A Randomized, Double-blind, Phase 3 Study to Evaluate 6 Dose Levels of Ad26.COV2.S Administered As a Two-Dose Schedule in Healthy Adults
Phase: PHASE3
Conditions: COVID-19 Prevention
Sponsor: Janssen Vaccines & Prevention B.V.

CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date: 16 September 2022
Janssen Vaccines & Prevention B.V.*
Clinical Protocol
Protocol Title
A Randomized, Double-blind, Phase 3 Study to Evaluate 6 Dose Levels of Ad26.COV2.S
Administered As a Two-Dose Schedule in Healthy Adults
Protocol VAC31518COV3003; Phase 3
AMENDMENT 7
VAC31518 (JNJ-78436735)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, B.V.; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term
“sponsor” is used throughout the protocol to represent these various legal entities; 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(s):
IND: 22657
EudraCT NUMBER: 2020-005801-14
Status: 
Approved
Date: 
16 September 2022
Prepared by: Janssen Vaccines & Prevention B.V.
EDMS number: 
EDMS-RIM-153625, 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.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved,  Date: 16 September 2022
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 7 
This document
Amendment 6 
01 June 2022
Amendment 5 
30 November 2021
Amendment 4 
3 August 2021
Amendment 3 
23 June 2021
Amendment 2 
10 May 2021
Amendment 1 
8 March 2021
Original Protocol 
15 December 2020
Amendment 7 (This document)
Overall Rationale for the Amendment:The order of the sequential non-inferiority assessment hypothesis
testing has been modified in this amendment. The main study recruited participants not previously infected
by SARS-CoV-2 and not previously vaccinated with a COVID-19 vaccine to evaluate the non-inferiority
of different dose levels on immune responses following 1 or 2 doses of Ad26.COV2.S. For the non-
inferiority analysis set, participants were to remain N serology negative at the respective timepoint of the
non-inferiority assessment. During the course of the study, an unexpectedly high number of participants
had symptomatic or asymptomatic infections and would therefore be eliminated from the analysis affecting
the power of the study to conclude non-inferiority. Participants that have been recruited in the sub study
and were not previously infected with SARS-CoV-2 or vaccinated with a COVID-19 vaccine will be part
of the non-inferiority analysis of the main study However, not all dose levels in the main study (6 dose
levels) are represented in the sub study (4 dose levels). Consequently, dose level groups that are in common
will have a larger sample size than those present only in the main study and will have a higher power to
conclude non-inferiority. As the non-inferiority assessment follows a sequential hypothesis testing, the
order of the sequential hypothesis testing has been modified in this amendment.
For all participants, given that approved COVID-19 vaccines exist for the adult population in all countries
in which VAC31518COV3003 is being conducted, if participants need to receive boosters, they may be
vaccinated outside of the study as a part of their national vaccination campaign after the participants have
completed their last study visit. Once the primary analysis results are available (post vaccination 2),
investigators will be notified to contact participants in groups who received a dose level of Ad26.COV2.S
that did not meet non-inferiority post vaccination 2 to advise them that they should receive a booster of a
COVID-19 vaccine that is licensed/authorized through their national COVID-19 vaccination health care
program if not done already.
In addition, due to extensive follow up data available after vaccination across the Ad26.COV2.S program,
including up to 12 months, the follow up in this protocol has been reduced from 12 months to 6 months
after last vaccination.
Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
1.4.1 2-dose Vaccination Schedule
for Participants in the Main Study
1.4.2 2-dose Vaccination Schedule
for the Sub Study Participants
4.1 Overall Design
4.4 End of Study Definition
9.5 Planned Analyses
Reduction of the follow up period
after last vaccination from 12
months to at least 6 months.
The Company has collected
sufficient long-term follow-up
safety information across the
program.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Status: Approved,  Date: 16 September 2022
Section number 
and Name
Description of Change 
Brief Rationale
10.2 Appendix 2: Clinical
Laboratory Tests
1.1 Synopsis 
4.1 Overall Design  
Study duration has been changed 
from 13-15 months to at least 8 
months and follow up changed
from 12 to 6 months.
Due to the reduction of follow up
from 12 to 6 months.
1.2 Schema for Participants in the 
Main Study  
1.3 Schema for Participants in the 
Sub Study  
1.4.1 2-dose Vaccination Schedule 
for Participants in the Main Study  
1.4.2 2-dose Vaccination Schedule 
for the Sub Study Participants
Given the follow up period has 
been reduced to 6 months, there are 
some participants in the study who 
would have already had their 6- 
month visit. For those participants,
a final phone call for safety follow
up has been added.
To capture any additional safety
information from participants who
already had been in the study
beyond 6 months post vaccination.
1.1 Synopsis 
9.1 Statistical Hypotheses 
Text has been added explaining the 
change in the sequential order of 
non-inferiority testing. 
The 2.5x1010 vp dose will be tested
before the 7x1010 vp in the
sequential testing due to an
increased risk to fail non-inferiority
as a consequence of a smaller
sample size in the 7x1010 vp group.
1.1 Synopsis 
9.2 Sample Size Determination  
Added the expected power based on 
% of dropout due to various reasons 
(eg, lost to follow-up, participants 
with major protocol deviations with 
impact on immunogenicity,
participants who become N-
seropositive during the study or
with a confirmed SARS-CoV-2
infection, and participants who
received their vaccination outside
the allowed window). Also, an
explanation for the possible
addition of the sub study
participants in the primary analysis
has been added.
The power calculations show why
the sub study participants need to
be added to the main study primary
analysis for non-inferiority.
1.1 Synopsis 
6.3 Measures to Minimize Bias: 
Randomization and Blinding9.5 
Planned Analyses 
Text has been added stating results 
from the main and sub study may 
be reported together rather than in 
separate reports.
Clarification that the results from
the main and sub study may be
available at the same time.
1.1 Synopsis 
2.1 Study Rationale 
3 OBJECTIVES AND 
ENDPOINTS  
9.1 Statistical Hypotheses
9.2 Sample Size Determination
9.2.1 Immunogenicity
9.4.2 Primary Endpoint(s)
The order of the sequential 
hypothesis testing has been 
modified. 
To reduce the increased risk to fail
non-inferiority as a consequence of
a smaller sample size in the 7x1010
vp group.
1.1 Synopsis 
9.5 Planned Analyses 
Made clear that the Sponsor would 
be unblinded to the data for the
main and sub study at the primary
analysis stage.
Clarification
1.1 Synopsis 
6.6 Continued Access to Study 
Vaccine After the End of Study  
Participants that do not meet non- 
inferiority in the group they have 
been assigned will no longer be 
offered a booster of study vaccine 
Currently there are several
authorized COVID-19 vaccines
available. The participants are
advised to receive a booster dose
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved,  Date: 16 September 2022
Section number 
and Name
Description of Change 
Brief Rationale
but rather are being advised to 
receive a nationally 
authorized/licensed vaccine outside
of the study. All other participants
are recommended to receive a
booster outside the study, if needed,
after the primary analysis.
following their national vaccination
scheme including follow up.
1.4.1 2-dose Vaccination Schedule 
for Participants in the Main Study  
1.4.2 2-dose Vaccination Schedule
for the Sub Study Participants
8STUDY ASSESSMENTS AND
PROCEDURES
Total blood volume has been 
adjusted. 
Due to the shorter follow up period
post vaccination.
1.4.1 2-dose Vaccination Schedule 
for Participants in the Main Study  
1.4.2 2-dose Vaccination Schedule 
for the Sub Study Participants
Humoral serum samples can be 
used for N serology testing. 
Clarification to add flexibility that
humoral samples may be used for N
serology testing.
9.3 Populations for Analysis Sets 
9.4.2 Primary Endpoint(s) 
The definition of the non-inferiority 
(NI) analysis set has been added.
To define the NI analysis set.
9.4 Statistical Analyses 
9.4.2 Primary Endpoint(s) 
There will only be one SAP 
describing the analyses for the main
and sub study.
Additional text has been added to 
explain further how the non-
inferiority analysis will be
conducted if a large number of
participants are N-seropositive.
Clarification
Clarification
1.1 Synopsis 
3 OBJECTIVES AND 
ENDPOINTS  
8.1 Immunogenicity Assessments 
Additional exploratory endpoint in 
the main and sub study added to 
allow for assessment of Spike 
circulating protein
To allow for the assessment of
Spike circulating protein following
vaccination
Throughout the protocol 
Minor grammatical, formatting, 
spelling changes or clarifications 
were made.
Minor errors and clarifications were
noted.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved,  Date: 16 September 2022
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 7
1. 
PROTOCOL SUMMARY..................................................................................................................... 8
1.1. 
Synopsis........................................................................................................................................... 8
1.2. 
Schema for Participants in the Main Study.................................................................................... 19
1.3. 
Schema for Participants in the Sub Study ..................................................................................... 20
1.4. 
Schedule of Activities (SoA)........................................................................................................... 21
1.4.1. 
2-dose Vaccination Schedule for Participants in the Main Study............................................... 21
1.4.2. 
2-dose Vaccination Schedule for the Sub Study Participants .................................................... 25
1.4.3. 
Participants with a Suspected AESI........................................................................................... 30
2. 
INTRODUCTION................................................................................................................................ 31
2.1. 
Study Rationale.............................................................................................................................. 34
2.2. 
Background .................................................................................................................................... 35
2.3. 
Benefit-Risk Assessment............................................................................................................... 39
2.3.1. 
Risks Related to Study Participation .......................................................................................... 39
2.3.2. 
Benefits for Study Participation .................................................................................................. 44
2.3.3. 
Benefit-Risk Assessment for Study Participation ....................................................................... 44
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 45
4. 
STUDY DESIGN ................................................................................................................................ 50
4.1. 
Overall Design................................................................................................................................ 50
4.2. 
Scientific Rationale for Study Design............................................................................................. 54
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 54
4.3. 
Justification for Dose...................................................................................................................... 55
4.4. 
End of Study Definition................................................................................................................... 56
5. 
STUDY POPULATION ...................................................................................................................... 56
5.1. 
Inclusion Criteria ............................................................................................................................ 56
5.2. 
Exclusion Criteria ........................................................................................................................... 58
5.3. 
Lifestyle Considerations................................................................................................................. 61
5.4. 
Screen Failures.............................................................................................................................. 61
5.5. 
Criteria for Temporarily Delaying Administration of Study Vaccine ............................................... 62
6. 
STUDY VACCINATION AND CONCOMITANT THERAPY ............................................................. 62
6.1. 
Study Vaccines Administered ........................................................................................................ 62
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 64
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 65
6.4. 
Study Vaccination Compliance ...................................................................................................... 67
6.5. 
Dose Modification........................................................................................................................... 67
6.6. 
Continued Access to Study Vaccine After the End of the Study ................................................... 67
6.7. 
Treatment of Overdose .................................................................................................................. 67
6.8. 
Prestudy and Concomitant Therapy .............................................................................................. 68
6.9. 
Study Vaccination Pausing Rules.................................................................................................. 69
7. 
DISCONTINUATION OF STUDY VACCINATION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 69
7.1. 
Discontinuation of Study Vaccination............................................................................................. 69
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 70
7.2.1. 
Withdrawal From the Use of Research Samples ....................................................................... 70
7.3. 
Lost to Follow-up............................................................................................................................ 71
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved,  Date: 16 September 2022
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 71
8.1. 
Immunogenicity Assessments ....................................................................................................... 73
8.2. 
Safety Assessments....................................................................................................................... 75
8.2.1. 
Physical Examinations................................................................................................................ 75
8.2.2. 
Vital Signs................................................................................................................................... 75
8.2.3. 
Pregnancy Testing...................................................................................................................... 76
8.2.4. 
Clinical Laboratory Assessments ............................................................................................... 76
8.3. 
Adverse Events, Serious Adverse Events, Medically-attended Adverse Events, Adverse
Events of Special Interest, and Other Safety Reporting ................................................................ 76
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 .................. 76
8.3.2. 
Method of Detecting Adverse Events, Medically-attended Adverse Events, Adverse
Events of Special Interest, and Serious Adverse Events ........................................................... 78
8.3.3. 
Follow-up of Adverse Events, Medically-attended Adverse Events, Adverse Events of
Special Interest, and Serious Adverse Events ........................................................................... 79
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 79
8.3.5. 
Pregnancy................................................................................................................................... 80
8.3.6. 
Adverse Events of Special Interest............................................................................................. 80
8.3.6.1. 
Thrombosis with Thrombocytopenia Syndrome...................................................................... 80
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 81
9.1. 
Statistical Hypotheses.................................................................................................................... 81
9.2. 
Sample Size Determination ........................................................................................................... 84
9.2.1. 
Immunogenicity........................................................................................................................... 86
9.3. 
Populations for Analysis Sets ........................................................................................................ 86
9.4. 
Statistical Analyses ........................................................................................................................ 86
9.4.1. 
General Considerations.............................................................................................................. 86
9.4.2. 
Primary Endpoint(s).................................................................................................................... 87
9.4.3. 
Secondary Endpoint(s)............................................................................................................... 87
9.4.4. 
Exploratory Endpoint(s).............................................................................................................. 89
9.4.5. 
Other Analyses ........................................................................................................................... 89
9.5. 
Planned Analyses .......................................................................................................................... 89
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 91
10.1. 
Appendix 1: Abbreviations and Definitions .................................................................................... 91
10.2. 
Appendix 2: Clinical Laboratory Tests ........................................................................................... 93
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 94
10.3.1. 
Regulatory and Ethical Considerations ...................................................................................... 94
10.3.2. 
Financial Disclosure.................................................................................................................... 97
10.3.3. 
Informed Consent Process ......................................................................................................... 97
10.3.4. 
Data Protection ........................................................................................................................... 98
10.3.5. 
Long-Term Retention of Samples for Additional Future Research ............................................ 99
10.3.6. 
Safety Monitoring Committees Structure.................................................................................... 99
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data ............................................................ 99
10.3.8. 
Data Quality Assurance............................................................................................................ 101
10.3.9. 
Case Report Form Completion................................................................................................. 101
10.3.10. Source Documents ................................................................................................................... 102
10.3.11. Monitoring ................................................................................................................................. 102
10.3.12. On-Site Audits........................................................................................................................... 103
10.3.13. Record Retention...................................................................................................................... 103
10.3.14. Study and Site Start and Closure ............................................................................................. 104
10.4. 
Appendix 4: Adverse Events, Medically-attended Adverse Events, Serious Adverse
Events, Adverse Events of Special Interest, Product Quality Complaints, and Other
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and
Reporting...................................................................................................................................... 105
10.4.1. 
Adverse Event Definitions and Classifications ......................................................................... 105
10.4.2. 
Attribution Definitions................................................................................................................ 106
10.4.3. 
Severity Criteria ........................................................................................................................ 107
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Status: Approved,  Date: 16 September 2022
10.4.4. 
Special Reporting Situations .................................................................................................... 107
10.4.5. 
Procedures ............................................................................................................................... 107
10.4.6. 
Product Quality Complaint Handling......................................................................................... 109
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality........................................... 109
10.5. 
Appendix 5: Contraceptive Guidance and Collection of Pregnancy Information......................... 110
10.6. 
Appendix 6: Toxicity Grading Scale............................................................................................. 111
10.7. 
Appendix 7: Summary of Guidance from CDC Website on Underlying Medical Conditions
That Lead or Might Lead to Increased Risk for Severe Illness From COVID-19......................... 116
10.8. 
Appendix 8: TTS AESI Form........................................................................................................ 118
10.9. 
Appendix 9: Thrombotic Events to be Reported as Suspected AESIs........................................ 122
10.10. Appendix 10: Protocol Amendment History................................................................................. 123
11. REFERENCES................................................................................................................................. 132
INVESTIGATOR AGREEMENT............................................................................................................... 137
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Schematic Overview of Study Design and Groups for the Main Study .................................... 51
Table 2: 
Schematic Overview of Study Design and Groups for the Sub Study...................................... 51
Table 3: 
Humoral Immunity Blood Sampling Schedule in Participants in All Groups of the Main
and Sub Study .......................................................................................................................... 52
Table 4: 
SARS-CoV-2 Non-S Serology Schedule in Participants in All Groups of the Main and
Sub Study ................................................................................................................................. 52
Table 5: 
Serum Sampling and PaxGene Schedule for Innate MoA in Participants in Groups 1,
3, 5 and 6 of the Sub Study ...................................................................................................... 52
Table 6: 
Summary of Humoral Immunogenicity Assaysa........................................................................ 74
Table 7: 
Power Based on % of Drop Out................................................................................................ 85
FIGURES
Figure 1: Schematic Overview................................................................................................................. 19
Figure 2: Decision Tree-Based Hypothesis Testing................................................................................. 84
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
8
Status: Approved,  Date: 16 September 2022
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Randomized, Double-blind, Phase 3 Study to Evaluate 6 Dose Levels of Ad26.COV2.S Administered
As a Two-Dose Schedule in Healthy Adults
Ad26.COV2.S (also known as Ad26COVS1) is a monovalent vaccine composed of a recombinant,
replication-incompetent human adenovirus type 26 (Ad26) vector, constructed to encode the severe acute
respiratory syndrome coronavirus-2 (SARS-CoV-2) spike (S) protein, stabilized in its prefusion
conformation, which will be assessed in this study.
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 FOR PARTICIPANTS IN THE MAIN STUDY
Objectives 
Endpoints
Primary
To demonstrate non-inferiority (NI) in the 
following sequential order: 
 
NI after 1-dose of Ad26.COV2.S 9x1010 vp vs
1-dose of Ad26.COV2.S 5x1010 vp (release 
titer) 
 
NI after 1 dose of Ad26.COV2.S 2.5x1010 vp 
vs 1-dose of Ad26.COV2.S 5x1010 vp (release 
titer) 
 
NI after 1 dose of Ad26.COV2.S 7x1010 vp vs
1-dose of Ad26.COV2.S 5x1010 vp (release
titer)
 
NI after 1 dose of Ad26.COV2.S 3.5x1010 vp
vs 1-dose of Ad26.COV2.S 5x1010 vp (release
titer)
 
NI after 1-dose of Ad26.COV2.S 1.25x1010 vp
vs 1-dose of Ad26.COV2.S 5x1010 vp (release
titer)
 
Binding 
antibody 
concentrations 
to
SARS-CoV-2 S protein as measured by
ELISA 28 days after vaccination
 
NI will be demonstrated in terms of humoral
immune response expressed by the GMCs of
S-ELISA, 28 days post-dose 1, using a NI
margin of 2/3 for the GMC ratio (GMC 9x1010
vp, 2.5x1010 vp, 7x1010 vp, 3.5x1010 vp, , or
1.25x1010 vp/GMC 5x1010 vp)
To demonstrate NI in the following sequential
order:
 
NI after 2-doses of Ad26.COV2.S 9x1010 vp
vs 1 dose of Ad26.COV2.S 5x1010 vp (release
titer)
 
NI after 2-doses of Ad26.COV2.S 9x1010 vp
vs 2-doses of Ad26.COV2.S 5x1010 vp
(release titer)
 
NI after 2-doses of Ad26.COV2.S 2.5x1010 vp
vs 1 dose of Ad26.COV2.S 5x1010 vp (release
titer)
 
Binding 
antibody 
concentrations 
to
SARS-CoV-2 S protein as measured by
ELISA 14 days after vaccination 2
 
NI will be demonstrated in terms of humoral
immune response expressed by the GMCs of
S-ELISA, 14 days post-dose 2 (9x1010 vp,
2.5x1010 vp, 7x1010 vp, 3.5x1010 vp, , or
1.25x1010 vp) and 28 days post-dose 1 or 14
days post-dose 2 (5x1010 vp), using a NI
margin of 2/3 for the GMC ratio (GMC 9x1010
vp, 2.5x1010 vp, 7x1010 vp, 3.5x1010 vp, or
1.25x1010 vp)/GMC 5x1010 vp)
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
9
Status: Approved,  Date: 16 September 2022
Objectives 
Endpoints
 
NI after 2-doses of Ad26.COV2.S 2.5x1010 vp
vs 2-doses of Ad26.COV2.S 5x1010 vp
(release titer)
 
NI after 2-doses of Ad26.COV2.S 7x1010 vp
vs 1 dose of Ad26.COV2.S 5x1010 vp (release
titer)
 
NI after 2-doses of Ad26.COV2.S 7x1010 vp
vs 2-doses of Ad26.COV2.S 5x1010 vp
(release titer)
 
NI after 2-doses of Ad26.COV2.S 3.5x1010 vp
vs 1 dose of Ad26.COV2.S 5x1010 vp (release
titer)
 
NI after 2-doses of Ad26.COV2.S 3.5x1010 vp
vs 2-doses of Ad26.COV2.S 5x1010 vp
(release titer)
 
NI after 2-doses of Ad26.COV2.S 1.25x1010
vp vs 1-dose of Ad26.COV2.S 5x1010 vp
(release titer)
 
NI after 2-doses of Ad26.COV2.S 1.25x1010
vp vs 2-doses of Ad26.COV2.S 5x1010 vp
(release titer)
Secondary
To assess the humoral immune response and 
durability to Ad26.COV2.S across all groups, at 
all blood collection timepoints. 
 
