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 at Different Stages of the Protocol
Sponsor: Janssen Vaccines & Prevention B.V.

CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved, Date: 15 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
Protocol VAC31518COV3001; 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
Status:
Approved
Date:
15 April 2022
EDMS number:
EDMS-RIM-50860, 10.0
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.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved, Date: 15 April 2022
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 7 
This document
Amendment 6 
04 September 2021
Amendment 5 
07 May 2021
Amendment 4 
22 February 2021
Amendment 3 
14 December 2020
Amendment 2 
29 October 2020
Amendment 1 
15 September 2020
Original Protocol 
22 July 2020
Amendment 7 (This document)
Overall Rationale for the Amendment:
Following emergency use authorization (EUA) by the United States (US) Food and Drug
Administration (FDA), the conditional marketing authorization by the European Commission, 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 vaccinations. The final analyses
of the study that described the double-blind phase has been completed and the primary and
secondary objectives have been met. Further efficacy evaluations of the open-label data have
limitations, due to 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, they
received another vaccine), and unblinding (eg, the participants’ knowledge of the number and type
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 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 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 COVD-19 events) and a
second end of study analysis is planned (using passive follow-up of COVID-19 events).The
changes made to the clinical protocol VAC31518COV3001 as part of Protocol Amendment 7 are
listed below, including the rationale of each change and a list of all applicable sections.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
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 Definition  
5.5 Criteria for Temporarily Delaying 
Administration of Study Vaccination 
6.5 Booster Vaccination 
6.10 Prestudy and Concomitant 
Therapy  
8 STUDY 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
8.2 Safety Assessments
8.2.1 Physical Examinations
8.2.2 Vital Signs
8.3.1 Time Period and Frequency for
Collecting Adverse Event, Medically-
attended Adverse Event, Adverse
Events of Special Interest, and Serious
Adverse Event Information
8.10 Assessment and Procedures
Related to Booster Vaccination
9.2.4.2 All Participants
10.2 Appendix 2: Clinical Laboratory
Tests
10.3.6 Committees Structure
10.4.1 Adverse Event Definitions and
Classifications
10.7Appendix 7: MRU Questionnaire
10.8 Appendix 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 by the site at Month 18 and 
Month 24 to document COVID-19 
participant-reported events as (S)AEs 
and MAAEs and to record 
concomitant therapies associated with 
COVID-19. 
eCOA has been decommissioned.
No further booster doses will be
provided.
With the cross-over vaccinations,
the initial double-blind,
randomized, placebo-controlled
design of this study has been
replaced with an open-label
design, where the placebo group
has been lost and received
primary and booster vaccination
(within or outside of the study).
Finally, constant evolution of the
COVID-19 pandemic has
impacted the practical
implementation of a strict
follow-up of new suspected
COVID-19 episodes.
Synopsis 
3 OBJECTIVES AND ENDPOINTS  
9.1 Statistical Hypotheses 
9.7Safety Analysis 
9.8 Analysis of the Open-label Cross- 
over Phase, Open-label Booster 
Vaccination Phase 
The endpoints of the open-label 
cross-over phase and passive 
follow-up phase have been added and 
more clarification on the open-label 
booster phase has been provided. The 
scope and endpoints of the end of 
study analysis have been added. 
To more clearly differentiate
between the endpoints of the
open-label cross-over phase and
the booster phase.
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.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved, Date: 15 April 2022
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. 
Correction of minor errors and
inconsistencies. Addition of
minor clarifications. Alignment
across sections in the protocol.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved, Date: 15 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
Synopsis........................................................................................................................................... 9
Schema.......................................................................................................................................... 36
Schedules of Activities ................................................................................................................... 38
1.3.1. 
Non-immunogenicity or Non-Booster Subset Participants (As of Amendment 7)...................... 38
1.3.2. 
Immunogenicity and Booster Subset Participants...................................................................... 41
1.3.3. 
All Participants (Prior to Amendment 7)..................................................................................... 45
1.3.4. 
Participants With (Suspected) COVID-19................................................................................... 56
1.3.4.1. 
Passive Follow-up (As of Amendment 7)................................................................................ 56
1.3.4.2. 
Active Follow-up (Prior to Amendment 7)................................................................................ 56
1.3.5. 
Participants with a Suspected AESI ........................................................................................... 60
2. 
INTRODUCTION................................................................................................................................ 61
Study Rationale.............................................................................................................................. 65
Background .................................................................................................................................... 67
Benefit-Risk Assessment............................................................................................................... 72
2.3.1 
Risks Related to Study Participation .......................................................................................... 73
2.3.2 
Benefits of Study Participation.................................................................................................... 78
2.3.3 
Benefit-Risk Assessment of Study Participation ........................................................................ 78
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 81
Double-blind Phase of the Study ................................................................................................... 81
Open-label Active Phase................................................................................................................ 87
3.2.1. 
Open-label Cross-over Phase .................................................................................................... 87
3.2.2. 
Open-label Booster Phase ......................................................................................................... 88
Open-label Passive Follow-up Phase............................................................................................ 92
4. 
STUDY DESIGN ................................................................................................................................ 93
Overall Design................................................................................................................................ 93
Scientific Rationale for Study Design........................................................................................... 100
4.2.1. 
Study-Specific Ethical Design Considerations ......................................................................... 101
Justification for Dose.................................................................................................................... 102
End-of-study Definition................................................................................................................. 102
5. 
STUDY POPULATION .................................................................................................................... 103
Inclusion Criteria.......................................................................................................................... 103
Exclusion Criteria......................................................................................................................... 106
Lifestyle Considerations............................................................................................................... 109
Screen Failures............................................................................................................................ 110
Criteria for Temporarily Delaying Administration of Study Vaccination ....................................... 110
6. 
STUDY VACCINATION AND CONCOMITANT THERAPY ........................................................... 111
Study Vaccines Administered ...................................................................................................... 111
Preparation/Handling/Storage/Accountability .............................................................................. 114
Measures to Minimize Bias: Randomization and Blinding........................................................... 115
Unblinding and Open-label Phase ............................................................................................... 117
Booster Vaccination ..................................................................................................................... 118
Study Vaccine Compliance .......................................................................................................... 119
Dose Modification......................................................................................................................... 120
Continued Access to Study Vaccine After the End of the Study ................................................. 120
Treatment of Overdose ................................................................................................................ 120
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved, Date: 15 April 2022
Prestudy and Concomitant Therapy ............................................................................................ 121
Study Vaccination Pausing Rules for Stages 1a and 2a............................................................. 122
7. 
DISCONTINUATION OF STUDY VACCINATION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL ............................................................................................. 123
Discontinuation of Study Vaccination........................................................................................... 123
Participant Discontinuation/Withdrawal From the Study.............................................................. 124
7.2.1. 
Withdrawal From the Use of Research Samples ..................................................................... 124
Lost to Follow-up.......................................................................................................................... 124
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................. 125
Efficacy and Immunogenicity Assessments................................................................................. 128
8.1.1. 
Prespecified Criteria for Suspected COVID-19 Prior to Protocol Amendment 7...................... 128
8.1.2. 
Procedures in the Event of (Suspected) COVID-19................................................................. 129
8.1.2.1. 
Passive Follow-up (As of Amendment 7).............................................................................. 129
8.1.2.2. 
Active Follow-up (Until Amendment 7).................................................................................. 130
8.1.3. 
Efficacy Assessments............................................................................................................... 137
8.1.3.1. 
Case Definition for Moderate to Severe/Critical COVID-19 .................................................. 138
8.1.3.2. 
Case Definition for Mild COVID-19........................................................................................ 139
8.1.3.3. 
US FDA Harmonized Case Definition for COVID-19............................................................. 140
8.1.3.4. 
Case Definition for Asymptomatic or Undetected COVID-19................................................ 140
8.1.3.5. 
SARS-CoV-2 Seroconversion Assessment........................................................................... 141
8.1.3.6. 
Clinical Severity Adjudication Committee.............................................................................. 141
8.1.4. 
Immunogenicity Assessments .................................................................................................. 142
Safety Assessments..................................................................................................................... 145
8.2.1. 
Physical Examinations (Until Amendment 7)............................................................................ 145
8.2.2. 
Vital Signs................................................................................................................................. 145
8.2.3. 
Pregnancy Testing.................................................................................................................... 146
8.2.4. 
Clinical Laboratory Assessments ............................................................................................. 146
Adverse Events, Serious Adverse Events, Medically-attended Adverse Events, Adverse
Events of Special Interest, and Other Safety Reporting .............................................................. 147
8.3.1. 
Time Period and Frequency for Collecting Adverse Event, Medically-attended Adverse
Event, Adverse Events of Special Interest, and Serious Adverse Event Information .............. 147
8.3.2. 
Method of Detecting Adverse Events, Medically-attended Adverse Events, Adverse
Events of Special Interest, and Serious Adverse Events ......................................................... 150
8.3.3. 
Follow-up of Adverse Events, Medically-attended Adverse Events, Adverse Events of
Special Interest, and Serious Adverse Events ......................................................................... 151
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ........................................... 152
8.3.5. 
Pregnancy................................................................................................................................. 152
8.3.6. 
Disease-related Events and Disease-related Outcomes Not Qualifying as Adverse
Events or Serious Adverse Events ........................................................................................... 152
8.3.7. 
Adverse Events of Special Interest........................................................................................... 152
8.3.7.1. 
Thrombosis with Thrombocytopenia Syndrome.................................................................... 153
Virology Assessments.................................................................................................................. 154
Biomarkers................................................................................................................................... 154
Medical Resource Utilization........................................................................................................ 154
Risk Factor Assessment .............................................................................................................. 155
Participant Medical Information Prior to, During and After the Study (Real-world Data)............. 155
Assessment and Procedures After EUA or Approval/Licensure and Implementation of
Protocol Amendment 4................................................................................................................. 155
Assessment and Procedures Related to Booster Vaccination .................................................... 156
9. 
STATISTICAL CONSIDERATIONS................................................................................................ 157
Statistical Hypotheses.................................................................................................................. 157
Sample Size Determination ......................................................................................................... 158
9.2.1. 
Efficacy (Total Sample Size) .................................................................................................... 158
9.2.2. 
Immunogenicity Subset (Double-blind Phase)......................................................................... 160
9.2.3. 
Immunogenicity Correlates (Correlates Subset) ...................................................................... 160
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 15 April 2022
9.2.4. 
Safety........................................................................................................................................ 160
9.2.4.1. 
Safety Subset ........................................................................................................................ 160
9.2.4.2. 
All Participants....................................................................................................................... 161
Populations for Analysis Sets ...................................................................................................... 161
Participant Information ................................................................................................................. 162
Efficacy Analyses......................................................................................................................... 162
9.5.1. 
Primary Endpoints Evaluation .................................................................................................. 162
9.5.1.1. 
Study Monitoring.................................................................................................................... 166
9.5.2. 
Secondary Endpoints................................................................................................................ 167
9.5.3. 
Exploratory Endpoints............................................................................................................... 168
9.5.4. 
Other Analyses ......................................................................................................................... 168
Immunogenicity Analyses ............................................................................................................ 169
9.6.1. 
Immunogenicity Subset ............................................................................................................ 169
9.6.2. 
Correlates of Risk..................................................................................................................... 169
Safety Analysis............................................................................................................................. 169
Analysis of the Open-label Cross-over Phase, Open-label Booster Vaccination Phase
and Open-label Passive Follow-up Phase................................................................................... 171
9.8.1. 
Sample Size Determination of Immunogenicity Subset (Open-label Booster Vaccination
Phase)....................................................................................................................................... 171
9.8.2. 
Immunogenicity Correlates (Correlates Subset) ...................................................................... 172
9.8.3. 
Efficacy Analyses...................................................................................................................... 172
Interim Analysis and Committees ................................................................................................ 173
Analyses for Cohort Unblinded Due to Administration of an Authorized/Licensed COVID-
19 Vaccine ................................................................................................................................... 174
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .......................... 175
Appendix 1: Abbreviations ........................................................................................................... 175
Appendix 2: Clinical Laboratory Tests ......................................................................................... 178
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations....................................... 181
10.3.1. 
Regulatory and Ethical Considerations .................................................................................... 181
10.3.2. 
Financial Disclosure.................................................................................................................. 184
10.3.3. 
Informed Consent Process ....................................................................................................... 184
10.3.4. 
Data Protection ......................................................................................................................... 185
10.3.5. 
Long-term Retention of Samples for Additional Future Research............................................ 186
10.3.6. 
Committees Structure............................................................................................................... 186
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data.......................................................... 188
10.3.8. 
Data Quality Assurance............................................................................................................ 189
10.3.9. 
Case Report Form Completion................................................................................................. 190
10.3.10. Source Documents ................................................................................................................... 190
10.3.11. Monitoring ................................................................................................................................. 191
10.3.12. On-Site Audits........................................................................................................................... 192
10.3.13. Record Retention...................................................................................................................... 192
10.3.14. Study and Site Start and Closure ............................................................................................. 192
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...................................................................................................................................... 194
10.4.1. 
Adverse Event Definitions and Classifications ......................................................................... 194
10.4.2. 
Attribution Definitions................................................................................................................ 195
10.4.3. 
Severity Criteria........................................................................................................................ 196
10.4.4. 
Special Reporting Situations .................................................................................................... 196
10.4.5. 
Procedures ............................................................................................................................... 197
10.4.6. 
Product Quality Complaint Handling......................................................................................... 198
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality........................................... 199
Appendix 5: Contraceptive Guidance and Collection of Pregnancy Information ......................... 200
Appendix 6: Symptoms of Infection with Coronavirus-19 (SIC)................................................... 201
Appendix 7: MRU Questionnaire ................................................................................................. 206
Appendix 8: Medically-attended COVID-19 (MA-COV) Form...................................................... 210
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VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 15 April 2022
Appendix 9: Toxicity Grading Scale............................................................................................. 216
Appendix 10: Symptoms of Coronavirus (US Centers for Disease Control and Prevention)...... 219
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....... 220
Appendix 12: Risk Factor Assessment........................................................................................ 221
Appendix 13: TTS AESI Form...................................................................................................... 222
Appendix 14: Thrombotic Events to be Reported as AESIs ........................................................ 226
Appendix 15: Protocol Amendment History................................................................................. 227
11. REFERENCES................................................................................................................................. 259
INVESTIGATOR AGREEMENT............................................................................................................... 264
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Vaccination Schedules of Study VAC31518COV1001 ............................................................. 70
Table 2: 
Vaccination Schedule VAC31518COV3001 ............................................................................. 95
Table 3: 
Sample Size and Distribution of the Immunogenicity Subset Between Active and
Placebo Groups ...................................................................................................................... 142
Table 4: 
Sample Size and Distribution of the Homologous Booster Subset Age Groups .................... 143
Table 5: 
Sample Size and Distribution of the Heterologous Booster Subset Primary Vaccination
Groups .................................................................................................................................... 143
Table 6: 
Immunogenicity and Transcriptomic Assays .......................................................................... 144
Table 7: 
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
40,000 Participants)................................................................................................................ 161
Table 8: 
Specification of Sequential Statistical Analyses ..................................................................... 166
FIGURES
Figure 1: Schematic Overview of Study VAC31518COV3001 ................................................................ 36
Figure 2: Decision Tree for COVID-19 Procedures ............................................................................... 131
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
9
Status: Approved, Date: 15 April 2022
1. 
PROTOCOL SUMMARY
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
With protocol Amendment 4, an unblinding visit was introduced at which participants who initially received
placebo in the double-blind phase, and consent, receive a single dose of Ad26.COV2.S vaccine. Following
the unblinding, the study is conducted in an open-label fashion.
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.
As of Amendment 7, the number of on-site visits for participants who are not part of the Immunogenicity
Subset or Booster Subset is reduced. For these participants, any outstanding Visits 8 and 9 are cancelled.
In addition, any outstanding Visits 10 and 11 are replaced by a phone call. No further booster vaccination
will be provided in the protocol. In addition, active follow-up of new suspected COVID-19 will be replaced
by passive surveillance (ie, follow-up by the site at Month 18 and Month 24 to document COVID‑19
participant-reported events as [S]AEs and MAAEs) and to record concomitant therapies associated with
COVID-19. During these calls, the protocol required safety information (eg SAEs, AESIs, MAAEs 6 month
post booster) are also collected.
This study is being conducted under the sponsorship of Janssen (Janssen Vaccines & Prevention B.V) in
collaboration with the COVID-19 Response Team (formerly known as Operation Warp Speed [OWS]),
which also encompasses the Biomedical Advanced Research and Development Authority (BARDA), the
National Institutes of Health (NIH), and the COVID-19 Prevention Trials Network (COVPN).
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.
OBJECTIVES AND ENDPOINTS
1. Double-blind phase
The primary and secondary objectives and endpoints of the main study (ie, the double blind phase) are:
Objectives 
Endpoints
Co-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 double-blind vaccination (Day
15)
 First occurrence of molecularly confirmeda,
moderate to severe/critical COVID-19b, with onset
at least 28 days after double-blind vaccination (Day
29)
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
10
Status: Approved, Date: 15 April 2022
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, severe/critical 
COVID-19b, as compared to placebo 
 First occurrence of molecularly confirmeda,
severe/critical COVID-19b, with onset at least
14 days after double-blind vaccination (Day 15)
 First occurrence of molecularly confirmeda,
severe/critical COVID-19b, with onset at least
28 days after double-blind vaccination (Day 29)
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 double-blind vaccination
 First occurrence of molecularly confirmeda,
moderate to severe/critical COVID-19b, with onset
at least 14 days after double-blind vaccination (Day
15)
 First occurrence of molecularly confirmeda,
moderate to severe/critical COVID-19b, with onset
at least 28 days after double-blind vaccination (Day
29)
To evaluate the efficacy of Ad26.COV2.S  in the
prevention of molecularly confirmeda moderate to
severe/critical COVID-19b as compared to placebo, with
onset 1 day after study vaccination
First occurrence of molecularly confirmeda, moderate to
severe/critical COVID-19b with onset 1 day after
double-blind vaccination
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
double-blind vaccination (Day 15)
 First occurrence of COVID-19 requiring medical
intervention and linked to any molecularly
confirmeda, COVID-19b,c at least 28 days after
double-blind vaccination (Day 29)
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
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 double-blind
vaccination (Day 15)
 First occurrence of molecularly confirmeda, mild
COVID-19c, at least 28 days after double-blind
vaccination (Day 29)
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 15 April 2022
Objectives 
Endpoints
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 ofmolecularly confirmeda COVID-
19d at least 14 days after double-blind vaccination
(Day 15)
 First occurrence of molecularly confirmeda COVID-
19d at least 28 days after double-blind vaccination
(Day 29)
To assess the effect of Ad26.COV2.S on all molecularly
confirmeda symptomatic COVID-19b,c, as compared to
placebo
 Burden of disease (BOD) endpointfderived 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 double-
blind vaccination (Day 15).
 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 28
days after double-blind vaccination (Day 29).
To assess the effect of Ad26.COV2.S on occurrence of
confirmed asymptomatic or undetected infections with
SARS-CoV-2, as compared to placebo
 Serologic conversions: between baseline (Day 1;
pre-vaccination) and Day 29, between Day 29 and
Day 71, between Day 71 and Month 6 /Unblinding
Visit, and Month 18 after double-blind vaccination
(approximately 12 months after initiation of the
open-label phase of the study) 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 at the
time of the Month 6 /Unblinding Visit
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 28 days after double-blind vaccination
(Day 29)
Safety
To evaluate safety in terms of serious adverse events
(SAEs) adverse events of special interest (AESIs)
(during the entire study), medically-attended adverse
events (MAAEs; until 6 months after double-blind or
open-label 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 [double-
blind or open-label] Ad26.COV2.S), and MAAEs
leading to study discontinuation (during the entire
study) for all participants following vaccination
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 double-blind
vaccination, and in terms of unsolicited AEs during 28
days after double-blind vaccination
Occurrence, intensity, duration, and relationship of
solicited local and systemic AEs during the 7 days
following vaccination and of unsolicited AEs during the
28 days after double-blind vaccination
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
12
Status: Approved, Date: 15 April 2022
Objectives 
Endpoints
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 a 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 the per-protocol (PP)analysis set, 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, durability of protection,
immunogenicity, and 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.
Hypotheses
The study is designed to test the co-primary hypotheses of vaccine efficacy (VE)in the PP population. For
both co-primary endpoints, the following hypothesis will be tested:
H0: VE ≤30% versus H1: VE >30% and each hypothesis will be evaluated at a 2.5% one-sided significance
level.
The co-primary endpoints 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 double-blind vaccination with Ad26.COV2.S
versus placebo, in the PP population, including all events from both age groups, with and without
comorbidities.
 
the first occurrence of molecularly confirmed, moderate to severe/critical COVID-19 according to
the case definition, with onset at least 28 days after double-blind vaccination with Ad26.COV2.S
versus placebo, in the PP population, including all events from both age groups, with and without
comorbidities.
If testing for both primary endpoint hypotheses 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% one-sided significance level.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
13
Status: Approved, Date: 15 April 2022
2. Open-label active phase
A diagram showing the study phases is provided below:
2.1 Open-label Cross-over Phase
Participant will enter the open-label crossover phase on the day that the participant received the cross-over
vaccination  or is unblinded until the day that the participant completed the booster visit. There are
2 main cohorts in the open-label phase:
- 
Early vaccinated cohort: participants who were initially randomized to the Ad26.COV2.S
group and received 1 dose of Ad26.COV2.S at Day 1 in the trial
- 
Late vaccinated cohort: participants who were initially randomized to the placebo group and
who received 1 dose of Ad26.COV2.S after unblinding
The main objective of the open-label phase of the study is to evaluate the COVID-19 outcomes after an
early vaccination and after a late vaccination. Efficacy evaluations may be performed if feasible, ie, if
pre-specified criteria are met, as specified in the SAP.
The secondary and exploratory objectives and endpoints for the open-label phase of the study are:
Objectives 
Endpoints
The secondary safety objective of the double-blind
phase (see secondary double-blind objective)
The secondary safety endpoint of the double-blind phase
(see secondary double-blind endpoint)
To evaluate molecularly confirmeda, symptomatic
COVID-19b
Incidence of symptomatic COVID-19 cases starting at
28 days after last vaccination
To evaluate molecularly confirmeda, severe/critical
COVID-19b
Incidence ofsevere/critical COVID-19 cases starting at
28 days after last vaccination
To evaluate molecularly confirmeda COVID-19b
requiring medical intervention (based on objective
criteria)
Incidence of COVID-19 cases requiring medical
intervention, starting at 28 days after last vaccination
To evaluate COVID-19 related death 
Incidence of COVID-19 related deaths starting at
28 days after last vaccination
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
14
Status: Approved, Date: 15 April 2022
Objectives 
Endpoints
To describe the severity of breakthrough infections 
The severity of COVID-19 cases may be evaluated by
the severity and number of symptoms (severity) of
COVID-19 cases, ratio of severe/critical COVID-19
cases and ratio of long COVID-19 cases (duration of
more than 28 days)
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.
Levels of immune responses (antibody titers) and RNA
sequencing analysis as available for participants having
COVID-19 compared to non-infected participants.
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 as determined by the Clinical Severity Adjudication
Committee (see below).
2.2 Open-label booster phase
Participants will enter the booster phase on the day that the participants completed the booster visit until
consenting to Amendment 7(or with the stop of the eCOA at each study site, which ever date comes first).
There are 3 main cohorts, based on vaccination schedules received during the booster phase:
- 
Homologous boost cohort consists of following 2 groups:
o participants who were initially randomized to the Ad26.COV2.S group and received
1 dose of Ad26.COV2.S at Day 1 within the trial and a booster dose preferably within
6 to 12 months after the initial vaccination, with a minimum of 3 months after the initial
vaccination with Ad26.COV.2.S
o participants who were initially randomized to the placebo group and who received
1 dose of Ad26.COV2.S after unblinding and a booster dose preferably within 6 to 12
months after the initial vaccination, with a minimum of 3 months after the last
vaccination with Ad26.COV.2.S
- 
Heterologous boost cohort: participants who were initially randomized to the placebo group
and who received an mRNA vaccination outside of the trial and an Ad26.COV2 booster dose
preferably within 6 to 12 months after the initial vaccination, with a minimum of 3 months after
the last outside vaccination
- 
Non-boost cohort: participants who received 1 Ad26.COV2.S vaccination, either at Day 1 or
as a cross-over vaccination. These participants remain in this cohort until they receive the
booster vaccination. Participants who opt not to receive a booster dose will continue in this
cohort.
Data from participants who received a different sequence of vaccinations (eg, Ad26.COV2 prime
vaccination and an outside booster)will be presented separately.
The main objective of the booster phase of the study is to evaluate the COVID-19 outcomes, safety, and
immunogenicity of the different schedules that were assessed: homologous Ad26.COV2 booster schedule,
1-dose schedule, and heterologous booster schedule. All analyses are descriptive, efficacy evaluations may
be done if feasible, ie, if pre-specified criteria are met, as described in the SAP.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
15
Status: Approved, Date: 15 April 2022
The primary and secondary objectives and endpoints for the booster phase of the study are:
Objectives 
Endpoints
Primary Objective of the Booster Phase
To 
assess 
the 
safety 
and 
reactogenicity 
of 
Ad26.COV2.S at the 5×1010 vp dose level administered 
as homologous or heterologous booster vaccination in
adults.
 
Solicited local and systemic AEs for 7days after
booster vaccination.
 
Unsolicited AEs for 28 days after booster
vaccination.
 
SAEs and AESIs from booster vaccination until
end of the study.
To measure the primary endpoints previously utilized
for the double-blind portion of the study in this
unblinded booster portion of the trial during the time
participants have and have not been boosted.
 
Incidence of the primary endpoints utilized in the
double-blind portion of the study, including
moderate to severe/critical COVID-19 cases
starting at 28 days by serostatus*, in the unblinded
booster portion of the study (see definitions of
terms in Section 10.1) during the times when they
have and have not been boosted.
To measure the primary endpoints previously utilized
for the double-blind portion of the study in participants
infected with selected variants and the reference strain
in this unblinded booster portion of the trial during the
time participants have and have not been boosted.
 
Incidence of the primary endpoints (Day 28 after
vaccination) in the main study as applicable as
described in the first objective but for variants of
concern and the reference strain.
Secondary Objectives of the Booster Phase
To evaluate the secondary endpoints previously utilized
for the double-blind portion of the study in this
unblinded booster portion of the trial during the time
participants have and have not been boosted.
 
Incidence of secondary endpoints (Day 28 after
vaccination) from the double-blind portion of the
study by serostatus* such as symptomatic
severe/critical disease, hospitalization, and death.
To evaluate the primary and secondary endpoints
utilized in the double-blind portion of the study in this
unblinded booster portion of the trial in participants
primed or boosted with Ad26.COV2.S, mRNA,
inactivated, protein, and other adenovector-based
vaccines during the time participants have and have not
been boosted.
 
Description  of the primary and secondary
endpoints (Day  28 after vaccination), such as
symptomatic, 
severe/critical 
disease,
hospitalization, and death, in the double-blind
portion of the study as applicable as described in
the first primary objective and first secondary
objective including variants of concern  and
reference variants.
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
immune responses at Day 28 after booster vaccination
in boosted compared to non-boosted participants.
 
Serological response to vaccination and antibody
titers (VNA) against the original strain, 28 days
after Ad26.COV2.S (5×1010 vp dose level) single-
dose booster vaccination.
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.
 
Levels of immune responses (antibody titers) and
RNA sequencing analysis as available.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
16
Status: Approved, Date: 15 April 2022
Objectives 
Endpoints
To compare the immune responses in the Heterologous 
and Homologous Booster Subsets 28 Days following 
booster dose administration. 
 
Qualitative comparison of responses in terms of
binding, neutralizing antibody against Wuhan
reference strain and variants of interest utilizing
wtVNA and/or psVNA, depending on feasibility.
 
Analysis of antibodies binding to the SARS- CoV-
2S protein by ELISA.
To evaluate SARS-CoV-2 infection (severe/critical, 
moderate 
to 
severe/critical, 
symptomatic, 
and 
asymptomatic infections, that are serologically and/or
molecularly confirmed**) for the different cohorts
 
Incidence 
of 
SARS-CoV-2 
infections
(serologically and/or molecularly confirmed**).
To describe the severity of breakthrough infections. 
 
The severity of COVID-19 cases may be evaluated
by the severity and number of symptoms (severity)
of COVID-19 cases and ratio of long COVID-19
cases (duration of more than 28 days)
To obtain samples to evaluate potential thromboembolic 
events following booster immunization by obtaining 
platelet counts and sufficient extra sera for specialized 
studies at the day of booster immunization and 28 days 
later.
Platelet count on the day of booster vaccination and
28 days after booster vaccination. Additional analysis
on kept sera samples in case of potential
thromboembolic events.
* Seronegative is defined as N-serology seronegative at the time of boosting or at the Year 1 visit if not boosted.
** 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.
4. Open-label Passive follow-up phase
With Amendment 7, the active follow-up of new suspected COVID-19 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, which ever date comes first)until end of study.
In the passive follow-up phase, the same cohorts as from the booster phase are included, and all data will
be descriptively presented by cohort depending on the vaccination schedule received during the follow-up.
Since COVID-19 reporting changed from an active approach to a passive approach, the effectiveness
evaluations may be limited and will be described in the SAP as applicable.
The secondary and exploratory objectives and endpoints for the passive follow-up phase of the study are:
Objectives 
Endpoints
The secondary safety objective of the double-blind
phase (see double-blind objectives).
 
The secondary safety endpoint of the double-blind
phase (see double-blind endpoints).
To evaluate COVID-19 in terms of (S)AEs MAAEs,
hospitalizations and fatal AEs linked to COVID-19*
 
SAEs and AEs linked to COVID-19.
 
MAAEs linked to COVID-19
 
SAEs 
linked 
to COVID-19 
that require
hospitalization
 
Fatal AEs linked to COVID-19
In the immunogenicity  subset of participants: to
evaluate the immunogenicity of Ad26.COV2.S at
available timepoints
 
Analysis of antibodies binding to the SARS-CoV-
2 S protein by ELISA
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
17
Status: Approved, Date: 15 April 2022
Objectives 
Endpoints
In the Heterologous and Homologous Booster Subsets: 
to compare the immune responses 28 days following 
booster dose administration
 
Analysis ofantibodies binding to the SARS-CoV-
2 S protein by ELISA
 
Qualitative comparison of responses in terms of
binding, neutralizing antibody against Wuhan
reference strain and variants of interest utilizing
wtVNA and/or psVNA, depending on feasibility
* Refer to Section 8.3 for the safety follow up and COVID 19 reporting requirements as of Protocol Amendment 7.
Case Definitions
The Clinical Severity Adjudication Committee will review all cases in the study, except for cases already
adjudicated as severe, as a supplement to the algorithm described in the SAP, as well as those 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),
including date of onset 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). 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 foranalysis. The Clinical Severity Adjudication Committee's
assessment will be considered the definitive classification of the case. 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 co-primary endpoints (see above), 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
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
18
Status: Approved, Date: 15 April 2022
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 (respiratoryrate ≥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
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).
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
19
Status: Approved, Date: 15 April 2022
 
Admission to the ICU
 
Death
All cases meeting the severe/critical criteria will be adjudicated by the Clinical Severity Adjudication
Committee to determine if the case is severe/critical in their judgement.
All cases meeting the moderate case definition and that include ≥3 signs and/or symptoms from the list of
signs and symptoms will be evaluated by the Clinical Severity Adjudication Committee to determine if the
case is severe/critical in their judgement.
Classification of a case as severe/critical by the Clinical Severity Adjudication Committee is considered
definitive.
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, moderate, or severe by the protocol definitions
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
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).
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
20
Status: Approved, Date: 15 April 2022
OR
 
develops a positive serology (non-S protein) test
Then, the participant will be considered to have experienced asymptomatic or undetected COVID-19.
Cases will be classified as being an "Asymptomatic SARS-CoV-2 infection" by the Clinical Severity
Adjudication Committee utilizing the following guidelines as applicable, which are described in more detail
in the charter for the committee.
 
The definition of any case that is either RT-PCR positive that was previously RT-PCR negative or
seropositive for N protein specific antibodies that was previously seronegative for N protein
specific antibodies and is clinically asymptomatic will be considered as an asymptomatic COVID-
19 case.
 
The definition of clinically asymptomatic COVID-19 is defined as no clinical symptoms that would
be classified as mild, moderate, or severe COVID-19 by the protocol case definition for symptoms
independent of the SARS-CoV-2 N protein specific antibody seroconversion or RT-PCR results.
Potential asymptomatic cases that are identified by N protein specific SARS-CoV-2 seroconversion will all
be examined by the Clinical Severity Adjudication Committee for the presence of any signs or symptoms
and if found, to determine if they would still be classified as asymptomatic COVID-19. Cases which are
moderate, severe, hospitalized, or fatal that are found by SARS-CoV-2 N protein specific antibody
seroconversion will be utilized in a sensitivity analysis to determine, if any conclusions would be changed
by adding to the primary case definition of a positive RT-PCR with appropriate signs and symptoms to
those cases which were identified by SARS-CoV-2 N protein specific antibody seroconversion with
appropriate signs and symptoms.
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 to <60 years of age and ≥60 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 study vaccine.
Following EUA, conditional licensure, or approval in any country for the single dose regimen, based on the
VAC31518COV3001 primary analysis results described in an interimreport, all participants from countries
where Amendment 4 is approved by the Health Authority and IEC/IRB will be unblinded at the on-site
Month 6/Unblinding Visit. The study will then be conducted in an open-label fashion. A final analysis of
the double-blind phase will be performed, using the data collected prior to unblinding, when all participants
have completed the Month 6/Unblinding Visit or discontinued earlier. Depending on the operational
implementation of the Month 6/Unblinding Visit, as well as the stage of the pandemic, this analysis may
be conducted when a minimum of 90% of the study population has been unblinded.
All participants will be invited for an on-site Month 6/Unblinding Visit and participants who initially
received placebo in the double-blind phase will be offered a single dose of Ad26.COV2.S 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 had an
acceptable safety profile. The sponsor has therefore decided to proceed with the single dose regimen at a
5×1010 virus particles (vp)dose level in this Phase 3 study.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
21
Status: Approved, Date: 15 April 2022
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 at the Year 1/Booster Visit (see also below). The
combination of homologous or heterologous prime/boost vaccination will not be randomized, but depends
on what participants received during the double-blind phase of the study as described in this protocol. The
start date of the first cross-over unblinding visit (implemented with Amendment 4) and the date of first
booster vaccine administration until 1-year follow-up of the last booster vaccination define the open-label
booster vaccination phase of the study. This phase will be utilized to describe safety, immunogenicity, and
efficacy during the time participants have and have not been boosted.
With Amendment 7, active follow-up of suspected COVID-19 will be replaced by passive surveillance (ie,
follow-up by the site at Month 18 and Month 24 to document new COVID‑19 participant-reported 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 SAEs, AESIs, MAAEs 6 month post
booster) are also collected.
Participants will be randomized in parallel in a 1:1 ratio 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. At the Month 6/Unblinding Visit, participants who initially received placebo and signed an
amended ICF will be offered a single dose of Ad26.COV2.S. vaccine at a dose level of 5×1010 vp. At the
Year 1/Booster Visit, all ongoing participants in the study who have previously received any COVID-19
vaccination(s) (as primary regimen or additional dose) with the Ad26.COV2.S vaccine, and/or an mRNA
vaccine or another COVID-19 vaccine authorized for primary vaccination including protein, inactivated,
and adenovector-based vaccines, will be offered a single booster dose of Ad26.COV2.S vaccine (5×1010 vp)
if the last vaccination was preferably 6 months but at least 3 months ago.
Table: 
Vaccination Schedule VAC31518COV3001
Group  N 
Day 1 
Month 6/Unblinding Visit* 
Year 1/Booster Visit
1 
20,000 
Ad26.COV2.S (5×1010 vp) 
- 
Ad26.COV2.S (5×1010 vp)
2 
20,000 
Placebo 
Ad26.COV2.S (5×1010 vp) 
Ad26.COV2.S (5×1010 vp)
EUA  Emergency Use Authorization; 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.
* All participants will be unblinded (informed whether they received placebo or Ad26.COV2.S) at the on site Month 6/
Unblinding Visit following EUA, conditional licensure or approval in any country and approval by regulatory and IEC/IRB
and the study will continue as an open label study. Participants who received placebo on Day 1 will be offered to receive a
single dose of Ad26.COV2.S 5×1010 vp.
The following enrollment strategy will be used:
 
Stage 1a: Initially, approximately 2,000 participants ≥18 to <60 years of age without comorbidities
that are associated with increased risk of progression to severe COVID-19 (including
approximately 1,000 Ad26.COV2.S recipients and approximately 1,000 placebo recipients)will be
enrolled, based on acceptable Day 29 safety and acceptable immunogenicity data, including T-
helper 1/T-helper 2 (Th1/Th2), from the corresponding age group (Cohort 1a) of the first-in-human
(FIH) study VAC31518COV1001.
 
