting Adverse 
Events, Medically-attended 
Adverse Events, and Serious 
Adverse Events 
Clarified that if solicited signs and 
symptoms are not resolved within 7
days post-vaccination, the
participant will continue to
complete the e-Diary until Day 29
post-vaccination or until they are
resolved, whichever comes first.
Similarly, the concomitant therapies
will also be collected by the
participants and recorded in the
eCRF until Day 29 post-vaccination
or until they are resolved,
whichever comes first.
Clarification
9.5.2 Secondary Endpoints 
The text about the endpoint of 
molecularly confirmed COVID-19 
cases requiring medical 
intervention has been added. 
Addition: to align the secondary
endpoints described with the
secondary endpoints that are part of
the hypothesis testing.
1.1 Synopsis 
9.3 Populations for Analysis Sets 
PP population has been corrected to 
include seronegative test at Day 71
sample.
Correction
5.2 Exclusion Criteria 
Text has been added to restrict the 
proportion of seropositive
participants in the study.
Clarification
8Study Assessments and 
Procedures 
Clarification has been added that 
visits apart from screening and
vaccination can be performed at
participant's home by the study staff
or designee
Clarification

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Section number 
and Name
Description of Change 
Brief Rationale
8Study Assessments and 
Procedures 
Clarification has been added that in 
case of home visit, assessments that
cannot be delegated to a designee
must be performed by an
appropriate Site staff member via a
phone call or telemedicine.
Clarification
1.3.2 Participants With (Suspected) 
COVID-19 
8.1.2 Procedures in the Event of 
(Suspected) COVID-19
Further clarifications are made to 
the procedures to be followed in
case of (suspected) COVID-19.
Clarification
6.9 Study Vaccination Pausing 
Rules for Stage 1 
8.2 Safety Assessments 
10.1 Appendix 1 Abbreviations 
10.3.6 Committees Structure 
Text has been corrected to remove 
the reference to collaboration
partners, PI and PSRT, as there will
be no collaboration partners
involved and PI review is not
planned.
The safety data will be reviewed by
Sponsor/Sponsor committee, as
applicable and not PSRT.
Correction
1.1 Synopsis 
1.3.1 All Participants 
2.1 Study Rationale 
2.3.1 Risks Related to Study 
Participation  
2.3.3 Benefit-Risk Assessment of 
Study Participation  
4.1 Overall Study Design
8.3.2 Method of Detecting Adverse
Events, Medically-attended
Adverse Events, and Serious
Adverse Events
Text about the equal distribution of 
participants in 2 age groups (≥18 to 
<60 years and ≥60 years of age) in 
Stage 1 and equal distribution of 
first 1000 participants has been 
deleted. 
Based on accumulating safety data
from study VAC31518COV3001,
safety evaluation of approximately
1000 participants without
comorbidities will trigger the
enrolment of participants with and
without comorbidities.
7.1 Discontinuation of Study 
Vaccination  
7.2 Participant 
Discontinuation/Withdrawal From
the Study
Further clarification was added on 
the consent withdrawal by the
participants.
Clarification
1.1 Synopsis 
2.1 Study Rationale 
4.1 Overall Design  
Clarification has been added that 
the enrollment might be stopped if
the primary endpoint will be
reached.
Clarification
2.3.1 Risks Related to Study 
Participation  
5.1 Inclusion Criteria 
11 REFERENCES  
It has been clarified that the use of 
condoms is not considered as an
acceptable contraceptive barrier
method due to the failure rate of
female and male condoms.
Clarification
Title Page 
Study Title has been changed from 
"HORIZON" to "ENSEMBLE 2". 
To clarify that this study is strongly
linked to study
VAC31518COV3001, which is
referred to as the ENSEMBLE
study. To allow harmonization
across our Ad26.COV2.S program
and to assist the public with
associating both studies and,
assisting the public with identifying
an appropriate study site, and