Serological response to vaccination and
binding antibody GMCs to SARS.COV-2 S
protein as measured by ELISA, or equivalent
assay
To assess the safety and reactogenicity of 
Ad26.COV2.S administered at several dose 
levels.
 
Solicited local and systemic AEs for 7 days
after each vaccination
 
Unsolicited AEs for 28 days after each
vaccination
 
SAEs throughout the study (from first
vaccination until end of the study)
 
Adverse events of special interest (AESIs
[from first vaccination until end of the study])
 
MAAEs (until 6 months post-dose 2)
 
AEs leading to study discontinuation (during
the entire study) for all participants following
vaccination
Exploratory
To further explore humoral immune responses to
Ad26.COV2.S across all groups at all or selected
blood collection timepoints.
Exploratory analyses may include the following:
 
SARS-CoV-2 neutralization as assessed by
SARS-CoV-2 neutralization assays VNA
(wtVNA 
and/or 
psVNA) including
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
10
Status: Approved,  Date: 16 September 2022
Objectives 
Endpoints
neutralization of emerging SARS-CoV-2
variants
 
SARS-CoV-2 binding antibodies against
emerging SARS-CoV-2 variants as assessed
by S-ELISA or equivalent assay
 
Adenovirus neutralization
 
Functional 
and 
molecular 
antibody
characterization including Fc-mediated viral
clearance, 
avidity, 
Fc 
characteristics,
immunoglobulin (Ig) subclass and IgG
isotype
 
Analysis of circulating Spike protein
 
Epitope-specificity 
characterization 
of
antibodies
 
Cytokine profiling: Analysis of cytokines,
chemokines, and other proteins of the innate
or adaptive immune response in the serum or
plasma
 
Passive transfer: Analysis of immune
mediators correlating with protection against
experimental SARS-CoV-2 challenge in a
suitable animal model
To assess the correlation between the binding
antibody (ELISA) titers and neutralizing antibody
(VNA) titers to SARS-CoV-2, in a subset of
participants at selected timepoints.
 
Correlation between ELISA (S-ELISA;
EU/mL) and VNA (wild-type virus [wt]VNA
and/or pseudovirion [ps]VNA) titers at
selected timepoints
To assess for the occurrence of asymptomatic
SARS-CoV-2 infection.
 
The number of participants with positive non-
S protein ELISA or equivalent assay  (eg,
nucleocapsid [N] protein ELISA)
To examine the immune response in vaccinated
individuals with prior or breakthrough infection.
 
SARS-CoV-2 neutralizing titers in serum
measured by a VNA (wild-type virus and/or
pseudovirion expressing S protein)
 
SARS-CoV-2-binding antibodies measured
by ELISA: Analysis of antibodies binding to
the SARS-CoV-2 S protein
To assess hematology laboratory parameters
before and after Ad26.COV2.S administration.
 
Including but not limited to: Lupus
anticoagulants, anti-β2 glycoprotein, anti-
cardiolipin, D-dimers, and anti-PF4
GMC=geometric mean concentration
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
11
Status: Approved,  Date: 16 September 2022
OBJECTIVES AND ENDPOINTS FOR PARTICIPANTS IN THE SUB STUDY
Objectives 
Endpoints
Secondary
To assess the humoral immune response and 
durability to Ad26.COV2.S across all groups in 
the sub study, at all blood collection timepoints. 
 
Serological response to vaccination and
binding antibody GMCs to SARS.COV-2 S
protein as measured by ELISA, or equivalent
assay
To assess the safety and reactogenicity of 
Ad26.COV2.S administered at several dose 
levels.
 
Solicited local and systemic AEs for 7 days
after each vaccination
 
Unsolicited AEs for 28 days after each
vaccination
 
SAEs throughout the study (from first
vaccination until end of the study)
 
Adverse events of special interest (AESIs
[from first vaccination until end of the study])
 
MAAEs (until 6 months post-dose 2)
Exploratory
To further explore humoral immune responses to
Ad26.COV2.S across all groups in the sub study
at all or selected blood collection timepoints.
Exploratory analyses may include the following:
 
SARS-CoV-2 neutralization as assessed by
SARS-CoV-2 neutralization assays VNA
(wtVNA 
and/or 
psVNA) including
neutralization of emerging SARS-CoV-2
variants
 
SARS-CoV-2 binding antibodies against
emerging SARS-CoV-2 variants as assessed
by S-ELISA or equivalent assay
 
Adenovirus neutralization
 
Functional 
and 
molecular 
antibody
characterization including Fc-mediated viral
clearance, 
avidity, 
Fc 
characteristics,
immunoglobulin (Ig) subclass and IgG
isotype
 
Analysis of circulating Spike protein
 
Epitope-specificity 
characterization 
of
antibodies
 
Cytokine profiling: Analysis of cytokines,
chemokines, and other proteins of the innate
or adaptive immune response in the serum or
plasma
To assess the correlation between the binding
antibody (ELISA) titers and neutralizing antibody
(VNA) titers to SARS-CoV-2, in a subset of
participants at selected timepoints.
 
Correlation between ELISA (S-ELISA;
EU/mL) and VNA (wild-type virus [wt]VNA
and/or pseudovirion [ps]VNA) titers at
selected timepoints
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
12
Status: Approved,  Date: 16 September 2022
Objectives 
Endpoints
To assess for the occurrence of asymptomatic 
SARS-CoV-2 infection. 
 
The number of participants with positive non-
S protein ELISA  or equivalent assay  (eg,
nucleocapsid [N] protein ELISA)
To examine the immune response in vaccinated 
individuals with prior or breakthrough infection  
 
SARS-CoV-2 neutralizing titers in serum
measured by a VNA (wild-type virus and/or
pseudovirion expressing S protein)
 
SARS-CoV-2-binding antibodies measured
by ELISA: Analysis of antibodies binding to
the SARS-CoV-2 S protein
To evaluate the innate, pro-inflammatory and
other potentially relevant responses to
Ad26.COV2.S vaccination at selected timepoints.
 
Analysis of messenger ribonucleic acid
(mRNA) expression levels of vaccine-induced
innate responses including inflammatory and
coagulation-related mediators
 
Analysis of cytokines, chemokines, and other
protein- or lipid mediators of the innate
immune response
To assess hematology laboratory parameters
before and after Ad26.COV2.S administration.
 
Including but not limited to: Lupus
anticoagulants, anti-β2 glycoprotein, anti-
cardiolipin, D-dimers, and anti-PF4
Ad26=adenovirus 26; GMC=geometric mean concentration
If a correlate or threshold for protection against COVID-19 is established in terms of humoral immunity,
then a statistical comparison to that correlate or threshold will substitute non-inferiority testing to immune
responses to vaccine at release, as outlined in a revised analytical plan.
Hypotheses
Formal non-inferiority (NI) testing will be applied to demonstrate NI of 1-dose and 2-doses of 9×1010 vp,
2.5x1010 vp, 7×1010 vp, 3.5x1010 vp, and 1.25x1010 vp Ad26.COV2.S versus 1-dose and 2-doses of
5x1010 vp Ad26.COV2.S (release titer), using a NI margin of 2/3 for the GMC ratios.
OVERALL DESIGN
Main Study
This is a randomized, double-blind Phase 3 study to evaluate 6 dose levels of Ad26.COV2.S administered
as a 2-dose schedule in healthy adults. In this main study, the safety, reactogenicity, and immunogenicity of
1 dose (dose 1 of the 2-dose regimen) and 2-doses of Ad26.COV2.S will be evaluated. The lower dose
(3.5x1010 vp, 2.5x1010 vp, and 1.25x1010 vp) levels mimic vaccine degradation to enable determination of
product expiry. In order to increase the end of shelf-life specifications a potential target release titer of
7x1010 vp will be evaluated. A higher titer of 9x1010 vp will also be evaluated as is the upper limit of the
release range (potential maximum vp at release). The study population will consist of healthy men and
women aged between 18 and 55 years (inclusive), who have not previously received a vaccine against
COVID-19 and have not had prior exposure to SARS-CoV-2 as assessed by local serology testing.
Participants will receive Ad26.COV2.S administered IM.
A target ofapproximately, 1,350 participants (225 participants per active vaccine group) in the main study
will be randomized in parallel in a 1:1:1:1:1:1 ratio to 1 of 6 vaccination groups in this study. Participants
NCT04908722

NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
14
Status: Approved,  Date: 16 September 2022
DOSAGE AND ADMINISTRATION
Participants will be vaccinated at the study site according to the schedule detailed above:
 
Ad26.COV2.S will be supplied at a concentration of 2x1011 vp/mL as a suspension in single-use vials,
with an extractable volume of 0.5 mL. Formulation buffer of Ad26.COV2.S will be supplied as diluent.
Dose levels throughout the different groups will be 9x1010 vp, 7x1010 vp, 5x1010 vp, 3.5x1010 vp,
2.5x1010 vp and 1.25x1010 vp.
A volume of 0.5 mL will be administered to all participants.
IMMUNOGENICITY EVALUATIONS
Blood for evaluation of humoral immune responses will be drawn from participants at the time points
specified in the Schedule of Activities. Immunogenicity assessments may include, but are not limited to,
the humoral immunogenicity assays (as available and feasible) summarized in the below table.
Table: Summary of Humoral Immunogenicity Assaysa
Assay 
Purpose
Humoral Immunogenicity
Primary/Secondary/Exploratory
endpoints
SARS-CoV-2 binding antibodies 
(ELISA) 
Analysis of antibodies binding to SARS-CoV-2 or individual SARS-CoV-2
proteins (eg, S protein)
Exploratory endpoints
SARS-CoV-2 neutralization
(VNA)
Analysis of neutralizing antibodies to the wild-type virus and/or
pseudovirion expressing S protein, including emerging SARS-CoV-2
variants.
SARS-CoV-2 binding antibodies 
(ELISA or equivalent assay) 
Analysis of binding antibodies to SARS-CoV-2 proteins (eg, S-protein),
including emerging SARS-CoV-2 variant proteins.
SARS-CoV-2 binding antibodies 
(non-S ELISA and/or SARS-CoV-
2 immunoglobulin assay)
Analysis of antibodies binding to the SARS-CoV-2 N protein
Adenovirus neutralization 
Adenovirus neutralization assay to evaluate neutralizing antibody responses
against the Ad26 vector
Functional and molecular antibody 
characterization  
Analysis of antibody characteristics including Fc-mediated viral clearance,
avidity, Fc characteristics, Ig subclass and IgG isotype
Epitope-specificity 
characterization
Analysis of site-specificity, epitope mapping
Cytokine profiling, and analysis of 
circulating Spike protein  
Analysis of cytokines, chemokines, and other proteins of the innate or
adaptive immune response in the serum or plasma, and analysis of
circulating Spike protein
Passive transfer 
Analysis of immune mediators correlating with protection against
experimental SARS-CoV-2 challenge in a suitable animal model
Innate Assessments (Exploratory endpoints)
Gene expression analysis 
Analysis of gene expression by RNA transcript profiling in whole blood (ex
vivo, PaxGene tubes)
Proteomic and/or lipidomic 
approaches, and analysis of 
circulating Spike protein
Analysis of protein translates (including circulating Spike protein)or lipid
mediators in serum or plasma.
ELISA = enzyme-linked immunosorbent assay; SARS-CoV-2 = severe acute respiratory syndrome coronavirus-2;
VNA = virus neutralization assay
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 serological testing outside the
study.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
15
Status: Approved,  Date: 16 September 2022
SAFETY EVALUATIONS
After each vaccination, participants will remain under observation at the study site for at least 15 minutes
for the presence of any acute reactions and solicited events. Participants will be asked to note in the 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). Participants will also be
instructed on how to note signs and symptoms in the diary on a daily basis for 7 days post vaccination (day
of vaccination and the subsequent 7 days), for the following events: fatigue, headache, nausea, and myalgia.
Participants will be instructed on how to record daily temperature using a thermometer provided for home
use. Participants should record the temperature in the diary in the evening of the day of vaccination, and
then daily for the next 7 days approximately at the same time each day.
AEs and special reporting situations, whether serious or non-serious, 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. Thrombosis with thrombocytopenia syndrome
is considered to be an AESI. Suspected AESIs (thrombotic events and thrombocytopenia [defined as platelet
count below 150,000/µLa]) will be reported from the moment of vaccination until the end of the study/early
withdrawal. An AESI Adjudication Committee with appropriate expertise will be established to evaluate
each suspected AESI and determine whether it is a case of TTS. All other unsolicited AEs will be reported
for each vaccination from the time of vaccination until 28 days post vaccination. All SAEs and AEs leading
to discontinuation from the study/vaccination (regardless of the causal relationship) will be reported from
the moment of first vaccination until completion of the participant’s last study-related procedure.
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 from the moment of vaccination until 6 months after the vaccination.
STATISTICAL METHODS
The number of participants chosen is to provide sufficient power for the non-inferiority comparisons.
The following assumptions were made in the sample size determinations:
 
Log transformed (log10 scale) immune response data are normally distributed
 
A common standard deviation (SD): SD=0.5 (log10 scale) of the immune response log transformed
data
 
Non-inferiority margin = log10(2/3) = -0.176
 
Alpha = 0.0125 (1-sided) for 1- and 2-dose NI comparisons
 
Power = 90%
Based on the above assumptions, a sample size of 225 per group is needed (assuming a 10.2% dropout rate)
to detect non-inferiority with 90% power. An additional 40 seronegative and 20 seropositive participants
per Groups 1, 3, 5, and 6 (a target of approximately 240 participants) will be enrolled to further characterize
the innate, pro-inflammatory and other relevant (eg, pro-thrombotic) responses to Ad26.COV2.S to better
understand a possible risk to TTS events.
a Reference for definition of thrombocytopenia: Brighton Collaboration. Interim Case Definition of Thrombosis with
Thrombocytopenia 
Syndrome 
(TTS). 
21 
April 
2021. 
https://brightoncollaboration.us/thrombosis-with-
thrombocytopenia-syndrome-interim-case-definition/. Accessed: 29 April 2021.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
16
Status: Approved,  Date: 16 September 2022
The primary objective of this study is to demonstrate the NI, in terms of humoral immune response, of
1-dose and 2-doses of 9x1010 vp, 2.5x1010 vp, 7x1010 vp, 3.5x1010 vp, and 1.25x1010 vp Ad26.COV2.S
versus 1-dose and 2-doses of 5x1010 vp Ad26.COV2.S (release titer).
Participants in the main study and sub-study (participants who are seronegative at enrollment or baseline)
may be combined for the analysis.
The table below shows how the power will be affected with 10%, 20%, 30%, 40%, 50% and 60% dropout
due to various reasons (eg, lost to follow-up, participants with major protocol deviations with impact on
immunogenicity, participants who become N-seropositive during the study or with a confirmed SARS-
CoV-2 infection, and participants who received their vaccination outside the allowed window).
Table: Power Based on % of Drop Out
% drop out since enrollment
Regimen 
sample size at 
enrollment per
arm
group 10% 
20% 
30% 
40% 
50%  
60%
9x1010 vp (sample size 
of main study and sub-
study)
252 (212+40) 
1 
92.00%  88.60%  83.70%  76.80%  68.10%  57.20%
2.5x1010 vp (sample 
size of main study and
sub-study)
252 (212+40) 
5 
92.00%  88.60%  83.70%  76.80%  68.10%  57.20%
7x1010 vp (main study) 
212 
2 
89.40%  85%  
79.90% 72.70%  63.70% 53.00%
5x1010 vp (sample size 
of main study and sub-
study)
252 (212+40) 
3 
92.00%  88.60%  83.70%  76.80%  68.10%  57.20%
3.5x1010 
vp 
(main 
study)
212 
4 
89.40%  85.00%  79.90% 72.70%  63.70% 53.00%
1.25x1010 vp (sample 
size of main study and
sub-study)
252 (212+40) 
6 
92.00%  88.60%  83.70%  76.80%  68.10%  57.20%
NCT04908722

NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
18
Status: Approved,  Date: 16 September 2022
Planned Analyses
The sponsor may be unblinded for this study, but the blind will be maintained at the participant and study
site level up to study end.
The primary analysis, which will be performed on unblinded data, will include safety up to Day 85 and
immunogenicity up to Day 71 in the main study and sub study for all groups and will be performed when
all participants have completed the visit that takes place 85 days after the first study vaccination or
discontinued earlier.
The final analysis for the main study will be performed when all included participants from the main study
have completed their last visit (at least 6 months post last vaccination) or discontinued earlier. Results from
participants in the sub study may be available with the main study. Results from the main study and sub
study may be combined in one report.
Depending on availability of results, primary and final analysis might be combined.
Further interim analyses may be performed for safety and/or immunogenicity to facilitate decision making
with regards to planning of future studies or for regulatory submission purposes.
For all participants, given that approved COVID-19 vaccines exist for the adult population in all countries
in which VAC31518COV3003 is being conducted, if participants need to receive boosters, they may be
vaccinated outside of the study as a part of their national vaccination campaign after the participants have
completed their last study visit. Once primary analysis results are available (post vaccination 2),
investigators will be notified to contact participants in groups who received a dose level of Ad26.COV2.S
that did not meet non-inferiority post vaccination 2 to advise them that they should receive a booster of a
COVID-19 vaccine that is licensed/authorized through their national COVID-19 vaccination health care
program if not already received.
Unblinding due to availability of an authorized/licensed COVID-19 vaccine
Investigators may receive requests to unblind study participants who become eligible to receive an
authorized/licensed COVID-19 vaccine at the efficacious dose if/when these become available, including
the sponsors. 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. The name and date(s) of administration of the other COVID-19 vaccine should be recorded
(see body of the protocol for more details).
If the participant prefers another company’s vaccine, they will be informed that there are no data on the
safety of receiving two different COVID-19 vaccines. In the event of the participant unblinding in order to
receive an authorized/licensed COVID-19 vaccine, no further study vaccination will be permitted.
Unblinded participants 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 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, if applicable and feasible. All data will be analyzed separately from the point
of unblinding, for safety and immunogenicity analysis, as described in the Statistical Analysis Plan (SAP).
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
19
Status: Approved,  Date: 16 September 2022
1.2. 
Schemafor Participants in the Main Study
Figure 1: 
Schematic Overview
VISIT
1
Screening:
Days -28 to 1
2 
Vaccination 1: Day 1
Phone
Call
Safety: 7 days post Vac 1
3 
Safety and Immunogenicity: 28 days post Vac 1
4 
Vaccination 2: Day 57
Phone
Call
Safety: 7 days post Vac 2
5 
Safety and Immunogenicity: 14 days post Vac 2
Phone
Call
Safety: 28 days post Vac 2
6 
Safety and Immunogenicity: 24 weeks (6 months)post Vac 2
Phone
Calla 
Safety: post Vac 2
a 
For those participants who have already had their 6-month post Vac 2 visit (Visit 6) but have not yet reached
12-months post Vac 2. Note: those participants that had already reached their 1-year follow-up prior to
implementation of Amendment 7 will also be included in the final analysis.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
20
Status: Approved,  Date: 16 September 2022
1.3. 
Schema for Participants in the Sub Study
VISIT
1
Screening:
Days -28 to 1
2 
Vaccination 1: Day 1
3 
Immunogenicity: 1 day post Vac 1
4 
Immunogenicity: 3 days post Vac 1
5 
Safety and Immunogenicity: 7 days post Vac 1
6 
Safety and Immunogenicity: 28days post Vac 1
7 
Vaccination 2: Day 57
8 
Immunogenicity: 1 day post Vac 2
9 
Immunogenicity: 3 days post Vac 2
10 
Immunogenicity: 7 days post Vac 2
11 
Safety and Immunogenicity: 14 days post Vac 2
Phone
Call
Safety: 28days post Vac 2
12 
Safety and Immunogenicity: 24 weeks (6 months)post Vac 2
Phone
Calla 
Safety post Vac 2
a 
For those participants who have already had their 6-month post Vac 2 visit (Visit 6) but have not yet reached
12-months post Vac 2. Note: those participants that had already reached their 1-year follow-up prior to
implementation of Amendment 7 will also be included in the final analysis.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
21
Status: Approved,  Date: 16 September 2022
1.4. 
Schedule of Activities (SoA)
1.4.1. 
2-dose Vaccination Schedule for Participants in the Main Study
Phase 
Screeninga
Study Periodb
Clinic Visit # 
1 
2 
Phone Callc 
3 
4 
Phone Callc 
5 
Phone Callc 
6 
Phone Call d
Exite
Visit Timing 
Vac 1
Post Vac 1
+ 7 d  
Post Vac 1 
+ 28 d
Vac 2
Post Vac 2
+ 7 d
Post Vac 2 
+14 d  
Post Vac 2
+ 28 d  
Post Vac 2
+ 24 w
Visit Day/Week 
-28 to 1 
Day 1 
Day 8 
Day 29 
Day 57 
Day 64* 
Day 71* 
Day 85* 
Week 32*
(6m post
Vac 2)
Visit Window  
±2 d 
±3 d 
-3/+7 d 
±2 d
±3 d
±3 d 
±21 d
+1 month
Visit Type 
Screening 
Vaccine 1 
Safety  
Safety and 
Immuno 
Vaccine 2 
Safety  
Safety and  
Immuno 
Safety  
Safety and
Immuno
Safety
Written informed consentf 

Inclusion/exclusion criteria 
 
1
Demographics 

Medical history/prestudy
meds

Physical examinationg 

Vital signsh incl. body
temperature
 
2 
2
 
 
Nasal swab sample and test
for SARS CoV 2 RNA
6 
7
Serological test for anti
SARS CoV 2 antibody  
(Local Laboratory)i
6[2 mL]
Randomization 
1
Prevaccination check  
j 
1 
1
Urine pregnancy testk 
 
1 
1
Humoral Immunity (serum),
blood draw, mL l 
1 10 
12 
1 10 
 
10 
 
10 
 
310
Clinical lab blood draw
(whole blood, plasma, 
serum), mLm
1 15 
15 
1 15 
 
15 
 
 
SARS CoV 2 N Serology,
mL (Central Laboratory)n 
 
2.5 
 
2.5 
 
 
Vaccination  
 

15 minutes post vaccination
observationo
 

NCT04908722

NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
23
Status: Approved,  Date: 16 September 2022
c. 
The site will contact the participant 7 days post vaccination 1, 7-days post vaccination 2, and 28 days post vaccination 2 to enquire about compliance of patient
diary completion that occurred between the actual vaccination visit and the current day.
d. 
Within 1 month, the site will contact any participants who have already had their 6-month post Vac 2 visit (Visit 6) but have not yet reached 12-months post Vac 2
for additional safety follow up.
e. 
For those participants who are unable to continue participation in the study up to Visit 7, 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). If the participant does not want to receive the second vaccination,
they can continue with other study procedures.
f. 
Signing of the ICF should be done before any study-related activity.
g. 
A history-directed physical examination, including height and body weight, will be carried out at screening. At other visits, an abbreviated, symptom-directed
examination will be performed if determined necessary by the investigator.
h. 
Heart rate, systolic and diastolic blood pressure, respiratory rate, and body temperature. Heart rate and blood pressure measurements should be taken in the supine
position and preceded by at least 5 minutes of rest. Vital signs measurements are recommended before blood sampling. Body temperatures will be measured
preferably via the oral route.
i. 
The blood draw at screening will be used to determine serostatus by serological testing for eligibility in the main and sub study by a local laboratory.
j. 
Investigator must check for acute illness or body temperature ≥38.0°C/100.4°F at the time of vaccination. If any of these events occur within 24 hours prior to
planned vaccination, the vaccination can be rescheduled as long as this is in agreement with the allowed windows. 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. The investigator should also check
if any other reasons, as listed in Section 7.1, Discontinuation of Study Vaccination, have been met and would prevent further study vaccination.
k. 
For women of childbearing potential only.
l. 
Serum collected can also be used for N-serology testing.
m. 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 stored for coagulation-related testing in a central
laboratory, some of which will be conducted retrospectively (See Section 10.2, Appendix 2).
n. 
This blood draw occurs in the ongoing study for monitoring breakthrough infections and will be performed by a central laboratory.
o. 
Participants will be closely observed for a minimum of 15 minutes post vaccination. Any solicited local (at injection site) and systemic AEs, unsolicited AEs,
SAEs, concomitant medications, and vital signs will be documented by study site personnel following this observation period and participants will be allowed to
leave the study site after it is documented that the 15 minutes post vaccination observation period is complete.
p. 
AEs and special reporting situations 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. All other unsolicited AEs and special reporting situations will be reported for each
vaccination from the time of vaccination until 28 days post vaccination.
q. 
All SAEs related to study procedures or non-investigational sponsor products will be reported for all participants 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 for all participants from the moment of first 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).
r. 
At each visit the participant will be asked if they have had a private/off-study COVID-19 test. If a participant receives a positive SARS-CoV-2 result from a
private/off-study test (whether through PCR or serological testing) during the study, and the positive result occurs within 28 days after vaccination, the event will
be reported as an AE. If it occurs after 28 days, the event will be recorded as an SAE only if the event qualifies as serious. If the event occurs after 28 days, and it
is not serious, it will be reported in the eCRF. The participant can continue in the study for safety follow-up if they choose to; however, this must be in accordance
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
24
Status: Approved,  Date: 16 September 2022
with local country and site level recommendations for COVID-19 and they will not be permitted to receive further study vaccination administrations. (see
Section 8.3.1).
s. 
MAAEs are to be reported for all participants from the moment of the 1st vaccination until 6 months after the last 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.
t. 
Concomitant therapies such as analgesic/antipyretic medications and non-steroidal anti-inflammatory drugs, corticosteroids, antihistamines, and vaccinations must
be recorded from the first dose of study vaccine until 28 days after administration of study vaccine, and thereafter, pre-dose on the day of subsequent vaccination
and for 28days after the subsequent dose of study vaccine. Refer to Section 6.8for collection and recording of concomitant therapies associated with SAEs,
solicited and unsolicited AEs, suspected AESIs, and MAAEs. All other concomitant therapies should also be recorded if administered in conjunction with new or
worsening AEs reported per protocol requirements outlined in Section 8.3.1.
u. 
At Visit 2, in addition to the diary, a ruler and thermometer will be distributed to each participant. At Visit 4, the site is to report the 2nd vaccination date in the
eCOA portal to ensure that the appropriate diary is visible in the electronic diary.
v. 
If an event is still ongoing on Day 8or Day 64, the participant should continue to collect the information until resolution.
(S)AE = (serious) adverse event; AESI = adverse event of special interest; COVID-19 = coronavirus disease-2019; d = day(s); ICF = informed consent form; MAAE =
medically-attended adverse event; meds = medication; m = months; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus-2; vac
= vaccination; vp = virus particles.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
25
Status: Approved,  Date: 16 September 2022
1.4.2. 
2-dose Vaccination Schedule for the Sub Study Participants
Phase 
Screeninga 
Study Periodb
ClinicVisit # 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11
Phone
Call
12
Phone
Calld 
Exite
Visit Timing 
Vac 1 
Post 
Vac 1 
+ 1 d** 
Post 
Vac 1 
+ 3 d** 
Post Vac 
1 
+ 7 d  
Post 
Vac 1 
+ 28 d  
Vac 2 
Post 
Vac 2 
+ 1 d** 
Post 
Vac 2 
+ 3 d** 
Post 
Vac 2 
+ 7 d  
Post
Vac 2
+14 d
Post
Vac 2
+ 28 d
Post
Vac 2
+ 24 w
Visit Day/Week  
-28 to 1 
Day 1 
Day 2 
Day 4 
Day 8 
Day 29 
Day 57 
Day 58 
Day 60 
Day 64* 
Day 71*
Day
85*c
Week
32*
(6m post
Vac 2)
Visit Window
±2 d  
±3 d  
-3/+7 d  
±2 d  
±3 d
±3 d  
±21 d 
+1
month
Visit Type 
Screening
Vaccine
1
Immuno 
Immuno
[Safety
and
Immuno]
Safety
and
Immuno
Vaccine
2
Immuno 
Immuno
Safety
and
Immuno
Safety
and
Immuno
Safety 
Safety
and 
immuno
Safety
Written informed
consentf

Inclusion/exclusion
criteria
 
1
Demographics 

Medical
history/prestudy 
meds

Physical
examinationg 

Vital signsh incl.
body temperature
 
2
2
 
Nasal swab sample
and test for SARS  
CoV 2 RNA
6 
7
Serological test for
anti SARS CoV 2
antibodyi (Local
Laboratory)
6[2 mL]
Randomization 
1
Prevaccination 
check  
j 
1
1
Urine pregnancy
testk 

1
1
Humoral Immunity
(serum), blood
draw, mLl
1 10 
12 
1 10 
 
10 
 
10 
 
310
NCT04908722

NCT04908722

NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
28
Status: Approved,  Date: 16 September 2022
includes the safety assessments of the early exit visit (no blood sampling for immunogenicity). If the participant does not want to receive the second vaccination,
they can continue with other study procedures.
f. 
Signing of the ICF should be done before any study-related activity.
g. 
A history-directed physical examination, including height and body weight, will be carried out at screening. At other visits, an abbreviated, symptom-directed
examination will be performed if determined necessary by the investigator.
h. 
Heart rate, systolic and diastolic blood pressure, respiratory rate, and body temperature. Heart rate and blood pressure measurements should be taken in the supine
position and preceded by at least 5 minutes of rest. Vital signs measurements are recommended before blood sampling. Body temperatures will be measured
preferably via the oral route.
i. 
The blood draw at screening will be used to determine serostatus by serological testing for eligibility in the sub study by a local laboratory.
j. 
Investigator must check for acute illness or body temperature ≥38.0°C/100.4°F at the time of vaccination. If any of these events occur within 24 hours prior to
planned vaccination, the vaccination can be rescheduled as long as this is in agreement with the allowed windows. 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. The investigator should also check
if any other reasons, as listed in Section 7.1, Discontinuation of Study Vaccination, have been met and would prevent further study vaccination.
k. 
For women of childbearing potential only.
l. 
Serum collected can also be used for N-serology testing.
m. 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 stored for coagulation-related testing in a central
laboratory, some of which will be conducted retrospectively (See Section 10.2, Appendix 2).
n. 
This blood draw occurs in the ongoing study for monitoring breakthrough infections and will be performed by a central laboratory.
o. 
Participants will be closely observed for a minimum of 15 minutes post vaccination. Any solicited local (at injection site) and systemic AEs, unsolicited AEs,
SAEs, concomitant medications, and vital signs will be documented by study site personnel following this observation period and participants will be allowed to
leave the study site after it is documented that the 15 minutes post vaccination observation period is complete.
p. 
AEs and special reporting situations 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. All other unsolicited AEs and special reporting situations will be reported for each
vaccination from the time of vaccination until 28 days post vaccination.
q. 
All SAEs related to study procedures or non-investigational sponsor products will be reported for all participants 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 for all participants from the moment of first 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).
r. 
At each visit the participant will be asked if they have had a private/off-study COVID-19 test. If a participant receives a positive SARS-CoV-2 result from a
private/off-study test (whether through PCR or serological testing) during the study, and the positive result occurs within 28 days after vaccination, the event will
be reported as an AE. If it occurs after 28 days, the event will be recorded as an SAE only if the event qualifies as serious. If the event occurs after 28 days, and it
is not serious, it will be reported in the eCRF. The participant can continue in the study for safety follow-up if they choose to; however, this must be in accordance
with local country and site level recommendations for COVID-19 and they will not be permitted to receive further study vaccination administrations. (see
Section 8.3.1).
s. 
MAAEs are to be reported for all participants from the moment of the 1st vaccination until 6 months after the last 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.
t. 
Concomitant therapies such as analgesic/antipyretic medications and non-steroidal anti-inflammatory drugs, corticosteroids, antihistamines, and vaccinations must
be recorded from the first dose of study vaccine until 28 days after administration of study vaccine, and thereafter, pre-dose on the day of subsequent vaccination
and for 28days after the subsequent dose of study vaccine. Refer to Section 6.8for collection and recording of concomitant therapies associated with SAEs,
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
29
Status: Approved,  Date: 16 September 2022
solicited and unsolicited AEs, suspected AESIs, and MAAEs. All other concomitant therapies should also be recorded if administered in conjunction with new or
worsening AEs reported per protocol requirements outlined in Section 8.3.1.
u. 
At Visit 2, in addition to the diary, a ruler and thermometer will be distributed to each participant. At Visit 7, the site is to report the 2nd vaccination date in the
eCOA portal to ensure that the appropriate diary is visible in the electronic diary.
v. 
If an event is still ongoing on Day 8or Day 64, the participant should continue to collect the information until resolution.
(S)AE = (serious) adverse event; AESI = adverse event of special interest; COVID-19 = coronavirus disease-2019; d = day(s); ICF = informed consent form; MAAE =
medically-attended adverse event; meds = medication; m = months; MoA= mechanism of action; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory
syndrome coronavirus-2; TTS= thrombosis with thrombocytopenia syndrome; vac = vaccination; vp = virus particles.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
30
Status: Approved,  Date: 16 September 2022
1.4.3. 
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 Hematology [American Society of Hematology 2021], British Society of
Haematology - Expert Haematology Panel [British Society for Haematology. Guidance 2021], and
the CDC [CDC 2021]). 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 Janssen Adjudication Committee.
In the event of a suspected thrombotic event or TTS, laboratory assessments (to be performed
locally) might be needed to facilitate diagnosis and determine treatment options, including but not
limited to platelet count and anti-PF4 tests.
Additional blood samples should be collected for central laboratory testing as detailed below.
However, results of central laboratory testing may not be available to guide immediate treatment
decisions.
Timing relative to onset of suspected AESI
AESI 
Day 1 a 
AESI
Day 29b
Visit Window  
 
±7 d
Site to report suspected AESIc 

Clinical lab blood sample (whole blood), mLd 
15 
15
TTS AESI forme 
---Continuous---
Concomitant therapiesf 
 