Stage 1b: After a vaccination pause (in the age group ≥18 to <60 years of age) to allow the Data
Safety Monitoring Board (DSMB, also known as an Independent Data Monitoring Committee
[IDMC]) to examine Day 3 safety data (ie, from Day 1 to Day 3; including safety data from the
ongoing clinical studies), if no safety concerns are identified enrollment will proceed, expanding
enrollment to include ≥18- to <60-year-old participants with and without comorbidities that are
associated with increased risk of progression to severe COVID-19.
In Stage 1a and 1b combined, the enrollment of participants aged ≥18 to <40 years will be limited to
approximately 20% of the total study population.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
22
Status: Approved, Date: 15 April 2022
 
Stage 2a: Initially, approximately 2,000 participants ≥60 years of age without comorbidities that
are associated with increased risk of progression to severe COVID-19 will be enrolled (including
approximately 1,000 Ad26.COV2.S  recipients and approximately 1,000 placebo recipients).
Considering the data from study VAC31518COV1001 (including data on elderly), Stage 2a will
run in parallel with Stage 1a, unless this is not allowed per local Health Authority guidance.
 
Stage 2b: After a vaccination pause (in the age group ≥60 years of age) to allow the DSMB to
examine Day 3 safety data (ie, from Day 1 to Day 3;including safety data from Stage 1 and the
ongoing clinical studies) from Stage 2a, if no safety concerns are identified in this population
enrollment will proceed, expanding enrollment to include ≥60-year-old participants with  and
without comorbidities that are associated with increased risk of progression to severe COVID-19.
Stage 2 will enroll a minimum of approximately 30% of the total study population.
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.
No additional participants will be recruited for the open-label phase.
The duration of individual participation, including screening, will be approximately 2 years and 1 month.
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 during the double-blind phase will
include the monitoring of solicited and unsolicited AEs in the Safety Subset only. Up to Amendment 7, all
participants who received booster vaccination at the Year 1/Booster Visit will record solicited signs and
symptoms in an e-Diary, if feasible. As of protocol Amendment 7, the collection of solicited AEs will stop.
Up to Amendment 7, for a subset of participants, the e-Diary will be reviewed by the study personnel at the
next visit, if feasible, and solicited AEs recorded. Unsolicited AEs will be recorded for all participants who
received booster vaccination at the Year 1/Booster Visit. As of protocol Amendment 7, the collection of
unsolicited AEs will stop.
In addition, key safety assessments throughout the study include the collection of SAEs and MAAEs in all
participants.
Up to Amendment 7, the viral load of SARS-CoV-2 will be assessed in confirmed COVID-19 cases.
Biomarkers correlating with SARS-CoV-2 infection and COVID-19 severity will also be studied. Medical
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 were not allowed to enroll in the study.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
23
Status: Approved, Date: 15 April 2022
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. 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. 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 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. The statistical analyses will be described in
detail in a Statistical Analysis Plan.
As of Amendment 7, participants will continue to be required to report safety events, such as SAEs, AESIs,
MAAEs. As mentioned above, participants who received booster vaccination will stop the reporting of
solicited or unsolicited AEs as of Amendment 7. Finally, the active follow-up of new suspected COVID-19
episodes will be replaced by passive follow-up, defined as follow-up by the site at Month 18 and Month 24
to document COVID-19 participant-reported events as SAEs, AEs, or MAAEs.
Up to Amendment 7, until 1 year after the Month 6/Unblinding Visit, 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 of1-year after
the Month 6/UnblindingVisit, until the end of the 2-year follow-up period, the frequency of this (suspected)
COVID-19 surveillance (symptom check) through the eCOA may decrease to once every 2 weeks
depending on epidemiology. All participants will be monitored for safety (including enhanced disease) for
approximately 1 year after the Year 1/Booster Visit, ie, until the last study visit. Every effort will be made
to document the status ofall 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 protocol 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. Ifa 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, any positive RT-PCR test result regardless if it is obtained outside the study or at a
study visit will be considered a trigger to start COVID-19 procedures. All participants with COVID-19-like
signs or symptoms meeting the prespecified criteria for suspected COVID-19 and all participants with at
least 1 positive RT-PCR test for SARS-CoV-2 on COVID-19 Day 1-2 or 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
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
24
Status: Approved, Date: 15 April 2022
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).
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,
the participant and participant’s medical care provider will be notified, and the participant will be asked to
adhere to the appropriate measures and restrictions as defined by local regulations.
A DSMB will be commissioned for this study.
NUMBER OF PARTICIPANTS
Overall, a target ofapproximately 40,000 adult participants (≥18- to <60-year-old and ≥60-year-old, with
and without relevant comorbidities) will be randomly assigned in this study. Efforts will be made to ensure
good representation in terms of race, ethnicity, and gender.
It is intended that a minimum ofapproximately 30% of recruited participants will be ≥60 years of age and
approximately 20% of recruited participants will be ≥18 to <40 years of age.
INTERVENTION GROUPS AND DURATION
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, all participants will receive Ad26.COV2.S or placebo at Day 1 of the double-blind
phase, using the same volume (ie, 0.5 mL). At the Month 6/Unblinding Visit, all placebo participants who
have signed a new ICF will receive a single dose of Ad26.COV2.S, using the same dose level and the same
volume (ie, 5×1010 vp per 0.5 mL). At the Year 1/Booster Visit, all participants who are eligible for booster
vaccination, desire to receive a booster vaccination, and have signed a new ICF will receive a single dose
of Ad26.COV2.S, using the same dose level and the same volume (ie, 5×1010 vp per 0.5 mL) as used for
the primary regimen.
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
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
25
Status: Approved, Date: 15 April 2022
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 (pre-vaccination), Day 29, Day 71, Month 6
/Unblinding Visit, Year 1, and Month 18.
IMMUNOGENICITY EVALUATIONS
Up to Amendment 7, blood will be collected from all non-Immunogenicity Subset (double-blind phase)
participants for humoral immunogenicity assessments at Day 1 (pre-vaccination), Day 29, Day 71, Month
6/Unblinding Visit, and Year 1.
For a total of approximately 400 participants in the Immunogenicity Subset (ie, 400 participants at sites
with access to appropriate processing facilities), blood will be collected for analysis of humoral immune
responses at Day 1 (pre-vaccination), Day 29, Day 71, Month 6/Unblinding Visit, Year 1, Month 18, and
Year 2 visit after double-blind vaccination, and additionally 28 days and 72 days after booster vaccination,
if applicable.
Note: Those participants in the Immunogenicity Subset that transfer to the Homologous Booster Subset at
the Year 1/Booster Visit (see below) will from that visit onwards follow the humoral immunogenicity
sample schedule of the Homologous Booster Subset and discontinue the schedule of the Immunogenicity
Subset.
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 Day 1-2
or Day 3-5), blood will be collected on COVID-19 Day 3-5 and on COVID-19 Day 29 for immunogenicity
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.
Booster Vaccination
Up to Amendment 7, blood will be collected from all non-Subset participants who received booster
vaccination for humoral immunogenicity assessments at the Year 1/Booster Visit and 28 days, 72 days, and
6 months after booster vaccination. A blood sample for transcriptomics will be collected from all
participants 28 days after booster vaccination.
Homologous Booster Subset: The Homologous Booster Subset will include approximately 200 participants.
This subset will include participants from the Immunogenicity Subset, who received Ad26.COV2.S in the
double-blind phase or after cross-over, and subsequently received an Ad26.COV2.S booster vaccination in
the study. This group may be augmented by other participants to replace participants who are not available.
Participants in the Homologous Booster Subset will have a blood sample collected pre-booster vaccination,
and 28 days, 72 days, 6 months, and 1 year post booster vaccination for humoral immunogenicity
assessment.
a 
World Health Organization  (WHO). Clinical management of severe acute respiratory infection (SARI) when
COVID-19 
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.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
26
Status: Approved, Date: 15 April 2022
Heterologous Booster Subset: The Heterologous Booster Subset will include approximately
400 participants. This subset will include participants in the study who received placebo in the double-blind
phase and have received primary vaccination with an mRNA vaccine or another authorized COVID-19
vaccine including protein, inactivated, and adenovector based vaccines outside the study, who subsequently
remained in the study and subsequently received an Ad26.COV2.S booster vaccination in the study.
Participants who already received an additional COVID-19 vaccination after the primary regimen outside
the study will not be included in the Heterologous Booster Subset. Participants will be selected out of
countries where these vaccines were authorized for emergency use or are licensed. Participants in the
Heterologous Booster Subset will have blood collected pre-booster vaccination, and 28 days, 72 days, 6
months, and 1 year post booster vaccination for humoral immunogenicity assessment.
Additionally, approximately the first 60 eligible participants once operationally feasible of the Homologous
Booster Subset and approximately the first 60 eligible participants once operationally feasible of the
Heterologous Booster Subset will have blood collected pre-booster and 1 day and 28 days post booster
vaccination for transcriptomics and cytokine/chemokine assessment.
Immunogenicity and Transcriptomic 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 Secondary and Exploratory Objectives
SARS-CoV-2 neutralization (VNA) 
Analysis of neutralizing antibodies against SARS-CoV-2 original strain
and/or variants, using a live VNA and/or pseudovirion expressing S
protein neutralization assay
SARS-CoV-2 binding antibodies to S 
protein (MSD) 
Analysis of antibodies binding to the original and/or variants 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
Cytokine profiling 
Analysis of cytokines, chemokines, and other proteins of the innate or
adaptive immune response in the serum or plasma
Transcriptomic Assay  
Purpose
Supportive of Exploratory Objectives
Gene expression analysis 
Analysis of gene expression by RNA transcript profiling in
unstimulated cells or whole blood
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; RNA  ribonucleic
acid; 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. This does not apply to the open-label phase of the study.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
27
Status: Approved, Date: 15 April 2022
A serologic test for past or current infection with SARS-CoV-2 may be performed for all participants at
Day 1 (pre-vaccination), Day 29, Day 71, Month 6/Unblinding Visit, Year 1/Booster Visit (prior to
vaccination, if applicable), Year 1 + 28 days for participants who received booster vaccination, Year 1 +
72 days for participants who received booster vaccination, and Month 18 (24 weeks after Year 1 Visit).
Samples for the serologic tests will be sent to a central laboratory for testing.a Participants who test positive
will be informed ofthe result by the study staff.
SAFETY EVALUATIONS
The first 2,000 participants in each of the 2 age groups will remain under observation at the study site for
at least 30 minutes post-vaccination to monitor for the development of acute reactions. If at the time of the
Day 3 safety review of the initial 2,000 participants no acute reactions have been observedin the age groups,
the observation period at the study site may be reduced to at least 15 minutes post-vaccination for the
remaining participants in the study.
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 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 signing of the
ICF and moment ofvaccination in the double-blind phase of the study will be collected on the Medical
History electronic case report form (eCRF) page as pre-existing conditions. This does not apply to the
open-label phase.
 
All SAEs and all AEs leading to study discontinuation (regardless of the causal relationship) are to be
reported from the moment of 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 each vaccination until
6 months after the vaccination(applicable for both the double-blind and open-label phases of the study),
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 from the time of each
vaccination until 28 days post-vaccination (applicable for both the double-blind and open-label phases
of the study).
 
Suspected AESIs (thrombotic events and thrombocytopenia [defined as platelet count below
150,000/µLb]) will be reported from the moment of vaccination until the end of the study/early
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).
b 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.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 15 April 2022
withdrawal. An AESI Adjudication Committee with appropriate expertise will be established to
evaluate each suspected AESI and determine whether it is a case of thrombosis with thrombocytopenia
syndrome (TTS). From the time of local approval of protocol Amendment 5 onwards, TTS is
considered an adverse event of special interest (AESI).
 
All AEs will be followed until resolution or until clinically stable.
As of Amendment 7, for all participants:
 
Active follow-up of suspected COVID-19 episodes will be replaced by passive surveillance: during
follow-up calls by the site at Month 18 and Month 24, new COVID‑19 participant-reported events are
to be reported as SAEs, AE or MAAEs.
 
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).
For participants in the Safety Subset (double-blind phase):
 
Solicited AEs, collected through an e-Diary, will be recorded from the time of vaccination until 7 days
post-vaccination.
 
All other unsolicited AEs, whether serious or non-serious, will be recorded from the time of
vaccination until 28 days post-vaccination.
Up to Amendment 7: For participants who received booster vaccination at the Year 1/Booster Visit:
 
Solicited AEs, collected through an e-Diary, will be recorded from the time of vaccination until 7 days
post-vaccination. All participants will collect signs and symptoms in the e-Diary, if feasible. For a
subset of participants, ie, participants included in the Safety Subset of the double-blind phase and all
participants who previously received a heterologous COVID-19 vaccination outside the study, the
e-Diary will be reviewed by the study personnel and solicited AEs recorded in the eCRF, if feasible.
All other unsolicited AEs, whether serious or non-serious, will be recorded from the time of
vaccination until 28 days post-vaccination for all participants.
As of Amendment 7, solicited and unsolicited AE reporting will stop for all participants.
STATISTICAL METHODS
Note: The below is only applicable to the double-blind phase of the study unless mentioned otherwise.
Sample Size Calculation
Efficacy (Total Sample Size)
The study target number of events (TNE) is determined using the following assumptions:
 
a VE for molecularly confirmed, moderate to severe/critical SARS-CoV-2 infection of 60%.
 
approximately 90% power to reject a null hypothesis of H0: VE≤30%.
 
type 1 error rate α = 2.5% to evaluate VE of the vaccine regimen (employing the sequential probability
ratio test [SPRT] to perform a fully sequential design analysis; detailed in the methods section).
 
a randomization ratio of1:1 for active versus placebo.
Events for the co-primary endpoints 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
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population at least 14 days after double-blind vaccination (Day 15) and at least 28 days after double-blind
vaccination (Day 29) with study vaccine.
Under the assumptions above, the TNE to compare the active vaccine versus placebo equals 154, based on
events in each active vaccination and placebo group, according to the primary endpoints case definition of
moderate to severe/critical COVID-19.
If the primary hypotheses 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%.
Further details on the sample size calculation are provided in the body of the protocol.
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.
No additional participants will be recruited for the open-label phase.
Immunogenicity Correlates (Correlates Subset)
Correlates will be assessed in a subset where immune responses and 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).
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:
 
Full Analysis Set (FAS): All randomized participants with a 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) population: Participants in the FAS who receive study vaccine and who
are seronegative at the time of vaccination and who have no other major protocol deviations that were
judged to possibly impact the efficacy of the vaccine. Participants who became aware of their study
vaccine allocation will cease to be part of the PP population. The PA of VE will be based on the PP
population. The PP will be the main analysis population for efficacy analyses.
 
Per-protocol Immunogenicity (PPI) population: All randomized and vaccinated participants,
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
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Status: Approved, Date: 15 April 2022
(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 cross-over, booster and 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 the
protocol deviation dataset of the clinical database before unblinding.
Efficacy Analyses
The study will have the following timepoints for efficacy analyses:
1. 
The evaluation of the primary objective will be performed as soon as the TNE has been reached in the
double-blind phase for both co-primary endpoints, or earlier based on sequential monitoring of both
co-primary endpoints. Sponsor unblinding will occur but investigator and participants remain blinded
until implementation of Amendment 4.
2. 
If an efficacy signal is triggered before the required 8-week follow-up after double-blind vaccination
of 50% of participants is reached, an additional analysis will be performed when that follow-up
timepoint is reached (8-week median follow-up timepoint). If the time between the efficacy signal and
the required 8-week  median follow-up is too short to make a difference in terms of preparing
two analyses, then a single analysis will take place at the time of the 8-week median follow-up. The
analysis at the time of the 8-week median follow-up is considered the primary analysis.
3. 
After the primary analysis, additional analyses to support health authority interactions will be planned,
as deemed appropriate.
4. A final analysis of the double-blind phase of the study, including all double-blind data, will be
performed when all participants have completed the Month 6/Unblinding Visit or discontinued earlier.
Depending on the operational implementation of the Month 6/Unblinding Visit, as well as the stage of
the pandemic, this analysis may be conducted when a minimum of 90% of the study population has
been unblinded.
During the open-label phase, 2 analysis can be performed:
5. 
The open-label cross-over and booster analysis (active follow-up).
6. 
An end-of-study analysis is planned 1 year after a minimum of 90% of the enrolled study population
have reached the Year 1/Booster Visit 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 cross-over and booster analysis may be combined with the end-of-study analysis.
At the end-of-study analysis, 90% of participants will have completed one year safety follow-up post
booster; the remaining active boosted participants will have at least 6 months of 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
The study is designed to test the co-primary hypotheses of VE in the PP population. For both co-primary
endpoints, the following hypothesis will be tested: H0: VE ≤30% versus H1: VE >30%. The co-primary
endpoints 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 double-blind vaccination
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(Day 15) and with onset at least 28 days after double-blind vaccination (Day 29) 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.
Evaluation of the Primary Endpoints
A fully sequential design with early stopping boundaries for efficacy based on the SPRT30 will be used on
the PP. The SPRT will control the type I error adjusting for the fully sequential approach. The decision
rules for harm and non-efficacy are detailed in the protocol.
To that end, the boundaries are derived to achieve approximately 90% power to detect VE=60% using an
alpha level of 2.5% against H0:VE≤30%.
To allow for durability assessment, sites and participants will continue the study and remain blinded until
the final analysis.
A successful primary efficacy conclusion will require:
1. 
Establishing the hypothesis H1: VE>30% for each co-primary endpoint
AND
2. 
A favorable split vaccine: placebo for the subset of primary endpoints meeting the severe/critical
COVID-19 case definition (expressed as a VE point estimate against severe/critical COVID-19
molecularly confirmed endpoints ≥50%) and a minimum of 5 events in the placebo group. This
requirement needs to be met for severe/critical events with onset at least 14 days after double-blind
vaccination and for severe/critical events with onset at least 28 days after double-blind vaccination
AND
3. 
A VE of at least 50% for each co-primary endpoint.
To evaluate the primary null hypotheses: H0: VE ≤30% versus H1: VE >30% for the co-primary endpoints,
the truncated sequential probability ratio test will be used based on accumulating event data for each
co-primary endpoint. This boundary is set up using the fully sequential design and is derived in such a way
to have approximately 90% power to detect a VE=60% using a one-sided alpha=0.025 against H0:VE≤30%.
For the evaluation of the favorable ratio against the severe/critical COVID-19 endpoints a sequential
boundary corresponding to a VE point estimate ≥50% and a minimum of 5 events in the placebo group will
be prespecified. The specific boundaries will be detailed in the SAP.
The monitoring can start as soon as the following conditions are met:
1. 
A minimum of 6 COVID-19 cases for the ≥60 years age group with onset at least 28 days after double-
blind vaccination
2. 
At least 42 cases meeting the primary endpoint definition of moderate to severe/critical COVID-19
with onset at least 28 days after double-blind vaccination.
3. 
A subset of at least 5 cases meeting the primary endpoint definition of severe/critical COVID-19 with
onset at least 28 days after double-blind vaccination.
No interim evaluation will be done, until those conditions are fulfilled. Monitoring for efficacy will not
start before the above conditions 1-3 are met and will occur at least once a week by the SSG of the DSMB
until the prespecified boundaries have been crossed.
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The efficacy analysis will be triggered by either:
1. 
a) An interim evaluation if all prespecified efficacy boundaries have been met OR if 154 cases
meeting the primary endpoint definition of moderate to severe/critical COVID-19 are observed for
events with onset at least 28 days after double-blind vaccination.
AND
b) The above 3 conditions are met.
OR, alternatively,
2. 
If the prespecified non-efficacy boundary has been met (evaluating events with start 28 days after
double-blind vaccination) or when the harm boundary has been crossed. The decision rules for harm
and non-efficacy are detailed in Section 9.5.1.1.
3. 
If an efficacy signal is triggered before the required 8-week follow-up after double-blind vaccination
of 50% of participants is reached (8-week median follow-up timepoint), an additional analysis will be
performed when that follow-up timepoint is reached. If the time between the efficacy signal and the
required 8-week median follow-up is too short to make a difference in terms of preparing two analyses,
then a single analysis will take place at the time ofthe 8-week median follow-up. The analysis at the
time of the 8-week median follow-up is considered the primary analysis.
If more than 154 primary endpoints are observed for events with onset at least 28 days after double-blind
vaccination before the 3 conditions above are met, a single analysis will take place as soon as the conditions
are met, using the full 2.5% one-sided significance level.
If the prespecified boundaries and above criteria are met, the SSG will inform the DSMB and if deemed
appropriate by the DSMB, a meeting with the DSMB and Oversight Group will be set up to discuss the
efficacy signal. Upon this meeting the sponsor representative on the Oversight Group can trigger internal
decision procedures to initiate health authority interactions based on the outcome of the study.
The primary efficacy analysis will pool data across populations (both age groups with and without
comorbidities) to evaluate the primary and secondary objectives. In addition, these will be supplemented
with a subgroup analysis for age group (18 to <60 years, ≥60 years) and comorbidities employing a
descriptive summary, including 95% confidence intervals to describe the VE in each subpopulation.
Depending on the recruited study population, the ≥60 years subgroup may be further subcategorized (≥70
years, ≥80 years).
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
All secondary endpoint analyses 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.
Immunogenicity Analyses
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).
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Status: Approved, Date: 15 April 2022
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). For SAEs, AESIs, and MAAEs, the full FAS is considered. New
onset of chronic disease will be collected as part of the MAAEs.
Safety endpoints following the open-label cross-over vaccination and following the booster vaccination
will be descriptively summarized. Pooled safety analyses with other studies may also be performed.
Analysis of the Open-label cross-over Phase, Open-label Booster Phase, and Passive Surveillance
Phase
Safety, immunogenicity, and efficacy endpoints following cross-over and/or booster vaccination will be
descriptively summarized by the different cohorts for the different phases (ie, for the open-label phase:
early vaccinated cohort and late vaccinated cohort; ie, for the booster phase: 1-dose cohort, homologous
booster cohort and the heterologous booster cohort).
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.
The following data sources will be explored:
1. If available, data of participants in the study who did not receive a booster and/or available data prior
to boosting.
2. Data of individuals outside the study who received a similar primary regimen but did not receive a
booster. It will be explored if external data (eg, real world evidence data, and/or published literature
data) is available to that end for the countries enrolled in this trial.
For 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 not limit to age, presence of co-morbidities as well as the spatiotemporal
evolution of variants and the epidemic. It is anticipated that comparative evaluation of efficacy against
asymptomatic infections using real world evidence of data of individuals outside the study will not be
feasible due to the difficulty of detecting asymptomatic infections in real world evidence.
Efficacy data may be compared following homologous versus heterologous booster vaccination. Efficacy
data after primary vaccination until booster vaccination may be summarized (as immediate, early versus
delayed, late vaccination).
Details will be provided in the SAP.
Interim Analyses and Committees
The study will be formally monitored by a DSMB (also known as an IDMC). In general, the DSMB will
monitor safety data on a regular basis to ensure the continuing safety of the participants. The DSMB will
review unblinded data.
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Status: Approved, Date: 15 April 2022
The DSMB will review Day 3 safety data (ie, from Day 1 to Day 3; including safety data from the ongoing
clinical studies) from participants enrolled in Stage 1a and Stage 2a, before enrollment of participants in
Stage 1b and Stage 2b, respectively. Vaccination of participants in the respective age groups will be paused
during these safety reviews. Enrollment will not be paused during other safety reviews. The DSMB
responsibilities, authorities, and procedures will be documented in the DSMB 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 efficacyanalysis is triggered. If the stopping boundary is met, then the SSG immediately informs
the Chair of the DSMB through secure communication procedures. At this point the DSMB will convene
and provide a recommendation to the Oversight Group, which includes a sponsor representative as a core
member. As such, the potential harm monitoring is in real-time, resulting in the earliest indication of harm
possible as soon as data come in. In addition, the DSMB will formally monitor the SARS-CoV-2 events to
conclude both non-efficacy and efficacy. The DSMB  will evaluate in an unblinded fashion whether
superiority is established for the co-primary endpoints or whether non-efficacy is shown based on a report
provided by the SSG, when the prespecified boundaries have been crossed.
The study will also be monitored for operational non-efficacyto evaluate whether enough events to perform
the PA can be collected within reasonable time. For that purpose, a monitoring rule will be set up to assess
the probability that the minimal needed target number of primary endpoints events to be able to perform
the PA in the PP set will be reached. For the double-blind phase of the study, two versions of the non-
efficacy monitoring report will be generated. A report provided to the DSMB will contain unblinded events
and a report provided to the sponsor will contain blinded events. While it is the primary responsibility of
the sponsor to make decisions regarding study operations and modifications based on monitoring of study
vaccine-blinded primary events from the study, the DSMB  can evaluate the progress towards primary
endpoints targets in the context of the study vaccine-unblinded data, and based on this review may
recommend to the Oversight Group, which includes a sponsor representative as a core member, to complete
the study early due to reaching a boundary for efficacy or non-efficacy to assess VE. During the open-label
phase, the DSMB will continue to monitor safety.
The monitoring rules will be detailed in the DSMB Charter, with the statistical details in the SAP.
A final analysis of the double-blind phase will be performed when all participants have completed the
Month 6/Unblinding Visit or discontinued earlier. Depending on the operational implementation of the
Month 6/Unblinding Visit, as well as the stage of the pandemic, this analysis may be conducted when a
minimum of 90% of the study population has been unblinded. This will provide an analysis of all endpoints
for the blinded portion of the study. This analysis will also incorporate data collected after the EUA
submission to the FDA. All data generated after the unblinding will be considered as part of an analytic
plan devoted to the open-label phase. More details will be provided in the SAP. This analysis may be
supplemented by independent measures of incidence and efficacy with real world data obtained in separate
studies, to be described in a separate protocol.
The SAP will describe the planned analyses in greater detail.
Unblinding due to availability of an authorized/licensed COVID-19 vaccine
In the double-blind-phase of the study, investigators may receive requests to unblind study participants who
become eligible to receive an authorized/licensed COVID-19 vaccine if/when these become available. In
these cases, the investigator will discuss with the participant available options and ramifications. If the
participant is eligible for an  authorized/licensed vaccine according to local immunization guidelines or
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recommendation and if the participant wishes to proceed with the unblinding, the investigator will follow
the unblinding procedures. 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 body of the protocol for
more details).
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 two different
COVID-19 vaccines. Unblinded participants, both in the double-blind and open-label phase, will be asked
to continue to be followed in this study in line with the Schedule of Activities to the extent that they permit.
Safety, efficacy, and immunogenicityevaluations 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,
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  analysis, as described in the
Statistical Analysis Plan.
Prior to EUA, conditional licensure or approval in any country, 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 study  VAC31518COV3001. Study
investigators should query participants to elicit and document such participation in other studies in the
VAC31518COV3001 study record.
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Schema
Figure 1: 
Schematic Overview of Study VAC31518COV3001
Active = Ad26.COV2.S; incl. = including; LTFU = long-term follow-up; rand. = randomization; Th = T-helper cell type 1/2
a At the time of protocol Amendment 1 writing, immunogenicity and safety data from Cohort 1a (≥18-≤55 years of age) and Cohort 3 (≥65 years of age)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 and that the dose is considered safe. Stage 2a can therefore be enrolled in parallel to Stage 1a,
unless this is not allowed per local Health Authority guidance.
* Upon implementation of protocol Amendment 4, all participants will be unblinded and the study will continue as an open-label study. Participants who received
placebo as vaccination 1 (Day 1) will be offered to receive Ad26.COV2.S at this Month 6/Unblinding Visit
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** Upon implementation ofprotocol Amendment 6, all ongoing participants who have previously received any COVID-19 vaccination(s) (as primary regimen or
additional dose) with the Ad26.COV2.S vaccine and/or an mRNA vaccine or another for primary vaccination authorized COVID-19 vaccine including protein,
inactivated, and adenovector based vaccines will be offered a single booster dose of Ad26.COV2.S vaccine (5×1010 vp)at the Year 1/Booster Visit. Participants
who choose to receive a booster vaccination with the Ad26.COV2.S vaccine (if recommended and available) or another authorized COVID-19 vaccine outside the
study or choose not to receive a booster vaccination will not be withdrawn from the study and will be encouraged to remain in the study.
A screening phase of up to 28 days is included, however, screening may also be performed prior to randomization on the day of vaccination.
In Stage 1a and 1b combined, the enrollment ofparticipants aged ≥18 to <40 years will be limited to approximately 20% of the total study population. Stage 2, including
participants aged ≥60 years, will enroll a minimum ofapproximately 30% of the total study population. 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 VAC31518COV3001 based on data from study VAC31518COV1001.
Refer to Section 2.2 for details about the VAC31518COV1001 study.
Refer to Section 5.2 for details on the relevant comorbidities.
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Status: Approved, Date: 15 April 2022
Phase 
Study Period
Long-term Follow-up  
Phone Calls 
Early Exit
Phone Call
Visit number 
6a
7 (previously numbered as Visit 10) 
8 (previously numbered as Visit 11) 
Exitb
Visit Timing
Primary Vac
+52 w
Booster 
+24 w  
Booster
+52 w
Visit Day/Week
Year 1
(Week 52)
Month 18 
(24 weeks after Year 1 Visit) 
Year 2
(52 weeks after Year 1 Visit)
Visit Window
Preferably 6 months,
but at least 3 months
after last COVID-19
vaccination*
±28 d  
±28 dn
Activities below are only applicable to
those that will receive a booster
vaccination under special
circumstancesm
No further booster vaccination is to be given as of Protocol Amendment 7**
Body temperatured 
#,+ 
 
Urine pregnancy teste 
#,+ 
 
Pre vaccination symptomsf 
#,+
Vaccination 
+ 
 
Clinical laboratory blood sample 
(whole blood), mLk,l 
#,+7 
 
 
Approx. blood draw range per visit, mL  
7ml
# pre vaccination
* ie, preferably within window of 100 to +170 days around Year 1, but no later than the expiry date of the Ad26.COV2.S vials available at your site.
** Except if there is a medical reason that prevents a participant to receive the Ad26COV2.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 the expiry date of the Ad26.COV2.S vials available at your site
+ applicable for participants who receive(d) a single dose of Ad26.COV2.S booster vaccination at the Year 1/Booster Visit under the conditions delineated in Section 6.5 (more details in
Section 8.10) and for participants who receive(d) a booster vaccination outside of the study. Participants who choose to receive a booster vaccination outside of the study are encouraged to
schedule their Year 1/Booster Visit prior to their booster vaccination, if feasible, and come in for the Year 1 + 28 Days visit within the specified visit window, if feasible, or as close as
possible to the visit window. As of protocol amendment 7, some participants may still receive a booster, for those subjects, the follow up should be a least 6 months post vaccination, but
the last visit can be shorter than 1 year post vaccination.
a. 
If allowed by local regulations, study visit 6 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 can be performed by a phone call or a telemedicine contact. Except for the vaccination
visit, assessments scheduled for the other visits may also be performed by a trained health care professional (HCP), if allowed per local regulations.
b. 
For those participants who are unable to continue participation in the study up to Visit 8, but for whom consent is not withdrawn, an early exit visit will be
conducted as soon as possible. Participants who wish to withdraw consent from participation in the study will be offered an optional visit for safety follow-up.
c. 
Reconsenting may take place at the Year 1/Booster Visit or, if Visit 6 already occurred, at an unscheduled visit and may be performed on-site or by phone as per
local regulations.
d. 
Body temperature will be measured preferably via the oral route, or in accordance with the local standard of care.
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e. 
For participants of childbearing potential only. 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 (see Section 6.5).
f. 
Investigator must check for acute illness or body temperature ≥38.0°C/100.4°F at the time of each vaccination. If any of these events occur at the scheduled time
for the booster vaccination, the Year 1/Booster Visit with active vaccine can be delayed within the preferred visit window.
g. 
MAAEs are to be reported for all participants from the moment of each vaccination until 6 months after the booster 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.
h. 
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 (regardless of the causal relationship) and AESIs are to be reported from the moment of vaccination until completion of the
participant’s last study-related procedure. 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 from the time of booster vaccination until 28
days post-vaccination.
i. 
From the moment the ICF for Amendment 7 is signed, the participant moves to the passive follow-up phase schedule. COVID-19 is to be reported as SAE, AE, or
MAAE until study end (see Section 8.3.1 for the reporting of COVID-19 events as of protocol amendment 7). Ongoing COVID 19 episodes from the date of
Amendment 7 approval will not be reported as SAEs, AEs, or MAAEs Participants may contact the site at any time in between scheduled visits to report COVID-
19 episodes.
j. 
Refer to Section 6.10 for collection and recording of concomitant therapies associated with SAEs, solicited and unsolicited AEs, suspected AESIs, and MAAEs
and COVID-19 (S)AEs or COVID-19 MAAEs.
k. 
To be collected pre-vaccination only from participants receiving Ad26.COV2.S as booster vaccination at Year 1/Booster Visit. Whole blood samples will be used
for a complete blood count, including platelets, in a local laboratory or a 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).
l. 
To be collected once operationally feasible.
m. No further booster doses will be administered under protocol amendment 7, except if there was a medical reason that prevented a participant to receive the
Ad26COV2.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.
n. 
The end-of-study analysis is planned 1 year after a minimum of 90% of the enrolled study population have reached the Year 1/Booster Visit or discontinued earlier
and will be conducted upon completion of the last participant visit. Hence, the end of study visit may occur at an earlier timepoint for those 10% of remaining
active participants. A minimum of 6 month safety follow-up should be done.
AE = adverse event; AESI = adverse event of special interest; approx.. = approximate; cont. = continuous; COVID-19 = coronavirus disease-2019; 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.
NCT04505722

NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
42
Status: Approved, Date: 15 April 2022
Visit Number 
6 
7++  
8+ 
9+ 
10 
11 
Exita
Visit Timing
Primary Vac
+52 w
Booster
+1 d  
Booster 
+28 d  
Booster
+72 d
Booster 
+24 w  
Booster
+52 w
Visit Day/Week  
Year 1 
(Week 52)/
Booster Visit
Year 1
+ 1 Day
Year 1 +28 
Days (Week 
56) 
Year 1 +72
Days (Week
62)
Month 18 
(24 weeks 
after Year 1 
Visit) 
Year 2
(52 weeks
after Year 1
Visit)
Visit Window
Preferably 6 months, but at least 3 months
after last COVID-19 vaccination*
+1 d  
±3 d  
±3 d  
±28 d  
±28 dt
Visit Type 
Safety and Immuno 
Immuno
Safety and 
Immuno 
Safety and 
Immuno 
Safety and 
Immuno 
Safety and 
Immuno 
Early
Exit
Phase 
Study Period
Long-term
Follow-up
Phase 
Study 
Period  
Long-term 
Follow-up  
Phase
Study
Period
IMMUNOGENICITY SUBSET
Humoral immunogenicity (serum),
mLp,o
15 
+,r15 
+,r15 
15 
15 
15
HOMOLOGOUS AND HETEROLOGOUS BOOSTER SUBSET
Humoral immunogenicity (serum),
mLq
#15 
15 
15 
15 
15 
15o
SUBSET OF HOMOLOGOUS AND HETEROLOGOUS BOOSTER SUBSETS
Blood cytokine/chemokine
assessment
#5 
5 
 