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Section number 
and Name
Description of Change 
Brief Rationale
distinguishing dosing across both
studies.
Title page 
Prepared by line removed. 
To align with internal guidelines on
legal entity to be mentioned on title
page.
Throughout the protocol 
Minor errors and inconsistencies 
were corrected, and minor 
clarifications were added 
throughout the protocol.
Correction of minor errors and
inconsistencies. Minor
clarifications are made.
Amendment 1 (25 September 2020)
Overall Rationale for the Amendment: The amendment is written to adjust the dose level of
Ad26.COV2.S from 1×1011 virus particle (vp)to 5×1010 vp based on data from the first-in-human
(FIH) study VAC31518COV1001, including safety and immunogenicity data from Cohort 1a,
safety data from Cohort 3 and immunogenicity data from the sentinel group  of Cohort 3.
Furthermore, throughout the protocol changes are made in response to the feedback received from
health authorities, partners, and the community. Finally, minor errors and inconsistencies were
corrected throughout the protocol.
The changes made to the clinical protocol of study VAC31518COV3009 are listed below,
including the rationale of each change and a list of all applicable sections.
Section number
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
2.1 Study Rationale
2.2 Background
4.1 Overall Design
4.3 Justification for Dose
4.4 End-of-study Definition
6.1 Study Vaccines Administered
8.1.4 Immunogenicity Assessments
The Ad26.COV2.S dose level has
been changed from 1×1011 vp to
5×1010 vp.
Immunogenicity data from
Cohort 1a and a sentinel
group of Cohort 3 of study
VAC31518COV1001 have
become available. The data
demonstrated that a single
dose of Ad26.COV2.S at a
dose level of 5×1010 vp is
sufficient to induce an
acceptable immune
response that meets
prespecified minimum
criteria: (1) wild-type virus
neutralization assay
(wtVNA)a response rate
(28days post-Dose 1):
lower limit of 95%
confidence interval (CI)
≥65%; (2) T-helper cell
type 1 (Th1)/T-helper cell
type 2 (Th2) response
magnitude ratio: Th1>Th2
within responder population
a psVNA was to be used for the seroconversion criterion, however, the psVNA was not sensitive enough to cover the
range of human responses, hence wtVNA was used instead.

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Brief Rationale
and (3) pseudovirus
(ps)VNA magnitude
associated with protection
in non-human primate
(NHP) studies is induced by
vaccination in humans:
estimated population mean
protection probability
≥40% and lower limit of
95% CI of estimated
population mean protection
probability ≥20%. This
finding was supplemented
with several sensitivity
analyses utilizing ELISA, a
more sensitive psVNA, and
statistical evaluation of
attributed values below the
level of sensitivity of the
original psVNA.
The safety data from
Cohort 1a and Cohort 3 of
the FIH study with the
Ad26.COV2.S 5×1010 vp
dose level were deemed
acceptable. Since all criteria
were met by the 5x1010 vp
dose, the sponsor decided
to use this dose for further
evaluation in the Phase 3
study
VAC31518COV3009.
1.1 Synopsis 
9.5.1 Primary Endpoint Evaluation  
9.5.1.1 Study Monitoring 
The trigger for the evaluation of 
the primary endpoint has been 
modified, adding one condition 
related to the number of COVID- 
19 cases (6) meeting the primary 
endpoint definition of moderate to 
severe/critical COVID-19 in the 
elderly population, that needs to
be met.
In order to ensure the
evaluation of the primary
endpoint provides sufficient
information to assess the
benefit/risk and potentially
support an Emergency Use
Authorization.
2.3.1 Risks Related to Study Participation  
6.8 Prestudy and Concomitant Therapy 
Guidance on the use of 
antipyretics during the study has 
been added. 
To clarify that antipyretics
are recommended post-
vaccination for symptom
relief, as needed.
Prophylactic antipyretic use
is not encouraged.
5.2 Exclusion Criteria 
6.6 Continued Access to Study Vaccine 
After the End of the Study  
6.8 Prestudy and Concomitant Therapy 
Guidance has been added on the 
use of licensed COVID-19
vaccines, when one might become
available, during the study.
Clarification purposes
1.1 Synopsis 
1.3.1 All Participants 
2.3.1 Risks Related to Study Participation  
It has been clarified that the post- 
vaccination observation period at 
the study site will be at least 
30 minutes for the first 1,000 
To align with the number of
participants included in
Stage 1 since the decision
to reduce the post-