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 8.3.6).
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 used 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 8.3.6 and Section 10.8,
Appendix 8 for further details.
f. Refer to Section 6.8for 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
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
31
Status: Approved,  Date: 16 September 2022
2. 
INTRODUCTION
Ad26.COV2.S (also known as Ad26COVS1)is a monovalent vaccine composed ofa recombinant,
replication-incompetent human adenovirus type 26 (Ad26) vector, constructed to encode the
severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike (S) protein, stabilized in
its prefusion conformation, which will be assessed in  this study.
For the most comprehensive nonclinical and clinical information regarding Ad26.COV2.S, refer
to the IB, Edition 6.0 (IB Ad26.COV2.S. 2022). As the IB might be further updated after protocol
finalization, refer to the latest version of the IB (and addenda, if applicable) for the most recent
information.
The term “study vaccine” throughout the protocol, refers to Ad26.COV2.S  as defined in
Section 6.2. 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”.
Study VAC31518COV3003 is being conducted under the sponsorship of Janssen (Janssen
Vaccines & Prevention B.V).
COVID-19 Vaccine and Considerations
Currently, there is only limited availability of licensed/authorized vaccines for the prevention
of coronavirus disease-2019 (COVID-19). The continued development of safe and effective
vaccines 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 (Chen 2005, Zhao 2017). 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 (Letko 2020,
Lu 2020, Zhou 2020). Therefore, a neutralizing antibody  response against the SARS-CoV-2 S
protein may also have a protective effect.
Adenoviral-vectored Vaccines
Recombinant, replication-incompetent adenoviral vectors are attractive candidates for expression
of foreign  genes for a number of reasons. The adenoviral genome is well characterized and
comparatively  easy  to manipulate. Adenoviruses exhibit broad tropism, infecting a variety of
dividing and non-dividing cells. The adenoviral vaccine (AdVac®) vector platform, developed by
Crucell Holland B.V. (now Janssen Vaccines & Prevention B.V.)allows for high-yield production
of replication-incompetent adenovirus vectors, eg, Ad26, with desired inserts. The adenovirus E1
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.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
32
Status: Approved,  Date: 16 September 2022
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 vaccination 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 (Th)1 responses and demonstrate predominantly interferon gamma (IFN-γ)
and tumor necrosis factor alpha (TNF-α)production in cluster ofdifferentiation (CD)4+ and CD8+
T cells (Barouch 2013, Milligan 2016, Janssen Vaccines & Prevention B.V. Data on file).
Ad26.COV2.S Candidate Vaccine
The aim ofthe COVID-19 vaccine clinical development program is to develop a safe and effective
vaccine for the prevention of COVID-19. The candidate vaccine to be assessed in this study is
Ad26.COV2.S, which  is a recombinant, replication-incompetent Ad26 encoding a prefusion
stabilizedvariant ofthe 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 (Chen 2005, Faber 2005, Modjarrad 2019). 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 (Zhou 2004).
SARS-CoV-2 Virology and COVID-19 Disease Burden
SARS-CoV-2 is an  enveloped, positive-sense, single-stranded RNA  Betacoronavirus
(Coronaviridae Study Group of the International Committee on Taxonomy of Viruses 2020,
Wu 2020). It was first identified following reports ofa cluster ofacute respiratory illness cases in
Wuhan, Hubei Province, China in December 2019 (Li 2020). Earlyepidemiological investigations
suggested that the majority ofearly cases were linked to a seafood market, with patients infected
through zoonotic or environmental exposure, followed by the subsequent spread ofinfection by
human-to-human transmission among close contacts (Li 2020). However, there is some
controversy about the initial origin of the virus (Cyranoski 2020). 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 (Lu 2020, WHO 2005a). Phylogenetic analysis of the complete viral genome
revealed that the virus, SARS-CoV-2, is part of the subgenus Sarbecovirus of the genus
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
33
Status: Approved,  Date: 16 September 2022
Betacoronavirus, and is most closely related (approximately 88% identity) to a group  of SARS-
CoV-like coronaviruses previously sampled from bats in China (Lu 2020).
SARS-CoV-2 has spread rapidly and globally since its emergence. The WHO declared that the
outbreak constituted a public health emergency of international concern on January 30, 2020 and
declared the outbreak to be a pandemic on March 11, 2020 (WHO 2005a, WHO 2020c). As of
December 11th, 2020, approximately69,688,577 cases ofCOVID-19 andapproximately1,584,063
COVID-19-related deaths have been reported (Johns Hopkins CSSE 2020).
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 (CDC 2020b). Severe
clinical presentations have been reported in as manyas 20% to 25% oflaboratory-confirmed cases
(ECDC 2020b). 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%)(Chen 2020). 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%)(US Dept Health 1998). Lymphopenia occurred in 70.3%
ofpatients, 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 ofcomplications, including acute respiratory  distress syndrome, arrhythmia, andshock.
Subsequent US Centers for Disease Control and Prevention (CDC) descriptions of COVID-19
clinical case definitions 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 offeet 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.
The identification  of SARS-CoV-2 follows the emergence of 2 other novel betacoronaviruses
capable of causing severe human disease over the past 18years: SARS-CoV and MERS-CoV,
which  have nucleotide sequence identity with  SARS-CoV-2 of approximately  79%  and 50%,
respectively  (Lu 2020). The first known  cases of SARS  occurred in  Southern  China in
November 2002 (WHO 2004). The etiological agent, SARS-CoV, is believed to be an  animal
virus thatcrossedthe species barrierto humans followedbyhuman-to-humantransmission, 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 (Zumla 2016). MERS-
CoV is considered to be a zoonotic virus capable ofnonsustained 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.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
34
Status: Approved,  Date: 16 September 2022
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 (Chan 2015, Zumla 2016). 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 8,098SARS cases and 774 deaths (case-fatality
rate: 10%) with substantial social, economic and health  service disruption  in  some affected
countries (Chan 2015, WHO 2004). The case-fatality  rate of MERS-CoV infections is estimated
to be 35% (Chan 2015).
It is not known if SARS-CoV-2 will remain as a worldwide pandemic. It is also not known if
immunityis 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 ofthe most important tools to help control
this highly contagious respiratory virus.
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 (2002-2003 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 antibodies (Buchholz 2004, Sui 2005, Zhang 2004, Zhou 2004)and the only
viral protein that can elicit protective immunity in animal models (Berry, 2004, Bisht 2004,
Bukreyev 2004, Subbarao 2004, Yang 2004). Based on these findings, the S protein was selected
as the sponsor’s candidate vaccine antigen.
2.1. 
Study Rationale
Detailed information about the rationale for the selected dose for the release titer (5x1010 vp) can
be found in Section 4.3.
The purpose of this study is to aid in the establishment of end-expiry specifications for the 1-dose
and 2-dose vaccine regimens being assessed in the Phase 3 efficacy studies VAC31518COV3001
and VAC31518COV3009, respectively. The lower dose (3.5 x1010 vp, 2.5x1010 vp, and 1.25x1010 vp)
levels mimic vaccine degradation to enable determination of product expiry. In order to increase the end of
shelf life specifications a potential target release titer of 7x1010 vpwill be evaluated. A higher titer of 9x1010
vp will also be evaluated as is the upper limit of the release range (potential maximum vp at release). For
this study’s purpose 6 dose levels of Ad26.COV2.S will be assessed: 9x1010 vp, 7x1010 vp, 5x1010
vp (release titer), 3.5x1010 vp, 2.5x1010 vp, and 1.25x1010 vp. The following NI comparisons by
sequential approach will be performed:
1-dose 9x1010 vp Ad26.COV2.S compared to 1-dose 5x1010 vp Ad26.COV2.S
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
35
Status: Approved,  Date: 16 September 2022
If the above is demonstrated, then:
1-dose 2.5x1010 vp Ad26.COV2.S compared to 1-dose 5x1010 vp Ad26.COV2.S
1-dose 7x1010 vp Ad26.COV2.S compared to 1-dose 5x1010 vp Ad26.COV2.S
If the above is demonstrated, then:
1-dose 3.5x1010 vp Ad26.COV2.S compared to 1-dose 5x1010 vp Ad26.COV2.S
If the above is demonstrated, then:
1-dose 1.25x1010 vp Ad26.COV2.S compared to 1-dose 5x1010 vp Ad26.COV2.S
To demonstrate the following in sequential order:
2-doses 9x1010 vp Ad26.COV2.S compared to 1-dose 5x1010 vp Ad26.COV2.S
2-doses 9x1010 vp Ad26.COV2.S compared to 2-doses 5x1010 vp Ad26.COV2.S
2-doses 2.5x1010 vp Ad26.COV2.S compared to 1-dose 5x1010 vp Ad26.COV2.S
2-doses 2.5x1010 vp Ad26.COV2.S compared to 2-doses 5x1010 vp Ad26.COV2.S
2-doses 7x1010 vp Ad26.COV2.S compared to 1-dose 5x1010 vp Ad26.COV2.S
2-doses 7x1010 vp Ad26.COV2.S compared to 2-doses 5x1010 vp Ad26.COV2.S
2-doses 3.5x1010 vp Ad26.COV2.S compared to 1-dose 5x1010 vp Ad26.COV2.S
2-doses 3.5x1010 vp Ad26.COV2.S compared to 2-doses 5x1010 vp Ad26.COV2.S
2-doses 1.25x1010 vp Ad26.COV2.S compared to 1-dose 5x1010 vp Ad26.COV2.S
2-doses 1.25x1010 vp Ad26.COV2.S compared to 2-doses 5x1010 vp Ad26.COV2.S
Prior to the start of the VAC31518COV3001 and VAC31518COV3009 studies, the Phase 1 and 2
studies VAC31518COV1001 and VAC31518COV2001 were initiated to assess several dose levels
of the vaccine including 1x1011 vp, 5x1010 vp, 2.5x1010 vp and 1.25 x1010 vp.
2.2. 
Background
Nonclinical Pharmacology
Nonclinical studies were performed to test the immunogenicity of different vaccine candidates,
leading to the selection ofthe current vaccine for this development program. In addition, vaccine
efficacy of Ad26.COV2.S has been shown in Syrian hamsters and NHP. Details are provided in
the IB (IB Ad26.COV2.S. 2022).
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
36
Status: Approved,  Date: 16 September 2022
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 ofthe Ad26 vector from the
tissues was observed. Both Ad26 vectors showed a comparable biodistribution despite carrying
different antigen transgenes. These data further indicate that the Ad26 vector does not replicate
and/or persist in the tissues following IM injection. These platform data are considered sufficient
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 studyin rats), testing the nonclinical safetyofvarious homologous and heterologous
regimens with  Ad26-based vaccines at full human  dose levels 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 ofa physiological response to the vaccines administered,
and seem to be independent ofthe antigen transgene. Overall, there were no safetysignals detected
in any ofthe available GLP toxicology studies with Ad26-based vaccines up to the highest dose
level tested (1.2×1011 vp). In a combined embryo-fetal and pre- and postnatal development GLP
studyin 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 start of this study, the safety and immunogenicity (post-Dose 1) of Ad26.COV2.S,
administered at several dose levels, has been demonstrated in healthy adults in the first-in-human
study VAC31518COV1001 (IB Ad26.COV2.S  2022, Sadoff2020) and is currently further
evaluated in Phase 2 study VAC31518COV2001. Based on the interim data of study
VAC31518COV1001, 2 clinical studies have been initiated to assess the protective efficacy of
Ad26.COV2.S at the 5x1010vp dose level, administered either as a 1-dose (study
VAC31518COV3001) or as a 2-dose schedule (study VAC31518COV3009).
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
37
Status: Approved,  Date: 16 September 2022
Refer to the IB for a high level description of all ongoing studies with Ad26.COV2.S
(IB Ad26.COV2.S 2022).
Clinical Safety Experience With Ad26-based Vaccines
As described above, replication-incompetent Ad26 is being used as a vectorin the development of
vaccine candidates against diseases such  as malaria, RSV, HIV, Ebola virus, Zika virus and
filovirus, and has been used in the now licensed Ebola virus vaccine (Zabdeno/Ad26.ZEBOV).
As of 04 September 2020, Ad26-based vaccines, developed by the sponsor, have been
administered to approximately  114,000 participants in ongoing and completed studies, including
more than 99,000 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 04 September 2020, more than 109,000 participants were enrolled in ongoing studies and
in  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-offdate, 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, Risks Related to Study
Participation for a summary of data from the AdVac® safety database report.
Th1/Th2 Profile of Ad26-based Vaccines in Clinical Studies
In the 1960s, a formalin-inactivated (FI) RSV vaccine was associated with enhanced respiratory
disease (ERD) in  young children, characterized by an increased rate of RSV-mediated, severe
lower respiratory tract infection in the vaccinated individuals compared with the control group
(Chin 1969, Fulginiti 1969, Kapikian 1969, Kim 1969). Although the mechanisms for ERD are
not fully understood, it is thought that the FI-RSV vaccine may have: 1)failed to induce adequate
neutralizing antibody titers; 2) led to an overproduction ofbinding 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 T-helper cell (Th) type
2-skewed type T-cell response (Moghaddam 2006).
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
38
Status: Approved,  Date: 16 September 2022
Vaccine-induced ERD has also been described for SARS-CoV and MERS-CoV in some animal
models in  which  candidate vaccines induced a Th2 biased immune response (Agrawal 2016,
Bolles 2011, Deming 2006, Honda-okubo 2015, Houser 2017, Smatti 2018) 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 ofmice 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 (IB Ad26.COV2.S. 2022). The Ad26 vector was chosen due to its ability to
induce humoral and strong cellular responses with  a Th1 immune phenotype (Anywaine 2019,
Barouch 2018, Colby 202, Milligan 2016, Mutua 2019, Salisch 2019, Stephenson 2020,
van der Fits 2020, Widjojoatmodjo 2015, Zhan 2012). This type 1 polarity ofthe immune response
minimizes the risk ofenhanced disease after SARS-CoV-2 infection.
The immunogenicity profile ofadenoviral 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.Mos4.HIV)and Ad26-vectored Ebola vaccine (Ad26.ZEBOV). These
data show predominantly IFNγ and TNFα production in CD4+ and CD8+ T cells (Anywaine 2019,
Barouch 2013, Barouch 2018). In the RSV  vaccine clinical development program,
Ad26.RSV.preF  w a s  evaluated in  healthy  RSV- seropositive toddlers aged 12 to 24 months
(Phase 1/2a study VAC18194RSV2001). Safety data fromthe primaryanalysis at28days afterthe
secondstudyvaccinationrevealedno safetyconcerns 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 a favorable Th1 bias, was confirmed.
In August 2020, the study had been completed and showed that Ad26.RSV.preF had an acceptable
safety and reactogenicity profile. 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 vaccination.
In Study COV1001, Ad26.COV2.S induced cellular immune responses were assessed by ICS and
ELISpot. Robust CD4+ T and CD8+ T-cell responses were seen following a single vaccination
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
39
Status: Approved,  Date: 16 September 2022
with 5×1010 vp or 1×1011 vp. Following vaccination, CD4+ T cells had a Th1-skewed phenotype
and no, or very limited, Th2 responses were observed. The Th1/Th2 ratio was above 1 (median of
7.60 for 5×1010 vp and 10.24 for 1×1011 vp) in all participants with a positive CD4+ T-cell response
(IB Ad26.COV2.S. 2022).
2.3. 
Benefit-Risk Assessment
More detailed information about the known and expected benefits and risks of Ad26.COV2.S may
be found in the IB (IB Ad26.COV2.S. 2022).
2.3.1. 
Risks Related to Study Participation
The following potential risks for Ad26.COV2.S  will be monitored during the study and are
specified in the protocol:
Risks Related to Ad26.COV2.S
At the start of this study, the post-dose 1 safety and reactogenicity profiles of Ad26.COV2.S
(5x1010 and 1x1011 vp) were considered acceptable, as demonstrated in the interim analyses of
blinded safety data from approximately 800 participants (18 to 55 years of age [Cohort 1] and
≥65 years of age [Cohort 3]) in the first-in-human study VAC31518COV1001 (Sadoff 2020).
Local adverse events were observed in 58% and 27% of participants in Cohorts 1a and 3,
respectively. Solicited systemic adverse events were reported in 64% and 36% of participants in
Cohorts 1 and 3, respectively. Fevers occurred in 19% (5% Grade 3) and 4% (0% Grade 3) of
participants of Cohorts 1 and 3, respectively, were mostly mild or moderate, and resolved within
1 to 2 days after vaccination. The most frequent local adverse event was injection site pain and the
most frequent solicited adverse events were fatigue, headache and myalgia. The safety and
reactogenicity profiles of 2 dose levels, 5x1010 and 1x1011  vp were considered acceptable.
For the most comprehensive nonclinical information regarding Ad26.COV2.S, refer to the latest
version of the IB (IB Ad26.COV2.S. 2022).
Sites should advise participants that side effects include fever as well as injection site pain,
headache, fatigue, myalgia, and nausea per the current ICF.
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
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
40
Status: Approved,  Date: 16 September 2022
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, 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 Hematology [American Society
of Hematology. COVID-19 resources 2021], British Society of Haematology - Expert
Haematology Panel [British Society for Haematology. Guidance produced from the Expert
Haematology Panel 2021] and the CDC [CDC 2021]). 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 Janssen
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
for thrombotic events, thrombocytopenia, and TTS (see Section 8.3.6), which may facilitate
diagnosis and clinical management of the event. Reports of adverse events following use of the
Ad26.COV2.S Vaccine under emergency use authorization (EUA) suggest an increased risk of
Guillain-Barré syndrome (GBS) during the 42 days following vaccination. Investigators should be
alert to GBS signs and symptoms to facilitate diagnosis, to initiate adequate supportive care and
treatment, and to rule out other causes. Refer to the latest version of the IB and its addenda (if
applicable) for further details.
Heparin-induced Immune Thrombotic Thrombocytopenia
TTS has been found to resemble heparin-induced thrombocytopenia with thrombosis (HITT),
which is mediated by antibodies against complexes of heparin and platelet factor 4 (PF4) that
induce Fc receptor-mediated activation of platelets and hypercoagulation (Arepally 2021). Current
evidence suggests that these 2 conditions may be linked (Streiff 2021). The exact mechanisms
remain to be investigated, but anti-PF4 antibodies are suspected to be involved in the pathogenesis
of TTS associated with vaccination.
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.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
41
Status: Approved,  Date: 16 September 2022
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 4-11 years, and 24.8% of children aged 12-17 years after vaccination with an Ad26-
based vaccine. For placebo, these percentages were 29.2% in children aged 4-11 years and 14.3%
in children aged 12-17 years. No children aged 1-3 years have received placebo.
Severe injection site pain was experienced by 1.0% of adult Ad26 participants and 0.8% of children
aged 4-11 years. No children in the other 2 age groups and no placebo participants experienced
severe injection site pain.
There was a trend toward an increase in the frequency of some local AEs with an increase in Ad26
dose, ie, injection site pain (18.7% of participants at the 0.8×1010 vp dose level, 38.7% of
participants at the 2×1010 vp dose level, 52.0% of participants at the 5×1010 vp dose level, and
77.1% of participants at the 1×1011 vp dose level), and to a lesser extent injection site swelling
(6.7%, 2.7%, 9.3%, and 17.6%, respectively). Injection site warmth was not collected at the
0.8×1010 vp and the 2×1010 vp dose level. The frequency of injection site warmth at the 5×1010 vp
and the 1×1011  vp dose level was 19.5%, and 26.7%, respectively. This trend needs to be
interpreted with caution since the participants in the lower dose groups (0.8×1010 vp and 2×1010 vp
dose level) were all from a single study (VAC52150EBL3002), and the majority of the participants
in the highest dose group (1×1011  vp dose level) were also from a single study
(VAC18193RSV2003).
The most frequently reported solicited systemic AEs (ie, reported in more than 30% of
participants) for adult Ad26 participants were malaise (53.8%), fatigue (48.3%), headache
(45.7%), and myalgia (38.3%), all of which were more frequent for Ad26 participants compared
with placebo (36.4%, 30.7%, 30.0%, and 17.7% of placebo participants, respectively). Most of
these events were considered related to the study vaccine. Pyrexia (9.9%) and vaccine-related
pyrexia (9.0%) were also reported more frequently after administration of an Ad26-based vaccine
compared with placebo (3.5% and 2.9%, respectively).
Solicited systemic AEs reported in ≥10% of children aged 1-3 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 4-11 years (reported in ≥15% of Ad26
participants) were headache (23.6%; no data are available for the placebo arm 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
12-17 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.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
42
Status: Approved,  Date: 16 September 2022
The majority of solicited systemic AEs were of mild or moderate severity. For adults, 6.5% of
Ad26 participants and 2.0% of placebo participants reported severe solicited systemic AEs, mostly
malaise and fatigue. Other severe solicited systemic AEs were reported in less than 3% of adult
Ad26 participants.
There was a trend toward an increase in the frequency of solicited systemic AEs with an increase
in Ad26 dose (35.3% at the 0.8×1010 vp dose level, 49.3% at the 2×1010 vp dose level, 64.5% at
the 5×1010 vp dose level, and 70.4% at the 1×1011 vp dose level). The frequency of severe solicited
systemic AEs also tended to increase with higher Ad26 dose, ie, 1.3% of participants at the
0.8×1010 vp and the 2×1010 vp dose level, 5.3% of participants at the 5×1010 vp dose level, and
14.4% of participants at the 1×1011 vp dose level. This trend needs to be interpreted with caution
since the participants in the lower dose groups (0.8×1010 vp and 2×1010 vp dose level) were all
from a single study (VAC52150EBL3002), and the majority of the participants in the highest dose
group (1×1011 vp dose level) were also from a single study (VAC18193RSV2003).
The most frequently reported unsolicited AE in adult Ad26 participants was upper respiratory tract
infection (5.3% vs. 7.0% in adult placebo participants). The most frequently reported unsolicited
AEs considered related to the vaccine were neutropenia (1.0% of adult Ad26 participants vs. 0.5%
of adult placebo participants) and dizziness (0.7% vs. 0.2%, respectively).
ForAd26, the most frequently reported unsolicited AE in children was malaria,a reported in 36.8%
of children aged 1-3 years, in 19.0% of children aged 4-11 years, and in 10.6% of children aged
12-17 years. One child in the 12-17 years group (4.8%) experienced malaria after placebo
vaccination. There were no other children in the placebo groups who experienced malaria. The
most frequently reported related unsolicited AE was hypernatremia (1.6% of children aged
4-11 years [vs. 4.2% with placebo] and 2.4% of children aged 12-17 years [vs. 4.8% with
placebo]). No AEs in children aged 1-3 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 intramuscular injection of a vaccine and/or placebo, including
fever, chills, rash, myalgia, nausea/vomiting, headache, dizziness, arthralgia, general itching, and
fatigue. These side effects will be monitored, but are generally short-term. Instructions regarding
use of antipyretic medication can be found in Section 6.8.
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,
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.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
43
Status: Approved,  Date: 16 September 2022
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 allergy, or history of anaphylaxis or other serious adverse reactions
to vaccines or their excipients (including specifically the excipients of the study vaccine) will be
excluded from the study.
After each vaccination, participants will remain at the study site for at least 15 minutes and will be
closely observed by study staff. Necessary emergency equipment and medications must be
available in the clinic to treat severe allergic reactions.
Pregnancy and Birth Control
The effect of the study vaccine on a fetus or on a 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). Participants who are
pregnant at screening will be excluded from the study. Participants who become pregnant during
the study will remain in the study and will continue to undergo all procedures and all safety follow-
up as outlined in the protocol for all participants but will not receive further vaccination.
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 Swabs
Collection of a nasal swab may cause a nosebleed. 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 models (Agrawal 2016, Bolles 2011, Deming 2006, Honda-okubo 2015, Houser 2017)and
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
44
Status: Approved,  Date: 16 September 2022
is associated with non-neutralizing antibodies and a Th2-skewed immune response, but proof of
human SARS-CoV or MERS-CoV VAERD does not exist as these candidate vaccines were never
tested for efficacy nor used in outbreak situations. In contrast, the Ad26-based vaccines have been
shown to induce a clear Th1-skewed immune response and generate potent neutralizing antibody
responses in both humans and animal models (see Section 2.2). Participants in the present study
will be informed of the theoretical risk of disease enhancement in the ICF.
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 for 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.
2.3.3. 
Benefit-Risk Assessment for Study Participation
Based on the available data and proposed safety measures, the overall benefit-risk assessment for
this clinical study is considered acceptable for the following reasons:
 
Only participants who meet all inclusion criteria and none of the exclusion criteria (specified
in Section 5) will be allowed to participate in this study. The selection criteria include adequate
provisions to minimize the risk and protect the well-being of participants in the study.
 