 
 
Biomarker RNAseq blood sample/
transcriptomics (PAXgene tubes, 
whole blood), mLg
#2.5 
2.5 
 
 
 
Approx. blood draw range per visit,
mLr
10.0 29.5 
0.0 7.5 
0.0 29.5 
0.0 15.0 
10.0 15.0 
0.0 15.0 
10 15
Approx. cumulative blood draw
range, mLr
62.0 101.5 
62.0 109.0 
62.0 138.5 
62.0 153.5 
72.0 168.5 
72.0-183.5
Activities below are only applicable
to those that will receive a booster
vaccination under special
circumstancesm
No further booster vaccination is to be given as of Protocol Amendment 7**
Urine pregnancy testf 
#,+
Pre vaccination symptomsh 
#
Vaccinations 
+
Post vaccination observationi 
+
Clinical laboratory blood sample
(whole blood), mLn
#,+,r7
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
43
Status: Approved, Date: 15 April 2022
# pre vaccination
* ie, preferably within window of 100 to +170 days around Year 1, but no later than the expiry date of the Ad26.COV2.S vials available at your site.
** Except if there is a medical reason that prevents a participant to receive the Ad26COV2.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 the expiry date of the Ad26.COV2.S vials available at your site
+ applicable for participants who receive(d) a single dose of Ad26.COV2.S booster vaccination at the Year 1/Booster Visit under the conditions delineated in Section 6.5 (more details in
Section 8.10) and for participants who receive(d) a booster vaccination outside of the study. Participants who choose to receive a booster vaccination outside of the study are encouraged to
schedule their Year 1/Booster Visit prior to their booster vaccination, if feasible, and come in for the Year 1 + 28 Days and Year 1 + 72 Days visits within the specified visit window, if
feasible, or as close as possible to the visit window.
++ only applicable for approximately the first 60 eligible participants once operationally feasible of the Homologous Booster Subset (approximately 15 per subgroup [1a, 1b, 2a, and 2b]) and
approximately the first 60 eligible participants once operationally feasible of the Heterologous Booster Subset (approximately 15 per subgroup [primary vaccination with mRNA vaccine,
protein vaccine, adenovector vaccine, and inactivated vaccine]) (see Section 8.1.4).
a. 
For those participants who are unable to continue participation in the study up to Visit 11, but for whom consent is not withdrawn, an early exit visit will be
conducted as soon as possible. Participants who wish to withdraw consent from participation in the study will be offered an optional visit for safety follow-up.
This includes the safety assessments of the early exit visit (no blood sampling for immunogenicity).
b. 
Reconsenting may take place at the Year 1/Booster Visit or, if Visit 6 already occurred, at an unscheduled visit and may be performed on-site or by phone as per
local regulations.
c. 
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. Blood pressure is to be graded by the investigator using the toxicity grading scale in Appendix 9.
d. 
Body temperature will be measured preferably via the oral route, or in accordance with the local standard of care.
e. 
If within 7days of the vaccination.
f. 
For participants of childbearing potential only. 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 (see Section 6.5).
g. 
Blood sample for exploration of biomarkers correlating with SARS-CoV-2 infection and COVID-19 severity.
h. 
Investigator must check for acute illness or body temperature ≥38.0°C/100.4°F at the time of each vaccination. If any of these events occur at the scheduled time
for the booster vaccination, the Year 1/Booster Visit with active vaccine can be delayed within the preferred visit window.
i. 
Participants in the study will be closely observed for at least 15 minutes post-vaccination. Participants will be allowed to leave the study site after it is documented
that the post-vaccination observation period is complete.
j. 
MAAEs are to be reported for all participants from the moment of each vaccination until 6 months after the booster 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.
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 are to be reported from the moment of vaccination until completion of the participant’s last study-related procedure.
AEs leading to study discontinuation (regardless of the causal relationship) are to be reported from the moment of vaccination until completion of the participant’s
last study-related procedure. 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 from the time of booster vaccination until 28 days post-
vaccination.
l. 
From the moment the ICF for Amendment 7 is signed, the participant moves to the passive surveillance phase schedule. COVID-19 is to be reported as SAE, AE,
or MAAE until study end (see Section 8.3.1 for the reporting of COVID-19 events as of protocol amendment 7). Participants may contact the site at any time in
between scheduled visits to report COVID-19 episodes.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
44
Status: Approved, Date: 15 April 2022
m. Refer to Section 6.10 for collection and recording of concomitant therapies associated with SAEs, solicited and unsolicited AEs, suspected AESIs, and MAAEs
and new COVID-19 (S)AEs or COVID-19 MAAEs.
n. 
Whole blood samples will be used for a complete blood count, including platelets, in a local laboratory or a 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).
o. 
Blood samples for immunogenicity will only be taken if the early exit visit is at least 10 days after the previous immunogenicity blood draw.
p. 
Blood sample for humoral immunity at Year 1/Booster Visit (prior to booster vaccination), Month 18, and Year 2, and additionally 28 days and 72 days after
booster vaccination, if applicable, may also include sample for sero-confirmation of SARS-CoV-2 infection. Samples will be collected for 400 participants at
selected sites.
q. 
Blood sample for humoral immunity at the Year 1/Booster Visit (pre-vaccination) and 28 days, 72 days, 6 months, and 1 year after booster vaccination, may also
include sample for sero-confirmation of SARS-CoV-2 infection. Samples will be collected for 600 participants at selected sites.
r. 
The approximate blood volume collected depends on which one of the immunogenicity or booster subgroups the participant is in.
s. 
No further booster doses will be administered under protocol amendment 7, except if there was a medical reason that prevented a participant to receive the
Ad26COV2.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.
t. 
The end-of-study analysis is planned 1 year after a minimum of 90% of the enrolled study population have reached the Year 1/Booster Visit or discontinued earlier
and will be conducted upon completion of the last participant visit. Hence, the end of study visit may occur at an earlier timepoint for those 10% of remaining
active participants. A minimum of 6 month safety follow-up should be done.
AE = adverse event; AESI = adverse event of special interest; approx.. = approximate; cont. = continuous; COVID-19 = coronavirus disease-2019; 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; vac
= vaccination; w = week(s).
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
45
Status: Approved, Date: 15 April 2022
1.3.3. 
All Participants (Prior to Amendment 7)
Phase Screeninga 
Study Period  
Long-term Follow-
up
Visit numberb 
1 
2 
3 
4 
5 
6 
7++  
8+ 
9+ 
10 
11 
Exitc
Visit Timing 
Vac
Vac 
+ 28 d  
Vac 
+ 70 d  
Vac + 24 w/
Post EUA,
conditional 
licensure or 
approval in any
country
Primary Vac 
+52 w  
Booster 
+1 d  
Booster 
+28 d  
Booster 
+72 d  
Booster 
+24 w  
Booster
+52 w
Visit Day/Week
Day -28 to
1
Day 1 
Day 29 
Day 71
Month 6
(Week 24)/
Unblinding Visit
Year 1
(Week 52)/
Booster Visit
Year 1
+ 1 Day
Year 1
+28
Days
(Week
56)
Year 1
+72
Days
(Week
62)
Month 18
(24 weeks
after Year
1 Visit)
Year 2
(52
weeks
after
Year 1
Visit)
Visit Window  
±3 d  
±3 d
As soon as possible
post Day 71 visit**
Preferably
6 months, but at
least 3 months
after last
COVID-19
vaccination***
+1 d  
±3 d  
±3 d  
±28 d  
±28 d
Visit Type 
Screening 
Vaccination 
Safety 
and 
Immuno 
Safety
and
Immuno 
Safety and Immuno
Safety and
Immuno
Immuno
Safety 
and 
Immuno 
Safety
and
Immuno 
Safety and
Immuno
Safety
and
Immuno
Early
Exit
Informed consentd 
 
 

Inclusion/exclusion
criteria
 
e
Demographics 

Risk factor
assessmentf
 
 
 
 

Optional consent to
access medical data
 
 
g
Relevant medical
historyh/prestudy 
therapiesi
 

Body weight and
height

Vital signsj 
 
 
Body temperaturek 
 
 
 
 
 
 
 
+ 
+ 
 
 
l
Urine pregnancy
testm 

 
 
 
*,kk 
+,kk
 
 
 
 
 
 
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
46
Status: Approved, Date: 15 April 2022
Phase Screeninga 
Study Period  
Long-term Follow-
up
Visit numberb 
1 
2 
3 
4 
5 
6 
7++  
8+ 
9+ 
10 
11 
Exitc
Visit Timing 
Vac
Vac 
+ 28 d  
Vac 
+ 70 d  
Vac + 24 w/
Post EUA,
conditional 
licensure or 
approval in any
country
Primary Vac 
+52 w  
Booster 
+1 d  
Booster 
+28 d  
Booster 
+72 d  
Booster 
+24 w  
Booster
+52 w
Visit Day/Week
Day -28 to
1
Day 1 
Day 29 
Day 71
Month 6
(Week 24)/
Unblinding Visit
Year 1
(Week 52)/
Booster Visit
Year 1
+ 1 Day
Year 1
+28
Days
(Week
56)
Year 1
+72
Days
(Week
62)
Month 18
(24 weeks
after Year
1 Visit)
Year 2
(52
weeks
after
Year 1
Visit)
Visit Window  
±3 d  
±3 d
As soon as possible
post Day 71 visit**
Preferably
6 months, but at
least 3 months
after last
COVID-19
vaccination***
+1 d  
±3 d  
±3 d  
±28 d  
±28 d
Visit Type 
Screening 
Vaccination
Safety
and
Immuno
Safety
and
Immuno
Safety and Immuno
Safety and
Immuno
Immuno
Safety
and
Immuno
Safety
and
Immuno
Safety and
Immuno
Safety
and
Immuno
Early
Exit
Pulse oximetry 
 
 
 
 
 
 
 
 
 
 
Randomization 

Nasal sample
collection for
SARS CoV 2
testingn
 
ll
Biomarker RNAseq
blood sample /
transcriptomics 
(PAXgene tubes,
whole blood), mLo
 
2.5 
2.5 
 
+,ss2.5
Blood sample
collection for
screening
serological test for
anti SARS CoV 2
antibody
p
 
MRU questionnaire
(baseline version)q 

NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
47
Status: Approved, Date: 15 April 2022
Phase Screeninga 
Study Period  
Long-term Follow-
up
Visit numberb 
1 
2 
3 
4 
5 
6 
7++  
8+ 
9+ 
10 
11 
Exitc
Visit Timing 
Vac
Vac 
+ 28 d  
Vac 
+ 70 d  
Vac + 24 w/
Post EUA,
conditional 
licensure or 
approval in any
country
Primary Vac 
+52 w  
Booster 
+1 d  
Booster 
+28 d  
Booster 
+72 d  
Booster 
+24 w  
Booster
+52 w
Visit Day/Week
Day -28 to
1
Day 1 
Day 29 
Day 71
Month 6
(Week 24)/
Unblinding Visit
Year 1
(Week 52)/
Booster Visit
Year 1
+ 1 Day
Year 1
+28
Days
(Week
56)
Year 1
+72
Days
(Week
62)
Month 18
(24 weeks
after Year
1 Visit)
Year 2
(52
weeks
after
Year 1
Visit)
Visit Window  
±3 d  
±3 d
As soon as possible
post Day 71 visit**
Preferably
6 months, but at
least 3 months
after last
COVID-19
vaccination***
+1 d  
±3 d  
±3 d  
±28 d  
±28 d
Visit Type 
Screening 
Vaccination
Safety
and
Immuno
Safety
and
Immuno
Safety and Immuno
Safety and
Immuno
Immuno
Safety
and
Immuno
Safety
and
Immuno
Safety and
Immuno
Safety
and
Immuno
Early
Exit
Pre vaccination
symptomsr
 
* 

eCOA training and
set ups

Distribution of
thermometer
 
 
 
 
Distribution of
pulse oximetert
 
 
 
 
Distribution of MA
COV formu
 
 
 
 
Training and
distribution: nasal
swab kit and saliva
recipients
 
 
 
 
 
 
NCT04505722

NCT04505722

NCT04505722

NCT04505722

NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
52
Status: Approved, Date: 15 April 2022
*** ie, preferably within window of 100 to +170 days around Year 1, but no later than the expiry date of the Ad26.COV2.S vials available at your site.
+ applicable for participants who receive(d) a single dose of Ad26.COV2.S booster vaccination at the Year 1/Booster Visit under the conditions delineated in Section 6.5 (more details in
Section 8.10) and for participants who receive(d) a booster vaccination outside of the study. Participants who choose to receive a booster vaccination outside of the study are encouraged to
schedule their Year 1/Booster Visit prior to their booster vaccination, if feasible, and come in for the Year 1 + 28 Days and Year 1 + 72 Days visits within the specified visit window, if
feasible, or as close as possible to the visit window.
++ only applicable for approximately the first 60 eligible participants once operationally feasible of the Homologous Booster Subset (approximately 15 per subgroup [1a, 1b, 2a, and 2b]) and
approximately the first 60 eligible participants once operationally feasible of the Heterologous Booster Subset (approximately 15 per subgroup [primary vaccination with mRNA vaccine,
protein vaccine, adenovector vaccine, and inactivated vaccine]) (see Section 8.1.4).
a. 
Screening will be performed within 28 days prior to the study vaccination or on the day of vaccination. If screening is performed on the day of vaccination
(recommended), Visit 1 and Visit 2 will coincide on Day 1. In that case, assessments should only be done once. Screening must be completed and all eligibility
criteria must be fulfilled prior to randomization and vaccination.
b. 
If allowed by local regulations, 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 can be performed by a phone call or a telemedicine contact. Except for the screening and
vaccination visits, assessments scheduled for the other visits may also be performed by a trained health care professional (HCP), if allowed per local regulations.
c. 
For those participants who are unable to continue participation in the study up to Visit 11, but for whom consent is not withdrawn, an early exit visit will be
conducted as soon as possible. Participants who wish to withdraw consent from participation in the study will be offered an optional visit for safety follow-up.
This includes the safety assessments of the early exit visit (no blood sampling for immunogenicity).
d. 
Signing of the ICF should be done before any study-related procedure. The ICF can be signed remotely prior to the Screening Visit. Downloading of an application
to the participant’s eDevice, to access materials for enrollment and study information, is not considered a study-related procedure. Participants entering the open-
label phase are required to sign a new ICF at the Month 6 /Unblinding Visit. All participants are required to sign a new ICF at the Year 1/Booster Visit. At the
Month 6/Unblinding Visit and at the time of booster vaccination (Year 1/Booster Visit), if applicable, all participants will be counselled about the importance of
continuing other public health measures to limit the spread of disease including social distancing, wearing a mask, and hand-washing (see Sections 8.9 and 8.10).
e. 
Check clinical status again before study vaccination.
f. 
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 on Day 1 (see Appendix 12) and, at other timepoints, on changes compared to Day 1. These data will be used for risk factor
analysis.
g. 
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 8.8). 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 (see Section 4.2.1).
h. 
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 comorbidities, history of any
medical conditions 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.
i. 
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 vaccination must be recorded at screening.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
53
Status: Approved, Date: 15 April 2022
j. 
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. Blood pressure is to be graded by the investigator using the toxicity grading scale in Appendix 9.
k. 
Body temperature will be measured preferably via the oral route, or in accordance with the local standard of care.
l. 
If within 7days of the vaccination.
m. For participants of childbearing potential only. At the Month 6/Unblinding Visit, participants who are pregnant and received placebo during the double-blind
phase, may be vaccinated 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 6.4). 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 (see Section 6.5).
n. 
Diagnostic molecular RT-PCR or other molecular diagnostic 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. 
Blood sample for exploration of biomarkers correlating with SARS-CoV-2 infection and COVID-19 severity.
p. 
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. This does not apply to the open-label phase of the
study.
q. 
MRU over the last 3 months before vaccination will be collected by interview with the participant and recorded in the eCRF.
r. 
Investigator must check for acute illness or body temperature ≥38.0°C/100.4°F at the time of each vaccination. If any of these events occur within 24 hours prior to
the planned vaccination in the double-blind phase, 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. If, at the start of the
open-label phase, any of the above listed events occur at the scheduled time for the vaccination, the Month 6/Unblinding Visit with active vaccine can be delayed
up to 28 days following unblinding. If any of the above listed events occur at the scheduled time for the booster vaccination, the Year 1/Booster Visit with active
vaccine can be delayed within the preferred visit window.
s. 
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.
t. 
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).
u. 
The Medically-attended COVID-19 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-19 or COVID-19 complications.
v. 
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.
w. The first 2,000 participants in each of the 2 age groups will be closely observed for at least 30 minutes post-vaccination to monitor for the development of acute
reactions. If at the time of the Day 3 safety review of the initial 2,000 participants no acute reactions have been observed in the age groups, the remaining
participants in the study will be closely observed for at least 15 minutes post-vaccination. For participants in the Safety Subset (double-blind phase), 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.
x. 
Until 1 year after the Month 6/Unblinding Visit, 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 1-year after the Month 6/Unblinding Visit, through the end of the 2-year
follow-up period, the frequency of this (suspected) COVID-19 surveillance (symptom check) through the eCOA may decrease to once every 2 weeks depending on
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epidemiology. 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.
y. 
MAAEs are to be reported for all participants from the moment of each vaccination until 6 months after the vaccination (applicable for both the double-blind and
open-label phases of the study), 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.
z. 
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 (regardless of the causal relationship) are to be reported from the moment of 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 from the time of each vaccination until 28 days post-vaccination (applicable for both the double-blind and open-label phases of the study).
Participants will be reminded once a month to contact the study site in case of an SAE.
aa. Refer to Section 6.10 for collection and recording of concomitant therapies associated with SAEs, solicited and unsolicited AEs, suspected AESIs, and MAAEs.
bb. To be collected pre-vaccination only from participants receiving Ad26.COV2.S (after unblinding and/or as booster vaccination at Year 1/Booster Visit) and
28 days post booster vaccination (if applicable). Whole blood samples will be used for a complete blood count, including platelets, in a local laboratory or a
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).
cc. Blood sample for humoral immunity at Day 1 (pre-vaccination), Day 29, Day 71, Month 6/Unblinding Visit, Year 1/Booster Visit (pre-vaccination, if applicable),
Year 1 + 28 days for participants who received booster vaccination, Year 1 + 72 days for participants who received booster vaccination, and Month 18 (24 weeks
after Year 1 Visit), also includes sample for sero-confirmation of SARS-CoV-2 infection.
dd. Blood samples for immunogenicity will only be taken if the early exit visit is at least 10 days after the previous immunogenicity blood draw.
ee. Blood sample for humoral immunity at Day 1 (pre-vaccination), Day 29, Day 71, Month 6/Unblinding Visit, Year 1/Booster Visit (prior to booster vaccination, if
applicable), Month 18, and Year 2, and additionally 28 days and 72 days after booster vaccination, if applicable, also includes sample for sero-confirmation of
SARS-CoV-2 infection. Samples will be collected for 400 participants at selected sites.
ff. 
Enrollment into the Homologous Booster Subset and Heterologous Booster subset will start once operationally feasible. Blood sample for humoral immunity at the
Year 1/Booster Visit (pre-vaccination) and 28 days, 72 days, 6 months, and 1 year after booster vaccination, also includes sample for sero-confirmation of SARS-
CoV-2 infection. Samples will be collected for 600 participants at selected sites.
gg. 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 vaccination until 7 days after double-blind vaccination.
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hh. All other unsolicited AEs will be reported for the vaccination from the time of vaccination until 28 days after double-blind vaccination. In order to perform the
safety assessment after 2,000 participants have been vaccinated in Stages 1a and 2a, 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.
ii. 
If within 28 days of the vaccination.
jj. 
A ruler to measure local injection site reactions will be distributed to each participant in the Safety Subset.
kk. To be repeated pre-vaccination if previous test was >1 day ago. Participants who originally received placebo and will not be receiving the Ad26.COV2.S vaccine
under EUA, do not need to complete a pregnancy test.
ll. 
To be repeated pre-vaccination ifprevious sample was >3 days ago.
mm. To be repeated pre-vaccination if previous sample was >5 days ago.
nn. The approximate blood volume collected depends on whether the participant is in one of the immunogenicity subgroups and/or received Ad26.COV2.S booster
vaccination at the Year 1/Booster Visit.
oo. Those participants in the Immunogenicity Subset that transfer to the Homologous Booster Subset at the Year 1/Booster Visit will from that visit onwards follow
the humoral immunogenicity sample schedule of the Homologous Booster Subset and discontinue the schedule of the Immunogenicity Subset.
pp. All participants will collect solicited signs and symptoms (including body temperature) in an e-Diary via the eCOA from the time of booster vaccination until 7
days after booster vaccination, if feasible. The diary will be reviewed by the study personnel and solicited AEs recorded for a subset of participants ie, participants
included in the Safety Subset of the double-blind phase and all participants who received a heterologous prime or booster vaccination outside the study, if feasible.
After the signing of informed consent of Amendment 7, no further solicited symptoms will be collected.
qq. Unsolicited AEs will be recorded for all participants from time of booster vaccination until 28 days after booster vaccination. After signing informed consent of
Amendment 7, no futher unsolicited symptoms will be collected.
rr. 
A ruler to measure local injection site reactions will be distributed to all participants, if feasible.
ss. To be collected once operationally feasible.
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; EUA = Emergency Use Authorization; 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).
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1.3.4. 
Participants With (Suspected) COVID-19
1.3.4.1. 
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 will not include any laboratory sampling. 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 contact the site at any time in between scheduled visits to report COVID-19 episodes. Concomitant therapies related to these events are
to be reported, as well as any confirmatory COVID-19 laboratory information, ifavailable.
Guidance on (S)AE coding may be provided.
Some participants will have an ongoing COVID-19 event at time of signing the informed consent of protocol amendment 7. Also, under
protocol amendment 7, the eCOA will be decommissioned. Hence participant will stop using the eCOA as of the consent visit. The outstanding
activities planned for the follow-up of COVID-19 events 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.
1.3.4.2. 
Active Follow-up (Prior to Amendment 7)
Timing relative to onset of signs and symptoms
COVID
-19
Day 1-2
COVID-19 
Day 3-5a 
2-day cycle to be
repeatedb,c,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 
 
 

Humoral immunity (serum), mL 
 
15 
15q
Biomarker RNAseq blood sample (PAXgene tubes, whole blood), mLr 
 
2.5 
2.5
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(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. 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).
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.
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 after COVID-19 Day 29, 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.
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 RT-PCR or other molecular diagnostic test performed at 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. Blood sample for exploration of biomarkers correlating with SARS-CoV-2 infection and COVID-19 severity.
s. Participants should complete the (suspected) COVID-19 surveillance (symptom check). 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 onset UNLESS both COVID-19 Day 1-2 and COVID-19 Day 3-5 are both 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.
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.
t. 
If the participant does not have symptoms at that time, he/she will only need to complete the (suspected) COVID-19 surveillance (symptom check).
u. 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.
v. 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.
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w. 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.
x. Data collected as part of the MRU will be recorded in the eCRF.
y. 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-19 or COVID-19 complications.
Upon closure of the COVID-19 episode and procedures, all participants will fall back to the default Schedule 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 re-start 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.
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1.3.5. 
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 Adjudication Committee. In the event of a
suspected thrombotic event 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- platelet factor 4 (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.
In the event of a suspected thrombotic event or TTS, laboratory assessments 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 testing requested by the sponsor
as detailed below. However, results of central laboratory testing may not be available to guide
immediate treatment decisions.
Timing relative to onset of suspected AESI
AESI 
Day 1a 
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 
 

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.
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. Whole blood samples will be used for 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 and plasma samples will be derived from the whole blood sample for coagulation-related testing
in a central laboratory (see Section 10.2, Appendix 2). For the follow-up visit, the volume of blood to be collected
may vary depending on the clinical evaluation of the case.
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.
AESI = adverse event of special interest; CDC = Centers for Disease Control and Prevention; PF4 = platelet factor 4;
TTS = thrombosis with thrombocytopenia syndrome
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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 July 2020. At that time, the Ad26.COV2.S Investigator’s
Brochure (IB) Edition 1.0 and its Addendum 1 were in place.41,42
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.” The “unblinding visit”
refers to the Month 6 visit that starts the open-label phase of the study, as described in Section 2.1.
Study VAC31518COV3001 is being conducted under the sponsorship of Janssen (Janssen
Vaccines & Prevention B.V) in collaboration with the coronavirus disease-2019 (COVID-19)
Response Team (formerly known as OWS), which also encompasses the Biomedical Advanced
Research and Development Authority (BARDA), the National Institutes of Health (NIH), and the
COVID-19 Prevention Trials Network (COVPN).
COVID-19 Vaccine and Considerations
Currently, there are no available vaccines for the prevention of 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.22,78 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.
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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
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.4,43,53
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 initial effort will be to rapidly demonstrate safety
and immunogenicity in adults aged ≤55 years in study VAC31518COV1001, in order to initiate
the efficacy study VAC31518COV3001 in this age group as soon as possible, and to evaluate
safety and immunogenicity in older adults aged ≥65 years. 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.22,33,54 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
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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
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.44
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.11  Severe clinical
presentations have been reported in as many as 20% to 25% of laboratory-confirmed cases.32 In a
study of 99 patients 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%).21 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 138 patients 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 definitions11  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.36 In contrast, a study of 2,143 children
aged <18 years in China with laboratory-confirmed (34.1%) or suspected (65.9%) COVID-19
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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,
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 18 years: 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.20,81 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.20,73 The case-fatality
rate of MERS-CoV infections is estimated to be 35%.20
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.
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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.
At the time of protocol Amendment 1 writing, initial immunogenicity and safety data (28 days
post-Dose 1 data from Cohort 1a and available data from Cohort 3) from study
VAC31518COV1001 have become available and demonstrate that a single dose of Ad26.COV2.S
at 5×1010 virus particles (vp) and 1×1011 vp induces an immune response that meets prespecified
minimum criteria and had an acceptable safety profile. These data support the sponsor’s decision
to proceed with the single dose regimen at a 5×1010 vp dose level in this Phase 3 study.
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,1,8,28,39,40 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 VAC31518COV3001 will include ≥18- to <60-year-old participants and participants
≥60 years of age.
Study VAC31518COV3001 will start with enrollment in Stage 1 (≥18- to <60-year-old
participants) based on all available safety and reactogenicity data, and all relevant and available
immunogenicity data from Cohort 1a (adults ≥18 to ≤55 years) of the first-in-human (FIH) study
with the vaccine candidate (Ad26.COV2.S; study VAC31518COV1001; see Section  2.2),
immunogenicity data (including Th1 responses) from non-human primates (NHPs), and efficacy
in hamsters and NHPs and all other relevant data. Immunogenicity data from Cohort 1a of study
VAC31518COV1001 will include virus neutralization assay (VNA), enzyme-linked
immunosorbent assay (ELISA)and Th1/Th2 response data.
Because the data from study VAC31518COV1001 (including data on elderly) demonstrated that
Ad26.COV2.S at 5×1010 vp is both immunogenic and safe, Stage 2a (participants ≥60 years of
age) of study VAC31518COV3001 will start enrolling in parallel to Stage 1a, unless this is not
allowed per local Health Authority guidance.
Within Stage 1a and Stage 2a, enrollment will be restricted to participants without comorbidities
that are associated with increased risk of progression to severe COVID-19 as described below.
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The study will start by enrolling approximately 2,000 participants (≥18- to <60-year-old) without
comorbidities that are associated with increased risk of progression to severe COVID-19
(including approximately 1,000 Ad26.COV2.S  recipients and approximately 1,000 placebo
recipients) (Stage 1a of the study), then vaccination will be paused to allow the Data Safety
Monitoring Board (DSMB) to examine Day 3 safety data (ie, from Day 1 to Day 3; including
safety data from the ongoing clinical studies). If no safety concerns are identified, enrollment will
proceed, expanding enrollment to ≥18- to <60-year-old participants with and without
comorbidities that are associated with increased risk of progression to severe COVID-19
(Stage 1b) (see Section 1.2 [Figure 1] for a schematic overview of the study and Section 5.2 for
the list of relevant comorbidities).
In parallel to Stage 1a, in Stage 2 of the study, approximately2,000 adults ≥60 years of age without
comorbidities that are associated with increased risk of progression to severe COVID-19 will be
enrolled (Stage 2a; including approximately 1,000 Ad26.COV2.S  recipients and approximately
1,000 placebo recipients). Following enrollment of these initial 2,000 participants in Stage 2a,
further vaccination in Stage 2 of the study will be paused to allow the DSMB to examine Day 3
safety data (ie, from Day 1 to Day 3; including safety data from Stage 1 and the ongoing clinical
studies). Upon confirmation that there are no safety concerns in this population or in the Stage 1
population up to that point, enrollment will proceed, including participants aged ≥60 years with
and without comorbidities that are associated with increased risk of progression to severe
COVID-19 (Stage 2b) (see Section 1.2 [Figure 1] for a schematic overview of the study and
Section 5.2 for the list of relevant comorbidities).
The total sample size for the study (including ≥18- to <60-year-old and ≥60-year-old participants,
and participants with and without comorbidities that are associated with increased risk of
progression to severe COVID-19) will be approximately 40,000 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.
Refer to Section 9.2.1 for details about the sample size determination.
Following EUA, conditional licensure, or approval in any country, a single dose of Ad26.COV2.S
will be offered to enrolled participants who initially received placebo, where Amendment 4 is
approved by the local Health Authority and IEC/IRB, resulting in de facto unblinding of
participants and investigators. Of note, after the primary analysis, sponsor personnel except
individuals directly in contact with study investigators are already unblinded according to the study
protocol. All participants will be encouraged to remain in the study and continue to be followed
for efficacy/effectiveness, safety and immunogenicity as originally planned up to 2 years after
double-blind vaccination. This will allow assessment of the duration of protection and
immunogenicity of a single dose of Ad26.COV2.S by comparing 2 groups vaccinated
approximately 4 to 6 months apart.
As of implementation of protocol Amendment 6, all ongoing participants in the study who have
previously received any COVID-19 vaccination(s) (as primary regimen or additional dose) with
the Ad26.COV2.S vaccine, and/or an mRNA vaccine or another COVID-19 vaccine authorized
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for primary vaccination including protein, inactivated, and adenovector based vaccines will be
offered a single booster dose of Ad26.COV2.S vaccine (5×1010 vp) if the last vaccination was
preferably 6 months but at least 3 months ago. Participants who choose to receive a booster
vaccination with the Ad26.COV2.S vaccine (if recommended and available) or another authorized
COVID-19 vaccine outside the study or choose not to receive a booster vaccination will not be
withdrawn from the study and will be encouraged to remain in the 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 final analyses of the study that described the double-blind phase have
been completed and the primary objective has been met. Further efficacy evaluations of the
open-label data have limitations, due to 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 of 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).
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.41,42
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
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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
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. As of 10 September 2020, a single injection of Ad26.COV2.S has been administered to
805 adult participants, aged 18 and older.
The FIH  study  VAC31518COV1001 will be ongoing at the time of initiation of study
VAC31518COV3001. 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 ≥18 to
≤55 years (Cohort 1). 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.
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The study includes the following cohorts (Table 1):
1. Cohort 1:
a. Cohort 1a: 375 participants (75 participants per group) aged ≥18 to ≤55 years who will
be randomized in parallel in a 1:1:1:1:1 ratio to 1 of 5 vaccination groups.
b. Cohort 1b: 25 participants (5 participants per group) aged ≥18 to ≤55 years who will be
enrolled at the Beth Israel Deaconess Medical Center (BIDMC) and randomized in
parallel in a 1:1:1:1:1 ratio to 1 of 5 vaccination groups. Additional exploratory
immunogenicity evaluations (eg, epitope mapping, passive transfer, and certain analyses
offunctional and molecular antibody characteristics) will be performed for Cohort 1b.
2. Cohort 2: 270 participants aged ≥18 to ≤55 years will be randomized to receive Ad26.COV2.S
(240 participants) or a placebo (30 participants) in the primary regimen. Cohort 2 will include
an evaluation of a single booster vaccination.
3. Cohort 3: 375 participants (75 participants per group) aged ≥65 years who will be randomized
in parallel in a 1:1:1:1:1 ratio to 1 of 5 vaccination groups.
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Table 1: 
Vaccination Schedules of Study VAC31518COV1001
Cohort 1a (Adults ≥18 to ≤55 years)
Group  
N 
Day 1 (Vaccination 1) 
Day 57 (Vaccination 2)
1 
75 
Ad26.COV2.S 5×1010 vp 
Ad26.COV2.S 5×1010 vp
2 
75 
Ad26.COV2.S 5×1010 vp 
Placebo
3 
75 
Ad26.COV2.S 1×1011 vp 
Ad26.COV2.S 1×1011 vp
4 
75 
Ad26.COV2.S 1×1011 vp 
Placebo
5 
75 
Placebo 
Placebo
Cohort 1b (Adults ≥18 to ≤55 years) a
Group  
N 
Day 1 (Vaccination 1) 
Day 57 (Vaccination 2)
1 
5 
Ad26.COV2.S 5×1010 vp 
Ad26.COV2.S 5×1010 vp
2 
5 
Ad26.COV2.S 5×1010 vp 
Placebo
3 
5 
Ad26.COV2.S 1×1011 vp 
Ad26.COV2.S 1×1011 vp
4 
5 
Ad26.COV2.S 1×1011 vp 
Placebo
5 
5 
Placebo 
Placebo
Cohort 2a (Adults ≥18 to ≤55 years)
Group  
N 
Day 1 (Vaccination 1) b 
Day 57 b
1-4 
120 
Ad26.COV2.S 5×1010 vpc 
No vaccination
5 
15 
Placebo 
No vaccination
Cohort 2b (Adults ≥18 to ≤55 years)
Group  
N 
Day 1 (Vaccination 1) b 
Day 57 (Vaccination 2) b
1-4 
120 
Ad26.COV2.S 5×1010 vp 
Ad26.COV2.S 5×1010 vp
5 
15 
Placebo 
Placebo
Cohort 3 (Adults ≥65 years)
Group  
N 
Day 1 (Vaccination 1) 
Day 57 (Vaccination 2)
1 
75 
Ad26.COV2.S 5×1010 vp 
Ad26.COV2.S 5×1010 vp
2 
75 
Ad26.COV2.S 5×1010 vp 
Placebo
3 
75 
Ad26.COV2.S 1×1011 vp 
Ad26.COV2.S 1×1011 vp
4 
75 
Ad26.COV2.S 1×1011 vp 
Placebo
5 
75 
Placebo 
Placebo
Total 
1,045
a. Cohort 1b comprises 5 participants in each group who will be enrolled at Beth Israel Deaconess Medical Center (BIDMC)
and for whom additional exploratory immunogenicity analyses will be performed.
b. Study vaccine will be administered as a single dose (Day 1) or 2 dose (Day 1 and Day 57) primary regimen. Cohort 2 will
also include an evaluation of a single booster vaccination at 6, 12, or 24 months after completion of the primary single dose
or 2 dose primary regimen.
c. Revised per VAC31518COV1001 protocol Amendment 6, dated 19 September 2020.
N  number of participants; vp  virus particles.
At the time of protocol Amendment 1 writing, 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 had an
acceptable safety profile. The sponsor has therefore decided to proceed with the single dose
regimen at a 5×1010 vp dose level in this Phase 3 study.
For more detailed information about the clinical experience with Ad26.COV2.S,refer to the IB.42
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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 938 adult 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.
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-inactivatedRSV vaccine was associated with enhanced respiratory disease
(ERD) in young children, characterized by an increased rate of RSV-mediated, severe lower
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respiratory tract infection in the vaccinated individuals compared with the control group.23,35,45,46
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,42 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 reminiscent of 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-2.42
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
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.
Benefit-Risk Assessment
More detailed information about the known and expected benefits and risks of Ad26.COV2.S may
be found in the IB.42
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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
VAC31518COV3001 protocol.
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).
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
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 (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 Adjudication 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
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for thrombotic events, thrombocytopenia, and TTS (see Section 8.3.7and Section 8.3.7.1), which
may facilitate diagnosis and clinical management of the event.
Risks Related to Ad26.COV2.S Administration after Previous Vaccination Ad26.COV2.S
Preliminary safety data of an Ad26.COV2.S booster administered at the 5×1010 vp dose level
≥6 months post-primary single-dose Ad26.COV2.S (5×1010 vp) vaccination 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.
Risks Related to Ad26.COV2.S Administration after Previous Vaccination with a Different
COVID-19 Vaccine
To date, no clinical data are available for Ad26.COV2.S vaccination after previous vaccination
with a different COVID-19 vaccine.
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.
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.
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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.
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).
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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 17years 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 monitoredbutare 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.
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 vaccination, participants will remain at the study site for close observation by study staffto
monitor for the development of any acute reactions. The first 2,000 participants in each of the
2 age groups will remain under observation at the study site for at least30 minutes after vaccination
to monitor for the development of acute reactions. Ifat the time of the Day 3 safety review of the
initial 2,000 participants no acute reactions have been observed in the age groups, the observation
period at the study site may be reduced to at least 15 minutes for the remaining participants in the
study. Necessary emergency equipment and medications must be available in the study site to treat
severe allergic reactions.
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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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 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 double-blind
phase of the study. Participants who are pregnant at their Month 6/Unblinding Visit and received
placebo during the double-blind phase, may be vaccinated 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  6.4). 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
become pregnant during the study will remain in the study and will continue to undergo all
procedures for surveillance and follow-up of COVID-19 and all safetyfollow-up as outlined in the
protocol for all participants. 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 models1,8,28,39,40, 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
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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). 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, if applicable. In case
of any 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. The subset
of cases with potential for severe disease 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) for approximately1 year
after the Year 1/ Booster Visit, ie, until the last study visit. 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 DSMB 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 DSMB 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.
The efficacy, immunogenicity and safety data to date support 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.
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:
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In general, safety evaluations will be performed at scheduled visits during the study, as
indicated in the Schedules of Activities.
 