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Section number 
and Name
Description of Change 
Brief Rationale
2.3.3 Benefit-Risk Assessment of Study 
Participation  
4.1 Overall Design  
8.3.2 Method of Detecting Adverse Events, 
Medically-attended Adverse Events, and 
Serious Adverse Events
participants (and not 2,000 
participants) and may be decreased 
to at least 15 minutes for the 
remaining participants, if no acute 
reactions are observed.
vaccination follow-up time
at the site will be based on
the planned Day 3 safety
evaluation.
1.1 Synopsis 
1.2 Schema 
2.1 Study Rationale 
4.1 Overall Design  
In Stages 1a and 1b combined, the 
enrollment of participants aged 
≥18 to <40 years will be limited to 
approximately 20% of the total 
study population. The aim of 
having a minimum of 
approximately 25% of recruited 
participants ≥60 years of age has 
been adjusted to 30%. 
The sponsor believes that
Ad26.COV2.S is more
likely to protect against
more severe disease and
progression of infection is
age related with twice the
level of severity in 50-year-
olds compared to 20-year-
olds. The cap of
approximately 20% of
participants 18-40 years
and the aim to enroll a
minimum of approximately
30% elderly participants,
will allow to enroll a more
representative population at
highest risk of severe
disease per the protocol
case definition.
9.2.1 Efficacy (Total Sample Size) 
The time to signal has been 
modified in the sample size 
section. 
To present time to signal
corresponding to the
assumed VE for powering
the study (VE=65%).
1.1 Synopsis 
1.3.1 All Participants 
4.1 Overall Design  
8.7 Baseline and Longitudinal Risk Factor 
Assessment 
9.4 Participant Information  
9.5.3 Exploratory Endpoints 
10.12 Appendix 12: Risk Factor Assessment 
It has been added that additional 
longitudinal characteristics related 
to current work situation, living 
situation, and community 
interactions, from participants who 
consent to this, will be collected 
for risk factor analysis, if allowed 
per local regulations. 
To assess baseline and
longitudinal characteristics
that are potentially useful to
identify the risk of
acquiring COVID-19 which
will be used for the
correlates of protection
analysis.
1.1 Synopsis 
1.3.2 Participants With COVID-19-like 
Signs and Symptoms 
4.1 Overall Design  
8.1.1 Prespecified Criteria for Suspected 
COVID-19 
8.1.2 Procedures in the Event of COVID-19- 
like Signs and Symptoms 
It has been clarified that because 
several of the prespecified criteria 
for suspected COVID-19 overlap 
with vaccine-related 
reactogenicity, investigators' 
clinical judgement is required to 
exclude vaccine-related events. 
To ensure that
vaccine-related events do
not trigger the COVID-19
related follow-up
procedures for mild disease,
to be able to include cases
of moderate disease that
were not classifiable by the
definition and for
simplification and
clarification purposes.
1.1 Synopsis 
2.1 Study Rationale 
4.1 Overall Design  
4.3 Justification for Dose 
Additional rationale for the 
assessment of the 2-dose regimen 
has been added. 
Even though a single-dose
regimen in study
VAC31518COV1001
showed good
immunogenicity, evaluation
of the 2-dose regimen is
still valuable as this

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Brief Rationale
regimen may show a higher
and more durable immune
response.
1.3.2 Participants With COVID-19-like 
Signs and Symptoms 
8.1.2 Procedures in the Event of COVID-19- 
like Signs and Symptoms 
10.2 Appendix 2: Clinical Laboratory Tests 
The sample for sero-confirmation 
of SARS-CoV-2 infection to be 
collected on Day 3-5 in 
participants with COVID-19 like 
signs and symptoms has been 
removed 
It is unlikely to detect
antibodies 3-5 days post
signs and symptoms or a
positive PCR for SARS-
COV-2 infection.
Antibodies will likely be
observed from 7 days post
signs and symptoms
onwards.
1.1 Synopsis 
1.3.1 All Participants 
4.1 Overall Design  
It is clarified that at the time of 
study entry, each participant will 
need to indicate to the study site, 
in case they would get infected
with SARS-CoV-2, the identity
and location of their routine
medical care physician and/or
facility and the identity and
location of where they would
obtain emergency care and
hospitalization if necessary. If this
information is not available, a plan
for where such care could be
obtained should be developed.
To ensure optimal follow
up of participants with
COVID-19.
10.3.3 Informed Consent Process 
Information about the caregiver’s 
consent form has been added.
For clarification purposes.
10.3.8 Data Quality Assurance 
10.3.11 Monitoring 
Source data verification has been 
replaced by review of the source 
data. 
To clarify that source data
verification will not be
done on most of the data.
3 OBJECTIVES AND ENDPOINTS  
An exploratory objective to assess 
the impact of the vaccine on other 
respiratory diseases has been 
added. 
To obtain epidemiology
data of other important
respiratory infections that
may be affected by
COVID-19 circulation.
3 OBJECTIVES AND ENDPOINTS  
A secondary endpoint looking at 
the first occurrence of molecularly 
confirmed, moderate to 
severe/critical COVID-19 with
onset 14 days after the 1st
vaccination has been added.
To allow for a pooled
analysis on this timepoint
across studies.
9.5.1 Primary Endpoint Evaluation 
It has been clarified that the data 
from this study may be pooled 
with data from other ongoing 
efficacy studies. 
To have a more robust data
package in support of
health authority
interactions.
Throughout the protocol 
Minor errors and inconsistencies 
were corrected, and minor 
clarifications were added 
throughout the protocol
Correction of minor errors
and inconsistencies. Minor
clarifications are made.

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11. 
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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Vaccines & Prevention B.V.
Signature: electronic signature appended at the end of the protocol 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD

Signature
User 
Date 
Reason
 
27-Apr-2022
15:38:13
(GMT)
Document Approval
PPD