Safety will be closely monitored throughout the study:
 
In general, safety evaluations will be performed at scheduled visits during the study, as
indicated in the Schedule of Activities (SoA).
 
After each vaccination, participants will remain at the study site for at least 15 minutes
and will be closely observed by study staff. Necessary emergency equipment and
medications must be available in the clinic to treat severe allergic reactions. Participants
will use a diary to document solicited signs and symptoms. Details are provided in
Section 8.3.
 
The investigator or the designee will document unsolicited adverse events, SAEs and
MAAEs as indicated in Sections 8.3 and 10.4.
 
TTS is considered to be an AESI (Section 8.3.6). Suspected AESIs (thrombotic events
and 
thrombocytopenia 
[defined 
as 
platelet 
count 
below 
150,000/µL
(Brighton Collaboration. Interim Case Definition of Thrombosis with Thrombocytopenia
Syndrome 2021)must be reported to the sponsor within 24 hours of awareness. Suspected
AESIs will be followed up as described in the Schedule of Activities in Section 1.4.3.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
45
Status: Approved,  Date: 16 September 2022
 
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 program IDMC has been established to monitor safety data on an ongoing basis in
specific studies. This committee will be provided with relevant safety data from this
study, such as SAEs, that will help the IDMC to have an overall view of the safety profile
of the vaccine. Additional ad hoc reviews may be performed further to the occurrence of
any SAE, or at the request of the IDMC or the sponsor’s medical monitor or designee.
The IDMC responsibilities, authorities, and procedures will be documented in the IDMC
Charter.
 
Several safety measures are included in this protocol to minimize the potential risk to
participants, including the following:
 
Eligibility will be reassessed pre-vaccination on Day 1.
 
Study vaccinations will be discontinued in participants for the reasons included in
Section 7.
 
Contraindications to vaccination are included in Section 5.5.
3. 
OBJECTIVES AND ENDPOINTS
OBJECTIVES AND ENDPOINTS FOR PARTICIPANTS IN THE MAIN STUDY
Objectives 
Endpoints
Primary
To demonstrate non-inferiority (NI) in the 
following sequential order: 
 
NI after 1-dose of Ad26.COV2.S 9x1010 vp vs
1-dose of Ad26.COV2.S 5x1010 vp (release  
titer) 
 
NI after 1 dose of Ad26.COV2.S 2.5x1010 vp 
vs 1-dose of Ad26.COV2.S 5x1010 vp (release 
titer) 
 
NI after 1 dose of Ad26.COV2.S 7x1010 vp vs
1-dose of Ad26.COV2.S 5x1010 vp (release
titer)
 
NI after 1 dose of Ad26.COV2.S 3.5x1010 vp
vs 1-dose of Ad26.COV2.S 5x1010 vp (release
titer)
 
NI after 1-dose of Ad26.COV2.S 1.25x1010 vp
vs 1-dose of Ad26.COV2.S 5x1010 vp (release
titer)
 
Binding 
antibody 
concentrations 
to
SARS-CoV-2 S protein as measured by
ELISA 28 days after vaccination
 
NI will be demonstrated in terms of humoral
immune response expressed by the GMCs of
S-ELISA, 28 days post-dose 1, using a NI
margin of 2/3 for the GMC ratio (GMC 9x1010
vp, 2.5x1010 vp, 7x1010 vp, 3.5x1010 vp, or
1.25x1010 vp/GMC 5x1010 vp)
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
46
Status: Approved,  Date: 16 September 2022
Objectives 
Endpoints
To demonstrate NI in the following sequential 
order: 
 
NI after 2-doses of Ad26.COV2.S 9x1010 vp
vs 1 dose of Ad26.COV2.S 5x1010 vp (release 
titer) 
 
NI after 2-doses of Ad26.COV2.S 9x1010 vp 
vs 2-doses of Ad26.COV2.S 5x1010 vp 
(release titer) 
 
NI after 2-doses of Ad26.COV2.S 2.5x1010 vp 
vs 1 dose of Ad26.COV2.S 5x1010 vp (release 
titer) 
 
NI after 2-doses of Ad26.COV2.S 2.5x1010 vp
vs 2-doses of Ad26.COV2.S 5x1010 vp
(release titer)
 
NI after 2-doses of Ad26.COV2.S 7x1010 vp
vs 1 dose of Ad26.COV2.S 5x1010 vp (release
titer)
 
NI after 2-doses of Ad26.COV2.S 7x1010 vp
vs 2-doses of Ad26.COV2.S 5x1010 vp
(release titer)
 
NI after 2-doses of Ad26.COV2.S 3.5x1010 vp
vs 1 dose of Ad26.COV2.S 5x1010 vp (release
titer)
 
NI after 2-doses of Ad26.COV2.S 3.5x1010 vp
vs 2-doses of Ad26.COV2.S 5x1010 vp
(release titer)
 
NI after 2-doses of Ad26.COV2.S 1.25x1010
vp vs 1-dose of Ad26.COV2.S 5x1010 vp
(release titer)
 
NI after 2-doses of Ad26.COV2.S 1.25x1010
vp vs 2-doses of Ad26.COV2.S 5x1010 vp
(release titer)
 
Binding 
antibody 
concentrations 
to
SARS-CoV-2 S protein as measured by
ELISA 14 days after vaccination 2
 
NI will be demonstrated in terms of humoral
immune response expressed by the GMCs of
S-ELISA, 14 days post-dose 2 (9x1010 vp,
2.5x1010 vp, 7x1010 vp, 3.5x1010 vp, or
1.25x1010 vp) and 28 days post-dose 1 or 14
days post-dose 2 (5x1010 vp), using a NI
margin of 2/3 for the GMC ratio (GMC
[9x1010 vp, 2.5x1010, 7x1010 vp, 3.5x1010 vp,
or 1.25x1010 vp)/GMC 5x1010 vp)
Secondary
To assess the humoral immune response and 
durability to Ad26.COV2.S across all groups, at 
all blood collection timepoints. 
 
Serological response to vaccination and
binding antibody GMCs to SARS.COV-2 S
protein as measured by ELISA, or equivalent
assay
To assess the safety and reactogenicity of 
Ad26.COV2.S administered at several dose 
levels.
 
Solicited local and systemic AEs for 7 days
after each vaccination
 
Unsolicited AEs for 28 days after each
vaccination
 
SAEs throughout the study (from first
vaccination until end of the study)
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
47
Status: Approved,  Date: 16 September 2022
Objectives 
Endpoints
 
Adverse events of special interest (AESIs
[from first vaccination until end of the study])
 
MAAEs (until 6 months post-dose 2)
 
AEs leading to study discontinuation (during
the entire study) for all participants following
vaccination
Exploratory
To further explore humoral immune responses to
Ad26.COV2.S across all groups at all or selected
blood collection timepoints.
Exploratory analyses may include the following:
 
SARS-CoV-2 neutralization as assessed by
SARS-CoV-2 neutralization assays VNA
(wtVNA 
and/or 
psVNA) including
neutralization of emerging SARS-CoV-2
variants
 
SARS-CoV-2 binding antibodies against
emerging SARS-CoV-2 variants as assessed
by S-ELISA or equivalent assay
 
Adenovirus neutralization
 
Functional 
and 
molecular 
antibody
characterization including Fc-mediated viral
clearance, 
avidity, 
Fc 
characteristics,
immunoglobulin (Ig) subclass and IgG
isotype
 
Analysis of circulating Spike protein
 
Epitope-specificity 
characterization 
of
antibodies
 
Cytokine profiling: Analysis of cytokines,
chemokines, and other proteins of the innate
or adaptive immune response in the serum or
plasma
 
Passive transfer: Analysis of immune
mediators correlating with protection against
experimental SARS-CoV-2 challenge in a
suitable animal model
To assess the correlation between the binding
antibody (ELISA) titers and neutralizing antibody
(VNA) titers to SARS-CoV-2, in a subset of
participants at selected timepoints.
 
Correlation between ELISA (S-ELISA;
EU/mL) and VNA (wild-type virus [wt]VNA
and/or pseudovirion [ps]VNA) titers at
selected timepoints
To assess for the occurrence of asymptomatic
SARS-CoV-2 infection.
 
The number of participants with positive non-
S protein ELISA  or equivalent assay  (eg,
nucleocapsid [N] protein ELISA)
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
48
Status: Approved,  Date: 16 September 2022
Objectives 
Endpoints
To examine the immune response in vaccinated 
individuals with prior or breakthrough infection. 
 
SARS-CoV-2 neutralizing titers in serum
measured by a VNA (wild-type virus and/or
pseudovirion expressing S protein)
 
SARS-CoV-2-binding antibodies measured
by ELISA: Analysis of antibodies binding to
the SARS-CoV-2 S protein
To assess hematology laboratory parameters
before and after Ad26.COV2.S administration.
 
Including but not limited to: Lupus
anticoagulants, anti-β2 glycoprotein, anti-
cardiolipin, D-dimers, and anti-PF4
GMC=geometric mean concentration
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
49
Status: Approved,  Date: 16 September 2022
OBJECTIVES AND ENDPOINTS FOR PARTICIPANTS IN THE SUB STUDY
Objectives 
Endpoints
Secondary
To assess the humoral immune response and 
durability to Ad26.COV2.S across all groups in 
the sub study, at all blood collection timepoints. 
 
Serological response to vaccination and
binding antibody GMCs to SARS.COV-2 S
protein as measured by ELISA, or equivalent
assay
To assess the safety and reactogenicity of 
Ad26.COV2.S administered at several dose 
levels.
 
Solicited local and systemic AEs for 7 days
after each vaccination
 
Unsolicited AEs for 28 days after each
vaccination
 
SAEs throughout the study (from first
vaccination until end of the study)
 
Adverse events of special interest (AESIs
[from first vaccination until end of the study])
 
MAAEs (until 6 months post-dose 2)
Exploratory
To further explore humoral immune responses to
Ad26.COV2.S across all groups in the sub study
at all or selected blood collection timepoints.
Exploratory analyses may include the following:
 
SARS-CoV-2 neutralization as assessed by
SARS-CoV-2 neutralization assays VNA
(wtVNA 
and/or 
psVNA) including
neutralization of emerging SARS-CoV-2
variants
 
SARS-CoV-2 binding antibodies against
emerging SARS-CoV-2 variants as assessed
by S-ELISA or equivalent assay
 
Adenovirus neutralization
 
Functional 
and 
molecular 
antibody
characterization including Fc-mediated viral
clearance, 
avidity, 
Fc 
characteristics,
immunoglobulin (Ig) subclass and IgG
isotype
 
Analysis of circulating Spike protein
 
Epitope-specificity 
characterization 
of
antibodies
 
Cytokine profiling: Analysis of cytokines,
chemokines, and other proteins of the innate
or adaptive immune response in the serum or
plasma
To assess the correlation between the binding
antibody (ELISA) titers and neutralizing antibody
(VNA) titers to SARS-CoV-2, in a subset of
participants at selected timepoints.
 
Correlation between ELISA (S-ELISA;
EU/mL) and VNA (wild-type virus [wt]VNA
and/or pseudovirion [ps]VNA) titers at
selected timepoints
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
50
Status: Approved,  Date: 16 September 2022
Objectives 
Endpoints
To assess for the occurrence of asymptomatic 
SARS-CoV-2 infection. 
 
The number of participants with positive non-
S protein ELISA  or equivalent assay  (eg,
nucleocapsid [N] protein ELISA)
To examine the immune response in vaccinated 
individuals with prior or breakthrough infection 
 
SARS-CoV-2 neutralizing titers in serum
measured by a VNA (wild-type virus and/or
pseudovirion expressing S protein)
 
SARS-CoV-2-binding antibodies measured
by ELISA: Analysis of antibodies binding to
the SARS-CoV-2 S protein
To evaluate the innate, pro-inflammatory and
other potentially relevant responses to
Ad26.COV2.S vaccination at selected timepoints.
 
Analysis of messenger ribonucleic acid
(mRNA) expression levels of vaccine-induced
innate responses including inflammatory and
coagulation-related mediators
 
Analysis of cytokines, chemokines, and other
protein- or lipid mediators of the innate
immune response.
To assess hematology laboratory parameters
before and after Ad26.COV2.S administration.
 
Including but not limited to: Lupus
anticoagulants, anti-β2 glycoprotein, anti-
cardiolipin, D-dimers, and anti-PF4
Ad26=adenovirus 26; GMC=geometric mean concentration
If a correlate or threshold for protection against COVID-19 is established in terms of humoral
immunity, then a statistical comparison to that correlate or threshold will substitute non-inferiority
testing to immune responses to vaccine at release, as outlined in a revised analytical plan.
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESES
Formal non-inferiority (NI) testing will be applied to demonstrate NI of 1-dose and 2-doses of
9×1010 vp, 2.5x1010 vp , 7×1010 vp, 3.5x1010 vp, and 1.25x1010 vp Ad26.COV2.S versus 1-dose
and 2-doses of 5x1010 vp Ad26.COV2.S (release titer), using a NI margin of 2/3 for the GMC
ratios (see Section 9.1).
The 2.5x1010 vp dose will be tested before the 7x1010 vp in the sequential testing due to an
increased risk to fail non-inferiority as a consequence of a smaller sample size in the 7x1010 vp
group.
4. 
STUDY DESIGN
4.1. 
Overall Design
Main Study
This is a randomized, double-blind Phase 3 study to evaluate 6 dose levels of Ad26.COV2.S
administered as a 2-dose schedule in healthy adults. In this main study, the safety, reactogenicity,
NCT04908722

NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
52
Status: Approved,  Date: 16 September 2022
Table 3: 
Humoral Immunity Blood Sampling Schedule in Participants in All Groups of the Main and
Sub Study
Month 1 
Month 2 
Month 3 
Month 6*
Groups** 
Day 1 
Day 29 
Day 57 
Day 71
1 6 
 
 
 
 

*post last vaccination
**Groups 1, 3, 5 and 6 in the sub study
Table 4: 
SARS-CoV-2 Non-S Serology Schedule in Participants in All Groups of the Main and Sub Study
Month 1 
Month 2 
Month 3 
Month 6*
Groups** 
Day 1 
Day 29 
Day 57 
Day 71
1 6 
 
 

*post last vaccination
** Groups 1, 3, 5 and 6 in the sub study
Table 5: 
Serum Sampling and PaxGene Schedule for Innate MoA in Participants in Groups 1, 3, 5 and 6
of the Sub Study
Groups 
Day 1* 
Day 2 
Day 4 
Day 8 
Day 57* 
Day 58 
Day 60 
Day 64
1, 3, 5 and
6
 
 
 
 
 
 
 