The first 2,000 participants in each of the 2 age groups will remain under observation at
the study site for at least 30 minutes after vaccination to monitor for the development of
acute reactions. If at the time of the Day 3 safety review of the initial 2,000 participants
no acute reactions have been observed in the age groups, the observation period at the
study site may be reduced to at least 15 minutes 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.
 
Suspected AESIs (thrombotic events and thrombocytopenia [defined as platelet count
below 150,000/µL]9) must be reported to the sponsor within 24 hours of awareness. From
the time of local approval of protocol Amendment 5 onwards, TTS is considered  an AESI
(Section 8.3.7). Suspected AESIs will be followed up as described in the Schedule of
Activities in Section 1.3.5. Refer to Section 10.14 Appendix 14 for a list of thrombotic
events to be reported to the sponsor as suspected AESIs.
 
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.
 
A DSMB 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 DSMB responsibilities, authorities, and procedures will be
documented in the DSMB Charter. The DSMB will also review Day 3 safety data (ie,
from Day 1 to Day 3; including safety data from the ongoing clinical studies) from
participants enrolled in Stages 1a and Stage 2a, before enrollment of participants in Stages
1b and Stage 2b, respectively. 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 DSMB will continue to monitor safety.
 
Several safety measures are included in this protocol to minimize the potential risk to
participants, including the following:
 
The study will use the following enrollment strategy to mitigate the risks for participants
at increased risk of progression to severe COVID-19:
o 
In Stage 1 (double-blind phase), the study will enroll ≥18- to <60-year-old
participants (Stage 1 of the study) based on immunogenicity and safety data from
Cohort 1a of study VAC31518COV1001 (see details in Section 2.1). In Stage 1a,
approximately  2,000 participants without comorbidities that are associated with
increased risk of progression to severe COVID-19 will be enrolled (including
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approximately 1,000 Ad26.COV2.S  recipients and approximately 1,000 placebo
recipients), then vaccination will be paused to allow the DSMB to examine Day 3
safety data (ie, from Day 1 to Day 3; including safety data from the ongoing clinical
studies). If no safety concerns are identified, enrollment will proceed, including ≥18-
to <60-year-old participants with and without comorbidities that are associated with
increased risk of progression to severe COVID-19 (Stage 1b) (see Section 1.2
[Figure 1] for a schematic overview of the study and Section 5.2 for the list of
relevant comorbidities).
o 
In Stage 2 (double-blind phase) of the study, approximately 2,000 adults ≥60 years
of age without comorbidities that are associated with increased risk of progression to
severe COVID-19 will be enrolled (Stage 2a; including approximately
1,000 Ad26.COV2.S  recipients and approximately 1,000 placebo recipients) (see
details in Section 2.1). Considering the data from study VAC31518COV1001
(including data on elderly), Stage 2a will be enrolled in parallel with Stage 1a, unless
this is not allowed per local Health Authority guidance. Following enrollment of the
initial 2,000 participants aged ≥60 years (Stage 2a), further vaccination in Stage 2 of
the study will be paused to allow the DSMB to examine Day 3 safety data (ie, from
Day 1 to Day 3; including safety data from Stage 1 and the ongoing clinical studies).
Upon confirmation that there are no safety concerns in this population or in the Stage
1 population up to that point, enrollment will proceed, including participants aged
≥60 years with and without comorbidities that are associated with increased risk of
progression to severe COVID-19 (Stage 2b) (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 Protocol 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 Stages 1a and 2a, that if met would result
in pausing of further vaccinations (see Section 6.11), preventing exposure of new
participants to study vaccine until the DSMB 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 EUA, conditional licensure, or approval in any country, the study will be
conducted in the open-label fashion. All enrolled participants who initially received
placebo will be offered to receive a single dose of Ad26.COV2.S and will continue to be
monitored for safety as mentioned in Section 8.3. At the Month 6/Unblinding Visit, all
participants will be counselled about the importance of continuing other public health
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measures to limit the spread of disease including social distancing, wearing a mask, and
hand-washing (Section 8.9).
 
Ninety% of the participants who receive a booster vaccination will be monitored for
safety until 1 year post booster vaccination as mentioned in Section 8.3. The remaining
10% of subjects will be monitored for safety at least 6 months. At the Year 1/Booster
Visit, all participants will be counselled about the importance of continuing other public
health measures to limit the spread of disease including social distancing, wearing a mask,
and hand-washing (Section 8.10).
3. 
OBJECTIVES AND ENDPOINTS
Double-blind Phase of the Study
Objectives 
Endpoints
Co-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 double-blind
vaccination (Day 15)
First occurrence of molecularly confirmeda,
moderate to severe/critical COVID-19b, with
onset at least 28 days after double-blind
vaccination (Day 29)
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, 
severe/critical COVID-19b, as compared to 
placebo
First occurrence of molecularly confirmeda,
severe/critical COVID-19b, with onset at least
14 days after double-blind vaccination (Day 15)
First occurrence of molecularly confirmeda,
severe/critical COVID-19b, with onset at least
28 days after double-blind vaccination (Day 29)
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 double-blind vaccination
First occurrence of molecularly confirmeda,
moderate to severe/critical COVID-19b, with
onset 14 days after double-blind vaccination
(Day 15)
First occurrence of molecularly confirmeda,
moderate to severe/critical COVID-19b, with
onset at least 28 days after double-blind
vaccination (Day 29)
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Objectives 
Endpoints
To evaluate the efficacy of Ad26.COV2.S  in the
prevention of molecularly confirmeda moderate to
severe/critical COVID-19b 
as compared to
placebo, with onset 1 day after study vaccination
First occurrence of molecularly confirmeda,
moderate to severe/critical COVID-19b with onset
1 day after double-blind vaccination
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
double-blind vaccination (Day 15)
First occurrence of COVID-19 requiring medical
intervention and linked to any molecularly
confirmeda, COVID-19b,c at least 28 days after
double-blind vaccination (Day 29)
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
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 double-blind
vaccination (Day 15)
First occurrence of molecularly confirmeda, mild
COVID-19c, at least 28 days after double-blind
vaccination (Day 29)
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 double-blind
vaccination (Day 15)
First occurrence of molecularly confirmeda
COVID-19d at least 28 days after double-blind
vaccination (Day 29)
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 9.5.2) derived from the first occurrence
of 
molecularly 
confirmeda 
symptomatic
COVID-19c (meeting the mild, moderate or
severe/critical COVID-19 case definition) with
onset at least 14 days after double-blind
vaccination (Day 15).
BOD endpoint (see Section 9.5.2) derived from
the first occurrence of molecularly confirmeda
symptomatic COVID-19c (meeting the mild,
moderate or severe/critical COVID-19 case
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
83
Status: Approved, Date: 15 April 2022
Objectives 
Endpoints
definition) with onset at least 28 days after
double-blind vaccination (Day 29).
To assess the effect of Ad26.COV2.S on
occurrence of confirmed asymptomatic or
undetected infections with SARS-CoV-2, as
compared to placebo
Serologic conversions: between baseline (Day 1;
pre-vaccination) and Day 29, between Day 29
and Day 71, between Day 71 and Month
6/Unblinding Visit, and Month 18 after double-
blind vaccination (approximately 12 months after
initiation of the open-label phase of the study)
using 
an 
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 at
the time of the Month 6/Unblinding Visit
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 28 days after double-blind
vaccination (Day 29)
Safety
To evaluate safety in terms of SAEs and AESIs
(during the entire study), MAAEs (until 6 months
after double-blind or open-label 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 [double-blind or open-label] Ad26.COV2.S),
and MAAEs leading to study discontinuation
(during the entire study) for all participants
following vaccination
In a subset of participants, to evaluate the safety
and reactogenicity in terms of solicited local and
systemic AEs during the 7 days after double-blind
vaccination, and in terms of unsolicited AEs during
the 28 days after double-blind vaccination
Occurrence, intensity, duration and relationship of
solicited local and systemic AEs during the 7 days
following vaccination and of unsolicited AEs
during the 28 days after double-blind 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 evaluate the long term durability of the efficacy
of Ad26.COV2.S in the prevention of molecularly
confirmeda, 
moderate 
to 
severe/critical
COVID-19b, by comparing 2 groups vaccinated
approximately 4 to 6 months apart
First occurrence of molecularly confirmeda,
moderate to severe/critical COVID-19b, defined as
having an onset of at least:
1 day after Ad26.COV2.S
14 days after Ad26.COV2.S
28 days after Ad26.COV2.S.
To assess the effect of Ad26.COV2.S on
occurrence of confirmed asymptomatic or
undetected infections with SARS-CoV-2, as
compared to placebo from Day 1 to Day 29
Serologic conversion between baseline (Day 1;
pre-vaccination) and Day 29 after double-blind
vaccination using an ELISA and/or SARS-CoV-2
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
84
Status: Approved, Date: 15 April 2022
Objectives 
Endpoints
immunoglobulin assay that is dependent on the
SARS-CoV-2 nucleocapsid (N) protein
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 double-blind vaccination (Day 15)
Health care utilization (such as hospitalization,
ICU admission, ventilator use) linked to any
molecularly confirmeda COVID-19 at least
28 days after double-blind vaccination (Day 29)
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 28 days after double-blind
vaccination (Day 29)
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 double-blind
vaccination (Day 15)
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 28 days after double-blind
vaccination (Day 29)
To explore the effect of Ad26.COV2.S on all-cause 
mortality, as compared to placebo 
Deaths occurring at least 14 days after double-
blind vaccination (Day 15)
Deaths occurring at least 28 days after double-
blind vaccination (Day 29)
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, as well as gene transcript
profiling (RNA sequencing), 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 glycosylation, and assessment of
antibody repertoire
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
85
Status: Approved, Date: 15 April 2022
Objectives 
Endpoints
 
Adenovirus neutralization as measured by
VNA
 
Analysis of antibodies to S and the receptor-
binding domain (RBD) of the SARS-CoV-2 S
protein
 
Original and/or emerging SARS-CoV-2 virus
lineage neutralization as measured by virus
neutralization assay (VNA; wild-type virus
and/or pseudovirion expressing 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 
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 COVID- 
19 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.
To examine the degree of frailty in terms of balance 
in participants receiving Ad26.COV2.S vs placebo, 
the effect of degree of frailty on vaccine efficacy, 
and the degree of frailty in cases occurring in the 
Ad26.COV2.S vs placebo group. 
Utilization of the frailty index as a measure of
frailty prior to double-blind vaccination comparing
the Ad26.COV2.S vs placebo group and as a
measure to compare cases in the Ad26.COV2.S
vaccine vs placebo group.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
86
Status: Approved, Date: 15 April 2022
Objectives 
Endpoints
If feasible, 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
duration of protection, and AEs (see Section 4.2
and Section 8.8).
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 All secondary efficacy endpoint analyses will occur in the Per-Protocol (PP)analysis set, in seronegative
participants unless otherwise indicated in the SAP.
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESES
The study is designed to test the co-primary hypotheses of VE in the per-protocol (PP)population.
For both co-primary endpoints the following hypothesis will be tested:
H0: VE ≤30% versus H1: VE >30% and each hypothesis will be evaluated at a 2.5% one-sided
significance level.
The co-primary endpoints 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 double-
blind vaccination with Ad26.COV2.S versus placebo, in the PP population, including all
events from both age groups, with and without comorbidities.
 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 28 days after
double-blind vaccination with Ad26.COV2.S versus placebo, in the PP population,
including all events from both age groups, with and without comorbidities.
If testing for both primary endpoint hypotheses are 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%.
Details are described in Section 9.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
87
Status: Approved, Date: 15 April 2022
Open-label Active Phase
3.2.1. 
Open-label Cross-over Phase
Participants will enter the open-label cross-over phase on the day that the participant received the
cross-over vaccination or are unblinded until the day that the participant completed the booster
visit. There are 2 main cohorts in the open label phase:
- Early vaccinated cohort: participants who were initially randomized to the
Ad26.COV2.S group and received 1 dose of Ad26.COV2.S at day 1 in the trial
- Late vaccinated cohort: participants who were initially randomized to the placebo
group and who received 1 dose of Ad26.COV2.S after unblinding
The main objective of the open-label phase of the study is to evaluate the COVID-19 outcomes
after an early vaccination and after a late vaccination. Efficacy evaluations may be performed if
feasible, ie, if pre-specified criteria are met, and will be specified in the SAP.
The exploratory objectives and endpoints for the open-label phase of the study are:
Objectives 
Endpoints
The secondary safety objective of the double-blind 
phase
See double-blind endpoint
To evaluate molecularly confirmeda, symptomatic 
COVID-19b 
Incidence of symptomatic COVID-19 cases
starting at 28 days after last vaccination
To evaluate molecularly confirmeda, severe/critical 
COVID-19b 
Incidence of severe/critical COVID-19 cases
starting at 28 days after last vaccination
To evaluate confirmeda COVID-19b requiring 
medical intervention (based on objective criteria) 
Incidence of COVID-19 cases requiring medical
intervention, starting at 28 days after last
vaccination
To evaluate COVID-19 related death 
Incidence of COVID-19 related deaths starting at
28 days after last vaccination
To describe the severity of breakthrough infections The severity of COVID-19 cases may be evaluated
by the severity and number of symptoms (severity)
of COVID-19 cases, ratio of severe/critical
COVID-19 cases and ratio of long COVID-19
cases (duration of more than 28 days)
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.
Levels of immune responses (antibody titers) and
RNA sequencing analysis as available for
participants having COVID-19 compared to non-
infected participants.
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 as determined by the Clinical Severity Adjudication
Committee (see below).
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
88
Status: Approved, Date: 15 April 2022
3.2.2. 
Open-label Booster Phase
Participants will enter the booster phase on the day that the participants completed the booster visit
until consenting to Amendment 7(or with the stop of the eCOA at each study site, which ever date
comes first). There are 3 main cohorts based on vaccination schedules received in the booster
phase:
- Homologous boost cohort consists of following 2 groups:
o participants who were initially randomized to the Ad26.COV2.S group and
received 1 dose of Ad26.COV2.S at day 1 within the trial and a booster dose
preferably within 6 to 12 months after the initial vaccination, with a minimum
of 3 months after the initial vaccination with Ad26.COV2.S
o participants who were initially randomized to the placebo group and who
received 1 dose of Ad26.COV2.S after unblinding and a booster dose
preferably within 6 to 12 months after the initial vaccination, with a minimum
of 3 months after the last vaccination with Ad26.COV.2.S
- Heterologous boost cohort: participants who were initially randomized to the placebo
group and who received an mRNA vaccination outside of the trial and an Ad26.COV2
booster dose preferably within 6 to 12 months after the initial vaccination, with a
minimum of 3 months after the last outside vaccination
- Non-boost cohort: participants who received 1 Ad26.COV2.S vaccination, either at
Day 1 or as a cross-over vaccination. These participants remain in this cohort until they
receive the booster vaccination. Participants who opt not to receive a booster dose will
continue in this cohort.
Data from participants who received a different sequence of vaccinations (eg, Ad26.COV2 prime
vaccination and an outside booster)will be presented separately.
The main objective of the booster phase of the study is to evaluate the COVID-19 outcomes, safety,
and immunogenicity of the different schedules that were assessed: homologous Ad26.COV2
booster schedule, 1-dose schedule, heterologous booster schedule. All analyses are descriptive,
efficacy evaluations may be done if feasible, ie, if pre-specified criteria are met, and will be
described in the SAP.
The primary, secondary, and exploratory objectives and endpoints for the booster phase of the
study are:
Objectives 
Endpoints
Primary (Booster Phase)
To assess the safety and reactogenicity of
Ad26.COV2.S at the 5×1010 vp dose level
administered as homologous or heterologous
booster vaccination in adults.
 
Solicited local and systemic AEs for 7days
after booster vaccination.
 
Unsolicited AEs for 28 days after booster
vaccination.
 
SAEs and AESIs from booster vaccination
until end of the study.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
89
Status: Approved, Date: 15 April 2022
Objectives 
Endpoints
To evaluate the primary endpoints previously
utilized for the double-blind portion of the study in
this unblinded booster portion of the trial during
the time participants have and have not been
boosted.
 
Incidence of primary endpoints utilized in the
double-blind portion of the study, including
moderate to severe/critical COVID-19 cases
starting at 28 days by serostatus*, in the
unblinded booster portion of the study (see
definitions of terms in Section 10.1) during
the times when they have and have not been
boosted.
To evaluate the primary endpoints previously
utilized for the double-blind portion of the study in
participants infected with selected variants and the
reference strain in this unblinded booster portion of
the trial during the time participants have and have
not been boosted.
 
Incidence of primary endpoints (Day 28 after
vaccination) in the main study as applicable as
described in the first objective but for variants
of concern and the reference variants.
Secondary (Booster Phase)
To evaluate the secondary endpoints previously
utilized for the double-blind portion of the study in
this unblinded booster portion of the trial during
the time participants have and have not been
boosted.
 
Incidence of secondary endpoints (Day 28
after vaccination) from the double-blind
portion of the study by serostatus* such as
symptomatic 
severe/critical 
disease,
hospitalization, and death.
To evaluate the primary and secondary endpoints
utilized in the double-blind portion of the study in
this unblinded booster portion of the trial in
participants 
primed 
or 
boosted 
with
Ad26.COV2.S, mRNA, inactivated, protein, and
other adenovector-based vaccines during the time
participants have and have not been boosted.
 
Description of the primary and secondary
endpoints (Day 28 after vaccination), such as
symptomatic, 
severe/critical 
disease,
hospitalization, and death, in the double-blind
portion of the study as applicable as described
in the first primary objective and first
secondary objective including variants of
concern and reference variants.
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 immune responses at Day 28 after
booster vaccination in boosted compared to non-
boosted participants.
 
Serological response to vaccination and
antibody titers (VNA) against the original
strain, 28 days after Ad26.COV2.S (5×1010 vp
dose level) single-dose booster vaccination.
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.
 
Levels of immune responses (antibody titers)
and RNA sequencing analysis as available.
To compare the immune responses in the
Heterologous and Homologous Booster Subsets
28 Days following booster dose administration.
 
Qualitative comparison of responses in terms
of binding, neutralizing antibody against
Wuhan reference strain and variants of
interest utilizing wtVNA and/or psVNA,
depending on feasibility.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
90
Status: Approved, Date: 15 April 2022
Objectives 
Endpoints
 
Analysis of antibodies binding to the SARS-
CoV-2S protein by ELISA.
To 
evaluate 
SARS-CoV-2 
infection
(severe/critical, 
moderate 
to 
severe/critical,
moderate, 
symptomatic, 
and 
asymptomatic
infections, 
that 
are 
serologically 
and/or
molecularly confirmed**) for the different cohorts
 
Incidence 
of SARS-CoV-2 
infections
(serologically 
and/or 
molecularly
confirmed**).
To describe the severity of SARS.COV2.S
infections
 
The severity of COVID-19 cases may be
evaluated by the severity and number of
symptoms (severity) of COVID-19 cases,
ratio of severe/critical COVID-19 cases and
ratio of long COVID-19 cases (duration of
more than 28 days)
To obtain samples 
to evaluate 
potential
thromboembolic 
events 
following 
booster
immunization by obtaining platelet counts and
sufficient extra sera for specialized studies at the
day of booster immunization and 28 days later.
 
Platelet count on the day of booster
vaccination and 28 days after booster
vaccination. Additional analysis on kept sera
samples in case of potential thromboembolic
events.
Exploratory (Booster Phase)
To measure the primary and secondary endpoints
previously utilized in the double-blind portion of
the study for all participants who have received any
SARS-CoV-2 booster vaccine outside the study
within 
the 
past 
month, 
are 
N-serology
seronegative*, and remained in the unblinded
booster portion of the study during the time when
they have and have not been boosted. To utilize this
data to explore estimates of efficacy comparing
boosted to unboosted periods and by utilization of
real-world data control groups constructed of
vaccinees that are not boosted, if feasible.
 
Estimation of the primary and secondary
endpoints in the main study, as applicable, and
described above.
To measure moderate to severe/critical and
severe/critical endpoints as defined for the double-
blind portion of the study in participants who were
N ELISA  sero-negative and those who were N
ELISA sero-positive at the time they received their
booster. To utilize this data to compare rates of
these 
endpoints 
in 
participants 
who 
are
seropositive vs those that are seronegative* at the
time they received their booster.
 
Describe rates of infection for moderate to
severe/critical as defined and determined by
the protocol in boosted participants who are
N-serology seropositive versus those that are
N-serology  seronegative* at the time of
booster vaccination.
An attempt to estimate the duration of protection
following booster vaccination with Ad26.COV2.S
for the primary and secondary endpoints will be
made as outlined in the SAP.
 
Estimation of the primary and selected
secondary endpoints in the main study as
applicable.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
91
Status: Approved, Date: 15 April 2022
Objectives 
Endpoints
To estimate if there is a relationship between
efficacy and the time period between priming
COVID-19 
vaccination 
regimen 
and
Ad26.COV2.S booster vaccination.
 
Estimation of the primary and selected
secondary endpoints in the main study as
applicable.
To compare the immune responses in the
Heterologous and Homologous Booster Subsets
compared to the immune responses observed in the
VAC31518COV2008 boosting study and in this
study after primary vaccination.
 
Qualitative comparison of responses in terms
of binding (S and/or RBD), neutralizing
antibody against Wuhan reference and
variants of interest utilizing wVNA and/or
psVNA, depending on feasibility.
To analyze for signs of inflammation, coagulation
pathway disorders, and markers of potential
correlates of protection in a subset of participants
from the Heterologous and Homologous Booster
Subsets at baseline (prior to booster vaccination),
1 day, and 28 days after booster vaccination,
depending on feasibility.
 
mRNA 
sequencing 
immediately 
after
immunization up to 28 days after vaccination
analyzed in participants who received booster
vaccination compared to responses after
primary 
immunization 
following
immunization of cross-over participants from
the placebo group 
at 
unblinding 
in
VAC31518COV3001 
and
VAC31518COV2008 for differences in gene
expression.
 
Cytokine profiling: Analysis of cytokines,
chemokines, and other proteins of the innate
or adaptive immune response in the serum or
plasma.
To further assess the humoral immune response to
Ad26.COV2.S, 
in 
participants 
from 
the
Homologous and Heterologous Booster Subsets
Exploratory analyses may include, but are not
limited to, the following assays:
 
SARS-CoV-2 neutralization as assessed by
alternative 
SARS-CoV-2 
neutralization
assays (VNA).
 
Adenovirus neutralization.
 
Functional 
and 
molecular 
antibody
characterization including Fc-mediated viral
clearance, avidity, Fc characteristics, Ig
subclass and IgG isotype.
 
Epitope-specificity 
characterization 
of
antibodies.
 
Passive transfer: Analysis of immune
mediators correlating with protection against
experimental SARS-CoV-2 challenge in a
suitable animal model.
* Seronegative is defined as N-serology seronegative at the time of boosting or at the Year 1 visit if not boosted
** 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.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
92
Status: Approved, Date: 15 April 2022
Open-label Passive Follow-up Phase
With Amendment 7, the active follow up ofsuspected 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, which ever comes first) until end of study.
In the passive follow-up phase, the same cohorts as from the booster 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.
The secondary and exploratory objectives and endpoints for the passive follow-up phase of the
study are:
Objectives 
Endpoints
The secondary safety objective of the double-blind
phase (see double-blind objectives).
 
The secondary safety endpoint of the double-
blind phase (see double-blind endpoints).
Exploratory
To evaluate COVID-19 in terms of (S)AEs
MAAEs, hospitalizations and fatal AEs linked to
COVID-19*
 
SAEs and AEs linked to COVID-19
 
MAAEs linked to COVID-19
 
SAEs linked to COVID-19 that require
hospitalization
 
Fatal AEs linked to COVID-19
In the immunogenicity  subset of participants: to
evaluate the immunogenicity of Ad26.COV2.S at
available timepoints
 
Analysis of antibodies binding to the
SARS-CoV-2 S protein by ELISA
In the Heterologous and Homologous Booster
Subsets: to compare the immune responses 28 days
following booster dose administration
 
Analysis of antibodies binding to the SARS-
CoV-2 S protein by ELISA
 
Qualitative comparison of responses in terms
of binding, neutralizing antibody against
Wuhan reference strain and variants of
interest utilizing wtVNA and/or psVNA,
depending on feasibility.
In the Heterologous and Homologous Booster
Subsets: to compare the immune responses
compared to the immune responses observed in the
VAC31518COV2008 boosting study and in this
study after primary vaccination
Qualitative comparison of responses in terms of
binding (S and/or RBD), neutralizing antibody
against Wuhan reference and variants of interest
utilizing wtVNA and/or psVNA, depending on
feasibility.
In a subset of participants from the Heterologous
and Homologous Booster Subsets: to analyze for
signs of inflammation, coagulation pathway
disorders, and markers of potential correlates of
protection 
at 
baseline 
(prior 
to 
booster
vaccination), 1 day, and 28 days after booster
vaccination, depending on feasibility.
 
mRNA 
sequencing 
immediately 
after
immunization up to 28 days after vaccination
analyzed in participants who received booster
vaccination compared to responses after
primary 
immunization 
following
immunization of cross-over participants from
the placebo group at 
unblinding in
VAC31518COV3001 
and
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Objectives 
Endpoints
VAC31518COV2008 for differences in gene
expression.
 
Cytokine profiling: Analysis of cytokines,
chemokines, and other proteins of the innate
or adaptive immune response in the serum or
plasma.
In the Homologous and Heterologous Booster
Subsets: to further assess the humoral immune
response to Ad26.COV2.S
Exploratory analyses may include, but are not
limited to, the following assays:
 
SARS-CoV-2 neutralization as assessed by
alternative 
SARS-CoV-2 
neutralization
assays (VNA).
 
Adenovirus neutralization.
 
Functional 
and 
molecular 
antibody
characterization including Fc-mediated viral
clearance, avidity, Fc characteristics, Ig
subclass and IgG isotype.
 
Epitope-specificity 
characterization 
of
antibodies.
 Passive transfer: Analysis of immune mediators
correlating 
with 
protection 
against
experimental SARS-CoV-2 challenge in a
suitable animal model.
* Refer to Section 8.3 for the safety follow-up and COVID-19 reporting requirements as of
Amendment 7.
4. 
STUDY DESIGN
Overall Design
This is a multicenter, randomized, double-blind, placebo-controlled, Phase 3, pivotal efficacy and
safety study in adults ≥18 to <60 years of age and ≥60 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 study vaccine.
Following EUA, conditional licensure, or approval in any country for a single dose regimen, 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 at the
on-site Month 6/Unblinding Visit. The study will then be conducted in an open-label fashion. A
final analysis of the double-blind phase will be performed, using the data collected prior to
unblinding, when all participants have completed the Month 6/Unblinding Visit or discontinued
earlier. Depending on the operational implementation of the Month 6/Unblinding Visit, as well as
the stage of the pandemic, this analysis may be conducted when a minimum of 90% of the study
population has been unblinded.
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All participants will be invited for an on-site Month 6/Unblinding Visit and will undergo the
procedures in the Schedule of Activities in Section 1.3. Participants who initially received placebo
in the double-blind phase and consent will receive a single dose of Ad26.COV2.S vaccine under
the conditions delineated in Section 6.4.
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 had an acceptable safety profile. The sponsor has therefore decided to
proceed with the single dose regimen at a 5×1010 vp dose level in this Phase 3 study.
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 at the Year 1/Booster Visit (see also
below). The combination of homologous or heterologous prime/boost vaccination will not be
randomized, but depends on what participants received during the double-blind phase of the study
as described in this protocol. The start date of the first cross-over unblinding visit (implemented
with Amendment 4) and the date of first booster vaccine administration until 1-year follow-up of
the last booster vaccination define the open-label booster vaccination phase of the study. This
phase will be utilized to describe safety, immunogenicity, and efficacy during the time participants
have and have not been boosted.
With Amendment 7, active follow-up ofsuspected COVID-19 episodes will be replaced by passive
follow-up (ie, follow-up by the site at Month 18 and Month 24 to document new COVID‑19
participant-reported events as safety endpoints [SAEs, AEs, MAAEs] and to record concomitant
therapies associated with COVID-19).
The study will consist of a screening phase of up to 28 days, a 62-week study period (including
the administration of 1 dose of study vaccine [on Day 1], after randomization, unblinding and, for
consenting participants, cross-over vaccination at the Month 6/Unblinding Visit, and, for
consenting participants, Ad26.COV2.S booster vaccination at the Year 1/Booster Visit), and a
long-term follow-up period until the Year 2 Visit (52 weeks after the Year 1/Booster Visit). The
duration of individual participation, including screening, will be approximately 2 years and
1 month. 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 to receive Ad26.COV2.S  or placebo
intramuscularly (IM) as shown in Table 2. Ad26.COV2.S will be administered at a dose level of
5×1010 vp.
At the Month 6/Unblinding Visit, participants who initially received placebo and signed a new ICF
will be offered a single dose of Ad26.COV2.S at a dose level of 5×1010 vp.
As of implementation of protocol Amendment 6, all ongoing participants in the study who have
previously received any COVID-19 vaccination(s) (as primary regimen or additional dose) with
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the Ad26.COV2.S vaccine, and/or an mRNA vaccine or another COVID-19 vaccine authorized
for primary vaccination including protein, inactivated, and adenovector-based vaccines will be
offered a single booster dose of Ad26.COV2.S vaccine (5×1010 vp) at the Year 1/Booster Visit
under the conditions delineated in Section 6.5.
Table 2: 
Vaccination Schedule VAC31518COV3001
Group  
N 
Day 1 
Month 6/Unblinding 
Visit*
Year 1/Booster Visit
1 
20,000 
Ad26.COV2.S (5×1010 vp) 
- 
Ad26.COV2.S (5×1010 vp)
2 
20,000 
Placebo 
Ad26.COV2.S (5×1010 vp) 
Ad26.COV2.S (5×1010 vp)
EUA  Emergency Use Authorization; 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.
* All participants will be unblinded (informed whether they received placebo or Ad26.COV2.S)at the on site Month 6/
Unblinding Visit following EUA, conditional licensure, or approval in any country and approval of protocol Amendment 4
by the local Health Authority and IEC/IRB the study will continue as an open label study. Participants who received placebo
on Day 1 will be offered to receive a single dose of Ad26.COV2.S 5×1010 vp under conditions delineated in Section 6.4.
Investigators are encouraged to consider current local public health guidance for determining the scheduling priority of
participants when feasible, eg, participants with co morbidities and/or of specific age groups can be scheduled prior to
participants without co morbidities 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 Month 6/Unblinding Visit.
The following enrollment strategy will be used in the double-blind phase:
 
Stage 1a: Initially, approximately  2,000 participants (≥18- to <60-year-old) without
comorbidities that are associated with increased risk of progression to severe COVID-19
(including approximately 1,000 Ad26.COV2.S  recipients and approximately 1,000 placebo
recipients) will be enrolled based on acceptable Day 29 safety and acceptable immunogenicity
data, including Th1/Th2, from the corresponding age group (Cohort 1a) of the FIH study
VAC31518COV1001 (see Section 2.2 for more details).
 
Stage 1b: After a vaccination pause (in the age group ≥18 to <60 years of age), to allow the
DSMB (also known as an independent data monitoring committee [IDMC])to examine Day 3
safety data (ie, from Day 1 to Day 3; including safety data from the ongoing clinical studies)
from Stage 1a, if no safety concerns are identified enrollment will proceed, expanding
enrollment to include ≥18- to <60-year-old participants with and without comorbidities that
are associated with increased risk of progression to severe COVID-19 (see Section 1.2
[Figure 1] for a schematic overview of the study and Section 5.2 for the list of relevant
comorbidities).
In Stage 1, the enrollment of participants aged ≥18 to <40 years will be limited to approximately
20% of the total study population.
 
Stage 2a: Initially, approximately 2,000 participants ≥60 years of age without comorbidities
that are associated with increased risk of progression to severe COVID-19 will be enrolled
(including approximately 1,000 Ad26.COV2.S  recipients and approximately 1,000 placebo
recipients). Considering the data from study VAC31518COV1001 (including data on elderly),
Stage 2a will be enrolled in parallel with Stage 1a, unless this is not allowed per local Health
Authority guidance.
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 
Stage 2b: After a vaccination pause (in the age group ≥60 years of age) to allow the DSMB to
examine Day 3 safety data (ie, from Day 1 to Day 3; including safety data from Stage 1 and
the ongoing clinical studies) from Stage 2a, if no safety concerns are identified in this
population, enrollment will proceed, expanding enrollment to include ≥60 year-old
participants with and without comorbidities that are associated with increased risk of
progression to severe COVID-19 (see Section 1.2 [Figure 1] for a schematic overview of the
study and Section 5.2 for the list of relevant comorbidities).
Stage 2 will enroll a minimum of approximately 30% of the total study population.
Overall, a target ofapproximately 40,000 adult participants (≥18- to <60-year-old and ≥60-year-
old, with and without relevant comorbidities)will be randomly assigned in this study. Efforts will
be made to ensure good representation in terms of race, ethnicity, and gender.
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.
The primary objective will be evaluated in real-time manner through sequential testing of
accumulating primary endpoints through the SSG and DSMB. Only if both co-primary endpoints
have crossed the sequential boundary, the DSMB will discuss the signal with the Oversight Group.
As soon as a decision is reached, the sponsor representative on the Oversight Group will initiate
internal decision procedures to trigger health authority interactions based on the outcome of the
study. Sponsor personnel will be unblinded at the time of the primary analysis. If an efficacy signal
is triggered before the required 8-week  follow-up after double-blind vaccination for 50% of
participants is reached, selected sponsor personnel will be unblinded at the time of the snapshot
analysis. Further details are described in Section 9.5.1.
In the open-label phase, participants who initially received placebo and consent will receive a
single dose of Ad26.COV2.S. No additional participants will be recruited for the open-label phase.
With Amendment 6, the open-label phase of the study was extended to include an open-label
booster vaccination with a single dose of Ad26.COV2.S. As of Amendment 7, no further booster
vaccinations will be provided with the following exceptions: 1) participants who could not receive
a booster vaccination prior to implementation of Amendment 7 due to medical reasons or
2)participants who cannot receive a booster vaccination outside of this study may still receive a
booster vaccination up to the expiry date of the vaccine. These participants will be followed for
less than 1 year after booster vaccination but for a minimum of 6 months.
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  (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 during the double-
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blind phase will include the monitoring of solicited and unsolicited AEs in the Safety Subset only.
Up to Amendment 7, all participants who received booster vaccination at the Year 1/Booster Visit
will record solicited signs and symptoms, collected throughan e-Diary. As of protocol Amendment
7, the collection of solicited AEs will stop. Up to Amendment 7, for a subset of participants, the
e-Diary will be reviewed by the investigator at the next visit, if feasible. Unsolicited AEs will be
recorded for all participants who received booster vaccination at the Year 1/Booster Visit. As of
protocol Amendment 7, the collection of unsolicited AEs will stop.
In addition, key safety assessments throughout the study include the collection of SAEs and
MAAEs in all participants (see Section 8.3).
Up to Amendment 7, the viral load of SARS-CoV-2 will be assessed in confirmed COVID-19
cases (see Section 8.4). Biomarkers correlating with SARS-CoV-2 infection and COVID-19
severity will also be studied (see Section 8.5). Medical resource utilization (MRU) following
vaccination will be recorded for all participants with molecularly confirmed, symptomatic
COVID-19 (see Section 8.6).
Additional 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. 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). For consenting participants in the US, 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
Section 4.2 and Section 8.8). 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.
The first 2,000 participants in each of the 2 age groups will be closely observed at the study site
for at least 30 minutes post-vaccination to monitor for the development of acute reactions. If at the
time of the Day 3 safety review of the initial 2,000 participants no acute reactions have been
observed in the age groups, the observation period at the study site may be reduced to at least
15 minutes post-vaccination for the remaining participants in the study. 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 (double-blind phase) 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. Concomitant therapies associated with COVID-
19 are also to be reported as of Amendment 7. The statistical analyses will be described in detail
in a Statistical Analysis Plan.
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Under protocol amendment 7, the protocol described safety follow-up will continue for all
participants (eg SAEs, MAAEs, AESIs - please refer to Section 8.3.1). As mentioned above,
participants who received booster vaccination will stop the reporting of solicited or unsolicited
AEs as of Amendment 7. Finally, the management of suspected COVID-19 episodes has been
changed from active to passive follow-up, defined as follow-up by the site at Month 18 and
Month 24 to document new COVID-19 participant-reported events as SAEs, AEs, or MAAEs (see
Section 8.3.3).
All participants will be followed-up until implementation of protocol amendment 7to monitor for
signs and symptoms ofCOVID-19 (to determine duration of protection) and to monitor for safety
(including enhanced disease). As of protocol amendment 7, COVID-19 events will be followed
through a passive follow-up 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 safetyand VE will be provided
in detail in the analytic plan. Participants in the Immunogenicity  Subset will additionally 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 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).
Until 1 year after the Month 6/Unblinding Visit, 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
1-year after the Month  6/Unblinding Visit, until the end of the 2-year follow-up period, the
frequency of this surveillance question through the eCOA may decrease to once every 2 weeks
depending on epidemiology. All participants will be monitored for safety (including enhanced
disease)for approximately 1 year after the Year 1/Booster Visit, ie, until the last study visit. Every
effort will be made to document the status ofall participants that are lost to follow-up due to not
completing the eCOAand 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 protocol Amendment 7 at each study site.
Enrolled participanICFts 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, any positive RT-PCR test regardless if it is obtained outside the study or at
a study visit will be considered a trigger to start COVID-19 procedures. All participants with
COVID-19-like signs or symptoms meeting the prespecified criteria for new suspected
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COVID-19a (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 or 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-19a 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.
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 the central laboratory.
Their routine HCP can obtain external diagnostics, including RT-PCR or other molecularly
confirmed viral tests, as medically needed.
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 participant’s medical care provider 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).
A DSMB  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.
a 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.
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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-
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).
When EUA, conditional licensure, or approval is granted in any country and upon implementation
of protocol Amendment 4, all participants will be invited for an on-site Month 6/Unblinding Visit
and will be unblinded at that visit. Participants who initially received placebo, will be offered to
receive a single dose of Ad26.COV.2 vaccine. All participants will be requested to provide a blood
sample and nasal swab, which will require a new informed consent.
Biomarker Collection (Up to Amendment 7)
For participants with a positive test result for SARS-CoV-2 infection, biomarker analysis
(PAXgene, RNAseq) may be performed to explore potentially informative biomarkers, eg, those
associated with severe COVID-19.
Medical Resource Utilization Data Collection (Up to Amendment 7)
Prophylaxis of COVID-19 with 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)
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 to gain insight into duration of efficacy and
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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
records, 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 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
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
Amendment 4. See Section 6.8 for details. In addition, the sponsor will offer a single booster dose
of Ad26.COV2.S vaccine (5×1010 vp) at the Year 1/Booster Visit booster to all ongoing
participants who have previously received any COVID-19 vaccination(s) (as primary regimen or
additional dose) with the Ad26.COV2.S vaccine and/or an mRNA vaccine or another for primary
vaccination authorized COVID-19 vaccine including protein, inactivated, and adenovector based
vaccines with the implementation of Amendment 6.
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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
For participants in the US 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.
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, where initial
immunogenicity and safety data (28 days post-Dose 1 data from Cohort 1a and available data from
Cohort 3) 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 had an acceptable
safety profile. The sponsor has therefore decided to proceed with the single dose regimen at a
5×1010 vp dose level in this Phase 3 study.
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.
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.
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All participants should have their last study contact visit completed by 31 March 2023. The
investigator (like for any lost to follow-up) should make three attempts to reach the participant for
the last call, whereafter the participant is considered to have finished participation in the study. At
that time point, 90% of the participants who receive a booster vaccination will have been monitored
for safety for 1 year post the booster vaccination. The remaining 10% of the participants will have
been monitored for safety at least for 6 months.
Study Completion Definition
A participant will be considered to have completed the study if he or she has completed the
assessments at the visit approximately 104 weeks after double-blind vaccination. 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 ≤28 days before randomization and
administration of the study vaccine, or on the day of the 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 (1a, 1b, 2a, and/or 2b), as
indicated below. 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, all participants who received placebo during the double-blind phase will be eligible
to receive vaccination with Ad26.COV2.S at the Month  6/Unblinding Visit if they agree and
consent to receive the active vaccine and meet the criteria described in Section 6.4.
As of Amendment 6, all ongoing participants who have previously received any COVID-19
vaccination(s) (as primary regimen or additional dose)with the Ad26.COV2.S vaccine, and/or an
mRNA vaccine or another COVID-19 vaccine authorized for primary vaccination including
protein, inactivated, and adenovector based vaccines will be eligible to receive a 1-dose booster
vaccination with Ad26.COV2.S at the 5x1010 vp dose level at the Year 1/Booster Visit if they
agree and consent to receive the active vaccine and meet the criteria described in Section 6.5.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2.
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. Criterion modified per Amendment 1:
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1.1 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. Stages 1a and 1b: Participant is ≥18 to <60 years of age on the day of signing the ICF.
Stages 2a and 2b: Participant is ≥60 years of age on the day of signing the ICF.
4. Criterion modified per Amendment 1:
4.1. Criterion modified per Amendment 2:
4.2 Criterion modified per Amendment 3:
4.3 Stages 1a and 2a: 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-19a,17 as specified in Exclusion Criterion 15), as long as
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 15, the
medication dose cannot have been increased within 12 weeks preceding 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 measurement at screening.
Stages 1b and 2b: In the investigator’s clinical judgement, participant may have a stable
and well-controlled medical condition  including comorbidities associated with an
increased risk of progression to severe COVID-19 as specified in Exclusion Criterion 15
(eg, stable/well controlled -HIV  infection)*. If participants are on medication for a
medical condition (including comorbidities associated with an increased risk of
progression to severe COVID-19), the medication dose cannot have been increasedwithin
12 weeks preceding vaccination and must be expected to remain stable for the duration
of the studyb. Participants will be included on the basis of relevant medical history and
BMI measurement at screening.
* Stable/well-controlled HIV infection includes:
a. Documented CD4 cell count ≥300 cells/µL within 6 months prior to screening.
b. Documented 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
aPer US CDC (Appendix 11). In this study, former or current smoking/vaping and mild hypertension (according to the
Toxicity Grading Scale in Section  10.9) 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 were not allowed to
enroll in the study.
b No longer applicable as of Protocol Amendment 7.
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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 HIVinfection that have
been clinically stable for the past 6 months are not an exclusion criterion.
Laboratory methods for confirming a diagnosis of HIVinfection are: Any evidence
(historic or current) from medical records, such as ELISA with confirmation with
Western Blot or RT-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
trial.
5. Criterion modified per Amendment 1:
5.1 Contraceptive (birth control) use should be consistent with local regulations regarding the
acceptable methods of contraceptiona 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 administration of study vaccine. Use of
hormonal contraception should start at least 28 days before the administration of
study vaccine. The investigator should evaluate the potential for contraceptive
method failure (eg, noncompliance, recently initiated) in relationship to the
vaccination. Acceptable effective methods 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;
a Use of condoms is not considered as an acceptable contraceptive barrier method due to the failure rate of female and
male condoms.19
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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 receiving 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 study
vaccine administration.
7. Participant agrees to not donate bone marrow, blood, and blood products from the study
vaccine administration until 3 months after receiving 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])a.
Exclusion Criteria
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 study vaccination; 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 1:
3.1 Criterion modified per Amendment 2:
3.2 Criterion modified per Amendment 3:
3.3 Participant has abnormal function of the immune system resulting from:
a Participants with visual impairment are eligible for study participation and may have caregiver assistance in
completing the eCOA questionnaires.
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a. Clinical conditions (eg, autoimmune disease or potential immune mediated disease
or known or suspected immunodeficiency, or participant 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
administration.
b. Chronic or recurrent use of systemic corticosteroids within 6 months before
administration of study vaccine and during 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 or inhaled steroids are allowed.
c. Administration of antineoplastic and immunomodulating agents or radiotherapy
within 6 months before administration of study vaccine and during the study.
4. Criterion modified per Amendment 3:
4.1 Participant received treatment with Ig in the 3 months or exogenous blood products
(autologous blood transfusions are not exclusionary) in the 4 months before the planned
administration of the study vaccine or has any plans to receive such treatment during the
study.
5. Participant received or plans to receive:
a. Licensed live attenuated vaccines - within 28 days before or after planned administration
of study vaccine.
b. Other licensed (not live) vaccines - within 14 days before or after planned administration
of study vaccine.
6. Participant previously received a coronavirus vaccine.
7. Criterion modified per Amendment 1:
7.1 Criterion modified per Amendment 2:
7.2 Criterion modified per Amendment 3:
7.3 Participant received an investigational drug (including investigational drugs for
prophylaxis of COVID-19) within 30 days or used an invasive investigational medical
device within 30 days or received investigational immunoglobulin (Ig) or 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
study vaccine or is currently enrolled or plans to participate in another investigational
study during the course of this study. See also Section 6.10.
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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 6.8.
8. Criterion modified per Amendment 1:
8.1 Participant is pregnant or planning to become pregnant within 3 months after study
vaccine administration.
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 assessments.
10. Participant has a contraindication to IM injections and blood draws, eg, bleeding disorders.
11. Criterion deleted per Amendment 1:
12. Criterion modified per Amendment 1:
12.1 Participant has had major psychiatric illness which in the investigator’s opinion would
compromise the participant’s safety or compliance with the study procedures.
13. Participant cannot communicate reliably with the investigator.
14. 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.
15. Criterion modified per Amendment 1:
15.1 Criterion modified per Amendment 2:
15.2 Stages 1a and 2a:
 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;
a 
Per 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. Gestational diabetes was
deleted from the list since it is not applicable as pregnant women were not allowed to enroll in the study.
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thalassemia; cerebrovascular disease; neurologic conditions (dementia); end stage
renal disease; organ transplantation; cancer; HIV infection and other
immunodeficiencies; hepatitis B infection; and sleep apnea.
 Participants with a history of or current Parkinson’s disease; seizures; ischemic strokes;
intracranial hemorrhage; encephalopathy and meningoencephalitis.
16. Stages 1a and 2a: 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).
17. Criterion Modified per Amendment 2:
17.1 Participant has a history of acute polyneuropathy (eg, Guillain-Barré syndrome).
18. Stages 1a and 2a:Participant had surgery requiring hospitalization (defined as inpatient stay
for longer than 24 hours or overnight stay), within 12 weeks before 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 study vaccine administration.
19. Stages 1a and 2a: 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 study
vaccination. If a participant’s clinical status changes (including any available laboratory results or
receipt of additional medical records) after screening but before the study vaccinationis 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 required documentation
to support meeting the enrollment criteria is described under Source Documents in Appendix 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-19 signs and
symptoms surveillance question in the eCOA.
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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 Stages 1a or 2a, but does meet the
criteria for participation in Stages 1b or 2b, 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.
All participants who are rescreened will be assigned a new participant number, undergo the
informed consent process, and then re-start a new screening phase.
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, at the start of the double-blind phase, any of these events occur at the scheduled time for the
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, at the start of the open-label phase, any of the above listed events occur at the scheduled time
for the vaccination, the Month 6/Unblinding Visit with active vaccine can be delayed up to 28 days
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following unblinding. In addition, a urine pregnancy test (for participants of childbearing potential,
according to the local guidelines) will be required for the Month 6/Unblinding Visitfor participants
who will be vaccinated at this visit. Participants who are pregnant at the Month 6/Unblinding Visit
and received placebo during the double-blind phase may be vaccinated 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 6.4).
If any of the above listed events occur at the scheduled time for the booster vaccination, the
Year 1/Booster Visit with active vaccine can be delayed within the preferred visit window, but not
occur later than May 15, 2022. In addition, a urine pregnancy test (for participants of childbearing
potential, according to the local guidelines) will be required for the Year 1/Booster Visit for
participants who will be vaccinated at this visit. Participants who are pregnant at the Year
1/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 Protocol Amendment 7, no further booster doses will be administered, except if there was a
medical reason that prevented a participant to receive the Ad26COV2.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.
6. 
STUDY VACCINATION AND CONCOMITANT THERAPY
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, all participants will receive Ad26.COV2.S  or placebo at Day 1 of the
double-blind phase (see Schedules of Activities), using the same volume (ie, 0.5 mL). At the
Month 6/Unblinding Visit, all placebo participants who have signed a new ICF will receive a single
dose of Ad26.COV2.S (Schedules of Activities, Section 1.3), using the same dose level and the
same volume (ie, 5×1010 vp per 0.5 mL). At the Year 1/Booster Visit, all participants who are
eligible for booster vaccination (see Section 6.5), desire to receive a booster vaccination, and have
signed a new ICF will receive a single dose of Ad26.COV2.S (Schedules of Activities,
Section 1.3), using the same dose level and the same volume (ie, 5×1010 vp per 0.5 mL) as used
for the primary regimen.
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.
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Ad26.COV2.S will be manufactured and provided under the responsibility of the sponsor. Refer
to the IB for a list of excipients.42
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.
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Description of Interventions
Group Name 
Group 1, Group 2 cross-over*participants, Booster 
Vaccination
Group 2
Intervention Name 
Ad26.COV2.S (1×1011 vp/mL) 
Placebo 0.9% Sodium Chloride
Type 
Biologic/vaccine (1 dose) 
Placebo (1 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
Unit Dose Strength(s) 
Ad26.COV2.S at a concentration of 1×1011 vp/mL 
0.9% NaCl
Dosage Level(s) 
Day 1: Ad26.COV2.S (5×1010 vp), Month 6/Unblinding 
Visit, Year 1/Booster Visit
Day 1: Placebo
Route of Administration 
IM injection  
IM injection
Use 
Experimental 
Placebo-comparator
Investigational Medicinal Product (IMP) 
Yes 
Yes
Non-Investigational Medicinal 
Product/Auxiliary Medicinal Product
(NIMP/AxMP)
No 
No
Sourcing 
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
*Cross-over refers to participants who initially received placebo and were administered a single dose of Ad26.COV2.S vaccine at the Month 6/Unblinding Visit.
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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, or otherwise qualified HCP) who will perform the injection.
At the Month 6/Unblinding Visit, all participants will be unblinded to their study vaccine
allocation. Participants, who initially received placebo, will be offered to receive a single dose of
Ad26.COV2.S vaccine. Vaccination at the Month 6/Unblinding Visit will be performed by a
trained and qualified study nurse, medical doctor, or otherwise qualified HCP.
Within the window ofthe Year 1/Booster Visit, eligible participants can choose to receive a single
booster dose of Ad26.COV2.S vaccine. Vaccination at the Year 1/Booster Visit will be performed
by a trained and qualified study nurse, medical doctor, or 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.
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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
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.
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study in the double-blind phase. 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 (≥18 to <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 15.
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.
Blinding: 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, biomarker, 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 Month 6/Unblinding Visit. Note thatsponsor personnel will be unblinded at the time of primary
analysis. Sites and participants will remain blinded until the Month 6/Unblinding Visit. Details
will be provided in the DSMB  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, 7days 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 safety evaluations.
In general, randomization codes will be disclosed fully only at the Month 6/Unblinding Visit.
In the double-blind phase of the study, investigators may receive requests to unblind study
participants who become eligible to receive an authorized/licensed COVID-19 vaccine if/when
these become available. In these cases, the investigator will discuss with the participant available
options and ramifications. 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, the investigator will follow the unblinding procedures described above. 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).
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 two
different COVID-19 vaccines. Unblinded participants, both in the double-blind and open-label
phase will be asked to continue to be followed in this study in line with the Schedule of Activities
to the extent that they permit. 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, 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.
Prior to EUA, conditional licensure, or approval in any country, 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 study
VAC31518COV3001. Study investigators should query participants to elicit and document such
participation in other studies in the VAC31518COV3001 study record.
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Once protocol Amendment 4 is approved, participants who were previously unblinded because
they were offered another approved/licensed vaccine will follow the procedures detailed in
Section 6.4.
Unblinding and Open-label Phase
Following Ad26.COV2.S EUA, conditional licensure, or approval in any country for a single dose
regimen based on the VAC31518COV3001 interim results, all participants from countries where
Amendment 4 is approved by the local Health Authority and IEC/IRB will be unblinded on-site at
the Month 6/Unblinding Visit.
Participants who received placebo at the start of the double-blind phase will be offered a single
dose of Ad26.COV2.S vaccine, under the following conditions:
 
Participants, who were already unblinded for any reason, might receive a single dose of
Ad26.COV2.S vaccine at the investigator’s discretion, provided they did not receive another
licensed/authorized COVID-19 vaccine.
 
Participants, who had met study discontinuation criteria under previous amendments, will be
offered a single dose of Ad26.COV2.S vaccine at the discretion of the investigator, except the
following participants (who are not eligible to receive the Ad26.COV2.S vaccine);
 
received another licensed/authorized COVID-19 vaccine or,
 
withdrew consent from the study or,
 
received any COVID-19-related experimental medication (including experimental
vaccines other than the study vaccine) or,
 
previously experienced TTS or heparin-induced thrombocytopenia (HIT) or,
 
previously experienced capillary leak syndrome
 
Participants who are pregnant and received placebo during the double-blind phase may be
vaccinated 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 a single dose of
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 is limited.
 
Participants who have become infected with SARS-CoV-2 during the double-blind phase of
the study may receive a single dose of 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.
 
Vaccination should be deferred in case of any other illness, until the person has recovered
from the acute illness (see Section 5.5).
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 
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.
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. This should be done in a blinded way, ensuring
that participants who were not previously unblinded for other reasons are not unblinded until the
Month 6/Unblinding Visit. 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 a single dose of Ad26.COV2.S will continue to follow the Schedule of
Activities in Section 1.3.
Booster Vaccination
All ongoing participants in the study who have received primary vaccination with the
Ad26.COV2.S vaccine, or an mRNA vaccine or another authorized COVID-19 vaccine including
protein, inactivated, and adenovector based vaccines and who have subsequently remained in the
study will be offered to receive a 1-dose booster vaccination with Ad26.COV2.S at the 5x1010 vp
dose level. Participants who have only received one dose of a two dose primary immunization
regimen are also eligible to receive the booster vaccination with Ad26.COV2.S in this study.
Participants in the study who have already received an additional COVID-19 vaccination after the
primary regimen outside the study with any vaccine as described above will also be eligible for
the Ad26.COV2.S booster in this study. Booster vaccination should occur preferably 6 months but
at least 3 months after the last COVID-19 vaccination, but no later than the expiry date of the
Ad26.COV2.S vials available at your site. Participants are free to choose when to receive the
booster vaccination within the window of the booster vaccination visit, to receive booster
vaccination outside the study, or not to receive booster vaccination. Participants who choose to
receive a booster vaccination with the Ad26.COV2.S vaccine (if recommended and available) or
another authorized COVID-19 vaccine outside the study or choose not to receive a booster
vaccination will not be withdrawn from the study and will be encouraged to remain in the study.
Participants may be offered the single booster dose of Ad26.COV2.S vaccine under the following
special conditions:
 
Participants, who had met study 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 are not eligible to receive the Ad26.COV2.S vaccine);
 
withdrew consent from the study or,
 
received any COVID-19-related experimental medication (including any experimental
vaccines other than the study vaccine) or,
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previously experienced TTS or heparin-induced thrombocytopenia (HIT) or,
 
previously experienced capillary leak syndrome 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 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.
 
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.
As of Protocol Amendment 7, no further booster doses will be administered, except if there was a
medical reason that prevented a participant to receive the Ad26COV2.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.
Study Vaccine Compliance
Study vaccines will be administered intramuscularly by a study vaccine administrator a trained
and qualified study nurse, medical doctor, or otherwise qualified HCP. The date and time of study
vaccine administration and the location used will be recorded in the eCRF.
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Dose Modification
Dose modification is not applicable in this study.
Continued Access to Study Vaccine After the End of the Study
Prior to EUA, conditional licensure, or approval in any country, 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 study
VAC31518COV3001. Study investigators should query participants to elicit and document such
participation in other studies in the VAC31518COV3001 study record.
Following EUA, conditional licensure, or approval in any country  and approval of protocol
Amendment 4 by the local Health Authority  and IEC/IRB, participants who initially received
placebo will be offered a single dose of Ad26.COV2.S study vaccine at no cost, as described in
Section 6.4.
With approval of Amendment 6 by the local Health Authority and IEC/IRB, ongoing participants
who have previously received any COVID-19 vaccination(s) (as primary regimen or additional
dose) with the Ad26.COV2.S vaccine, and/or an mRNA vaccine or another COVID-19 vaccine
authorized for primary vaccination including protein, inactivated, and adenovector based vaccines
will be offered a single booster dose of Ad26.COV2.S study vaccine at no cost, as described in
Section 6.5.
At the time when another COVID-19 vaccine is determined to be efficacious and
authorized/licensed for use, some participants may become eligible to receive such vaccine,
depending 
on 
country-specific 
conditions 
(eg 
registration 
status, 
local
recommendations/regulations, vaccine availability or the specific target group for vaccination).
The investigator will discuss with the participants the available information and options to allow
the participant to make an informed choice as to whether they qualify to receive the
authorized/licensed vaccine and whether they should request individual unblinding to take up the
offer of an authorized/licensed COVID-19 vaccine. Safety 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. Access to Ad26.COV2.S vaccine for participants already
unblinded will be under the conditions delineated in Section 6.4. All data will be analyzed from
the point of unblinding for safety, efficacy, and immunogenicity, as described in the SAP.
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.
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 
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.
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 vaccination must be
recorded at screening.
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 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
vaccination until 6 months after (double-blind or open-label) Ad26.COV2.S. 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
electronic eCRF for the duration of the study. This will still be applicable after implementation of
Protocol Amendment 7. Hence, under protocol amendment 7, concomitant medication in case of
COVID-19 (S)AEs and COVID-19 MAAEs need to be recorded, as well 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 vaccination  through 28 days after
double-blind vaccination. Concomitant therapies associated with solicited AEs will be collected
by the participants and recorded in the eCRF from the time of vaccination through 7 days after
double-blind vaccination.
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 (including investigational drugs for
prophylaxis of COVID-19) within 30 days or used an invasive investigational medical device
within 30 days or received investigational Ig or 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
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before the planned administration 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 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 another licensed/authorized COVID-19 vaccine by a study participant 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 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.
Depending on the time of the occurrence, any participant who receives a prohibited concomitant
therapy will not be included in the immunogenicity analyses.
Study Vaccination Pausing Rules for Stages 1a and 2a
A committee consisting of the representatives of the sponsor and collaboration partners, along with
the principal investigator (the protocol safety review team [PSRT])and the Janssen Medical Safety
Council will monitor safety in a blinded manner, including the study vaccination pausing rules
(applicable to Stages 1a and 2a only). Adverse events that may lead to the study vaccination
pausing rules (applicable to Stages 1a and 2a only) are described below and will be assessed by
the Janssen Medical Safety Council to confirm that the study pause is warranted.
The occurrence of any of the following events in Stages 1a and 2a will lead to a pause in further
study vaccination:
a Note: Ocular, topical or inhaled steroids are allowed.
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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, in consultation with the Janssen Medical Safety Council, then
decides whether a study pause is warranted and informs the DSMB 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 DSMB  members and coordination of a DSMB
meeting in the event of a study pause.
The DSMB 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 DSMB. The clinical site(s) will be allowed to resume activities
upon receipt of a written notification from the sponsor. The formal recommendation from the
DSMB 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.
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 DSMB 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.
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 DSMB, participant safety may be
threatened.
7. 
DISCONTINUATION OF STUDY VACCINATION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
Discontinuation of Study Vaccination
Not applicable.
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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
 
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.
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.
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 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,
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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
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 and all participants who receive booster vaccination at the Year
1/Booster Visit, if feasible. 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.
As of Amendment 7, the number of on-site visits for participants who are not part of the
Immunogenicity or Booster Subsets is reduced. For these participants, any outstanding Visits 8
and 9 are cancelled. In addition, any outstanding Visits 10 and 11 are replaced by a phone call. 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 by the site at Month 18 and Month 24 to document COVID-19 participant-
reported events as SAE, AE, or MAAE 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 and all
participants who receive booster vaccination at the Year 1/Booster Visit 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
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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
from participants in the Safety Subset (double-blind phase) and a subset of participants who
received booster vaccination at the Year 1/Booster Visit, ie, participants included in the Safety
Subset of the double-blind phase and all participants who received a heterologous prime or
heterologous additional COVID-19 vaccination outside the study, if feasible, 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
approximately a maximum of 168.5 mL for participants in the immunogenicity  subsets and a
maximum of 72.0 mL for the other participants. Additional blood samples (up to 35 mL) will be
collected from participants that experience COVID-19-like signs and symptoms meeting
prespecified criteria for suspected COVID-19. For participants who experience a suspected AESI,
an additional 30 mL of blood will 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 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 the Month 6/Unblinding Visit or vaccination window is missed due to a study/vaccination 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 the visit window.
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 vaccination.
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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 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
Until 1 year after the Month 6/Unblinding Visit, 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 1-year after the Month 6/Unblinding Visit,
until the end of the 2-year follow-up period, the frequency of this (suspected) COVID-19
surveillance (symptom check) through the eCOA may decrease to once every 2 weeks depending
on epidemiology. All participants will be monitored for safety (including enhanced disease) for
approximately 1 year after the Year 1/Booster Visit, ie, until the last study visit. 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 8.1.1. 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)
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 
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)
 
eCRF completion guidelines
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 Protocol
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, which lasts for at least 24 hours,
not otherwise explained:
o 
Headache
o 
Malaise (appetite loss, generally unwell, fatigue, physical weakness)
o 
Myalgia (muscle pain)
o 
Chest congestion
o 
Cough
o 
Runny nose
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o 
Shortness of breath or difficulty breathing (resting or on exertion)
o 
Sore throat
o 
Wheezing
o 
Eye irritation or discharge
o 
Chills
o 
Fever (≥38.0°C or ≥100.4°F)
o 
Pulse oximetry value ≤95%, which is a decrease from baseline
o 
Heart rate ≥90 beats/minute at rest, which is an increase from baseline
o 
Gastrointestinal symptoms (diarrhea, vomiting, nausea, abdominal pain)
o 
Neurologic symptoms (numbness, difficulty forming or understanding speech)
o 
Red or bruised looking toes
o 
Skin rash
o 
Taste loss or new/changing sense of smell
o 
Symptoms of blood clots: pain/cramping, swelling or redness in your legs/calves
o 
Confusion
o 
Bluish lips or face
o 
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 as of
the consent.
c. No further sampling for participants and no Day 1-2, Day 3-4, and Day 29 visit will be
performed
d. MRU and MA-COV forms are no longer to be completed
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The eCOA will be stopped based on approval of protocol 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 contact the site at any time in
between scheduled visits to report 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.
8.1.2.2. 
Active Follow-up (Until 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 site context, whether symptomatic or asymptomatic, are detailed
in the Schedules of Activities. A high-level schematic overview is presented in Figure 2.
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Figure 2: 
Decision Tree for COVID-19 Procedures
Ifthe participant no longer meets the prespecified criteria at Day 3 5 and results from the nasal sample at Day 1 2 and/or Day 3 5 are latently positive (i.e. ≥14 days to result), the participant
will be contacted and asked to proceed with COVID 19 procedures (2 day cycles).
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 are both 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.
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 after COVID 19 Day 29, 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.
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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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 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.
Note: if for any reason a site visit per the procedures described below is not feasible, a member of
the study staff 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. More details are provided in the PRO
completion guidelines.
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-
related events when assessing suspected COVID-19. Ifthe participant would actively reach out to
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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:
o 
SIC (including body temperature): every day, preferably in the evening around the
same time each day.
o 
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 site 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 ofthe positive RT-PCR test will
be considered COVID-19 Day 1. Regardless of whether the participant is symptomatic or
asymptomatic, they 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.
 
The participant will be asked to 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 with (suspected)
COVID-19, 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 at least one nasal sample from COVID-19 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 exploration of biomarkers that correlate with SARS-CoV-2 infection and
COVID-19 severity 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
and/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 Schedule of Activities, until the end of
the study/early withdrawal.
Procedures during the 2-day cycles
If a participant has signs and symptoms that still 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 nasal sample for
SARS-CoV-2 at COVID-19 Day 1-2 or COVID-19 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
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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.
 
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 Schedule of Activities, due to lack of signs and symptoms and
unavailability of results from nasal swabs collected on Day 1-2 and/or 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.
Notes:
o 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, 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 and exploration of biomarkers that correlate
with SARS-CoV-2 infection and COVID-19 severity. 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 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 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).
Notes: 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.
This visit can be combined with a regular study visit if within the applicable visit windows.
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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:
 
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 Schedule 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, then the 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 are both 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.
 
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 after COVID-19 Day 29, 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.
a long-term sequelae ofCOVID-19 will not be followed until their resolution if not resolved within a month.
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All confirmed COVID-19 episodes will be communicated to the respective participant and to other
authorities according to local regulations.
If the participant experiences new signs or symptoms suggesting possible COVID-19 at a later
point in time, the participant would re-start 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 8.1.2.2.
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-19 and Section 8.1.3.2 for Case Definition
of Mild COVID-19. As of Amendment 7, no identification or molecular confirmation of SARS-
CoV-2 infection and symptomatic COVID-19 will be done.
Molecular confirmation of SARS-CoV-2 infection by a central laboratory will be used for the
analysis of the case definition.
All 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 and 8.1.3.2).
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.
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 (up to protocol amendment 7).
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
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infection. This assay will be performed on samples obtained (if prior to Amendment 7) at Day 1
(pre-vaccination), Day 71, Month 6/Unblinding Visit, and Month 18.
8.1.3.1. 
Case Definition for Moderate to Severe/Critical COVID-19
For the co-primary endpoints (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 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.
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).
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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 observationq:
 
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
All cases meeting the severe/critical criteria will be adjudicated by the Clinical Severity
Adjudication Committee to determine if the case is severe/critical in their judgement.
All cases meeting the moderate case definition and that include ≥3 signs and/or symptoms from
the list of signs and symptoms will be evaluated by the Clinical Severity Adjudication Committee
to determine if the case is severe/critical in their judgement.
Classification of a case as severe/critical by the Clinical Severity Adjudication Committee is
considered definitive.
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
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).
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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. All cases will be evaluated by the Clinical Severity
Adjudication Committee. Classification by the Clinical Severity Adjudication Committee is
considered definitive.
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
 
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.
All cases will be evaluated by the Clinical Severity Adjudication Committee. Classification by the
Clinical Severity Adjudication Committee is considered definitive.
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
which would classify them as mild, moderate, or severe by the protocol definitions per
Section 8.1.1,
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.
Cases will be classified as being an "Asymptomatic SARS-CoV-2 infection" by the Clinical
Severity Adjudication Committee utilizing the following guidelines, which are described in more
detail in the charter for the committee.
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 
The definition of any case that is either RT-PCR positive that was previously RT-PCR
negative or seropositive for N protein specific antibodies that was previously seronegative for
N protein specific antibodies and is clinically asymptomatic will be considered as an
asymptomatic COVID-19 case.
 