*pre vaccination
MoA=mechanism of Action
An  IDMC has been commissioned for the Ad26.COV2.S program. Any significant safety
information will be shared with the IDMC. Refer to Committees Structure in Section 10.3, for
details.
A diagram of the study design is provided in Section 1.2, Schema.
Study Duration
The study duration from screening until the last follow-up visit will be at least 8 months per
participant. The study will consist of a 28-day screening phase with vaccinations on Day 1 and
Day 57, and a follow-up of at least 6 months after the last vaccination.
The vaccination phase consists of the administration of 1-dose of Ad26.COV2.S on Day 1 and
1-dose of Ad26.COV2.S on Day 57. A follow-up of at least 6 months after vaccination 2, is
foreseen.
If a participant is unable to complete the study(post vaccination 1), but has not withdrawn consent,
an early exit visit will be conducted, or the participant can continue with other study procedures.
The end of study is considered as the last visit for the last participant in the study.
Study Procedures
For each group, safety will be assessed by collection of solicited local (at injection site) and
systemic AEs, unsolicited AEs, MAAEs, AESIs, and SAEs. Other safety assessments include vital
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
53
Status: Approved,  Date: 16 September 2022
signs measurements (heart rate, supine systolic and diastolic blood pressure, respiratory rate, and
body temperature) and physical examinations at the time points indicated in Section 1.4.
After each vaccination, participants will remain under observation at the study site for at least
15 minutes for presence of any acute reactions and solicited events. Any solicited local or systemic
AEs, unsolicited AEs, MAAEs, AESIs, SAEs, concomitant medications, and vital signs will be
documented by study-site personnel following this observation period. In addition, participants
will record solicited signs and symptoms in a diary for 7 days post vaccination.
The reporting periods of AEs, MAAEs, AESIs, and SAEs, and special reporting situations are
detailed in Section 8.3. Reporting periods for concomitant therapy are outlined in Section 6.8. At
each visit the participant will be asked if they have had a private/off-study COVID-19 test. If a
participant receives a positive SARS-CoV-2 result from a private/off-study test (whether through
PCR or serological testing)
 the participant can continue in the study for safety follow-up if they choose to:
o This should be in accordance with local country and site level recommendations,
including requirements for quarantine
o They will not be permitted to receive further study vaccination administrations
o The study staff will recommend the participant informs their medical care
provider.
o If there are no local country recommendations for COVID-19, the sponsor
recommends the participant self-quarantines and does not come for a clinic visit
until 2 consecutive negative PCR tests could be obtained.
In case the participant experiences signs or symptoms of COVID-19 after obtaining a positive
SARS-CoV-2 test result, they should contact the study site at the time of symptom onset for
recommendations on actions to follow for further care per local guidance.
See Section 8.3.1 on the reporting periods of this event.
A final safety follow-up visit is foreseen at least 6 months after the last vaccination for all
participants.
From all participants, blood samples will be collected at selected timepoints indicated in
Section 1.4, Schedule of Activities for humoral immunogenicity assessments, with an emphasis
on neutralizing and binding antibody responses. Further details about the immunogenicity
assessments are provided in Section 8.1.
An independent IDMC has been  installed for the different studies throughout the COVID-19
vaccine program. Refer to Section 10.3.6 for details.
The planned primary and final analyses are detailed in Section 9.5.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
54
Status: Approved,  Date: 16 September 2022
A diagram of the study design is provided in Section 1.2.
4.2. 
Scientific Rationale for Study Design
Dose Level Selection
The rationale behind the selection of the dose level of the release titer (5x1010 vp) is described in
Section 4.3.
Blinding, Control, Study Phase/Periods, Vaccine Groups
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
by 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. The sponsor may be unblinded for this study.
Rationale for the Sub Study
The mechanism for the rare thrombosis with thrombocytopenia syndrome (TTS) events that have
been reported after vaccination with Johnson & Johnson’s Ad26.COV2.S vaccine is not known.
Examining gene expression in blood cells may inform on the inflammation signals and pro-
thrombotic signaling pathways triggered by Ad26.COV2.S that can predispose for TTS. Gene
expression profiles will be generated from blood obtained from clinical trials to provide insights
into putative signaling pathways that may predispose for TTS and that are triggered by
Ad26.COV2.S. Whole blood RNA will be sampled on early timepoints after vaccination with
Ad26.COV2.S at different dose levels, examining if the innate gene expression patterns are dose
dependent. In addition, serum samples collected at early timepoints can inform on systemic
cytokines and chemokines and lipid mediators of innate activation to complement the
transcriptome analysis. To further characterize the innate, pro-inflammatory and other relevant
(eg, pro-thrombotic) responses to Ad26.COV2.S to better understand a possible risk to TTS events,
an additional sub study consisting of a target of approximately 40 seronegative and 20 seropositive
participants to Groups 1, 3, 5 and 6 has been added to the study. This sub study will obtain blood
samples at additional timepoints for additional analyses of transcriptome and serum innate
responses as outlined above to further explore the mechanism of these TTS events.
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
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
55
Status: Approved,  Date: 16 September 2022
withdrawn at any time with no reason given and without penalty or loss of benefits to which they
would otherwise be entitled. Potential 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 benefit from participation in the study, except for compensation for the time and
inconveniences that may arise from participation in the study. See Section 2.3, Benefit-Risk
Assessment for details on potential and known benefits and risks, and for the safety measures taken
to minimize risk to participants.
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 up 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 (US FDA 1998,
US DHHS 1998), and as wellas the European Commission guidelines of 500 mL per donation and
3 L per consecutive 12 month period (EC 1998).
4.3. 
Justification for Dose
The release titer of Ad26.COV2.S 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). 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 2.2.
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 is safe. The sponsor
has therefore decided to proceed with a 5×1010 vp as the release titer dose in this Phase 3 study.
The additional dose levels of 9×1010 vp, 7×1010 vp, 3.5×1010 vp, 2.5×1010 vp and 1.25×1010 vp
were chosen to be evaluated based on data from the COV2001 study. The lower dose (3.5 x1010
vp, 2.5x1010 vp, and 1.25x1010 vp) levels mimic vaccine degradation to enable determination of
product expiry. In order to increase the end of shelf-life specifications a potential target release
titer of 7x1010 vpwill be evaluated. A higher titer of 9x1010 vp will also be evaluated as is the upper
limit of the release range (potential maximum vp at release). The present study incorporates a
2-dose regimen, as this dosing schedule is also being evaluated by the sponsor across clinical trials.
While a 1-dose regimen demonstrated efficacy and safety for emergency use in a pandemic setting,
the long-time efficacy and safety are still being evaluated. The duration of immunity of 2-doses
may be preferable post-acute pandemic setting.
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
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
56
Status: Approved,  Date: 16 September 2022
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.
4.4. 
End of Study Definition
End of Study Definition
The end of study is considered as 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.
Study Completion Definition
A participant will be considered to have completed the study if he or she has completed
assessments at the 6-month  follow-up visit post-dose 2 vaccination for their respective study
group.
Participants who prematurely discontinue study vaccination for any reason before the second
vaccination will not be considered to have completed the study.
5. 
STUDY POPULATION
Screening for eligible participants will be performed within 28 days before administration of the
study vaccine. Refer to Section 5.4, Screen Failures 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. 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.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening.
If a participant’s clinical status changes (including any available laboratory results or receipt of
additional medical records) after screening but before the first dose of study vaccination is given
such that he or she no longer meets all eligibility criteria, then the participant should be excluded
from participation in the study (See Section 5.4, Screen Failures, describes options for retesting).
The required source documentation to support meeting the enrollment criteria is noted in
Section 10.3.1.
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. Participant must sign an ICF 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.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
57
Status: Approved,  Date: 16 September 2022
2. Participant is willing and able to adhere to the prohibitions and restrictions specified in this
protocol.
3. Participant is 18 to 55 years of age, inclusive, on the day of signing the ICF.
4. Criterion modified per Amendment 1:
4.1 
Participant must have a BMI <35.0 kg/m2.
5. Criterion modified per Amendment 1:
5.1 Participant must be healthy, in the investigator’s clinical judgment, as confirmed by medical
history, physical examination, and vital signs performed at screening. Participant may have
underlying illnesses, as long as the symptoms and signs are medically controlled and not
considered to be comorbidities related to an increased risk of severe COVID-19a, except for
smoking, which is allowed (see also exclusion criterion 21). If on medication for a condition,
the medication dose must have been stable for at least 12 weeks preceding vaccination and
expected to remain stable for the duration of the study. Participant will be included on the
basis of physical examination, medical history, and vital signsb.
6. Criterion modified per Amendment 1:
6.1 Contraceptive (birth control) use should be consistent with local regulations regarding the
acceptable methods of contraceptionc for those participating in clinical studies.
Before randomization, participants must be either (as defined in Section 10.5):
a. Not of childbearing potential
b. Of childbearing potential and practicing a highly effective method of contraception
and agrees to remain on such a method of contraception from signing the consent until
3 months after the last dose of study vaccine. Use of hormonal contraception should
start at least 28 days before the 1st administration of study vaccine. The investigator
should evaluate the potential for contraceptive method failure (eg, noncompliance,
recently initiated) in relationship to the 1st vaccination. Highly 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)
a Participants may have hypertension of mild severity, as long as it is stable and medically controlled as defined by no change in
medication over the past 6 months (except for issues of tolerability or use of similar drug with same mechanism of action, eg,
thiazides, Beta blockers, Alpha blockers at the same effective dose).
b Participants can be enrolled with Grade 1 or Grade 2 values for vital signs measurements.
c Use of condoms is not considered as an acceptable contraceptive barrier method due to the failure rate of female and male condoms
(CDC 2021).
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
58
Status: Approved,  Date: 16 September 2022
2. intrauterine device;
3. intrauterine hormone-releasing system;
4. bilateral tubal occlusion/ligation procedure;
5. vasectomized partner (the vasectomized partner should be the sole partner for
that participant);
6. sexual abstinence*.
*Sexual abstinence is considered an effective method only if defined as refraining from
heterosexual intercourse from signing the consent until 3 months after the last dose of study
vaccine. The reliability of sexual abstinence needs to be evaluated in relation to the duration of
the study and the preferred and usual lifestyle of the participant.
7. Criterion modified per Amendment 1:
7.1 All female 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 immediately on the day of and prior
to each study vaccine administration.
8. Participant agrees to not donate bone marrow, blood, and blood products from the first study
vaccine administration until 3 months after receiving the last dose of study vaccine.
9. Participant must be willing to provide verifiable identification, has means to be contacted and
to contact the investigator during the study.
5.2. 
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 first dose of study vaccine; randomization at a later date is
permitted at the discretion of the investigator and after consultation with the sponsor.
2. Participant has a history of malignancy within 5 years before screening (exceptions are
squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or
malignancy, which is considered cured with minimal risk of recurrence).
3. 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 IB).
4. Criterion modified per Amendment 1
4.1 
Participant has abnormal function of the immune system resulting from:
a. Clinical conditions (eg, autoimmune disease, potential immune mediated disease or
known or suspected immunodeficiency, chronic kidney disease [with dialysis])
expected to have an impact on the immune response of the study vaccine. Participants
with clinical conditions stable under non-immunomodulator treatment eg, autoimmune
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
59
Status: Approved,  Date: 16 September 2022
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 substantial
immunosuppressive steroid dose is considered to be >2 weeks of daily receipt of
20 mg 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.
5. Participant has a history of any neurological disorders or seizures including Guillain-Barré
syndrome, with the exception of febrile seizures during childhood.
6. Participant has a history of chronic urticaria (recurrent hives), eczema or adult atopic
dermatitis.
7. Criterion modified per Amendment 1
7.1 Participant received treatment with immunoglobulins in the 3 months or exogenous blood
products (autologous blood transfusions are not exclusionary) in the 4 months before the
planned administration of the first dose of study vaccine or has any plans to receive such
treatment during the study.
8. Participant received or plans to receive:
a. Licensed live attenuated vaccines
within 28 days before or after planned administration
of the first or subsequent study vaccinations
b. Other licensed (not live) vaccines within 14 days before or after planned administration
of the first or subsequent study vaccinations.
9. Criterion modified by Amendment 1
9.1 Participant received an investigational drug (including investigational drugs for
prophylaxis of COVID-19) 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 within 6 months before the planned administration of the first
dose of study vaccine or is currently enrolled or plans to participate in another
investigational study during the course of this study.
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 19) and during the
studyexcept under the conditions described in Section 6.6  .
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
60
Status: Approved,  Date: 16 September 2022
10. Participant is a woman who is pregnant or planning to become pregnant within 3 months after
the last dose of study vaccine.
11. 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.
12. 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 the last dose of study vaccine administration.
13. Participant has a contraindication to IM injections and blood draws eg, bleeding disorders.
14. Criterion reintroduced per Amendment 2.
14.1 Participant is an employee of the investigator or study site, with direct involvement in
the proposed study or other studies under the direction of that investigator or study site,
as well as family members of the employees or the investigator, or an employee of the
sponsor.
15. Participant has chronic active hepatitis B or hepatitis C infection per medical history.
16. Participant has had major psychiatric illness or drug or alcohol abuse which in the
investigator’s opinion would compromise the participant’s safety or compliance with the
study procedures.
17. Participant cannot communicate reliably with the investigator.
18. 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.
19. Participant previously received a coronavirus vaccine.
20. Criterion modified by Amendment 4
20.1 Criterion modified by Amendment 6
20.2 Participant has a positive diagnostic test result for past (serological testing) or current
(PCR based viral RNA detection) SARS-CoV-2 infection at screening in the main
study.
Note: For participants in the sub study, a positive diagnostic test for past SARS-CoV-2 testing
(serological testing) does not exclude the participant from the study as a target of
approximately 40 seronegative and 20 seropositive participants per group (Group 1, 3, 5 and
6) will be enrolled in the sub study. Seropositive participants are not excluded up to the point
when 20 seropositive participants are recruited only.
21. Criterion modified by Amendment 1
21.1 Participants with comorbidities that are or might be associated with an increased risk
of progression to severe COVID-19, ie, participants with moderate-to-severe asthma;
chronic lung diseases such as 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
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
61
Status: Approved,  Date: 16 September 2022
heart disease, cardiomyopathies, and (pulmonary) hypertension or high blood pressure;
obesity (BMI ≥35 kg/m2); chronic liver disease, including cirrhosis; sickle cell disease;
thalassemia; cerebrovascular disease; neurologic conditions (dementia); end stage renal
disease; organ transplantation; cancer; and other immunodeficiencies; hepatitis B
infection; and sleep apnea, and participants who live in nursing homes or long-term
care facilities. This list is consistent with the list of conditions that increase the risk of
progression to severe COVID-19 available at the CDC website at the time of writing
of this protocol (CDC 2020c), except forsmoking, which is allowed. The data from the
CDC website is summarized in Section 10.7. Participants may have hypertension of
mild severity, as long as it is stable and medically controlled as defined by no change
in medication over the past 6 months (except for issues of tolerability or use of similar
drug with same mechanism of action, eg, thiazides, Beta blockers, Alpha blockers at
the same effective dose).
22. Participant who is currently working in an occupation with a high risk of exposure to
SARSCoV-2 infection (eg, health care worker or emergency response personnel who work in
close contact with SARSCoV-2 infected patients) or considered at the investigator’s discretion
to be at increased risk to acquire COVID-19 for any other reason.
23. Participant who has had a known exposure to an individual with confirmed COVID-19 or
SARS-CoV-2 infection within 2 weeks of screening.
24. History of confirmed SARS or MERS.
25. Criterion added per Amendment 3
25.1 History of capillary leak syndrome
26. Criterion added per Amendment 6
26.1 History of TTS or heparin-induced thrombocytopenia and thrombosis (HITT)
5.3. 
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions
during the course of the study to be eligible for participation:
1. 
Refer to Section  6.8, Concomitant Therapy  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).
5.4. 
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy
identification of each participant during and after the study. This document will be reviewed by
the sponsor study site contact for completeness.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
62
Status: Approved,  Date: 16 September 2022
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.
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened once only. Participants who are rescreened will be assigned a new participant number,
undergo the ICF process again, and then restart a new screening phase.
5.5. 
Criteria for Temporarily Delaying Administration of Study Vaccine
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) within 24 hours prior to the planned time of vaccination.
If any of these events occur at the scheduled time for the first vaccination, randomization at a later
date within the screening window is permitted at the discretion of the investigator and after
consultation with the sponsor. If randomization cannot occur within the screening window,
rescreening is required. If any of these events occur at the scheduled time for one of the subsequent
vaccinations, the vaccination can be rescheduled, as long as this is in agreement with the allowed
windows (see Visit Windows in Section 1.4.1, Schedule of Activities).
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.
6. 
STUDY VACCINATION AND CONCOMITANT THERAPY
6.1. 
Study Vaccines Administered
Ad26.COV2.S will be supplied at a concentration of 2x1011  vp/mL as a suspension in single-use
vials, with an extractable volume of 0.5 mL. Formulation buffer of Ad26.COV2.S will be supplied
as diluent containing 15 mM citrate, 5% (w/w) hydroxypropyl-β-cyclodextrin, 0.4% (w/w)
ethanol, 0.03% (w/w) polysorbate 80, 75 mM NaCl, pH 6.2.
Participants will be vaccinated on Day 1 and Day 57.
A volume of 0.5 mL will be administered to all participants.
9x1010 vp dose level (Group 1):
 0.5 mL is withdrawn from vial 1 containing 0.75 mL 2x1011 vp/mL and added to vial 2
containing 0.75 mL of 2x1011 vp/mL. 0.15 mL is withdrawn from a vial containing 1.2 mL
formulation buffer and is added to vial 2 containing 1.25 mL 2x1011 vp/mL. The solution is mixed
and 0.5 mL is withdrawn from vial 2 (Ad26.COV2.S vial) for dosing 9x1010 vp.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
63
Status: Approved,  Date: 16 September 2022
7x1010 vp dose level (Group 2):
 0.3 mL is withdrawn from a vial containing 1.2 mL formulation buffer and added to a vial
containing 0.75 mL 2x1011 vp/mL. The solution is mixed and 0.5 mL is withdrawn from the
Ad26.COV2.S vial for dosing 7x1010 vp.
5x1010 vp dose level (Group 3):
 0.75 mL of formulation buffer is added to a vial containing 0.75 mL 2x1011 vp/mL, providing
1x1011 vp/mL in a vial with an extractable volume of more than 1 mL. Then 0.5 mL will be
withdrawn from this vial for dosing 5x1010 vp.
3.5x1010 vp dose level (Group 4):
 0.5 mL is withdrawn from vial 1 (Ad26.COV2.S vial) containing 0.75 mL 2x1011 vp/mL and
added to a vial containing 1.2 mL formulation buffer, leading to solution A. 0.15 mL is
withdrawn from vial 2 (Ad26.COV2.S vial) containing 0.75 mL 2x1011 vp/mL and added to
solution A, leading to solution B. Solution B is mixed and 0.5mL withdrawn from solution B for
dosing 3.5x1010 vp.
2.5x1010 vp dose level (Group 5):
 0.4 mL is withdrawn from a vial containing 0.75 mL 2x1011 vp/mL and added to a vial
containing 1.2 mL formulation buffer. The solution is mixed and 0.5mL is withdrawn from
the formulation buffer vial for dosing 2.5x1010 vp.
1.25x1010 vp dose level (Group 6):
 Withdrawal 0.9 mL from a vial containing 1.2 mL formulation buffer and add it to vial 2
containing 1.2 mL formulation buffer. Withdrawal 0.3 mL from a vial containing 0.75 mL
2x1011 vp/mL and add to vial 2 with formulation buffer. The solution is mixed, and 0.5 mL is
withdrawn from the formulation buffer vial 2 for dosing 1.25x1010 vp.
Study vaccine will be administered by IM injection into the deltoid muscle, preferably of the non-
dominant arm. Subsequent vaccinations are preferably administered in the opposite arm. If an
injection cannot be given in the deltoid muscle 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. If alternative locations are used for vaccine
administration, these locations should consistently be used for later vaccinations. In all
circumstances, IM injections in other locations than the upper arm are not considered protocol
deviations.
For information on vaccination windows, see Section  1.4.1 (for the sub study), Schedule of
Activities. If a participant cannot be vaccinated within the allowed window (eg, if the window is
missed due to a study pause [see Section 6.9 Study Pausing Rules]), the decision regarding
vaccination  will be assessed on a case-by-case basis, upon discussion between sponsor and
investigator.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
64
Status: Approved,  Date: 16 September 2022
Study vaccine administration must be captured in the source documents and the electronic case
report form (eCRF).
Ad26.COV2.S will be manufactured and provided under the responsibility of the sponsor. Refer
to the IB for a list of excipients (IB Ad26.COV2.S. 2022).
Refer to the study site investigational product and procedures manual (SIPPM) for additional
guidance on study vaccine administration.
6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study vaccine must be stored in a secured location with no access for unauthorized personnel
and at controlled temperatures as indicated on the clinical labels. If study vaccine is exposed to
temperatures outside the specified temperature range, all relevant data will be sent to the sponsor
to determine if the affected supplies can be used or will be replaced. The affected study vaccine
must be quarantined and not used until further instruction from the sponsor is received.
Refer to the SIPPM for additional guidance on study vaccine preparation, handling, and storage.
An unblinded study site pharmacist, or other qualified individual, who will have no other study
function, will prepare the appropriate vials and syringes, labeled with the participant’s identification
number, and provide the syringes for the study vaccine in a blinded manner to the blinded vaccine
administrator (a trained and qualified study nurse, medical doctor, otherwise qualified health care
professional [HCP])who will perform the injection.
Accountability
The investigator is responsible for ensuring that all studyvaccine 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
study 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.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
65
Status: Approved,  Date: 16 September 2022
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 supplied 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.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Vaccine Allocation
Procedures for Randomization
Central randomization will be implemented in this study. Participants will be randomly assigned
to 1 of 6 groups 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. The interactive web response system (IWRS) will assign a unique intervention
code, which will dictate the intervention assignment and matching study intervention kit 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.
If, due to the urgency of study initiation during the ongoing pandemic, the IWRS is not yet
available at the planned time of randomization of the first participant, randomization may be
started based on a paper randomization list until the IWRS is live. In the event that randomization
is started based on a paper randomization list, sealed randomization codes will be provided for
each participant containing coded details of study vaccine allocation. All randomization codes,
whether opened or sealed, will be collected after the end of the participant’s participation in the
study.
Blinding
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 sponsor may be unblinded for this study.
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
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
66
Status: Approved,  Date: 16 September 2022
potential for bias is minimized. This can include making special provisions, such as segregating
the data in question from view by the investigators, or others as appropriate until the time of
database lock and unblinding.
Under normal circumstances, the blind should not be broken until the database is finalized for the
primary analysis. The investigator may in an emergency determine the identity of the intervention
by contacting the IWRS or by opening the sealed code (if IWRS is not available yet). While the
responsibility to break the intervention code in emergency situations resides solely with the
investigator, it is recommended that the investigator contact the sponsor or its designee, if possible,
to discuss the particular situation, before breaking the blind. Telephone contact with the sponsor
or its designee will be available 24 hours per day, 7 days per week. In the event the blind is broken,
the sponsor must be informed as soon as possible. The date, time, and reason for the unblinding
must be documented in the IWRS and in the source document.
Participants who have had their intervention assignment unblinded should continue to return for
scheduled evaluations. Participants should not be allowed to receive further study vaccinations and
are only to be followed for safety and immunogenicity evaluation visits.
In general, randomization codes will be disclosed fully only if the study is completed, and the
clinical database is closed.
If randomized participants are withdrawn from vaccination before the first dose of study vaccine
is administered, additional participants may be recruited to replace these participants at the
discretion of the sponsor. Any replacement participant will be assigned to the same group as the
original (discontinued) participant. If randomized participants are withdrawn after the first dose of
study vaccine is administered, they will not be replaced.
Investigators may receive requests to unblind study participants who become eligible to receive an
authorized/licensed COVID-19 vaccine at the efficacious dose if/when these become available,
including the sponsors. 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. The name and date(s) of administration of the other
COVID-19 vaccine should be recorded (see Section 6.8).
If the participant prefers another company’s vaccine, they will be informed that there are no data
on the safety of receiving two different COVID-19 vaccines. In the event of the participant
unblinding in order to receive an authorized/licensed COVID-19 vaccine, no further study
vaccination will be permitted. Unblinded participants will be asked to continue to be followed in
this study in line with the Schedule of Activities (SoA) to the extent that they permit. Safety 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, if
applicable and feasible. All data will be analyzed separately from the point of unblinding, for safety
and immunogenicity analysis, as described in the Statistical Analysis Plan (SAP).
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
67
Status: Approved,  Date: 16 September 2022
6.4. 
Study Vaccination Compliance
Study vaccines will be administered intramuscularly by blinded qualified study-site personnel at
the study site. Details of each administration will be recorded in the eCRF (including date and time
of injection [deltoid or alternative location]). For blinding procedures, see Section 6.3, Measures
to Minimize Bias: Randomization and Blinding.
6.5. 
Dose Modification
Dose modification is not applicable in this study.
6.6. 
Continued Access to Study Vaccine After the End of the Study
For all participants, given that approved COVID-19 vaccines exist for the adult population in all
countries in which VAC31518COV3003 is being conducted, if participants need to receive
boosters, they may be vaccinated outside of the study as a part of their national vaccination
campaign after the participants have completed their last study visit. Once primary analysis results
are available (post vaccination 2), investigators will be notified to contact participants in groups
who received a dose level of Ad26.COV2.S that did not meet non-inferiority post vaccination 2 to
advise them that they should receive a booster of a COVID-19 vaccine that is licensed/authorized
through their national COVID-19 vaccination health care program if not already received.
At the time when a COVID-19 vaccine is determined to be efficacious and authorized/licensed for
use, some participants may become eligible to receive such vaccine at the efficacious dose,
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. In the event of the participant unblinding in
order to receive an authorized/licensed COVID-19 vaccine, no further study vaccination will be
permitted. 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, if
applicable and feasible. All data will be analyzed separately from the point of unblinding for safety,
efficacy and immunogenicity (under the conditions outlined in Section 6.3), as described in the
SAP.
6.7. 
Treatment of Overdose
For this study, any dose ofAd26.COV2.S greater than the highest dose tested in the study will be
considered an overdose. The sponsor does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator or treating physician should:
 
Contact the Medical Monitor immediately.
 
Closely monitor the participant for AEs/MAAEs/AESIs/SAEs (ie, the participant will remain
at the study site for at least 15 minutes and will be closely monitored for allergic or other
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
68
Status: Approved,  Date: 16 September 2022
reaction 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 eCRF.
 
Report as a special reporting situation.
6.8. 
Prestudy and Concomitant Therapy
Prestudy specific therapies such as analgesic/antipyretic medications and non-steroidal
anti-inflammatory drugs, corticosteroids, antihistamines, and vaccinations administered up to
30 days before first dose of study vaccine must be recorded at screening.
Concomitant therapies such as analgesic/antipyretic medications and non-steroidal
anti-inflammatory drugs corticosteroids, antihistamines, and vaccinations must be recorded from
the first dose of study vaccine until 28 days after administration of study vaccine and thereafter,
pre-dose on the day of vaccination and for 28 days after each subsequent dose of study vaccine.
All other concomitant therapies should also be recorded if administered in conjunction with new
or worsening adverse events reported per protocol requirements outlined in Section 8.3.1, Time
Period and Frequency for Collecting Adverse Event and Serious Adverse Event Information.
For all participants, concomitant therapies associated with an SAE, or suspected AESI meeting the
criteria outlined in Section 10.4.1 and Section 8.3.6, respectively, will be collected and recorded
in the eCRF from the moment of vaccination 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 vaccination. 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 unsolicited AEs will be collected and
recorded in the eCRF from the time of vaccination through 28 days after 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 vaccination.
Use of any experimental medication (including experimental vaccines other than  the study
vaccine) during the study is not allowed. Any participant who has been given an anti-COVID-19
vaccine (other than study vaccine) or treatment will not receive further study vaccination.
Participants may not receive an investigational drug (including investigational drugs for
prophylaxis of COVID-19) or use an invasive investigational medical device within 30 days or
receive an investigational Ig or monoclonal antibodies within 3 months, or receive convalescent
serum for COVID-19 treatment within 4 months or receive an investigational vaccine (including
investigational Adenoviral-vectored vaccines) within 6 months before the planned administration
of the first dose of study vaccine.
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, tetanus, hepatitis A, hepatitis B, rabies)
should be given at least 14 days before or at least 14 days after administration of study vaccine in
order to avoid potential confusion of adverse reactions and potential immune interference. The use
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
69
Status: Approved,  Date: 16 September 2022
of any coronavirus vaccine (licensed or investigational) other than Ad26.COV2.S is disallowed at
any time prior to vaccination and during the study. If a vaccine is indicated in a post-exposure
setting (eg, rabies or tetanus), it must take priority over the study vaccine.
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.
Chronic or recurrent use of systemic corticosteroidsa at immunosuppressive dose and
administration of antineoplastic and immunomodulating agents or radiotherapy is prohibited
during the study and within 6 months before the planned administration of the first dose of 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, Exclusion Criteria 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.
6.9. 
Study Vaccination Pausing Rules
The occurrence of a study pause in any other ongoing study with Ad26.COV2.S may trigger a
study pause in further vaccination in the current study, if considered to be medically relevant. Any
subsequent study visits out of window during a study pause are not considered to be protocol
violations, however, the data at these timepoints may be eliminated from some statistical analyses.
7. 
DISCONTINUATION OF STUDY VACCINATION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Vaccination
Study vaccinations will be withheld for the reasons listed below. These participants must not
receive any further doses of study vaccine but should remain on study for follow-up with
assessments of safety and immunogenicity as indicated in Section 1.4.1 and Section 1.4.2 (for the
sub study), Schedule of Activities. Additional unscheduled visits may be performed for
safety/reactogenicity reasons, if needed. In case of questions, the investigator is encouraged to
contact the sponsor.
 
Any related AE, worsening of health status or intercurrent illnesses that, in the opinion of the
investigator, requires discontinuation from study vaccine
 
The participant becomes pregnant
 
Unblinding on the participant level that, in the opinion of the sponsor, would compromise the
integrity of the data
a Note: Ocular, topical or inhaled steroids are allowed.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
70
Status: Approved,  Date: 16 September 2022
 
Unblinding of a study participant in order to receive an authorized/licensed COVID-19
vaccine
 
Anaphylactic reaction following vaccination, not attributable to causes other than vaccination
 
SAE or other potentially life-threatening (Grade 4) event that is determined to be related to
study vaccine
 
Chronic or recurrent use of systemic corticosteroids at immunosuppressive dose, and
administration of antineoplastic and immunomodulating agents or radiotherapy
 
Withdrawal of consent to receive further study vaccination
 
Participant has a positive test result for SARS-CoV-2 infection during the study  after
screening and enrollment (see Section 8.3.1).
 
Participant receives any experimental medication (including experimental vaccines other than
the study vaccine) or receives an anti-COVID-19 vaccine or treatment
 
Participant previously experienced TTS, including CVST or HITT or GBS.
 
Participant experiences capillary leak syndrome after the first dose.
7.2. 
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:
 
Lost to follow-up
 
Withdrawal of consent from the study
 
Death
 
Repeated failure to comply with protocol requirements
When a participant withdraws before study  completion, the reason for withdrawal is to be
documented in the eCRF and in the source document. If the reason for withdrawal from the study
is withdrawal ofconsent, then no additional assessments are allowed, but an optional safety visit
will still be offered.
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 Section 10.3.5). 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.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
71
Status: Approved,  Date: 16 September 2022
7.3. 
Lost to Follow-up
To reduce the chances of a participant being deemed lost to follow-up, prior to randomization
attempts should be made to obtain contact information from each participant, eg, home, work, and
mobile telephone numbers and email addresses for both the participant as well as appropriate
family members.
A participant will be considered lost to follow-up if he or she repeatedly fails to return for
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed
lost to follow-up until all reasonable efforts made by the study-site personnel to contact the
participant are deemed futile. The following actions must be taken if a participant fails to return to
the study site for a required study visit:
 
The study-site personnel must attempt to contact the participant to reschedule the missed visit
as soon as possible, to counsel the participant on the importance of maintaining the assigned
visit schedule, to ascertain whether the participant wishes to or should continue in the study.
 
Before a participant is deemed lost to follow-up, the investigator or designee must make every
reasonable effort to regain contact with the participant where possible, 3 telephone calls, e-
mails, fax, and, if necessary, a certified letter to the participant’s last known mailing address,
or local equivalent methods. Locator agencies may also be used as local regulations permit.
These contact attempts should be documented in the participant’s medical records.
 
Should the participant continue to be unreachable, they will be considered to have withdrawn
from the study.
Should a study site close, eg, for operational, financial, or other reasons, and the investigator cannot
reach the participant to inform them, their contact information will be transferred to another study
site.
8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities (Section 1.4) summarizes the frequency and timing of safety,
reactogenicity, immunogenicity, and other measurements applicable to this study. All participants
in the study will be counselled on COVID-19 prevention each time that they have a contact with
study site staff in line with local 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 at another day within the applicable visit window. Actual dates and times of
assessments will be recorded in the source document and in the eCRF.
Participants will be provided a thermometer (to measure body temperature), ruler (to measure local
injection site reactions), and participant diary to record body temperature and solicited local (at
injection site) and systemic signs and symptoms. The diary includes instructions on how to capture
the data and grading scales to assess severity of the signs and symptoms post vaccination
(reactogenicity). The study staff is responsible for providing appropriate training to the participant
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
72
Status: Approved,  Date: 16 September 2022
to avoid missing or incorrect data. The diary will be reviewed by the study personnel at visits
indicated in Section 1.4, Schedule of Activities. If the diary review is missed, the diary will be
reviewed during the following visit. If a participant misses a vaccination, the diary covering the
period after the missed vaccination does not have to be completed.
The total blood volume to be collected from each participant over the course of the main study will
be approximately 119 mL. The total blood volume to be collected from each participant over the
course of the sub study will be approximately 163 mL. Repeat or unscheduled samples may be
taken for safety reasons or for technical issues with the samples. For participants who experience
a suspected AESI, an additional 30 mL of blood will be collected.
At each visit the participant will be asked if they have had a private/off-study COVID-19 test. If a
participant receives a positive SARS-CoV-2 result from a private/off-study test (whether through
PCR or serological testing), the participant should contact the study site at the time the positive
SARS-CoV-2 test result is obtained. The participant can continue in the study for safety follow-
up if they choose to; however, this must be in accordance with local country and site level
recommendations for COVID-19, including requirements for quarantine. These participants will
not be permitted to receive further study vaccination administrations. The study staff will
recommend the participant informs their medical care provider. If there are no local country
recommendations for COVID-19, the sponsor recommends the participant self-quarantines and
does not come for a clinic visit until 2 consecutive negative PCR tests could be obtained. If the
participant experiences signs or symptoms of COVID-19 after obtaining a positive SARS-CoV-2
test result, they should contact the study site at the time of symptom onset for recommendations
on actions to follow for further care. See section 8.3.1 on the reporting periods of this event.
Visit Windows
Visit windows are provided in  Section 1.4, Schedules of Activities. The participant should be
encouraged to come on the exact day planned and use the visit window only if absolutely
necessary.
The timings of the post vaccination visits will be determined relative to the actual day of the
corresponding vaccination.
If a vaccination window is missed due to a study pause (see Section 6.9), efforts will be made to
still vaccinate the participant as soon as possible, even if out of window. The timings of the post
vaccination visits will be determined relative to the actual day of the vaccination, unless they
overlap with other scheduled visits, in which case the sponsor should be contacted to discuss
optimal scheduling for these visits. If the participant does not want to receive the second
vaccination, they can still continue with other study procedures.
Screening
Screening will be performed within 28 days prior to the first study vaccination or on the day of
vaccination. If screening is performed on the day of vaccination, Visit 1 and Visit 2 will coincide
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
73
Status: Approved,  Date: 16 September 2022
on Day 1. Screening must be completed and all eligibility criteria must be fulfilled prior to
randomization and vaccination.
Screening may be conducted in part via a sponsor- and IRB/IEC-pre-approved non-study-specific
screening consent process, but only if the relevant pre-screening tests are identical to the per
protocol screening tests and are within 4 weeks prior to first 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. Participants who test positive will be
informed of the result by the study staff. The study-specific ICF date will be entered into the eCRF.
The non-study-specific ICF will be considered source data.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory
requisition form. Refer to Section 1.4, Schedule 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)
 