The definition of clinically asymptomatic COVID-19 is defined as no clinical symptoms that
would be classified as mild, moderate, or severe COVID-19 by the protocol case definition
for symptoms independent of the SARS-CoV-2 N protein specific antibody seroconversion or
RT-PCR results.
Potential asymptomatic cases that are identified by N-serology  seroconversion will all be
examined by the Clinical Severity Adjudication Committee for the presence of any signs or
symptoms and if found, to determine if they would still be classified as asymptomatic COVID-19.
Moderate, severe, hospitalized, or fatal cases that are found by SARS-CoV-2 N protein specific
antibody seroconversion will be utilized in a sensitivity analysis to determine if any conclusions
would be changed by adding the primary case definition of a positive RT-PCR, with appropriate
signs and symptoms, to those cases which were identified by SARS-CoV-2 N protein specific
antibody seroconversion with appropriate signs and symptoms.
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
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 on samples obtained at Day 1 (pre-vaccination), Day 29, Day 71, Month
6/Unblinding Visit, Year 1 + 28 days for participants who received booster vaccination, Year 1 +
72 days for participants who received booster vaccination, and Month 18 (24 weeks after Year 1
Visit). (see Section 8.1.4).
8.1.3.6. 
Clinical Severity Adjudication Committee
The Clinical Severity Adjudication Committee will review all cases in the study, except for cases
already adjudicated as severe, as a supplement to the algorithm described in the SAP, as well as
those 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), including onset 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). More 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
assessment will be considered the definitive classification of the case. The case review including
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severity assessments after implementation of Protocol Amendment 7 may change and will be
reflected in the charter of the committee.
8.1.4. 
Immunogenicity Assessments
Blood will be collected from all non-Immunogenicity  Subset participants for humoral
immunogenicity assessments at Day 1 (pre-vaccination), Day 29, Day 71, Month 6/Unblinding
Visit, and Year 1 (if Year 1 visit occurred prior to implementation of protocol amendment 7).
For a total of approximately 400 participants in the ImmunogenicitySubset (ie, participants at sites
with access to appropriate processing facilities), blood will be collected for analysis of humoral
immune responses on Day 1 (pre-vaccination), Day 29, Day 71, Month 6/Unblinding Visit, Year 1,
Month 18, and Year 2 visit after double-blind vaccination, and additionally 28 days and 72 days
after booster vaccination, if applicable.
Note: Those participants in the Immunogenicity Subset that transfer to the Homologous Booster
Subset at the Year 1/Booster Visit (see below) will from that visit onwards follow the humoral
immunogenicity sample schedule of the Homologous Booster Subset and discontinue the schedule
of the Immunogenicity Subset.
Participants in the Immunogenicity Subset will be divided into 4 groups as presented in Table 3.
Table 3: 
Sample Size and Distribution of the Immunogenicity Subset Between Active and Placebo
Groups
Study Vaccine
(Double-blind)
Subgroup 1a 
Subgroup 1b 
Subgroup 2a 
Subgroup 2b
5×1010 vp 
50 
50 
50 
50
Placebo 
50 
50 
50 
50
Total 
100 
100 
100 
100
vp  virus particles
Subgroup 1a: healthy ≥18 to <60 year old adults without relevant comorbidities, enrolled during Stage 1a.
Subgroup 1b: ≥18 to <60 year old adults with relevant comorbidities, enrolled during Stage 1b.
Subgroup 2a: healthy ≥60 year old adults without relevant comorbidities, enrolled during Stage 2a.
Subgroup 2b: ≥60 year old adults with relevant comorbidities, enrolled during Stage 2b.
Up to Amendment 7, during a COVID-19 episode, blood will be collected on COVID-19 Day 3-5
and on COVID-19 Day 29 for immunogenicity assessments, including the assays summarized in
Table 6. As from Amendment 7, active follow-up will no longer be pursued and blood sampling
for this purpose will no longer be performed.
Booster Vaccination
Up to Amendment 7, blood will be collected from all non-Subset participants who received booster
vaccination for humoral immunogenicity assessments at the Year 1/Booster Visit and 28 days, 72
days, and 6 months after booster vaccination. A blood sample for transcriptomics will be collected
from all participants 28 days after booster vaccination.
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Homologous Booster Subset: The Homologous Booster Subset will include approximately
200 participants, as described in Table 4. This subset will include participants from the
Immunogenicity Subset (Table 3), who received Ad26.COV2.S in the double-blind phase or after
cross-over, and subsequently received an Ad26.COV2.S booster vaccination in the study. This
group may be augmented by other participants to replace participants who are not available.
Participants in the Homologous Booster Subset will have a blood sample collected pre-booster
vaccination, and 28 days, 72 days, 6 months, and 1 year post booster vaccination for humoral
immunogenicity assessment (see Section 1.3).
Table 4: 
Sample Size and Distribution of the Homologous Booster Subset Age Groups
Study Vaccine
Subgroup 1a 
Subgroup 1b 
Subgroup 2a 
Subgroup 2b
5×1010 vp 
50 
50 
50 
50
vp  virus particles
Subgroup 1a: healthy ≥18 to <60 year old adults without relevant comorbidities.
Subgroup 1b: ≥18 to <60 year old adults with relevant comorbidities.
Subgroup 2a: healthy ≥60 year old adults without relevant comorbidities.
Subgroup 2b: ≥60 year old adults with relevant comorbidities.
Heterologous Booster Subset: The Heterologous Booster Subset will include approximately
400 participants, as described in Table 5. This subset will include participants in the study who
received placebo in the double-blind phase and have received primary vaccination with an mRNA
vaccine or another authorized COVID-19 vaccine including protein, inactivated, and adenovector
based vaccines outside the study, who subsequently remained in the study and subsequently
received an Ad26.COV2.S booster vaccination in the study. Participants who already received an
additional COVID-19 vaccination after the primary regimen outside the study will not be included
in the Heterologous Booster Subset. Participants will be selected out of countries where these
vaccines were authorized for emergency use or are licensed. Participants in the Heterologous
Booster Subset will have blood collected pre booster vaccination, and 28 days, 72 days, 6 months,
and 1 year post booster vaccination for humoral immunogenicity assessment (see Section 1.3).
Table 5: 
Sample Size and Distribution of the Heterologous Booster Subset Primary Vaccination Groups
Age group for
participants who
received a booster dose
mRNA vaccine 
subgroup  
Protein vaccine 
subgroup  
Adenovector 
vaccine subgroup  
Inactivated
vaccine subgroup
18-59 years old 
50 
50 
50 
50
>60 years old 
50 
50 
50 
50
Total 
100 
100 
100 
100
vp  virus particles
Enrollment into the Homologous Booster Subset and Heterologous Booster subset will start once
operationally feasible.
Additionally, approximately the first 60 eligible participants once operationally feasible of the
Homologous Booster Subset (approximately 15 per subgroup  [1a, 1b, 2a, and 2b]) and
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approximately the first 60 eligible participants once operationally feasible of the Heterologous
Booster Subset (approximately 15 per subgroup [primary vaccination with mRNA vaccine, protein
vaccine, adenovector vaccine, and inactivated vaccine]) will have blood collected pre-booster and
1 day and 28 days post booster vaccination for transcriptomics and cytokine/chemokine
assessment (see Section 1.3).
Table 6: 
Immunogenicity and Transcriptomic 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 Secondary and Exploratory Objectives
SARS-CoV-2 neutralization 
(VNA) 
Analysis of neutralizing antibodies against SARS-CoV-2 original
strain and/or variants, using a live VNA and/or pseudovirion
expressing S protein neutralization assay
SARS-CoV-2 binding antibodies 
to S protein (MSD) 
Analysis of antibodies binding to the original and/or variants
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
Cytokine profiling 
Analysis of cytokines, chemokines, and other proteins of the
innate or adaptive immune response in the serum or plasma
Transcriptomic Assay  
Purpose
Supportive of Exploratory Objectives
Gene expression analysis 
Analysis of gene expression by RNA transcript profiling in
unstimulated cells or whole blood
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; RNA
 ribonucleic
acid; 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. This does not apply to
the open-label phase of the study.
A serologic test for past or current infection with SARS-CoV-2 may  be performed for all
participants at Day 1 (pre-vaccination), Day 29, Day 71, Month 6/Unblinding Visit, Year 1/Booster
Visit (prior to vaccination, if applicable), Year 1 + 28 days for participants who received booster
vaccination, Year 1 + 72 days for participants who received booster vaccination, and Month 18
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(24 weeks after Year 1 Visit). Samples for the 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.
Safety Assessments
Details regarding the DSMB are provided in Section 9.8 and 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 PSRT and the Janssen Medical Safety Council will monitor safety in a blinded manner in the
double-blind phase (see Section 6.11)as well as in the open-label phase.
8.2.1. 
Physical Examinations (Until 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, 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.
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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Participants in the Safety Subset (double-blind phase) will utilize an e-Diary to record body
temperature measurements from the time of vaccination until 7 days post-vaccination in the eCOA
(see Section 8).
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,
before double-blind vaccination, before open-label vaccination, and before the booster
vaccination. Participants of childbearing potential who originally received placebo and will not be
receiving the Ad26.COV2.S vaccine under EUA do not need to complete a pregnancy test.
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 or TTS, every effort should be made to collect local
hospital/laboratory test results obtained by the treating physician to allow rapid diagnosis and
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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 1.3.5 and Section 10.2, Appendix 2). 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.
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,
suspected AESIs, MAAEs, 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, suspected AESIs, MAAEs, and PQCs can be found in Appendix 4.
8.3.1. 
Time Period and Frequency for Collecting Adverse Event, Medically-
attended Adverse Event, Adverse Events of Special Interest, and
Serious Adverse Event Information
All Adverse Events
For all participants (throughout the study regardless of any protocol amendment)a:
 
(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
signing of the ICF and moment of vaccination in the double-blind phase of the study will be
collected on the Medical History eCRF page as pre-existing conditions. This does not apply
to the open-label phase.
a   90% of the participants who received a booster vaccination will be monitored for safety until 1 year post booster
vaccination. The remaining 10% of the active participants who receive a booster vaccination will be monitored for
safety at least for 6 months
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 
All SAEs and all AEs leading to study discontinuation (regardless of the causal relationship)
are to be reported from the moment of 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 each vaccination until 6 months after the vaccination (applicable for both the
double-blind and open-label phases of the study), 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 from the time of
each vaccination until 28 days post-vaccination  (applicable for both  the double-blind and
open-label phases of the study).
 
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 by the site at Month 18 and
Month 24 to document new COVID-19 participant-reported episodes as SAEs, AEs, or
MAAEs. Participants may contact the site at any time in between scheduled visits to report
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).
 
Participants may contact the site at any time in between scheduled visits to report COVID-19
episodes.
 
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.
 
90% of the participants who received a booster vaccination will be monitored for safety until
1 year post booster vaccination. The remaining 10% of the active participants who receive a
booster vaccination will be monitored for safety at least for 6 months.
For participants in the Safety Subset (double-blind phase):
 
Solicited AEs, collected through an e-Diary, will be recorded from the time of vaccination
until 7 days post-vaccination.
 
All other unsolicited AEs, whether serious or non-serious, will be recorded from the time of
vaccination until 28 days post-vaccination.
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Up to Amendment 7: For all participants who received booster vaccination at the Year 1/Booster
Visit:
 
Solicited AEs, collected through an e-Diary, will be recorded from the time of vaccination
until 7 days post-vaccination. All participants will collect signs and symptoms in the e-Diary,
if feasible. For a subset of participants, ie, participants included in the Safety Subset of the
double-blind study phase and all participants who received a heterologous COVID-19
vaccination outside the study, the e-Diary will be reviewed by  the study personnel and
solicited AEs recorded in the eCRF, if feasible. All other unsolicited AEs, whether serious or
non-serious, will be recorded from the time of vaccination until 28 days post-vaccination for
all participants who received the booster at Year 1/Booster Visit.
As of Amendment 7, solicited and unsolicited AE reporting will stop for all participants.
Adverse Events of Special Interest
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 Adjudication Committee with appropriate expertise will
be established to evaluate each suspected AESI and determine whether it is a case of TTS. From
the time of local approval of protocol Amendment 5 onwards, TTS is considered an AESI.
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.
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 Protocol Amendment 7, this is replaced by the passive follow-up approach.
All study participants will be monitored for SAEs for up to 2 years after their double-blind
vaccination.
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 in the Main Study
(a) Refer to Section 10.4.4; eg, this includes AEs related to study procedures which are procedures related to
interventions (eg, blood drawn for immunogenicity sampling) that may result in an AE (eg, bruise).
(b) Adverse events of special interest (AESIs that require reporting to the sponsor within 24 hours).
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 Adverse Events (Applicable for Double-blind phase only)
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 2,000 participants in each of the 2 age groups will remain under observation at the study
site for at least 30 minutes post-vaccination to monitor for the development of acute reactions. If
at the time of the Day 3 safety review of the initial 2,000 participants no acute reactions have been
observed in the age groups, the observation period at the study site may be reduced to at least 15
minutes post-vaccination for the remaining participants in the study.
In addition, participants in the Safety Subset (double-blind phase) will record solicited signs and
symptoms in an  e-Diary from time of double-blind vaccination until 7 days post-vaccination.
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
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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.
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 post-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.37,47
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 vaccination, and then daily for the next 7days approximately at the same time each day. 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 7days post-vaccination (day of vaccination and the subsequent 7days), for the following
events: fatigue, headache, nausea, myalgia.
Unsolicited Adverse Events (Applicable for Double-blind phase only)
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, suspected
AESI, MAAE, SAE, or PQC as fully as possible. This may include laboratory tests or
investigations, histopathological examinations, or consultation with other HCPs.
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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
must be reported using an SAE reporting form. Any participant who becomes pregnant during the
study 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.
Participants who are pregnant and received placebo during the double-blind phase may be
vaccinated 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 6.4).
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 (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 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.
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Adverse events of special interest 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  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 Adjudication 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
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 1.3.5). 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
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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.
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.
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.
Biomarkers
Up to Amendment 7, during a COVID-19-episode, blood will be collected on COVID-19 Day 3-
5 and on COVID-19 Day 29 for evaluation of biomarkers (eg, those associated with severe
COVID-19).
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 double-blind 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 double-blind 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:
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 
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)
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 double-blind 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
the correlate analysis.
Risk factor data initially collected from participants at screening prior to implementation of
protocol Amendment 3 will also be used for the planned risk-factor analysis.
Participant Medical Information Prior to, During and After the Study (Real-
world Data)
For consenting participants in the US, 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 9.5.4). The utilization of tokenization and matching procedures allows for the medical data
to be obtained without violation of participant confidentiality (Section 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.
Assessment and Procedures After EUA or Approval/Licensure and
Implementation of Protocol Amendment 4
Following EUA, conditional licensure, or approval in any country for a single dose regimen based
on the VAC31518COV3001 study interim results, all participants from countries where
Amendment 4 is approved by the local Health Authority and IEC/IRB will be unblinded at the on-
site Month 6/Unblinding Visit. The study will then be conducted in an open-label fashion. A final
analysis of the double-blind phase will be performed, using the data collected prior to unblinding,
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when all participants have completed the Month 6/Unblinding Visit or discontinued earlier.
Depending on the operational implementation of the Month 6/Unblinding Visit, as well as the stage
of the pandemic, this analysis may be conducted when a minimum of 90% of the study population
has been unblinded.
Participants in the Ad26.COV2.S group will be assured they received at a minimum the dose level
that was submitted for EUA approval (single-dose regimen of 5x1010 vp Ad26.COV2.S) and will
be asked to continue to be followed in this study in line with the Schedules of Activities.
A Month 6/Unblinding Visit will take place for all participants. A nasal swab and blood sample
for serology  will be collected from all participants. In addition, body temperature and urine
pregnancy test (for participants of childbearing potential) will be collected from participants who
will be vaccinated at this visit. Participants from placebo group will be offered to receive 1 dose
of Ad26.COV2.S vaccine under the conditions delineated in Section 6.4. After vaccination,
participants should remain under observation at the study site for at least 15 minutes for the
presence of any acute reactions after vaccination and will be followed for SAEs until 1 year after
Ad26.COV2.S administration.
The importance to continue practicing other public health  or 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, will be emphasized.
Assessment and Procedures Related to Booster Vaccination
As ofProtocol Amendment 7:
No further booster doses will be administered after implementation of Protocol Amendment 7,
except if there is a medical reason that prevented a participant to receive the Ad26COV2.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.
Up to Protocol Amendment 7:
The Year 1/Booster Visit will take place for all ongoing participants. Participants who have
previously received any COVID-19 vaccination(s) (as primary regimen or additional dose) with
the Ad26.COV2.S vaccine, and/or an mRNA vaccine or another COVID-19 vaccine authorized
for primary vaccination including protein, inactivated, and adenovector based vaccines will be
offered to receive a 1-dose booster vaccination with Ad26.COV2.S at the 5x1010 vp dose level.
Participants who choose not to receive booster vaccination at this time will be informed that they
can still choose to receive the booster vaccination at a later date within the visit window. In
addition, body temperature and urine pregnancy test (for participants of childbearing potential)
will be collected from participants who will be vaccinated at this visit. After vaccination,
participants should remain under observation at the study site for at least 15 minutes for the
presence of any acute reactions after vaccination and will be followed for SAEs until 1 year after
Ad26.COV2.S administration.
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Participants who choose to receive a booster vaccination outside of the study are encouraged to
schedule their Year 1/Booster Visit prior to their booster vaccination, if feasible, and come in for
the Year 1 + 28 Days and Year 1 + 72 Days visits within the specified visit window, if feasible, or
as close as possible to the visit window.
During the Year 1/Booster Vaccination visit, the investigator should ask the participant if he/she
received any other COVID-19 vaccines and record type and date of administration.
The importance to continue practicing other public health or 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, will be emphasized.
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 9.1 to 9.7 are applicable to the double-blind phase of the study. Considerations for the
analysis of the open-label booster vaccination phase (introduced with Amendment 6) of the study
are described in Section 9.8; details will be provided in a separate SAP.
Statistical Hypotheses
Refer to Section 3 for the statistical hypotheses.
The study will have the following timepoints for analysis:
1. The evaluation of the primary objective will be performed as soon as the target number of
events (TNE) has been reached in the double-blind phase for both co-primary endpoints,
or earlier based on sequential monitoring of both co-primary endpoints (details in Section
9.5.1). Sponsor unblinding will occur but investigator and participants remain blinded until
implementation of Amendment 4 (see Section 6.4).
2. If an efficacy signal is triggered before the required 8-week follow-up after double-blind
vaccination of 50% of participants is reached, an additional analysis will be performed
when that follow-up timepoint is reached (8-week median follow-up timepoint). If the time
between the efficacy signal and the required 8-week median follow-up is too short to make
a difference in terms of preparing two analyses, then a single analysis will take place at the
time of the 8-week  median follow-up. The analysis at the time of the 8-week  median
follow-up is considered the primary analysis.
3. After the primary analysis, additional analyses to support health authority interactions will
be planned, as deemed appropriate.
4. A final analysis of the double-blind phase of the study, including all double-blind data, will
be performed when all participants have completed the Month 6/Unblinding Visit or
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discontinued earlier. Depending on the operational implementation of the Month
6/Unblinding Visit, as well as the stage of the pandemic, this analysis may be conducted
when a minimum of 90% of the study population has been unblinded.
During the open-label phase 2 possible analysis timepoints will be foreseen:
5. The open-label cross-over and booster analysis (active follow-up) can be triggered when a
minimum of 90% of participants consented to Amendment 7. The timing of this analysis
may be once all study sites have approved Amendment 7 or later.
6. An end-of-study analysis is planned 1 year after a minimum of 90% of the enrolled study
population have reached the Year 1/Booster Visit or discontinued earlier (31 March 2023)
and will be conducted upon completion of the last participant visit. Depending on the
timing of approval of Amendment 7 across study sites, the 2 analysis timepoints may be
combined. At the end-of-study analysis, 90% of participants will have completed one year
safety follow-up; the remaining 10% of participants will have at least 6 months of 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.
Sample Size Determination
9.2.1. 
Efficacy (Total Sample Size)
The study TNE is determined using the following assumptions:
 
a VE for molecularly confirmed, moderate to severe/critical SARS-CoV-2 infection of 60%.
 
approximately 90% power to reject a null hypothesis of H0: VE≤30%.
 
type 1 error rate α
2.5% to evaluate VE of the vaccine regimen (employing the sequential
probability ratio test [SPRT] to perform a fully sequential design analysis; detailed in
Section 9.5.1).
 
a randomization ratio of 1:1 for active versus placebo
Events are defined as first occurrence of molecularly confirmed, moderate to severe/critical
COVID-19 according to the case definition in Section 8.1.3.1 in the PP population. The two
co-primary endpoints will evaluate the events at least 14 days after double-blind vaccination (Day
15) and at least 28 days after double-blind vaccination (Day 29)with study vaccine.
Under the assumptions above, the TNE to compare the active vaccine versus placebo equals 154,
based on events in the active vaccination and placebo group, according to the primary endpoints
case definition of moderate to severe/critical COVID-19 (Section 8.1.3.1).
If the co-primary hypothesis testing is successful for both co-primary endpoints, secondary
objectives will be evaluated against a null hypothesis employing a lower limit VE>0%. The
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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 epidemiological modeling for the targeted study countries, province/states of the various
site locations, the annualized incidence of moderate to severe/critical COVID-19 cases meeting
the primary endpoints definitions has been predicted to be 1.4% for the October-November
timeframe. The estimate incorporates that real-world-evidence data and literature data only
detected and reported a fraction of SARS-CoV-2 infections.
Furthermore, it includes that, based on literature and real-world-evidence data, only a fraction of
all infections meets the moderate and severe/critical COVID-19 case definition and the fraction
varies by age as well (increasing with higher ages). Moreover, projections for the selected study
regions indicate that incidences will decline over time. Finally, seroprevalence rates are expected
to vary between 5-15%.
For the purpose of sample size evaluation, an incidence assumption of moderate to severe/critical
COVID-19 cases meeting the primary endpoints definition of 1.4% during the first 3 months of
the study, with a 50% reduction in Month 4, and 62% reduction in the months thereafter is assumed
in combination with a seroprevalence rate of 10%.
At the time of protocol planning, the epidemiological situation was uncertain: actual
seroprevalence rates, degree of social distancing and use of personal protective equipment during
the study, local regulations (eg, potential lockdowns, other vaccines if available) potentially
becoming in effect during the course of the study and potential drop-outs from the study could
impact the disease incidence rate.
To that end, the maximum sample size of approximately 60,000 participants was selected. This
sample size was selected, based on 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
8 months of the study for a vaccine with an assumed 60% VE.
Based on an estimated case-hospitalization ratio of 2.5% and estimates obtained from reported
real-world-evidence data of 3-10%  of all SARS-CoV-2 infections meeting the severe/critical
COVID-19 definition, this would provide a reasonable likelihood of observing 5 severe cases in
the placebo group within the same time frame (8 months).
At the time of writing protocol Amendment 3, the incidence of moderate to severe COVID-19
seen in the US and reported in other COVID-19 vaccine studies is significantly higher than
assumed at the time of protocol planning as described above. Furthermore, based on that incidence
and modeling there is a high degree of probability that an efficacy signal meeting the prespecified
criteria in this amendment will be reached at, or prior to, the time when approximately
40,000 participants will have been followed for a median of 8 weeks from the time of vaccination.
Therefore, the sample size is reduced from 60,000 to approximately 40,000.
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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.
No additional participants will be recruited for the open-label phase.
9.2.2. 
Immunogenicity Subset (Double-blind Phase)
All participants included in the Immunogenicity Subset (N 400) will be added randomly at each
stage of the enrollment. Healthy adults (Subset 1a) will be enrolled in Stage 1a, adults with
comorbidities (Subset 1b) in Stage 1b, healthy elderly (Subset 2a) in Stage 2a, and elderly with
comorbidities (Subset 2b)in Stage 2b, with approximately 100 participants per group as displayed
in Table 3. Although Stage 1b and 2b will also enroll participants without comorbidities, only
participants with comorbidities will be included in Immunogenicity Subset 1b and Subset 2b.
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 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.
Controls will be matched with cases from the same stage (age, comorbidities) and other co-factors
as deemed appropriate. These will be detailed in the Correlates SAP.
9.2.4. 
Safety
9.2.4.1. 
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 double-blind vaccination. Solicited
and unsolicited AEs will be captured in the Safety Subset, ie, approximately 6,000 participants
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(~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).
9.2.4.2. 
All Participants
Adverse events of special interest (from protocol Amendment 5 onwards) 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 (double-blind or open-label)
vaccination with Ad26.COV2.S, except for MAAEs leading to study discontinuation which are to
be reported during the entire study. Based on a sample size of approximately 40,000 participants,
and approximately 20,000 in the active vaccination group, for SAEs, the observation of 0 events
in the database would be associated with 95% confidence that the true rate is less than 0.015%.
Table 7shows the probabilities of observing at least 1 event (solicited, unsolicited, or SAE) in 1 of
the groups at given true AE rates.
Table 7: 
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 40,000 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=20,000
0.01% 
26% 
86%
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
As of Amendment 7, a passive follow-up approach is adopted: the investigator will place a phone
call at Month 18 and Month 24 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. Note that 90% of the participants who
receive a booster vaccination will be monitored for safety until 1 year post booster vaccination as
mentioned in Section 8.3. The remaining 10% of the participants who receive a booster vaccination
will be monitored for safety at least for 6 months.
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:
Full Analysis Set (FAS): All randomized participants with a 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) population: Participants in the FAS who receive double-blind study
vaccine and who are seronegative at the time of double-blind vaccination and who have no other
major protocol deviations that were judged to possibly impact the efficacy of the vaccine.
Participants who became aware of their study vaccine allocation will cease to be part of the PP
population. The PA of VE will be based on the PP population. The PP will be the main analysis
population for efficacy analyses.
Per-protocol Immunogenicity (PPI) population: All randomized and vaccinated participants,
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 cross-over, booster and 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
the protocol deviation dataset of the clinical database before database lock and unblinding.
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 from participants at screening prior to implementation of protocol Amendment 3 will
also be used for the planned risk-factor analysis. See also Section 9.5.3.
Efficacy Analyses
The SAP  will be finalized prior to first participant in and it will include 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.
9.5.1. 
Primary Endpoints Evaluation
The study is designed to test the co-primary hypotheses of VE in the PP population. For both
co-primary endpoints the following hypothesis will be tested:
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H0: VE ≤30% versus H1: VE >30% and each hypothesis will be evaluated at a 2.5% one-sided
significance level.
The co-primary endpoints 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
double-blind vaccination (Day 15) with Ad26.COV2.S versus placebo, in the PP
population, including all events from both age groups, with and without comorbidities.
 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 28 days after double-
blind vaccination (Day 29) 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 (double-blind) baseline.
Considering the current COVID-19 pandemic, early detection of VE will be very important. The
proposed current analysis setup is designed for continuous sequential analyses (see
Section 9.5.1.1), where statistical hypothesis testing is conducted repeatedly on accumulating data,
generating an earliest possible signal if and when the splits between the number of events in
placebo recipients are much larger compared to the Ad26.COV2.S-vaccinated group for both
co-primary endpoints and in such a way that they are unlikely to be due to chance alone using a
truncated SPRT. A successful primary efficacy conclusion will require:
1. Establishing the hypothesis H1: VE>30% for each co-primary endpoint
AND
2. A favorable split vaccine:placebo for the subset of primary endpoints meeting the
severe/critical COVID-19 case definition (expressed as a VE point estimate against
severe/critical COVID-19 molecularly confirmed endpoints ≥50%) and a minimum of 5
events in the placebo group. This requirement needs to be met for severe/critical events with
onset at least 14 days after double-blind vaccination and for severe/critical events with onset
at least 28 days after double-blind vaccination.
AND
3. A VE of at least 50% for each co-primary endpoint.
To evaluate the primary null hypotheses: H0: VE ≤30% versus H1: VE >30% for the co-primary
endpoints, the truncated sequential probability ratio test will be used based on accumulating event
data for each co-primary endpoint. This boundary is set up using the fully sequential design and is
derived in such a way to have approximately 90% power to detect a VE 60% using a one-sided
alpha 0.025 against H0:VE≤30%. For the evaluation of the favorable ratio against the
severe/critical COVID-19 endpoints a sequential boundary corresponding to a VE point estimate
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≥50% and a minimum of 5 events in the placebo group will be prespecified. The specific
boundaries will be detailed in the SAP.
The monitoring can start as soon as the following conditions are met:
1. A minimum of 6 COVID-19 cases for the ≥60 years age group with onset at least 28 days
after double-blind vaccination
2. At least 42 cases meeting the primary endpoints definition of moderate to severe/critical
COVID-19 with onset at least 28 days after double-blind vaccination
3. A subset of at least 5 cases meeting the primary endpoints definition of severe/critical
COVID-19 with onset at least 28 days after double-blind vaccination
No interim evaluation will be done, until those conditions are fulfilled. Monitoring for efficacy
will not start before the above conditions 1-3 are met and will occur at least once a week by the
SSG of the DSMB until the prespecified boundaries have been crossed.
The efficacy analysis will be triggered by either:
1. a) An interim evaluation if all prespecifiedefficacy boundaries have been met ORif 154 cases
meeting the primary endpoints definition of moderate to severe/critical COVID-19 are
observed for events with onset at least 28 days after double-blind vaccination
AND
b) The above 3 conditions are met.
OR, alternatively,
2. If the prespecified non-efficacy boundary has been met (evaluating events with start 28 days
after double-blind vaccination) or when the harm boundary has been crossed. The decision
rules for harm and non-efficacy are detailed in Section 9.5.1.1.
If an efficacy signal is triggered before the required 8-week  follow-up after double-blind
vaccination of 50% of participants is reached, an additional analysis will be performed when that
follow-up timepoint is reached. If the time between the efficacy signal and the required 8-week
median follow-up is too short to make a difference in terms of preparing two analyses, then a single
analysis will take place at the time of the 8-week median follow-up. The analysis at the time of the
8-week median follow-up is considered the primary analysis.
If more than 154 primary endpoints are observed for events with onset at least 28 days after
double-blind vaccination before the 3 conditions above are met, a single analysis will take place
as soon as the conditions are met, using the full 2.5% one-sided significance level.
Ifthe prespecified boundaries and above conditions are met, the SSG will inform the DSMB and,
if deemed appropriate by the DSMB, a meeting with the DSMB and the Oversight Group will be
set up to discuss the efficacy signal. Upon this meeting the sponsor representative on the Oversight
Group can trigger internal decision procedures to initiate health authority interactions based on the
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outcome of the study. However, the study sites and participants will remain blinded to allow for
evaluation of durability of VE. Sponsor personnel will be unblinded at the time of the primary
analysis. If an efficacy signal is triggered before the required 8-week follow-up after double-blind
vaccination of 50% of participants is reached (defined as “snapshot analysis”), selected sponsor
personnel will be unblinded at the time of the snapshot analysis.
A positive RT-PCR or other molecular diagnostic test result obtained from a central laboratory
will be utilized to define a molecularly confirmed case of COVID-19. Sensitivity analysis
comparing cases also including a positive RT-PCR test result from any source, including external
to the study, will be performed for each diagnostic category individually (mild, moderate, severe,
moderate+severe, and medical utilization [hospitalization, ICU care, mechanical ventilation,
ECMO]).
The primary efficacy analysis will pool data across populations (both age groups with and without
comorbidities) to evaluate the primary and secondary objectives. In addition, these will be
supplemented with a subgroup analysis for age group (18 to <60 years, ≥60 years) and
comorbidities employing a descriptive summary including 95% confidence intervals to describe
the VE in each subpopulation. Depending on the recruited study population, the ≥60 years
subgroup may be further subcategorized (≥70 years, ≥80 years).
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%]. Divergence of vaccine and
placebo curves may be utilized to estimate onset of efficacy following immunization.
Furthermore, VE will be evaluated in seronegative participants, counting primary endpoints since
onset after double-blind vaccination.
At the time of unblinding, one additional analysis will be performed to assess the VE of
Ad26.COV2.S  vaccination versus placebo repeating analyses on all primary and secondary
endpoints for the blinded portion of the study.
For the statistical analysis, individual data will be included up to the Month 6/Unblinding Visit for
the double blind, placebo-controlled period. For the analysis of the open-label phase for an
individual subject, data as of the Month 6/Unblinding Visit will be included in the analysis. For
the evaluation of the durability of vaccine efficacy, the analyses of the open label part of the study
will employ methods as described in Follmann (2020).34 Details will be provided in the SAP.
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9.5.1.1. 
Study Monitoring
Table 8: 
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
Non efficacy  
PP
H0: VE ≥40%
vs.
H1: VE <40%
Exact 95% CI 
Upper limit of the
95%CI <40%
Every 2 weeks, starting
from the 20th  event after
14 days following double
blind vaccination
(Day 15)b
Efficacy 
PP
H0: VE ≤50%
vs.
H1: VE >50%
Sequential probability
ratio test
Controlling the family
wise error rate ⍺at
2.5%
Starting from the 42nd
eventc 14 days following
double blind vaccination
(Day 15), then at least
once a week
Efficacy 
PP
H0: VE ≤30%
vs.
H1: VE >30%
Sequential probability
ratio test
Controlling the family
wise error rate ⍺at
2.5%
Starting from the 42nd
eventc 28 days following
double blind vaccination
(Day 29), then at least
once a week
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 9.5.1 are met.
All boundaries will be monitored by an SSG. Once a boundary has been crossed, the SSG will
inform the DSMB and a DSMB 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 DSMB Charter.
Sequential Probability Ratio Test
Following the notation of Dragalin et al. (2002) and Dragalin and Fedorov (2006),30,31  consider,
 and  the number of events in respectively the placebo group  and the vaccine group. The
distribution of  and  can be approximated by a Poisson distribution with the following
parameters:   =     (ℎ = 1,2). Thus, the conditional distribution of  given  =  +
 = t approximately follows a binomial distribution with parameters (, ), where  =

() =

 =
 !" 
 !" , with VE 1-RR, ## =

, assuming a vaccine group  allocation ratio of 1:1.
Consequently, testing the null hypothesis $0:'( = '() against $1:'( = '(∗is equivalent to
testing $0: = ) against H1: 
* the conditional binomial test.
Consider , = -(./0/1 $0|'( = '(0)and 3 = -(411/  $0|'( = '(∗). Rejecting H0 occurs
when  <= 67 with 67 67() calculated to preserve , over all the sequential looks such that
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-( <= 67| = )) = 8(67; , )) ≤,. With 8(.; , ) the cumulative binomial distribution
function with parameter T and . The solution to the above equation, ∗, is the smallest  such
that 8(8 (,; , )); , ∗) ≥1 −3, with 8 (,; ; ) the ,-quantile of the cumulative 
binomial distribution function with parameters T and .
The implemented critical boundaries for success are based on the truncated SPRT for which
success boundaries are set based on observing  events on the vertical axis out of total T events
on the horizontal axis.
9.5.2. 
Secondary Endpoints
All secondary endpoint analyses 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 double-blind vaccination (Day 15)
and with onset at least 28 days after double-blind vaccination (Day 29)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 vaccine efficacy against
milder infections). The BOD evaluates the severity-adjusted VE against preventing symptomatic
incidence. The hypothesis to evaluate the vaccine efficacy 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.
VE against severe/critical infections with onset at least 14 days after double-blind vaccination
(Day 15) and with onset 28 days after double-blind vaccination will be evaluated. Exact Poisson
regression will be used to estimate the VE and associated confidence interval in seronegative
participants in the PP analysis set.
The co-primary endpoints and BOD endpoint will be evaluated at the time of efficacy signal, and
again at the time when the 8-week median follow-up requirement is reached (should the efficacy
signal occur earlier).
VE against any SARS-CoV-2 infection and against asymptomatic infections will be evaluated as
soon as a sufficient number of participants have data available. This timepoint will be detailed in
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the Statistical Analysis Plan and may occur at any of the planned analysis timepoints. Available
N-serology measurements will be incorporated to evaluate VE against any infection, including
asymptomatic infection and against asymptomatic/undetected infection only. 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). Poisson regression will be used to estimate the VE and associated 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 for events with onset at least
14 days after double-blind vaccination and with onset at least 28 days after double-blind
vaccination. 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. Exact Poisson regression will be used to estimate the VE and
the associated confidence interval in seronegative participants in the PP analysis set.
All VE evaluations will be repeated regardless of their serostatus.
Supportive and/or descriptive analysis will be reported with 95% confidence intervals;
confirmatory endpoints will have an adjusted confidence interval reported at the time of hypothesis
testing whereby the alpha level is determined according to the FWER-controlled testing strategy.
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 9.5.1.
9.5.3. 
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.
9.5.4. 
Other Analyses
Biomarkers Analyses
Exploratory biomarker analyses will be part of a separate report.
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Participant Medical Information Prior to, During and After the Study (Real-world Data)
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.
Immunogenicity Analyses
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).
9.6.1. 
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 double-blind vaccination. For participants, who
received vaccination with Ad26.COV2.S at the Month 6/Unblinding Visit in the open-label phase
after having received placebo initially, descriptive statistics of available data after vaccination will
be provided. 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 ImmunogenicitySubset; ~200
from the active group, ~200 from the placebo group), humoral immunogenicity samples are taken
on more occasions.
9.6.2. 
Correlates of Risk
If VE is demonstrated, correlates of risk will be explored. More details with appropriate methods
will then be provided in a separate analysis plan.
Safety Analysis
No formal statistical testing of safety data is planned. Safety data according to the vaccination
schedules 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.
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.
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Safety endpoints following the open-label cross-over 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)
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 double-blind vaccination up to 28 days post-
vaccination), and all SAEs/AESIs/MAAEs will be included in the analysis. (S)AEs and MAAEs
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. Solicited
and unsolicited AEs collected following booster vaccination will be summarized descriptively, as
of amendment 7, the collection of these AEs will stop.
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.
Analysis of the Open-label Cross-overPhase, Open-label Booster
Vaccination Phase and Open-label Passive Follow-up Phase
No additional participants will be recruited for the open-label phase.
Safety, immunogenicity, and efficacy endpoints following cross-over and/or booster vaccination
will be descriptively summarized by the different cohorts for the different phases (ie, for the
open-label phase: early vaccinated cohort and late vaccinated cohort; ie, for the booster phase:
1-dose cohort, homologous booster cohort and the heterologous booster cohort).
Additional analyses may be conducted to support health authority interactions and/or based on
public health demand in case of emerging variants.
9.8.1. 
Sample Size Determination of Immunogenicity Subset (Open-label
Booster Vaccination Phase)
Homologous Booster Subset: The Homologous Booster Subset will include approximately
200 participants. This subset will include participants from the Immunogenicity Subset, who
received Ad26.COV2.S in the double blind phase or after cross-over, and subsequently received
an Ad26.COV2.S booster vaccination in the study. This group may be augmented by other
participants to replace participants who are not available. Participants in the Homologous Booster
Subset will have a blood sample collected pre-booster vaccination, and 28 days, 72 days, 6 months,
and 1 year post booster vaccination for humoral immunogenicity assessment.
Heterologous Booster Subset: The Heterologous Booster Subset will include approximately
400 participants. This subset will include participants in the study who received placebo in the
double-blind phase and have received primary vaccination with an mRNA vaccine or another
authorized COVID-19 vaccine including protein, inactivated, and adenovector based vaccines
outside the study, who subsequently  remained in the study and subsequently received an
Ad26.COV2.S booster vaccination in the study. Participants who already received an additional
COVID-19 vaccination after the primary regimen outside the study will not be included in the
Heterologous Booster Subset. Participants will be selected out of countries where these vaccines
were authorized for emergency use or are licensed. Participants in the Heterologous Booster Subset
will have blood collected pre booster vaccination, and 28 days, 72 days, 6 months, and 1 year post
booster vaccination for humoral immunogenicity assessment.
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A sample size of approximately 600 participants, distributed as described in Table 4 and Table 5,
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 a booster dose of Ad26.COV2.S vaccine in
participants who received homologous Ad26.COV2.S primary vaccination or heterologous
primary vaccination with an mRNA, protein, inactivated or adenovector based vaccine.
9.8.2. 
Immunogenicity Correlates (Correlates Subset)
Correlates for participants who received a booster dose will be assessed in a subset where immune
responses and 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.
9.8.3. 
Efficacy Analyses
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.
The following data sources will be explored:
1. If available, data of participants in the study who did not receive a booster and/or available
data prior to boosting.
2. Data of individuals outside the study who received a similar primary regimen but did not
receive a booster. It will be explored if external data (eg, real world evidence data, and/or
published literature data) is available to that end for the countries enrolled in this study.
For 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 not limit to age, presence of co-morbidities as well as
the spatiotemporal evolution of variants and the epidemic. It is anticipated that comparative
evaluation of efficacy against asymptomatic infections using real world evidence of data of
individuals outside the study will not be feasible due to the difficulty of detecting asymptomatic
infections in real world evidence.
Efficacy data may be compared following homologous versus heterologous booster vaccination.
Efficacy data after primary vaccination until booster vaccination may be summarized (as
immediate, early versus delayed, late vaccination).
All of the above will be detailed in an SAP prior to conducting the analysis.
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Interim Analysis and Committees
The study will be formally monitored by a DSMB (also known as an IDMC). In general, the DSMB
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 1a (2,000
participants) and stage 2a (2,000 participants). The DSMB will review unblinded data. The DSMB
responsibilities, authorities, and procedures will be documented in the DSMB Charter.
The DSMB will also review Day 3 safety data (ie, from Day 1 to Day 3; including safety data from
the ongoing clinical studies)from participants enrolled in Stage 1a and Stage 2a, before enrollment
of participants in Stage 1b and Stage 2b, respectively. Vaccination of participants in the respective
age groups will be paused during these safety reviews.
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 the 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 DSMB through
secure communication procedures. At this point the DSMB  will convene and provide a
recommendation to the Oversight Group, which includes a sponsor representative as a core
member. As such, the potential harm monitoring is in real-time, resulting in the earliest indication
of harm possible as soon as data come in. In addition, the DSMB will formally monitor the SARS-
CoV-2 events to conclude both non-efficacy and efficacy (for more details on the evaluation of
and monitoring for efficacy, see section 9.5.1 and 9.5.1.1, respectively). The DSMB will evaluate
in an unblinded fashion whether superiority is established for the primary endpoints or whether
non-efficacy is shown based on a report provided by the SSG, when the prespecified boundaries
have been crossed.
The study will also be monitored for operational non-efficacy to evaluate whether enough events
to perform the PA can be collected within reasonable time. For that purpose, a monitoring rule will
be set up to assess the probability that the minimal needed target number of primary endpoints
events to be able to perform the PA in the PP set will be reached. For the double-blind phase of
the study, two versions of the non-efficacy monitoring report will be generated. A report provided
to the DSMB  will contain unblinded events and a report provided to the sponsor will contain
blinded events. While it is the primary responsibility of the sponsor to make decisions regarding
study operations and modifications based on monitoring of study vaccine-blinded primary events
from the study, the DSMB can evaluate the progress towards primary endpoints targets in the
context of the study vaccine-unblinded data, and based on this review may recommend to the
Oversight Group, which includes a sponsor representative as a core member, to complete the study
early due to reaching the boundaries for efficacy or non-efficacy to assess VE (see Section 9.5.1).
During the open-label phase, the DSMB will continue to monitor safety.
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The monitoring rules will be detailed in the DSMB Charter, with the statistical details in the SAP.
A final analysis of the double-blind phase will be performed when all participants have completed
the Month 6/Unblinding Visit. Depending on the operational implementation of the
Month 6/Unblinding Visit, as well as the stage of the pandemic, this analysis may be conducted
when a minimum of 90% of the study population has been unblinded. This will provide an analysis
of all endpoints for the blinded portion of the study. This analysis will incorporate data collected
after the EUA submission to the FDA. All data generated after the unblinding will be considered
as part of an analytic plan devoted to the open-label phase. This analysis may be supplemented by
independent measures of incidence and efficacy with real world data obtained in separate studies,
to be described in a separate protocol. More details will be provided in the SAP.
The SAP will describe the planned analyses in greater detail.
Analyses for Cohort Unblinded Due to Administration of an
Authorized/Licensed COVID-19 Vaccine
In the double-blind phase of the study, investigators may receive requests to unblind study
participants who become eligible to receive an authorized/licensed COVID-19 vaccine if/when
these become available. In these cases, the investigator will discuss with the participant available
options and ramifications. 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, 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, both in the double-blind and open-label
phase, will be asked to continue to be followed in this study in line with the Schedule of Activities
to the extent that they permit. Safety, efficacy, and immunogenicity evaluations will be identical
for all participants, if applicable and feasible, including participants who 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
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
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
MedDRA  
Medical Dictionary for Regulatory Activities
MERS  
Middle East respiratory syndrome
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MERS-CoV  
Middle East respiratory syndrome coronavirus
MIS  
multisystem inflammatory syndrome
MRU  
medical resource utilization
MSD  
Meso Scale Discovery
N 
nucleocapsid
NHP  
non-human primate
NIAID  
National Institute of Allergy and Infectious Diseases
OL 
open-label
PA 
primary analysis
PaO2 
partial pressure of oxygen
PP 
Per-protocol (efficacy)
PPI 
Per-protocol Immunogenicity
PQC  
product quality complaint
PSRC  
Prevention Science Review Committee
PSRT 
protocol safety review team
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
SPRT  
sequential probability ratio test
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.
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Unblinding Visit 
The Month 6 visit will be used as an unblinding visit when all participants will be called in
for an on-site visit and will be made aware of their study vaccine allocation, upon
implementation ofprotocol Amendment 4.
Cross-over 
Term used when the participants who initially received placebo will be administered a single
dose of Ad26.COV2.S vaccine (only upon EUA, conditional licensure or approval in any
country).
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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:
 
Protocol and amendment(s), if any, signed and dated by the principal investigator
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 
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
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must be submitted promptly to the IEC/IRB for review and approval before implementation of the
change(s).
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
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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
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. Participants entering the open-label
phase are required to sign a new ICF at the Month 6/Unblinding Visit or at an unscheduled visit
beyond the Month 6/Unblinding Visit if this visit has already been conducted. All participants are
required to sign a new ICF at the Year 1/Booster Visit.
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
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regulatory inspection. This consent also addresses the transfer of the data to other entities and to
other countries.
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 biomarker and 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
A DSMB (also known as 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 1a (2,000 participants) and stage 2a (2,000
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.
The DSMB will also review Day 3 safety data (ie, from Day 1 to Day 3; including safety data from
the ongoing clinical studies) from participants enrolled in Stage 1a and Stage 2a, before enrollment
of participants in Stage 1b and Stage 2b, respectively. Vaccination of participants in the respective
age groups will be paused during these safety reviews.
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 DSMB of any
AE of concern.
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If the SSG assesses that the stopping boundary is met (see below), the Chair of the DSMB will
immediately be informed through secure communication procedures. At this point, the DSMB will
convene and provide a recommendation to the Oversight Group, which includes a sponsor
representative as a core member.
In addition, the DSMB will formally monitor the infections in all groups to conclude both non-
efficacy and efficacy. The DSMB will evaluate in an unblinded fashion whether superiority is
established for the primary endpoints 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. The boundaries
are based on the SPRT. Following the EUA and treatment group unblinding, the DSMB will
continue to monitor participant safety during the open-label phase.
The PSRT and the Janssen Medical Safety Council review all clinical and laboratory safety data
during the course of the study.
Statistical Support Group
The SSG is the statistical support group to the DSMB; they are unblinded and provide the DSMB
with the statistical analysis based on unblinded data. As the DSMB, 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 DSMB  through secure
communication procedures. At this point the DSMB will convene and provide a recommendation
to the Oversight Group, which includes a sponsor representative as a core member. 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
The Clinical Severity Adjudication Committee will review all cases in the study, except for cases
already adjudicated as severe, as a supplement to the algorithm described in the SAP, as well as
those 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), including onset 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). More 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
assessment will be considered the definitive classification of the case. The case review including
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severity assessments after implementation of Protocol Amendment 7 may change and will be
reflected in the charter of the committee.
Oversight Group
The Oversight Group’s responsibilities, authorities, procedures and their interactions with the
DSMB will be documented in the Oversight Group charter.
AESI Adjudication Committee
An AESI Adjudication 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 of the 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
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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
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 18 months 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.
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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,
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 h and i 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 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
source data.
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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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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
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 
Is Medically Important*
*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: the investigator will place a phone
call at Month 18 and Month 24 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)
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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.
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.
NCT04505722

VAC31518 (JNJ-78436735) 
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 15 April 2022
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:
 
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 site 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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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 15 April 2022
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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VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
200
Status: Approved, Date: 15 April 2022
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.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
201
Status: Approved, Date: 15 April 2022
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
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
202
Status: Approved, Date: 15 April 2022
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
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
203
Status: Approved, Date: 15 April 2022
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
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
204
Status: Approved, Date: 15 April 2022
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
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
205
Status: Approved, Date: 15 April 2022
*Please rate the severity of your symptoms inthe last 24 hours?
No Symptoms
Mild
Moderate
Severe
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VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
206
Status: Approved, Date: 15 April 2022
Appendix 7: MRU Questionnaire
As of Amendment 7, this is no longer applicable since the MRU questionnaire will be
decommissioned 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
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
207
Status: Approved, Date: 15 April 2022
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
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
208
Status: Approved, Date: 15 April 2022
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
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
209
Status: Approved, Date: 15 April 2022
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
NCT04505722

NCT04505722

NCT04505722

NCT04505722

NCT04505722

NCT04505722

NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
216
Status: Approved, Date: 15 April 2022
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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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
217
Status: Approved, Date: 15 April 2022
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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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 15 April 2022
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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VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
219
Status: Approved, Date: 15 April 2022
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:
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
220
Status: Approved, Date: 15 April 2022
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.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
221
Status: Approved, Date: 15 April 2022
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.
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
If yes, is this person someone that you live with?
                               ☐  Yes                         ☐  No                            ☐  Not applicable / Don’t want to tell
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
222
Status: Approved, Date: 15 April 2022
Appendix 13: TTS AESI Form
The form below represents the type of information that may be collected in case of a suspected
AESI 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:
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
223
Status: Approved, Date: 15 April 2022
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 (ie, 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 participant 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 have any 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 (eg, heparin, warfarin, DOACs)
Hormone replacement therapy (including contraceptives)
Phlebitis 
Lupus
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
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
224
Status: Approved, Date: 15 April 2022
Inflammatory bowel disease 
Myeloproliferative disorders
Diabetes mellitus 
Hyperlipidemia
Hypertension                                                                       
Dehydration
Other significant medical comorbidities 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
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 15 April 2022
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:
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
226
Status: Approved, Date: 15 April 2022
Appendix 14: Thrombotic Events to be Reported as 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
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
227
Status: Approved, Date: 15 April 2022
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 (04 September 2021)
Overall Rationale for the Amendment: The main purpose of this amendment is to offer a 1-dose
booster vaccination with Ad26.COV2.S at the 5x1010 vp dose level to all ongoing participants in
the study, regardless of their primary vaccination regimen (Ad26.COV2.S vaccine or a single or
two dose regimen of an mRNA vaccine or another authorized COVID-19 vaccine including
protein, inactivated, and adenovector based vaccines). The booster vaccination will be
administered in the open-label phase of the study. The combination of homologous or heterologous
prime/boost vaccination will not be randomized, but depend on what participants received during
the double-blind phase of the study as described in this protocol. Booster vaccination should occur
preferably 6 months but at least 3 months after the primary vaccination regimen. Participants in
the study who have already received an additional COVID-19 vaccination after the primary
regimen outside the study with any vaccine as described above will also be eligible for the
Ad26.COV2.S booster in this study preferably 6 months but at least 3 months after their last
COVID-19 vaccination. Participants are free to choose when to receive the booster vaccination
within the window of the booster vaccination visit, to receive booster vaccination outside the study,
or not to receive booster vaccination. Participants who choose to receive a booster vaccination
with the Ad26.COV2.S vaccine (if recommended and available) or another authorized COVID-19
vaccine outside the study or choose not to receive a booster vaccination will not be withdrawn
from the study and will be encouraged to remain in the study. All participants who received a
booster vaccination within the study or received a booster vaccination outside the study and
remained in the study will be monitored for safety, immunogenicity, and efficacy. Immunogenicity
will be assessed with blood draws on the day of booster vaccination (prior to booster vaccination,
if feasible), and 28 days, 72 days, and 6 months post booster vaccination. In addition,
immunogenicity subsets with more extensive blood draws for immunogenicity assessments will
be included. Safety blood draws will include a platelet count at Baseline (prior to booster
vaccination, if feasible), and 28 days after booster vaccination and extra blood, aside from that
required for immunogenicity and N serology for determination of infection, to assess relevant
parameters in case of an adverse event of interest. With implementation of this amendment, the
start date of the first cross-over unblinding visit (implemented with Amendment 4) and the date of
first booster vaccine administration until 1-year follow-up of the last booster vaccination define
the open-label booster vaccination phase of the study. This phase will be utilized to describe safety,
immunogenicity, and efficacy during the time participants have and have not been boosted.
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 for at least 8 months.
Despite this durability, signs of waning immunity in terms of the numbers of participants with
undetectable antibody have been observed, especially in the older population, where as many as
28% have no detectable neutralizing antibody at 6 months post vaccination. Furthermore, while
protection against variants of concern such as the Beta variant, the Gamma variant, and the B.1.621
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
228
Status: Approved, Date: 15 April 2022
variant in this study24 and the Delta variant in the Sisonke study remains high against serious
disease, hospitalization, and death, this protection is somewhat lower against, for example, the
Delta variant compared to the reference Wuhan strain.38 Protection against mild to moderate
disease against the Delta variant is very low at the late time points when measured in the Sisonke
study, although it is unknown if this is due to waning immunity or biologic factors related to the
Delta variant. Waning immune responses and less protection against moderate to severe disease
against the Delta variant has also been observed for mRNA vaccines. Based on these findings,
regulatory and advisory bodies including the FDA are planning to recommend booster doses for
vaccines when data supports such recommendations. Therefore, based on this recommendation for
a booster vaccination and the availability of booster vaccinations outside the study, this
amendment will permit boosting of all ongoing participants in this study who have previously
received any COVID-19 vaccine(s) (either as part of a primary regimen or as an additional dose
administered after the primary regimen). All participants who received vaccination with
Ad26.COV2.S, an mRNA vaccine and/or another COVID-19 vaccine authorized for primary
vaccination, if the last vaccination was preferably 6 months but at least 3 months ago, and who
subsequently remained in the study will be eligible to receive the booster.
These and other changes made to the clinical protocol of study VAC31518COV3001 are listed
below, including the rationale for each change and a list of all applicable sections.
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
1.2 Schema 
1.3.1 Schedule of Activities “All 
Participants” 
2.1 Study Rationale 
2.3.3 Benefit-Risk Assessment of 
Study Participation  
4.1 Overall Design  
5 STUDY POPULATION  
5.5 Criteria for Temporarily Delaying 
Administration of Study Vaccination 
6.1 Study Vaccines Administered 
6.2 Preparation/Handling/Storage/
Accountability  
6.8 Continued Access to Study Vaccine 
After the End of the Study  
8 STUDY ASSESSMENTS AND 
PROCEDURES
8.1.3 Efficacy Assessments 
8.1.3.5 SARS-CoV-2 Seroconversion 
Assessment 
8.1.4 Immunogenicity Assessments 
8.2.3 Pregnancy Testing 
8.3.1 Time Period and Frequency for 
Collecting Adverse Event, Medically- 
attended Adverse Event, Adverse 
Events of Special Interest, and Serious 
Adverse Event Information  
8.3.5 Pregnancy
At the 1 Year visit, all ongoing 
participants 
who 
have 
previously 
received any COVID-19 vaccination(s)
(as primary regimen or additional dose)
with Ad26.COV2.S, an mRNA vaccine
and/or another for primary vaccination
authorized 
protein, 
inactivated, 
or
adenovector based vaccine will be offered
a single booster dose of Ad26.COV2.S
vaccine (5×1010 vp) if the last vaccination
was preferably 6 months but at least
3 months ago.
The window of the 1 Year visit has been
widened to allow booster vaccination as
of approximately ≥3 months following
the last previous COVID-19 vaccination.
A visit 28 days post booster vaccination
has been added for all participants who
received a booster vaccination at the
Year 1/Booster Visit for follow up of
safety and immunogenicity, and 72 days
post booster vaccination for follow up of
immunogenicity. 
Immunogenicity
subsets (a total of 600 participants) with
more 
extensive 
blood 
draws 
for
immunogenicity assessments were added.
See 
overall 
rationale 
for
amendment.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
8.10 Assessments and Procedures 
Related to Booster Vaccination 
9.2.2 Immunogenicity Subset (Double- 
blind Phase and Booster Vaccination  
10.1 Appendix 1: Abbreviations 
10.2 Appendix 2: Clinical Laboratory
Test 
10.3.3 Informed Consent Process 
A visit 1 day post booster vaccination has
been 
added 
for 
additional
immunogenicity and safety assessment
for a subgroup of the immunogenicity
subsets (120 participants).
The timing of the Month 18 and Year 2
visits have been adjusted to accommodate
6- 
and 
12-months 
follow-up 
for
participants 
who 
received 
booster
vaccination at the Year 1/Booster Visit.
An additional urine pregnancy test at the
Year 1/Booster Visit was added for
participants of childbearing potential who
choose to receive booster vaccination.
Added that a new ICF needs to be signed
at the Year 1/Booster Visit.
1.1 Synopsis 
3.2 Booster Vaccination 
Objectives & Endpoints were added for 
the open-label booster vaccination phase 
of the study. 
To 
obtain 
information
regarding 
the 
safety,
immunogenicity, and efficacy
of a booster vaccination.
6.5 Booster Vaccination 
Describes the conditions under which 
participants 
may 
receive 
booster 
vaccination.
To 
provide 
appropriate
guidance.
1.1 Synopsis 
1.3.1 Schedule of Activities “All 
Participants” 
8.1.4 Immunogenicity Assessments 
9.8.1 Immunogenicity Subset (Open- 
label Booster Vaccination Phase) 
Immunogenicity subsets (Homologous 
Booster Subset and Heterologous Booster 
Subset) were added for the open-label 
booster vaccination phase of the study. 
Of the total 600 participants with 
extensive 
blood 
draws 
for 
immunogenicity, 200 participants will be 
from the Homologous Booster Subset and 
400 from the Heterologous Booster 
Subset. 
Of the 120 participants with additional
immunogenicity and safety assessment at
the visit 1 day post booster vaccination 60
will be from the Homologous Booster
Subset and 60 from the Heterologous
Booster Subset.
To investigate the magnitude
and kinetics of the humoral
response induced by a booster
dose of Ad26.COV2.S vaccine
in participants who received
homologous 
Ad26.COV2.S
primary 
vaccination 
or
heterologous 
primary
vaccination with an mRNA,
protein, 
inactivated 
or
adenovector based vaccine.
1.1 Synopsis
9 STATISTICAL
CONSIDERATIONS
9.2.1 Efficacy (Total Sample Size)
9.8 Analysis of the Open-label Booster
Vaccination Phase
9.8.1 Immunogenicity Subset (Open-
label Booster Vaccination Phase)
9.8.2 Immunogenicity Correlates
(Correlates Subset)
9.8.3 Efficacy Analyses
Statistical considerations for the analysis
of the open-label booster vaccination
phase were added.
It was clarified that Sections 9.1 to 9.7 are
only applicable to the double-blind phase
of the study.
Text was added to indicate that details of
the statistical analysis of the open-label
To describe the statistical
considerations of the open-
label 
booster 
vaccination
phase.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
booster vaccination phase will be
specified in a separate SAP.
It was clarified that no additional
participants will be recruited for the open-
label phase.
It was clarified that analysis of the open-
label booster vaccination phase data is
planned to be performed 6 months and
1 year after all participants were offered
the booster vaccination. Additional
analyses may be conducted to support
health authority interactions and/or based
on public health demand in case of
emerging variants.
2.3.1 Risks Related to Study 
Participation  
It was added that no clinical data are 
available 
for 
Ad26.COV2.S
administration after previous vaccination
with a COVID-19 vaccine other than
Ad26.COV2.S. 
Available 
clinical
information on the administration of an
Ad26.COV2.S 
booster 
vaccination
following a single dose Ad26.COV2.S
was added.
Text was added that 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.
To update the potential risks.
1.3.1 Schedule of Activities “All 
Participants” 
8 STUDY ASSESSMENTS AND 
PROCEDURES  
Blood volumes to be collected in the 
study were updated to include additional
blood samples added for the open-label
booster vaccination phase.
Update
1.3.3 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
1.1 Synopsis 
11 REFERENCES  
The 
reference 
to 
the 
Brighton 
Collaboration 
case 
definition 
of
thrombotic events and thrombocytopenia
was updated.
Update
6.4 Unblinding and Open-label Phase 
Text was added that participants with a 
history of capillary leak syndrome are not
eligible for cross-over vaccination with
Ad26.COV2.S 
at 
the 
Month 
6/
Unblinding Visit (nor are they eligible to
receive a booster vaccination at the
Year 1/Booster Visit).
Update
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
231
Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
10.2 Appendix 2: Clinical Laboratory 
Test 
Added that, as part of investigation of any 
AESI, samples from appropriate controls
within the study could be used for
coagulation-related assays.
Clarification
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.
Amendment 5 (07 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 (EUA) in the United States (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 an adverse event
of special interest (AESI) that needs to be reported to the sponsor within 24 hours of awareness.
In addition, anaphylaxis has been added as an important identified risk.
In addition, this amendment has been created to reinstate the use of a central laboratory for RT-
PCR tests or other molecular diagnostic test to confirm cases of SARS-CoV-2 infection  upon
health authority (HA) request.
These and other changes made to the clinical protocol of study VAC31518COV3001 are listed
below, including the rationale for each change and a list of all applicable sections.
Section Number
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
1.3.1 All Participants
1.3.3 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
6.9 Prestudy and Concomitant Therapy
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
Thrombosis with thrombocytopenia
syndrome (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 assessment 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 to
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.
NCT04505722

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Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
Event of Special Interest, 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
8.3.7Adverse Events of Special
Interest
8.3.7.1 Thrombosis with
Thrombocytopenia Syndrome
9.2.4.2 All Participants
9.7Safety 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 AESIs
11 REFERENCES
1.1 Synopsis 
1.3.1 Schedule of Activities “All 
Participants” 
1.3.2 Schedule of Activities 
“Participants With (Suspected)
COVID-19”
3 OBJECTIVES AND ENDPOINTS
4.1 Overall Design
8.1.3 Efficacy Assessments
9.5.1 Primary Endpoint Evaluation
10.2 Appendix 2: Clinical Laboratory
Test
Reinstated text to use a central 
laboratory for RT-PCR tests or other
molecular diagnostic test to confirm
cases of SARS-CoV-2 infection.
Changed upon HA request.
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
identified risks. Added anaphylaxis
as
identified risk.
1.3.1 All Participants 
2.3.1 Risks Related to Study 
Participation  
5.5 Criteria for Temporarily Delaying 
Administration of Study Vaccination 
6.4 Unblinding and Open-label Phase 
It has been further clarified that 
participants who are pregnant at the
Month 6/unblinding visit 
and
previously received placebo during
the double-blind phase may be
vaccinated with Ad26.COV2.S, if the
For clarification purposes.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
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Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
8.2.3 Pregnancy Testing 
8.3.5 Pregnancy  
investigator 
considers 
that 
the
potential benefits outweigh the
potential risks.
Participants who originally received
placebo and will not be receiving the
Ad26.COV2.S vaccine under EUA,
do not need to complete a pregnancy
test.
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.
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.
1.1 Synopsis 
4.1 Overall Design  
8.9 Assessment and Procedures after 
EUA or Approval/Licensure and 
Implementation of Protocol 
Amendment 4 
9.1 Statistical Hypotheses 
9.8 Interim Analysis and Committees 
Clarified that the final analysis of the 
double-blind phase may be 
conducted when a minimum of 90% 
of the study population has been
unblinded depending on the
operational implementation of
Month 6 unblinding visit, as well as
the stage of the pandemic.
To 
update 
the 
analysis 
as
appropriate for the change to an
open-label design.
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.
Amendment 4 (22 February 2021)
Overall Rationale for the Amendment: The main purpose of this amendment is to outline the
procedures to be followed after Emergency Use Authorization (EUA), conditional licensure, or
approval in any country and approval of the protocol Amendment 4 by both Health Authority and
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) where a single dose of
Ad26.COV2.S vaccine will be offered to enrolled participants who initially received placebo,
resulting in de facto unblinding of participants and investigators. All participants will be
encouraged to remain in the study and continue to be followed for efficacy/effectiveness, safety
and immunogenicity as originally planned for up to 2 years post-vaccination on Day 1. This will
allow assessment of the duration of protection and immunogenicity of a single dose of
Ad26.COV2.S by comparing 2 groups vaccinated approximately 4 to 6 months apart.
In addition, clarification is provided that RT-PCR test results obtained from any source (including
local laboratories) may be used for analyses and that confirmation by the central laboratory will
no longer be required as part of the case definitions.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
234
Status: Approved, Date: 15 April 2022
These and other changes made to the clinical protocol of study VAC31518COV3001 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 
1.2 Study Schema 
1.3.1 Schedule of Activities 
2 Introduction  
2.1 Study Rationale 
2.3.3 Benefit-Risk Assessment of 
Study Participation  
3 Objectives and endpoints 
4.1 Overall Design  
4.2 Scientific Rationale for Study 
Design  
5. Study Population 
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  
8.9 Assessment and Procedures 
After EUA or Approval/Licensure 
and Implementation of protocol 
Amendment 4 
10.2 Appendix 2: Clinical 
Laboratory Test 
10.3.3 Informed Consent Process 
At the 6 Month/unblinding visit, all 
participants who initially received 
placebo will be offered a single 
dose of Ad26.COV2.S vaccine 
(5×1010 vp), starting an open-label 
phase of the study. This is to occur 
as soon as possible after the Day 71 
visit. 
All participants at the Month 
6/unblinding visit will have a blood 
draw and nasal swab. 
Relevant sections were updated 
regarding the open-label phase. 
Participants to be reminded there is 
no data on the safety of receiving 2 
different COVID-19 vaccines. 
Removed the following sentence at 
the end of Section 6.6: "At such 
time, an amendment will be
submitted to permit individual 
unblinding and to determine the 
approach to this situation in the 
Statistical Analysis Plan." 
As the vaccine is highly efficacious
against 
severe 
disease,
hospitalization and death, it is
considered ethical to offer the active
vaccine to the placebo controls in
this study. Hereby, an unblinding
visit will be scheduled to inform all
participants 
about 
their 
study
vaccine allocation as well as to offer
all 
placebo 
recipients
Ad26.COV2.S 
after 
EUA,
conditional licensure or approval in
any country. 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 Month 6/unblinding
visit, as well as having a new
baseline read-out for the remainder
of the study.
The 6 Month visit with a broadened
visit window will be used as an
unblinding visit to allow for rapid
cross-over in the context of logistic
issues. 
Investigators 
will 
be
encouraged 
to 
follow 
health
authority 
guidelines 
on
prioritization of immunization when
feasible. 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.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
235
Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
6.3 Measures to Minimize Bias: 
Randomization and Blinding 
6.7 Continued Access to Study 
Vaccine After the End of the Study  
Additional changes needed to allow 
unblinding prior to 
authorization/licensure 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 for
Ad26.COV2.S 
prior 
to 
EUA,
conditional licensure or approval in
any country to continue to be
followed in VAC31518COV3001.
6.4 Unblinding and Open-label 
Phase (added) 
Describes the conditions under 
which participants who received 
placebo initially may be vaccinated 
with Ad26.COV2.S. 
To provide guidance on the
appropriate 
vaccination 
of
participants at the start of the open-
label phase.
1.1 Synopsis 
9.5.1 Primary Endpoint Evaluation 
Text has been added describing a 
final analysis of the double-blind 
phase which will be performed 
when all participants will have
completed the Month 6/unblinding
visit and will provide an analysis of
all endpoints for the blinded portion
of the study.
To provide an analysis on all data
that can be considered part of the
double-blind phase of the study.
3 Objectives and endpoints 
Reference to "post-vaccination" in 
objectives and endpoints has been 
updated to "after double-blind." 
To clarify changes  required by
adding the open-label phase of the
study.
3 Objectives and endpoints 
9.5.1 Primary Endpoint Evaluation 
The following secondary endpoint 
was added: 
- Asymptomatic infection detected
by RT-PCR at the time of the
Month 6/unblinding visit.
The following exploratory
objectives were added:
- To evaluate the long term
durability of the efficacy of
Ad26.COV2.S in the prevention of
molecularly confirmed, moderate to
severe/critical COVID-19, in adults
by comparing 2 groups of
participants vaccinated
approximately 4 to 6 months apart.
- 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.
To gather information regarding
long term efficacy and efficacy
against variants.
1.1 Synopsis 
9 Statistical Considerations 
Added text describing analysis of 
the data once EUA, conditional 
licensure or approval in any 
country is obtained and all 
participants are unblinded. 
To ensure assessment of the
duration 
of 
protection 
and
immunogenicity of a single dose of
Ad26.COV2.S by comparing 2
groups vaccinated approximately 4
to 6 months apart.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
236
Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
1.3.1 Schedule of Activities 
3 Objectives and Endpoints 
4.1 Overall Design  
8.1.3 Efficacy Assessments 
9.5.1 Primary Endpoint Evaluation 
10.2 Appendix 2: Clinical 
Laboratory Test 
Added text to clarify that a RT-PCR 
test obtained from any source will 
be used for all analyses. These 
include RT-PCR tests performed by 
local laboratories that have utilized 
RT-PCR testing devices approved 
by the COVID-19 Response Team 
(formerly 
known 
as 
OWS),
laboratories that are designated as
substitutes for local laboratories
within the context of the study or
any PCR test utilized for a
hospitalized study participant for
diagnosis and treatment of COVID-
19. In addition, any RT-PCR test not
meeting the above criteria can only
be used for determination of an
asymptomatic case. Confirmation
by the central laboratory will not be
required as part of any of the case
definitions.
Based on data seen thus far, there
was a high concordance of results
between the central and local
laboratories, therefore it is deemed
reasonable to use RT-PCR results
from local  laboratories to confirm
cases of SARS-CoV-2 infection.
1.1 Synopsis 
8.1.3.6 Clinical Severity 
Adjudication Committee 
10.3.6 Committees Structure 
Added text describing adjudication 
of asymptomatic, mild, moderate, 
severe, and cases requiring 
hospitalization, ICU, ventilator 
support or ECMO and death 
including date of onset and reasons 
for the classification. As new 
information becomes available, 
cases may be readjudicated.
The role of the Clinical Severity
Adjudication Committee is being
expanded 
to 
improve 
the
classification of the cases. The SAP
will be amended to include the new
adjudication process in the efficacy
assessment of the vaccine (endpoint
selection for the analysis).
1.1 Synopsis 
8.1.3.4 Case Definition for 
Asymptomatic or Undetected 
COVID-19 
9.5.1 Primary Endpoints Evaluation  
Clarification about the definition of 
asymptomatic infection. 
The current definition does not
clearly eliminate cases that are
SARS-CoV-2 N antibody sero-
converters but RT-PCR negative
and have symptoms consistent with
COVID-19.
1.1 Synopsis 
1.3.1 Schedule of Activities 
4.1 Overall Design  
8 Study Assessments and 
Procedures
Updated the twice weekly eCOA 
assessments to occur 1 year 
following the Month 6/unblinding 
visit. 
To ensure that all participants have
1 year of eCOA assessments
following the Month 6/unblinding
visit.
6.9 Prestudy and Concomitant 
Therapy  
A statement was added that receipt 
of another COVID-19 vaccine by a 
study participant at any time during 
the study should be recorded along 
with the name and date(s) of the 
vaccine. 
This was added so receipt of another
COVID-19 
vaccine 
can 
be
accounted 
for 
in 
determining
efficacy, 
duration 
of efficacy
calculations and safety evaluations.
Participants that have received
another COVID-19 vaccine will not
be allowed to receive a single dose
of Ad26.COV2.S
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
237
Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
9.5.1 Primary Endpoints Evaluation  
Include the study success criterion 
of the point estimate of VE being 
>50% for both co-primary 
endpoints. 
A consequence of using a VE of
30% in the hypothesis testing is that
the null hypothesis could be rejected
with a result for either co-primary
VE of less than 50%. It is specified
that this would not be considered a
successful study.
6.3 Measures to Minimize Bias: 
Randomization and Blinding 
9.9 Analyses for Cohort Unblinded
Due to Administration of an
Authorized/Licensed COVID-19
Vaccine
Changed SARS-COV-2 to 
Ad26.COV2.S
Consistency
1.3.1 Schedule of Activities 
8.1.4 Immunogenicity Assessments 
Blood draw at the 1-Year visit will 
be replaced by Month 18 visit for 
non-immunogenicity subset 
participants (10 mL). 
To evaluate the levels of
immunogenicity 1 year after
beginning of the open label phase
of the study.
1.3.1 Schedule of Activities 
2.3.1 Risks Related to Study 
Participation  
6.3 Measures to Minimize Bias: 
Randomization and Blinding 
8.2.3 Pregnancy Testing
Added an additional urine 
pregnancy test at the time of 
Month 6/unblinding visit for 
cross-over participants who initially 
received placebo. 
In order to be aware of potential
pregnancy before administering
Ad26 vaccine. Vaccination of
pregnant may be allowed depending
on local guidelines.
1.1 Synopsis 
8.1.4 Immunogenicity Assessments 
8.2 Safety Assessments 
8.3.1 Time Period and Frequency 
for Collecting Adverse Event, 
Medically-attended AdverseEvent, 
and Serious Adverse Event 
Information 
8.3.2 Method of Detecting Adverse 
Events, Medically-attended Adverse 
Events, and Serious Adverse Events 
9.2.4 Safety
Clarified that the Safety and 
Immunogenicity Subsets are 
applicable for the double-blind 
phase only, but special reporting 
situations will be recorded until 28
days as well as MAAEs will be
reported until 6 months after
(double-blind or open-label)
vaccination with Ad26.COV2.S
and SAEs will be reported until
end-of-study.
To be consistent with the safety
reporting requirements following
administration of an investigational
vaccine.
1.1 Synopsis 
9 Statistical Considerations 
Added statement to indicate that 
samples from open-label phase will 
be analyzed separately. 
The double-blind and the open-
label phases will be analyzed
separately and will be described in
separate SAPs.
Synopsis 
9.8Interim Analysis and 
Committees 
Text was added to describe the 
final analysis of the double-blind 
data and the open-label data, 
supplemented by real-world data. 
The double-blind and the open-
label phases will be analyzed
separately. Interpretation of the
open-label data may be
supplemented by real-world data
from other studies if applicable.
8.1.2 Procedures in Event of 
(Suspected) COVID-19 
Clarified procedures around 
suspected COVID-19 cases.
Clarification
2.3.2 Benefits of Study Participation Added statement about recent data 
suggesting efficacy/safety of
Ad26.COV2.S from primary
analysis of COV3001.
Updated text
10.12 Appendix 12: Risk Factor 
Assessment 
Updated the assessment form to 
change any references to “2020” to 
“the near future.”
To extend the data collection
period, as the study is still ongoing.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
238
Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
Throughout the protocol 
Specified “double-blind” 
vaccination throughout as 
applicable 
Updated terminology from 
“COVID-19 infection” to “SARS-
CoV-2 infection”
Minor errors and inconsistencies 
were corrected, and minor 
clarifications were added 
throughout the protocol.
This was done to clarify that the
timing of follow-up (except for
MAAEs and special reporting
situations) is relative to the first
vaccination for participants who
cross-over to open-label active
vaccine.
To differentiate the disease from its
causative agent.
Correction of minor errors and
inconsistencies. Addition of minor
clarifications. Alignment across
sections in the protocol.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
239
Status: Approved, Date: 15 April 2022
Amendment 3 (14 December 2020)
Overall Rationale for the Amendment: The main purpose of this amendment is to add first
occurrence of molecularly confirmed, moderate to severe/critical COVID-19, with onset at least
28 days post double-blind vaccination as a co-primary endpoint in addition to the current primary
endpoint counting as of 14 days post double-blind vaccination. The applicable secondary and
exploratory endpoints were updated similarly to also include COVID-19 cases with onset at least
28 days post double-blind vaccination. In addition, the total sample size was reduced from 60,000
to approximately 40,000 participants. The protocol is further amended to change the conditions
for monitoring whether efficacy greater than 30% is achieved using the sequential monitoring
algorithm: (1) The minimum number of COVID-19 cases meeting the primary case definition
needed to start the efficacy monitoring was modified to at least 42 instead of 20, (2) The need for
a follow-up of 8 weeks for 50% of the participants prior to an initial look at an efficacy signal if
the other conditions are met was removed.
These and other changes made to the clinical protocol of study VAC31518COV3001 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
3 OBJECTIVES AND
ENDPOINTS
4.1 Overall Design
8.1.3.1 Case Definition for
Moderate to Severe/Critical
COVID-19
8.1.3.6 Clinical Severity
Adjudication Committee
9.1 Statistical Hypotheses
9.2.1 Efficacy (Total Sample Size)
9.5.1 Primary Endpoints Evaluation
9.5.1.1 Study Monitoring
9.5.2 Secondary Endpoints
9.8 Interim Analysis and
Committees
10.3.6 Committees Structure
A co-primary endpoint was added
counting COVID-19 cases from
28 days post-vaccination (Day 29),
in addition to from 14 days post-
vaccination (Day 15).
The applicable secondary and
exploratory endpoints were updated
to also include COVID-19 cases
with onset at least 28 days post-
vaccination, in addition to from 14
days post-vaccination.
This change will allow for formal
testing and reporting of the primary
endpoint counting cases from 28
days post-vaccination as an
additional condition for success
along with the 14 days post-
vaccination endpoint results.
Maintaining the original primary
endpoint will preserve trial
integrity. This approach will allow
to provide the most accurate
description of the vaccine efficacy
and to assess vaccine efficacy as
early as 14 days post-vaccination.
3 OBJECTIVES AND
ENDPOINTS
Deletion of the exploratory
endpoint relating to evaluation of
the occurrence, severity and
duration of COVID-19 episodes in
participants who received
Ad26.COV2.S, as compared to
placebo, by the Clinical Severity
Adjudication Committee,
previously known as the Clinical
Evaluation Committee.
The Clinical Severity Adjudication
Committee only exists to determine
severe/critical cases of COVID-19.
NCT04505722

VAC31518 (JNJ-78436735) 
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Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
9.2.1 Efficacy (Total Sample Size) 
9.2.4 Safety Subset 
The total sample size was reduced 
from 60,000 to approximately 
40,000. 
The paragraph on the operational
futility was removed.
The incidence of moderate to
severe COVID-19 seen in the US
and reported in other COVID-19
vaccine studies is significantly
higher than assumed at the time of
protocol planning. Furthermore,
based on that incidence and
modeling, there is a high degree of
probability that an efficacy signal
meeting the prespecified criteria in
this amendment will be reached at,
or prior to, the time when 50% of
participants will have been
followed for 8 weeks from the time
of vaccination.
1.1 Synopsis 
9.5.1 Primary Endpoints Evaluation 
The conditions for monitoring 
whether efficacy greater than 30% 
is achieved using the sequential 
monitoring algorithm were 
changed: 
(1) The minimum number of 
COVID-19 cases with onset at least 
28 days after vaccination meeting 
the primary case definition needed 
to start the efficacy monitoring was 
modified to at least 42 instead of 
20. 
(2) The need for a follow-up of 
8 weeks for 50% of participants 
prior to an initial look at an efficacy
signal if the other conditions are
met, was removed.
In addition, text was added to
clarify the timing of primary and
interim analyses.
(1) The minimum number of
COVID-19 cases was increased to
have a more robust signal at the
time of the efficacy declaration.
(2) This change was made to
expedite submissions to ensure the
vaccine is made available to the
public as soon as possible.
Following 50% of participants for
8 weeks from the day of
vaccination meets the sponsor’s
understanding of the requirement
for 8 weeks median follow-up for a
40,000-participant study.
1.1 Synopsis 
3 OBJECTIVES AND 
ENDPOINTS  
9.5.2 Secondary Endpoints 
A secondary objective and endpoint 
were added assessing the efficacy 
of the vaccine in the prevention of 
molecularly confirmed, 
severe/critical COVID-19 with 
onset at least 14 days 
post-vaccination and 28 days post- 
vaccination. 
With the increased incidence of
disease that is being observed, the
likelihood of having enough severe
cases of COVID-19 to examine
vaccine efficacy against this
endpoint has increased. Vaccine
efficacy against severe disease is
considered an important endpoint
for a 1-dose vaccine.
1.1 Synopsis 
1.3.1 All Participants 
3 OBJECTIVES AND 
ENDPOINTS  
8.1.3 Efficacy Assessments 
8.1.3.5 SARS-CoV-2 
Seroconversion Assessment 
8.1.4 Immunogenicity Assessments
10.2 Appendix 2: Clinical
Laboratory Tests
An exploratory objective and 
endpoint were added assessing the 
effect of the vaccine on confirmed 
asymptomatic or undetected 
infections by testing serologic 
conversion between baseline and 28
days post-vaccination.
This change allows the evaluation
of the effect of the vaccine on
asymptomatic infections up to Day
29, in line with other efficacy
endpoints.
NCT04505722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3001 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
241
Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
3 Objectives and Endpoints 
OBJECTIVES AND 
ENDPOINTS  
An exploratory objective and 
endpoint to examine the degree of 
frailty were added. 
The vaccine will be especially
useful in the elderly population
with co-morbidities. The frailty
index has been utilized as a tool to
summarize the degree of frailty that
a participant has.
1.1 Synopsis 
2.3.1. Risks Related to Study 
Participation  
3 OBJECTIVES AND 
ENDPOINTS  
8.1.3 Efficacy Assessments
8.1.3.6 Clinical Severity
Adjudication Committee
10.3.6 Committees Structure
The Clinical Evaluation Committee 
was replaced by the Clinical 
Severity Adjudication Committee. 
The standard case definition of
severe/critical disease may not
cover all situations where clinical
judgement would disagree with the
classification on clinical grounds.
1.1 Synopsis 
8.1.3.1 Case Definition for 
Moderate to Severe/Critical 
COVID-19 
Addition of text defining the 
definitive role of the Clinical 
Severity Adjudication Committee 
in determining whether cases are 
severe/critical cases of COVID-19. 
Clarification of the definitive role
of the Clinical Severity
Adjudication Committee in
defining the severity of cases of
COVID-19.
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 
8.8 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 
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 
United States (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
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 
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.
1.3.1 All Participants 
1.3.2 Participants With (Suspected) 
COVID-19 
Further clarifications are made to 
the procedures to be followed in 
case of (suspected) COVID-19.
Alignment across the protocol and
clarifications on the procedures to
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Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
4.1 Overall Design  
8.1.2 Procedures in the Event of 
(Suspected) COVID-19
be followed in case of (suspected)
COVID-19.
5.1 Inclusion Criteria 
Inclusion criterion 4 was updated to 
clarify that all comorbidities need
to be stable and well-controlled,
those that are associated with
severe COVID-19 AND those that
are not associated with severe
COVID-19. In addition, a time
frame was added for criteria a and b
for stable/well-controlled HIV
infection.
Clarification
5.1 Inclusion Criteria 
In inclusion criterion 4, 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
5.1 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
5.2 Exclusion Criteria 
In exclusion criterion 3, “Patients 
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 
In exclusion criterion 4, it was 
clarified that autologous blood
transfusions are not excluded.
Clarification
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 
6.3 Measures to Minimize Bias: 
Randomization and Blinding 
6.7Continued Access to Study 
Vaccine After the End of the Study  
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.
10.8 Appendix 8: Medically- 
attended COVID-19 (MA-COV) 
Form  
The MA-COV form has been 
updated to also capture 
hyperinflammatory syndrome. 
To ensure collection of all
necessary information in order to
determine the severity of
COVID-19 per the case definitions
and clarification purposes.
2.3.1 Risks Related to Study 
Participation  
It was clarified that the use of 
condoms is not considered an
Clarification
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Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
5.1 Inclusion Criteria 
acceptable contraceptive barrier
method due to the failure rate of
female and male condoms.
8 STUDY ASSESSMENTS AND 
PROCEDURES  
It was clarified that in case of home 
visits, assessments that cannot be
delegated to a designee must be
performed by an appropriate site
staff member via a phone call or
telemedicine.
Clarification
8.7Risk Factor Assessment 
9.4 Participant Information 
It was 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
6.3 Measures to Minimize Bias: 
Randomization and Blinding 
9.5.1 Primary Endpoints Evaluation 
The timepoints of analyses at which 
the sponsor will be unblinded were
clarified.
Clarification
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.
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Status: Approved, Date: 15 April 2022
Amendment 2 (29 October 2020)
Overall Rationale for the Amendment: This 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. Also, some errors, have been corrected, including the clarification that blood will
be drawn on Day 29 for biomarker RNAseq analyses (PAXgene tube), which is needed in order to
assess the current objectives. Finally, some minor errors have been corrected.
The changes made to the clinical protocol of study VAC31518COV3001 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
8 STUDY ASSESSMENTS AND
PROCEDURES
8.1.1 Prespecified Criteria for Suspected
COVID-19
8.1.2 Procedures in the Event of (Suspected)
COVID-19
8.1.3.4 Case Definition for Asymptomatic or
Undetected COVID-19
10.3.10 Source Documents
Clarified that all participants
that have a RT-PCR positive
finding for SARS-CoV-2
from outside the study, even if
asymptomatic, will be
followed until there are two
consecutive negative PCRs.
To ensure safety of staff and
other persons coming in contact
with the infected participant.
1.3.1 All Participants
8 STUDY ASSESSMENTS AND
PROCEDURES
10.2 Appendix 2: Clinical Laboratory Tests
It has been clarified that at
Day 29 2.5 mL blood will be
collected from participants for
biomarker RNAseq analyses
(PAXgene tube).
Correction. In order to assess
the objectives as currently stated
in the protocol, a blood
sampling for biomarker
RNAseq (PAXgene)performed
after the participants have
received the vaccination is
required.
1.1 Synopsis
2.1 Study Rationale
2.3.3 Benefit-Risk Assessment of Study
Participation
4.1 Overall Design
9.2.2 Immunogenicity Subset
It has been clarified that Stage
1b and Stage 2b will enroll
participants with and without
comorbidities. However,
participants in the
Immunogenicity Subset 1b
and 2b will be participants
with comorbidities.
Clarification
5.2 Exclusion Criteria
6.8 Prestudy and Concomitant Therapy
The specification of ‘(>10
days)’ when referring to the
chronic use of systemic
corticosteroids has been
removed from the exclusion
criterion 3.
To remove ambiguity as within
the same exclusion criterion 3 a
substantial immunosuppressive
steroid dose is defined as ≥2
weeks of daily receipt of 20 mg
of prednisone or equivalent
1.3.1 All Participants
1.3.2 Participants With (Suspected) COVID-
19
8.6 Medical Resource Utilization
The MA-COV form has been
updated to also capture if a
participant has clinical or
radiological evidence of
pneumonia and if the oxygen
To ensure collection of all
necessary information in order
to determine the severity of
COVID-19 per the case
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Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
10.8 Appendix 8: Medically-attended 
COVID-19 (MA-COV) Form  
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
completed by the study site
personnel.
definitions and clarification
purposes.
10.3.11 Monitoring 
Source data verification has 
been replaced by review of 
the source data. 
Source document review will be
done instead of source
document data verification.
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
VAC31518COV3001.
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
VAC31518COV3001 as
pregnant women are not
allowed to participate in the
study.
9.5.1.1 Study Monitoring 
Clarified that there will be no 
adjustment for multiple 
testing for the potential harm 
monitoring of severe cases, ie, 
an exact 1-sided binomial test 
of the fraction of infections 
assigned to who receive the
vaccine will be used with an
unadjusted p-value ⍺at 5%.
Adjusted in line with HA
feedback to start monitoring of
severe events as soon as 5
events and subsequently after
every new event without
adjustment for multiple testing
1.1 Synopsis 
1.3.1 All Participants 
1.3.2 Participants With (Suspected) COVID- 
19 
4.1 Overall Design  
8.7 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 and
6 months and 1 year post
vaccination and at COVID-19
Day 3-5.
Clarification on when
participants will be interviewed
on additional characteristics that
will be used for risk factor
analysis.
5.2 Exclusion Criteria 
6.8 Prestudy and Concomitant Therapy 
Exclusion criterion 7 was 
adjusted to exclude 
participants who received 
investigational
Alignment across
Ad26.COV2.S Phase 3 study
protocols
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Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
immunoglobulin or
monoclonal antibodies within
3 months, or received
convalescent serum for
COVID-19 treatment within 4
months.
5.2 Exclusion Criteria 
Chronic kidney disease (with 
dialysis) has been removed 
from the examples of clinical 
conditions expected to have 
an impact on the immune
response of the study vaccine.
There is no evidence that
dialysis has an impact on
antibody concentration in the
blood.
1.1 Synopsis 
5.2 Exclusion Criteria 
It is clarified Parkinson’s 
disease, seizures, ischemic
strokes, intercranial
hemorrhage encephalopathy,
meningoencephalitis are not
part of the CDC list of
comorbidities that are
associated with increased risk
of progression to severe
COVID-19.
Clarification
5.2 Exclusion Criteria 
It is clarified that participants 
with Guillain-Barré syndrome
are excluded from the study
altogether and not only in
Stage 1a and Stage 2a of the
study.
Correction
5.1 Inclusion Criteria 
Clarifications have been made 
to the inclusion criterion 4,
indicating that for Stages 1a
and 2a participants can have a
condition that is stable and
well controlled except the
ones listed in exclusion
criterion 15 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 
9.8 Interim Analysis and Committees 
Reference to a possible 
sample size adjustment has 
been deleted. 
Correction; per the
VAC31518COV3001
Amendment 1, the sample size
of approximately 60,000
participants was selected based
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VAC31518 (JNJ-78436735) 
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Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
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
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.
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Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
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. Addition of
minor clarifications. Alignment
across sections in the protocol.
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VAC31518 (JNJ-78436735) 
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Status: Approved, Date: 15 April 2022
Amendment 1 (15 September 2020)
Overall Rationale for the Amendment: The amendment is written to adjust the dose level for
Ad26.COV2.S from 1×1011 virus particles (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.
Additional changes such as the determination of the sample size, further fine tuning of the case
definitions for COVID-19, and the addition of target percentages (min/max) for enrollment of
certain age groups are made based on emerging epidemiology information and advancing insights.
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 VAC31518COV3001 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
4.4 End-of-study Definition
4.3 Justification for Dose
6.1 Study Vaccines Administered
8.1.4 Immunogenicity Assessments
The Ad26.COV2.S dose level
has been lowered 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
(28 days 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 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
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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Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
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 for proceeding to
Phase 3 were met by the
5x1010 vp dose, the sponsor
decided to use this dose for
further evaluation in the Phase 3
study VAC31518COV3001.
1.1 Synopsis 
2.1 Study Rationale 
4.1 Overall Design  
9.2.1 Efficacy (Total Sample Size) 
9.2.4 Safety (Safety Subset) 
The protocol has been 
adjusted to reflect the selected 
sample size of approximately 
60,000 participants. A 
detailed rationale for the 
sample size selection has been 
added to Section 9.2 Sample
Size Determination of the
protocol.
Based on epidemiological
modeling and currently
available data (further explained
in Section 9.2.1), the maximum
sample size of 60,000
participants was selected.
1.1 Synopsis 
9.5.1 Primary Endpoint Evaluation  
The trigger for the evaluation 
of the primary endpoint has 
been modified, adding 
3 conditions, one related to 
available follow-up 
information, one related to the 
number of severe/critical
COVID-19 cases and one
related to the number of cases
meeting the primary endpoint
definition of moderate to
severe/critical COVID-19 in
the elderly population, that
need 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.
1.1 Synopsis 
1.3.1 All Participants 
3 OBJECTIVES AND ENDPOINTS  
8 STUDY ASSESSMENTS AND 
PROCEDURES  
8.1.4 Immunogenicity Assessments 
9.2.1 Efficacy (Total Sample Size) 
9.5.1 Primary Endpoint Evaluation  
9.5.2 Secondary Endpoints
9.5.1.1 Study Monitoring
10.2 Appendix 2: Clinical Laboratory Tests
The time to begin counting 
COVID-19 cases after 
vaccination with 
Ad26.COV2.S has been 
decreased from at least 
28 days post-vaccination to at 
least 14 days post-vaccination 
(Day 15).
Based on preliminary data from
Cohort 1b of study
VAC31518COV1001, showing
robust immunology data
14 days after vaccination that
are similar to the data seen
28 days after vaccination.
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VAC31518 (JNJ-78436735) 
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Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
2.1 Study Rationale 
4.1 Overall Design  
9.2.1 Efficacy (Total Sample Size) 
9.5.1 Primary Endpoint Evaluation 
The assumed vaccine efficacy 
(VE) has been adjusted from a 
VE=65% VE to a 60%=VE. 
The target number of events 
(TNE) has been adjusted 
accordingly from 104 to 154 
events 
The study power was adjusted
to have approximately 90%
power to detect an assumed
vaccine efficacy as low as 60%,
in line with Health Authority
guidance. The target number of
events has been adjusted
accordingly.
1.1 Synopsis 
1.2 Schema 
2.1 Study Rationale 
2.3.3 Benefit-Risk Assessment of Study 
Participation  
4.1 Overall Design  
9.2.2 Immunogenicity Subset 
It has been clarified that Stage 
2a (adults ≥60 years of age) 
can start in parallel to Stage 
1a (adults ≥18 to <60 years of 
age) unless this is not allowed 
per local Health Authority 
guidance. 
After a review of the currently
available safety and
immunogenicity data from
Cohort 1a and Cohort 3 of study
VAC31518COV1001 (see
above), staggered enrollment of
Stage 2 is no longer deemed
necessary.
5.1 Inclusion Criteria 
5.2 Exclusion Criteria 
A clarification was added to 
the eligibility criteria on blood 
pressure for Stage 1a and 
Stage 2a. 
Following discussion with the
agency on the
VAC31518COV1001 protocol,
it was agreed that the blood
pressure criteria from the CDC
list of comorbidities associated
with COVID-19 progression
could be modified. The
VAC31518COV3001 protocol
has been harmonized with the
VAC31518COV1001 protocol.
1.1 Synopsis 
5.1 Inclusion Criteria 
5.2 Exclusion Criteria 
10.10 Appendix 10: Symptoms of 
Coronavirus (US Centers for Disease 
Control and Prevention) 
It has been clarified that the 
current list of CDC 
comorbidities applicable to 
the in- and exclusion criteria 
will not be adjusted during the 
conduct of the study even if 
the source CDC list is 
updated. 
Changing the CDC list of
comorbidities during the study
would be operationally very
difficult and should not be
required since they are only
used in the initial part of the
study, ie, in enrollment of the
first 2,000 participants in each
of the age groups, which will
occur only a few weeks apart.
1.3.1 All Participants 
5.1 Inclusion Criteria 
5.2 Exclusion Criteria 
8.4 Virology Assessments 
9.7Safety Analysis 
The eligibility criteria, HIV 
RNA viral load and CD4 cell 
count assessment and 
subanalyses of the data related 
to HIV positive participants in 
this study has been updated.
To provide objective criteria for
stable/well-controlled HIV
infection and details regarding
this subpopulation on various
other study aspects.
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Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
3 OBJECTIVES AND ENDPOINTS  
9.2.3 Immunogenicity Correlates (Correlates 
Subset) 
9.5.2 Secondary Endpoints 
The endpoint used to assess 
the effect of Ad26.COV2.S on 
all molecularly confirmed 
symptomatic COVID-19, as 
compared to placebo was 
adjusted to the Burden of 
Disease endpoint. 
Following a Health Authority
question on how the different
groups of mild, moderate and
severe COVID-19 cases will be
analyzed, the Burden of Disease
(BOD) secondary endpoint has
been added to the protocol. The
BOD endpoint will be evaluated
based on the first occurrence of
molecularly confirmed COVID-
19, including mild, moderate
and severe/critical case
definitions.
1.1 Synopsis 
9.5.1 Primary Endpoint Evaluation  
9.5.1.1 Study Monitoring 
9.8 Interim Analysis and Committee(s) 
The severe harm monitoring 
rule has been modified to 
indicate that monitoring will 
start from the 5th  severe event
onwards instead of the 8th
severe event and monitoring
will be done until the primary
analysis is triggered instead of
until the end of the study. In
addition, monitoring for
efficacy will start from the
20th  event onward at least
once a week instead of after
each event.
Based on Health Authority
request to start monitoring
earlier.
1.1 Synopsis 
3 OBJECTIVES AND ENDPOINTS  
9.5.2 Secondary Endpoints 
It has been clarified that all 
secondary endpoint analyses 
will occur in the per protocol 
analysis set, in seronegative
participants unless otherwise
indicated.
To clarify the analysis set used
to evaluate the secondary
endpoints.
1.1 Synopsis 
8.1.3.1 Case Definition for Moderate to 
Severe/Critical COVID-19 
8.1.3.2 Case Definition for Mild COVID-19 
The case definitions of both 
mild and moderate COVID-19 
have been modified and 
terminology has been aligned 
across case definitions.
To incorporate additional key
conditions in the case definition
of mild disease and for
clarification purposes.
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.
4.2.1 Study-Specific Ethical Design 
Considerations 
6.6 Continued Access to Study Vaccine 
After the End of the Study  
It has been clarified that the 
sponsor will also look into the 
possibility of offering placebo 
recipients the study vaccine, if 
this vaccine is determined to 
be efficacious, considering
country-specific conditions
and ethical considerations.
Based on a partner request to
clarify the plans of providing
vaccine, if it is determined to be
efficacious, to participants who
received placebo.
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Section Number 
and Name
Description of Change 
Brief Rationale
5.2 Exclusion Criteria 
It has been clarified that every 
effort will be made to avoid 
inclusion of participants who 
have been previously enrolled
in coronavirus studies and to
prevent subsequent
enrollment of a participant in
other coronavirus studies
during their participation in
this study.
To ensure that co-enrollment in
other efficacy studies is
avoided.
1.1 Synopsis 
8.1.3.4 Case Definition for Asymptomatic or 
Undetected COVID 19 
8.1.3.5 SARS-CoV-2 Seroconversion 
Assessment 
A subsection on case 
definition of asymptomatic or 
undetected COVID-19 and
SARS-CoV-2 seroconversion
assessment has been added to
the Efficacy Assessment
section.
To clarify what is considered an
asymptomatic infection.
5.2 Exclusion Criteria 
It has been clarified that 
planning to become pregnant
within 3 months after study
vaccine administration will
lead to exclusion from
participation in the study.
For clarification purposes.
1.1 Synopsis 
8.1.4 Immunogenicity Assessments 
It has been added that 
serology testing outside the 
study is discouraged and if 
testing would be needed, the 
site will guide the participant 
to an appropriate assay. 
Vaccination with Ad26.COV2.S
may interfere with some
serologic assays utilized at local
community health
clinics/commercial laboratories
and may result in unblinding the
participant.
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 in the 
prestudy and concomitant 
therapy section of the 
protocol.
To clarify that antipyretics are
recommended post-vaccination
for symptom relief, as needed.
Prophylactic antipyretic use is
not encouraged.
1.1 Synopsis 
1.3.1 All Participants 
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 
It has been clarified that the 
post-vaccination observation 
period at the study site will be 
at least 30 minutes for the first
2,000 participants in each of
the 2 age groups and may be
decreased to 15 minutes for
the remaining participants, if
no acute reactions are
observed.
To decrease the burden for the
participant and for clarification
purposes.
1.1 Synopsis 
4.1 Overall Design  
8.1.4 Immunogenicity Assessments 
It has been clarified that the 
participant will be notified of
a confirmed positive SARS-
CoV-2 infection and positive
serology test.
For clarification purposes.
6.2 
Preparation/Handling/Storage/Accountability  
6.4 Study Vaccine Compliance 
It has been clarified that the 
unblinded pharmacist cannot 
vaccinate participants. 
Administration of the vaccine
by an unblinded pharmacist is
not permitted.
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Section Number 
and Name
Description of Change 
Brief Rationale
8.1.2 Procedures in the Event of COVID-19- 
like Signs and Symptoms 
It has been clarified that the 
study staff visiting 
participants at home will use 
personal protective equipment 
according to local regulations.
Based on partner
recommendations to include
protective measures for site staff
visiting participants at home.
8.2.2 Vital Signs 
It has been clarified that any 
vital signs measures 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.
Based on a partner request to
clarify if a participant with a
positive test will be referred to a
health care provider.
1.1 Synopsis 
1.3.1 All Participants 
4.1 Overall Design  
8.7Baseline and Longitudinal Risk Factor 
Assessment 
9.4 Participant Information 
9.5.3 Exploratory Endpoints 
10.12 Appendix 12: Baseline Risk Factor 
Assessment 
It has been added that 
additional baseline and 
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.
5.2 Exclusion Criteria 
Exclusion of participants with 
drug or alcohol abuse has 
been removed from exclusion 
criterion 12.
To avoid redundancy as this is
also covered in exclusion
criterion 14.
1.1 Synopsis 
9.1 Statistical Hypotheses 
It has been clarified that 
additional analyses after the
primary analysis can be
planned, if deemed
appropriate.
For clarification purposes.
1.1 Synopsis 
3 Objectives and Endpoints 
8.1.4 Immunogenicity Assessments 
An exploratory 
immunogenicity 
objective/endpoint and 
respective assays have been 
added to assess other 
coronavirus immune 
responses at baseline.
To assess the impact of pre-
existing humoral immunity
against coronaviruses other than
SARS-CoV-2 at baseline on
Ad26.COV2.S vaccine
immunogenicity.
2.3.1 Risks Related to Study Participation 
5.2 Exclusion Criteria 
It has been clarified that 
breastfeeding women can 
participate in the study. 
To allow the enrollment of
breastfeeding women in the
study, as the risk of getting
infected outweighs the risk of
exposing the child to vaccine
induced antibodies.
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Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
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.
5.2 Exclusion Criteria 
6.8 Prestudy and Concomitant Therapy 
In the exclusion criteria and 
the concomitant medication 
section, it has been further 
clarified that the use of any
investigational or approved
COVID-19 vaccine (other
than Ad26.COV2.S) is
disallowed at any time prior to
and during the study.
Clarification of an inconsistency
and alignment across sections
within the protocol.
1.1 Synopsis 
1.3.1 All Participants 
3 OBJECTIVES AND ENDPOINTS  
8 STUDY ASSESSMENTS AND 
PROCEDURES  
8.1.3 Efficacy Assessments 
8.1.4 Immunogenicity Assessments 
10.2 Appendix 2: Clinical laboratory Tests 
Blood draws for immunologic 
testing for SARS-CoV-2 
seroconversion (ELISA 
and/or SARS-CoV-2 
immunoglobulin assay) based
on SARS-CoV-2 N protein,
have been added on Day 71
and 6 months in order to
identify cases of
asymptomatic infection. Visit
4 has therefore become a
mandatory visit for all
participants.
To allow for the identification
of a possible signal for the
prevention of asymptomatic
infection at earlier timepoints.
1.3.1 All Participants 
1.3.2 Participants With COVID-19-like 
Signs and Symptoms 
2.3.1 Risks Related to Study Participation 
8 Study Assessments and Procedures 
8.1.2 Procedures in the Event of COVID-19- 
like Signs and Symptoms 
10.2 Appendix 2: Clinical Laboratory Tests
10.8 Medically-attended COVID-19 (MA-
COV) Form
The term "mid-turbinate" in 
relation to the nasal swabs 
collection has been removed 
throughout the protocol. 
To remove any confusion
around the type of swabs used
during the study as the swabs
currently used are not mid
turbinate swabs but their
performance can be considered
equivalent.
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Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
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 has been clarified that 
enrolled participants will be
counselled on SARS-COV-2
infection prevention.
In addition, it is clarified that
at the time of study entry,
each participant will need to
indicate to the study site
where, 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.
For clarification purposes.
1.3.2 Participants With COVID-19-like 
Signs and Symptoms 
8.1.2 Procedures in the Event of COVID19- 
like Signs and Symptoms
10.3.3 Informed Consent Process
It has been clarified that the 
caregiver can only assist with 
the eCOA. 
To provide clarity on the roles
and responsibilities of the
caregiver.
1.3.2 Participants With COVID-19-like 
Signs and Symptoms 
8.1.2 Procedures in the Event of COVID19- 
like Signs and Symptoms
Term "episode" was added to 
include all aspects of the
COVID-19 illness.
For clarification purposes.
5.1 Inclusion Criteria
8.3 Adverse Events, Serious Adverse Events,
Medically-attended Adverse Events, and
Other Safety Reporting
10.3.3 Informed Consent Process
10.3.4 Data Protection
References to a legally
Acceptable Representative
being allowed to provide
consent instead of the
potential participant has been
removed from the protocol.
A participant needs to fully
understand and be able to
provide consent themselves
given there may be no benefit to
participation. Participants
unable to consent for
themselves should not be
enrolled in the study.
1.1 Synopsis
2.1 Study Rationale
2.3.3 Benefit-Risk Assessment of Study
Participation
4.1 Overall Design
9.8 Interim Analysis and Committee(s)
10.3.6 Committees Structure
Reference to Grade 4 AEs and
SAEs in the context of Day 3
safety review by the DSMB
has been deleted from the
protocol.
The DSMB review of the Day 3
safety data from Stage 1a and 2a
prior to enrollment of Stage 1b
and 2b, respectively, will not be
limited to Grade 4 AEs and
SAEs. All available safety data
will be reviewed.
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Status: Approved, Date: 15 April 2022
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
2.1 Study Rationale 
4.1 Overall Design  
9.5.1 Primary Endpoint Evaluation  
9.8 Interim Analysis and Committee(s) 
10.3.6 Committees Structure 
The role of the Sponsor 
Committee has been replaced
either by the role of the
Oversight Group (as described
in the Oversight Group
Charter) or the role of the
sponsor.
For clarification purposes.
2.3.1 Risks Related to Study Participation 
Influenza will not be used as a 
control in the surveillance 
system for detection of 
COVID-19. 
Influenza may not serve as a
good positive control due to
social distancing measures and
the need for significant
sampling to have a valid
comparison.
6.10 Study Vaccination Pausing Rules for 
Stages 1a and 2a 
It has been clarified that based 
on the pausing criteria, the
sponsor’s medical monitor or
designee decides whether a
study pause is warranted and
informs the DSMB of the
decision, instead of the PSRT
deciding whether a pausing
rule is warranted.
For clarification purposes.
9.5.2 Secondary Endpoints 
It has been clarified that 
among participants with
SARS-CoV-2 infection, the
effect of vaccination 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.
For clarification purposes.
1.1 Synopsis 
3 OBJECTIVES AND ENDPOINTS  
The exploratory efficacy 
objective assessing both 
symptomatic and 
asymptomatic infections 
combined, (that are
serologically and/or
molecularly confirmed)
compared to placebo has been
moved to the secondary
objectives.
This endpoint was moved to
secondary as it will be included
in the inferential testing
strategy.
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.
1.1 Synopsis 
8.1.4 Immunogenicity Assessments 
Analysis of neutralizing 
antibodies to SARS-CoV-2 
using a reporter SARS-CoV-2
virus has been added.
To add a new assay that may
become available.
10.7Appendix 7: MRU Questionnaire 
Clarifications were made in 
the MRU Questionnaire.
For clarification purposes
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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.
Correction of minor errors and
inconsistencies. Addition of
minor clarifications.
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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): 
Jerald Sadoff, MD
Institution: 
Janssen Research & Development
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 study, written notification will be
provided by the investigator to the sponsor, and a protocol amendment will not be required.
NCT04505722

Signature
User 
Date 
Reason
Sadoff Jerry 
 
15-Apr-2022
16:19:00
(GMT)
Document Approval
PPD
NCT04505722