Pharmacy manual/SIPPM/IPPI
 
Laboratory manual and laboratory supplies
 
eCOA Manual
 
IWRS Manual
 
eCRF completion guidelines
 
Sample ICF
 
Participant Diaries
 
Contact information pages
8.1. 
Immunogenicity Assessments
No generally accepted immunological correlate of protection has been demonstrated for
SARS-CoV-2 to date. If a correlate or threshold for protection against COVID-19 is established in
terms of humoral immunity, then a statistical comparison to that correlate or threshold will
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
74
Status: Approved,  Date: 16 September 2022
substitute non-inferiority testing to immune responses to vaccine at release, as outlined in a revised
analytical plan.
Venous blood samples will be collected for assessment of humoral immune responses in all
participants. Sample volumes and time points are detailed in the Schedule of Activities in
Section 1.4.
If the participant is unable to complete the study without withdrawing consent, immunogenicity
samples will be taken at the early exit visit, but only if the early exit visit is at least 10 days after
the previous immunology blood draw. See Section 1.4, Schedule of Activities for further details.
Humoral immunogenicity assays may include, but are not limited to, the assays summarized in
Table 6.
Table 6: 
Summary of Humoral Immunogenicity Assaysa
Assay 
Purpose
Humoral Immunogenicity
Primary/Secondary/Exploratory
endpoints
SARS-CoV-2 binding antibodies 
(ELISA) 
Analysis of antibodies binding to SARS-CoV-2 or individual SARS-CoV-2
proteins (eg, S protein)
Exploratory endpoints
SARS-CoV-2 neutralization
(VNA)
Analysis of neutralizing antibodies to the wild-type virus and/or
pseudovirion expressing S protein, including emerging SARS-CoV-2
variants.
SARS-CoV-2 binding antibodies 
(ELISA or equivalent assay) 
Analysis of binding antibodies to SARS-CoV-2 proteins (eg, S-protein),
including emerging SARS-CoV-2 variant proteins.
SARS-CoV-2 binding antibodies 
(non-S ELISA and/or SARS-CoV-
2 immunoglobulin assay)
Analysis of antibodies binding to the SARS-CoV-2 N protein
Adenovirus neutralization 
Adenovirus neutralization assay to evaluate neutralizing antibody responses
against the Ad26 vector
Functional and molecular antibody 
characterization  
Analysis of antibody characteristics including Fc-mediated viral clearance,
avidity, Fc characteristics, Ig subclass and IgG isotype
Epitope-specificity 
characterization
Analysis of site-specificity, epitope mapping
Cytokine profiling, and analysis of 
circulating Spike protein  
Analysis of cytokines, chemokines, and other proteins of the innate or
adaptive immune response in the serum or plasma, and analysis of
circulating Spike protein.
Passive transfer 
Analysis of immune mediators correlating with protection against
experimental SARS-CoV-2 challenge in a suitable animal model
Innate Assessments (Exploratory endpoints)
Gene expression analysis 
Analysis of gene expression by RNA transcript profiling in whole blood (ex
vivo, PaxGene tubes)
Proteomic and/or lipidomic 
approaches, and analysis of 
circulating Spike protein
Analysis of protein translates (including circulating Spike protein) or lipid
mediators in serum or plasma.
ELISA = enzyme-linked immunosorbent assay; SARS-CoV-2 = severe acute respiratory syndrome coronavirus-2;
VNA = virus neutralization assay
aVaccination 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 serological testing outside the study.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
75
Status: Approved,  Date: 16 September 2022
8.2. 
Safety Assessments
Details regarding the IDMC are provided in Section 10.3.6.
AEs will be reported and followed by the investigator as specified in Section 8.3 and Section 10.4.
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 time
points provided in the Schedule of Activities (Section 1.4).
8.2.1. 
Physical Examinations
A history-directed physical examination, including height and body weight, will be carried out at
screening. To obtain the actual body weight, participants must be weighed lightly clothed. The
height should be measured without footwear.
At all other visits, an abbreviated, symptom-directed examination might be performed by the
investigator based on any clinically relevant issues or symptoms, and medical history. This
symptom-directed physical examination will also include basic neurological examination, if
warranted. Symptom-directed physical examination may be repeated if deemed necessary by the
investigator.
Physical examinations will be performed by the investigator or designated medically trained
clinician. 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
Body temperature (oral route preferred, or in accordance with the local standard of care),
pulse/heart rate, respiratory rate, and blood pressure will be assessed.
Participants will utilize a diary to record body temperature measurements post vaccination (see
Section 8).
Blood pressure and pulse/heart rate measurements will be assessed preferably supine with a
completely automated device. Manual techniques will be used only if an automated device is not
available.
Blood pressure and pulse/heart rate measurements should be preceded by at least 5 minutes of rest
in a quiet setting without distractions (eg, television, cell phones). Vital signs are recommended
before blood sampling.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
76
Status: Approved,  Date: 16 September 2022
8.2.3. 
Pregnancy Testing
A urine pregnancy test for participants of childbearing potential will be performed at screening
and before each vaccination.
Additional 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 will be collected as described in the Schedules
of Activities in Section 1.4 and Section 10.2, Appendix 2. 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 treatment. This information should be reported through the
TTS AESI form (see Section 10.8, Appendix 8) 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 1.4 and
Section 10.2, Appendix 2). The Investigator will review the laboratory test results to assist the
investigation of the AESI.
See Section 8.3.6.1 for details on laboratory test details to be reported for an AE of
thrombocytopenia.
8.3. 
Adverse Events, Serious Adverse Events, Medically-attended Adverse
Events, Adverse Events of Special Interest, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including AEs, SAEs,
MAAEs, suspected AESIs, and 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 for the duration of the study. Further details on AEs, SAEs,
MAAEs, suspected AESIs, and PQC can be found in Section 10.4.
8.3.1. 
Time Period and Frequency for Collecting Adverse Event, Medically-
attended Adverse Event, Adverse Event of Special Interest, and
Serious Adverse Event Information
All Adverse Events
AEs and special reporting situations, whether serious or non-serious, that are related to study
procedures or that are related to non-investigational sponsor products will be reported for all
participants from the time a signed and dated ICF is obtained until the end of the study/early
withdrawal.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
77
Status: Approved,  Date: 16 September 2022
Clinically relevant medical events not meeting the above criteria and occurring between signing
of the ICF and moment of first vaccination will be collected on the Medical History eCRF page as
pre-existing conditions.
Solicited AEs, collected through a diary, will be recorded for each vaccination from the time of
vaccination until 7 days post vaccination.
All other unsolicited AEs and special reporting situations, whether serious or non-serious, will be
reported for each vaccination from the time of vaccination until 28 days post vaccination.
Unsolicited AEs with the onset date outside the timeframe defined above (>28 days after previous
study vaccination), which are ongoing on the day of the subsequent vaccination, should be
recorded as such.
At each visit the participant will be asked if they have had a private/off-study COVID-19 test. If a
participant receives a positive SARS-CoV-2 result from a private/off-study test (whether through
PCR or serological testing; for participants seropositive at baseline, only PCR testing applies)
during the study, and the positive result occurs within 28 days after vaccination, the event will be
reported as an AE. If it occurs after 28 days, the event will be recorded as an SAE only if the event
qualifies as serious. If the event occurs after 28 days, and it is not serious, it will be reported in the
eCRF. The participant can continue in the study for safety follow-up if they choose to; however,
this must be in accordance with local country and site level recommendations for COVID-19 and
they will not be permitted to receive further study vaccination administrations. Any positive
SARS-CoV-2 result should be recorded in the eCRF.
All SAEs and AEs leading to discontinuation from the study/vaccination (regardless of the causal
relationship) will be reported for all participants from the moment of first 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
vaccination until 6 months after the vaccination, except for MAAEs leading to study
discontinuation which are to be reported during the entire study.
Adverse Events of Special Interest
Thrombosis with Thrombocytopenia Syndrome is considered to be an AESI. Suspected AESIs
(thrombotic events and thrombocytopenia [defined as platelet count below 150,000/µL[Brighton
Collaboration. Interim Case Definition of Thrombosis with Thrombocytopenia Syndrome (TTS)
2021])will be recorded from the moment of vaccination until the end of the study/early withdrawal
(see Section 8.3.6). An AESI Adjudication Committee with appropriate expertise will be
established to evaluate each suspected AESI and determine whether it is a case of TTS.
All AEs will be followed until resolution or until clinically stable.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
78
Status: Approved,  Date: 16 September 2022
Serious Adverse Events
All SAEs, as well as PQC, 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, 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.
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.
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
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 diary.
After each vaccination, participants will remain under observation at the study site for at least
15 minutes for the presence of any acute reactions and solicited events.
In addition, participants will record solicited signs and symptoms in a diary for 7 days post
vaccination. All participants will be provided with a diary and instructions on how to complete the
diary (see Overview in Section 8, Study Assessments and Procedures). Electronic diary
information will be transferred from the Safety Diary source to the sponsor. After review and
verbal discussion of the initial electronic diary entries with the participant, the investigator will
complete his/her own assessment in the relevant sections of the eCRF. Once a solicited sign or
symptom from a diary is considered to be of severity Grade 1 or above, it will be recorded as a
solicited adverse event.
Solicited Injection Site (Local) Adverse Events
Participants will be asked to note in the 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 (Gidudu 2012, Kohl 2007).
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
79
Status: Approved,  Date: 16 September 2022
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 diary in the evening of the day of
vaccination, and then daily for the next 7 days 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 used in
the eCRF.
Fever is defined as endogenous elevation of body temperature ≥38° C, as recorded in at least
1 measurement (Marcy 2004).
Participants will also be instructed on how to note signs and symptoms in the diary on a daily basis
for 7 days post vaccination (day of vaccination and the subsequent 7 days), for the following
events: fatigue, headache, nausea, and myalgia.
Unsolicited Adverse Events
Unsolicited AEs are all AEs for which the participant is not specifically questioned in the
participant diary.
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 8.3.6.
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 AEs, MAAEs,
SAEs, suspected AESI, or PQC as fully as possible. This may include additional laboratory tests
or investigations, histopathological examinations, or consultation with other health care
professionals.
AEs, including pregnancy, will be followed by the investigator as specified in Section 10.4.
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 Independent Ethics
Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless otherwise
required and documented by the IEC/IRB. A SUSAR will be reported to regulatory authorities
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
80
Status: Approved,  Date: 16 September 2022
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 must discontinue further study vaccination but will remain in the study and will continue to
undergo all procedures for follow-up and all safety follow-up as outlined in the protocol for all
participants.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
infant will be required.
8.3.6. 
Adverse Events of Special Interest
Adverse events of special interest (AESIs) are significant AEs that are judged to be of special
interest because of clinical importance, known or suspected class effects, or based on nonclinical
signals. Adverse events of special interest will be carefully monitored during the study by the
sponsor.
AESIs must be reported to the sponsor within 24 hours of awareness irrespective of seriousness
(ie, serious and non-serious AEs) or causality following the procedure described above for SAEs.
Specific requirements for the AESI are described below.
8.3.6.1. 
Thrombosis with Thrombocytopenia Syndrome
As described in Section 2.3.1, Risks Related to Study Participation, TTS has been observed very
rarely following vaccination with Ad26.COV2.S and is considered to be an AESI in this study.
TTS is a syndrome characterized by a combination of both a thrombotic event and
thrombocytopenia (American Society of Hematology 2021, Brighton Collaboration. Interim Case
Definition of Thrombosis with Thrombocytopenia Syndrome 2021).
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 10.8, Appendix 8. A suspected TTS case is defined as:
 
Thrombotic events: suspected deep vessel venous or arterial thrombotic events as detailed in
Section 10.9, Appendix 9
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
81
Status: Approved,  Date: 16 September 2022
 
Thrombocytopenia, defined as platelet count below 150,000/µL (Brighton Collaboration.
Interim Case Definition of Thrombosis with Thrombocytopenia Syndrome 2021)
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 may 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 1.4.3). 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 10.8, Appendix 8is intended as a guide for assessment of the AESIs
to facilitate diagnosis and determine treatment options. If the investigator is not the treating
physician, every effort should be made to collect the information requested in the form from the
treating physician and enter the available information in the eCRF.
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 immunogenicity and safety data is
outlined below. Specific details will be provided in the SAP.
9.1. 
Statistical Hypotheses
Formal NI testing will be applied to demonstrate NI of 1-dose and 2-doses of 9x1010 vp, 2.5x1010
vp, 7x1010 vp, 3.5x1010 vp, and 1.25x1010 vp Ad26.COV2.S versus 1- dose and 2-doses of 5x1010
vp Ad26.COV2.S (release titer), using a NI margin of 2/3 for the GMC ratios.
The 2.5x1010 vp dose will be tested before the 7x1010 vp in the sequential testing due to an
increased risk to fail non-inferiority as a consequence of a smaller sample size in the 7x1010 vp
group as shown in Table 7.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
82
Status: Approved,  Date: 16 September 2022
The following 2 sets of hypotheses (1 dose and 2 doses) will independently be tested sequentially:
Post-dose 1
1a) 
NI after 1-dose of Ad26.COV2.S 9x1010 vp versus 1-dose of Ad26.COV2.S 5x1010 vp
(release titer)
1b) 
NI after 1-dose of Ad26.COV2.S 2.5x1010 vp versus 1-dose of Ad26.COV2.S 5x1010 vp
(release titer)
1c) 
NI after 1-dose of Ad26.COV2.S 7x1010 vp versus 1-dose of Ad26.COV2.S 5x1010 vp
(release titer)
1d) 
NI after 1-dose of Ad26.COV2.S 3.5x1010 vp versus 1-dose of Ad26.COV2.S 5x1010 vp
(release titer)
1e) 
NI after 1-dose of Ad26.COV2.S 1.25x1010 vp versus 1-dose of Ad26.COV2.S 5x1010 vp
(release titer)
In this set, NI will be demonstrated in terms of humoral immune response expressed by the GMCs
of S-ELISA, 28 days post-dose 1, using a NI margin of 2/3 for the GMC ratio (GMC [9x1010 vp,
2.5x1010, 7x1010 vp, 3.5x1010 vp, or 1.25x1010 vp]/GMC 5x1010 vp).
Post-dose 2
2a1) NI after 2-doses of Ad26.COV2.S 9x1010 vp versus 1-dose of Ad26.COV2.S 5x1010 vp
(release titer)
2a2) NI after 2-doses of Ad26.COV2.S 9x1010 vp versus 2-doses of Ad26.COV2.S 5x1010 vp
(release titer)
2b1) NI after 2-doses of Ad26.COV2.S 2.5x1010 vp versus 1-dose of Ad26.COV2.S 5x1010 vp
(release titer)
2b2) NI after 2-doses of Ad26.COV2.S 2.5x1010 vp versus 2-doses of Ad26.COV2.S 5x1010 vp
(release titer)
2c1) NI after 2-doses of Ad26.COV2.S 7x1010 vp versus 1-dose of Ad26.COV2.S 5x1010 vp
(release titer)
2c2) NI after 2-doses of Ad26.COV2.S 7x1010 vp versus 2-doses of Ad26.COV2.S 5x1010 vp
(release titer)
2d1) NI after 2-doses of Ad26.COV2.S 3.5x1010 vp versus 1-dose of Ad26.COV2.S 5x1010 vp
(release titer)
2d2) NI after 2-doses of Ad26.COV2.S 3.5x1010 vp versus 2-doses of Ad26.COV2.S 5x1010 vp
(release titer)
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
83
Status: Approved,  Date: 16 September 2022
2e1) NI after 2-doses of Ad26.COV2.S 1.25x1010 vp versus 1-dose of Ad26.COV2.S 5x1010 vp
(release titer)
2e2) NI after 2-doses of Ad26.COV2.S 1.25x1010 vp versus 2-doses of Ad26.COV2.S 5x1010
vp (release titer)
In this set, NI will be demonstrated in terms of humoral immune response expressed by the GMCs
of S-ELISA, 14 days post-dose 2 (9x1010 vp, 2.5x1010 vp, 7x1010 vp, 3.5x1010 vp, or 1.25x1010 vp)
and 28 days post-dose 1 or 14 days post-dose 2 (5x1010 vp), using a NI margin of 2/3 for the GMC
ratio (GMC 9x1010 vp, 2.5x1010 vp, 7x1010 vp, 3.5x1010 vp, or 1.25x1010 vp]/GMC 5x1010 vp).
Figure 2 depicts a tree-based schema for testing the 2 sets of non-inferiority hypotheses (1 dose
and 2 doses) controlling the family-wise error rate at alpha  0.025 (1-sided).
NCT04908722

NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
85
Status: Approved,  Date: 16 September 2022
 
Alpha  0.025 (one-sided). Using a Bonferroni correction, Type I error will be split
equally over the 1-dose and 2-dose comparisons: 0.0125 (1-sided) for 1- and 2-dose NI
comparisons
 
Power  90%
Based on the above assumptions, assuming approximately a 10.2% dropout, a sample size of
225 participants per active vaccine group (see Table 1) is needed to detect non-inferiority of testing
1-dose and 2-doses of 9x1010 vp, 2.5x1010 vp, 7x1010 vp, 3.5x1010 vp, and 1.25x1010 vp
Ad26.COV2.S as the test groups versus 1-dose and 2-doses of 5x1010 vp Ad26.COV2.S (release
titer) as the reference groups, with 90% power.
A target of approximately 240 participants (40 seronegative and 20 seropositive participants) per
dose regimen in Groups 1, 3, 5, and 6 will be enrolled to further characterize the innate, pro-
inflammatory and other relevant (eg, pro-thrombotic) responses to Ad26.COV2.S to better
understand a possible risk to TTS events. This target may not be met due to the challenges of
enrolling seronegative subjects into the study, so sub-study enrollment may stop at lower numbers.
Participants in the main study and sub-study (participants who are seronegative at enrollment or
baseline)may be combined for the analysis.
Table 7 shows how the power will be affected with 10%, 20%, 30%, 40%, 50% and 60% dropout
due to various reasons (eg, lost to follow-up, participants with major protocol deviations with
impact on immunogenicity, participants who become N-seropositive during the study or with a
confirmed SARS-CoV-2 infection, and participants who received their vaccination outside the
allowed window).
Table 7: 
Power Based on % of Drop Out
% drop out since enrollment
Regimen 
sample size at 
enrollment per
arm
group 10% 
20% 
30% 
40% 
50%  
60%
9x1010 vp (sample size 
of main study and sub-
study)
252 (212+40) 
1 
92.00%  88.60%  83.70%  76.80%  68.10%  57.20%
2.5x1010 vp (sample 
size of main study and
sub-study)
252 (212+40) 
5 
92.00%  88.60%  83.70%  76.80%  68.10%  57.20%
7x1010 vp (main study) 
212 
2 
89.40%  85%  
79.90% 72.70%  63.70% 53.00%
5x1010 vp (sample size 
of main study and sub-
study)
252 (212+40) 
3 
92.00%  88.60%  83.70%  76.80%  68.10%  57.20%
3.5x1010 
vp 
(main 
study)
212 
4 
89.40%  85.00%  79.90% 72.70%  63.70% 53.00%
1.25x1010 vp (sample 
size of   main study and
sub-study)
252 (212+40) 
6 
92.00%  88.60%  83.70%  76.80%  68.10%  57.20%
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
86
Status: Approved,  Date: 16 September 2022
9.2.1. 
Immunogenicity
The primary objective of this study is to demonstrate the NI, in terms of humoral immune response,
of a 1-dose and 2-doses of 9x1010 vp, 2.5x1010 vp, 7x1010 vp, 3.5x1010 vp, and 1.25x1010 vp
Ad26.COV2.S versus a 1-dose and 2-doses of 5x1010 vp Ad26.COV2.S (release titer).
The S-ELISA has been selected as primary endpoint since samples from all participants will be
analyzed using this assay, which has an improved throughput as compared to VNA. The ELISA
will be used as primary endpoint for NI comparison, provided that a robust correlation can be
confirmed between ELISA and VNA. Otherwise, VNA may  be considered for the primary
endpoint. In this case, to accelerate availability of results, only samples collected 28 days post-dose
1 or 14 days post-dose 2 will be tested with VNA but not baseline samples.
9.3. 
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:
FAS: The full analysis set will include all participants with at least one vaccine administration
documented.
PPI: The per protocol immunogenicity population will include all randomized and vaccinated
participants for whom immunogenicity data are available excluding participants with major
protocol deviations expected to impact the immunogenicity outcomes. In addition, samples
obtained after missed vaccinations or samples obtained after natural SARS-CoV-2 infection (if
applicable) will be excluded from the analysis set.
NI: The NI analysis set will include all PPI participants who are SARS-COV-2 seronegative at
study entry.
9.4. 
Statistical Analyses
The SAP will be finalized prior to the first data base lock (DBL)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. One Statistical Analysis Plan (SAP) will be provided for both the main
study and the sub study.
9.4.1. 
General Considerations
Analysis populations are defined in Section 9.3. Planned analyses are defined in Section 9.5.
For safety and immunogenicity analyses, results will be analyzed by vaccine group.
Immunogenicity sub-analyses will also be performed by BMI, ethnicity, and other factors as will
be described in the SAP.
If a participant has a positive SARS-CoV-2 test after vaccination, this participant will remain in
the study, but samples obtained after SARS-CoV-2 infection will not be included in the per
protocol immunogenicity analysis set.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
87
Status: Approved,  Date: 16 September 2022
9.4.2. 
Primary Endpoint(s)
Immunogenicity Endpoints
For each NI comparison between post-dose 1 ([9x1010 vp, 2.5x1010, 7x1010 vp, 3.5x1010 vp, or
1.25x1010 vp] versus 5x1010 vp), estimated humoral immune responsedifferences will be expressed
as ratios of GMCs of S-ELISA (GMC [9x1010 vp, 2.5x1010, 7x1010 vp, 3.5x1010 vp, or 1.25x1010
vp]/GMC 5x1010 vp), 28 days post-dose 1 with corresponding 97.5% confidence interval (CI)
(2-sided) (Type 1 error 0.0125 for each comparison).
Similarly, for each NI comparison between post-dose 2 ([9x1010 vp, 2.5x1010, 7x1010 vp, 3.5x1010
vp, or 1.25x1010 vp] versus 1- or 2-doses of 5x1010 vp), estimated humoral immune response
differences will be expressed as ratios of GMCs of S-ELISA (GMC [9x1010 vp, 2.5x1010, 7x1010
vp, 3.5x1010 vp, or 1.25x1010 vp]/GMC 5x1010 vp), 28 days post-dose 1 or 14 days post-dose 2
with corresponding 97.5% confidence interval (CI) (2-sided) (Type 1 error 0.0125 for each
comparison).
In both sets (1 dose and 2 doses) of comparisons above, 97.5% CIs (2-sided) for mean difference
in log10-transformed S-ELISA titers between 2 groups will first be calculated and then back-
transformed to the original scale to obtain the GMC ratios and the associated 97.5% CIs (2-sided).
Non-inferiority between the groups will be established if the 97.5% CI of the estimated GMC ratio
of the groups entirely lies above 2/3.
In the 1-dose (dose 1 of the 2-dose regimen) and 2-dose set NI comparisons, hierarchical testing
after administration of a single-dose and 2 doses will be applied independently, as reflected in the
Decision Tree-based Hypothesis Testing (Figure 2 and Section 9.1). The non-inferiority analyses
will be done on the NI analysis set.
 
Note: If a large number of participants become infected during the study (as assessed eg,
by N-seroconversion or by PCR confirmation) or are SARS-CoV-2 seropositive at
baseline, the main study and sub-study participants (seronegative at baseline) may be
combined.
 
If the power of the combined main study and sub-study is less than 80% then seropostive
subjects at baseline will be included in the analysis. Further details of the analysis will be
provided in the SAP.
9.4.3. 
Secondary Endpoint(s)
Immunogenicity Endpoints
Descriptive statistics (geometric mean and confidence intervals, or median and interquartile range
Q1-Q3, as appropriate) will be calculated for continuous immunologic parameters. Several
definitions of serological response will be applied as applicable (GMC [S-ELISA]). Graphical
representations of immunologic parameters will be made as applicable. Frequency tabulations will
be calculated for discrete (qualitative) immunologic parameters, as applicable.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
88
Status: Approved,  Date: 16 September 2022
In addition, the ratio between neutralizing and binding antibodies as determined by S-ELISA and
VNA, respectively, will be calculated together with confidence intervals. More details will be
provided in the SAP.
The immunogenicity analyses will be performed on the PPI population. Immunogenicity analyses
will also be done on the FAS (participants who became infected during the study will be analyzed
as a subgroup and shown in the graphs using different colors and symbols).
Safety Endpoints
No formal statistical testing of safety data is planned. Safety data will be analyzed descriptively
by vaccine group. In addition, for selected tables, tabulations pooled by vaccine dose will also be
provided. All safety analyses will be made on the FAS.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the
Medical Dictionary for Regulatory Activities (MedDRA). All reported AEs with onset during the
active vaccination phase (ie, AEs occurring after vaccination up to 28 days post vaccination), and
all SAEs/MAAEs/AESIs will be included in the analysis. (S)AEs caused by molecularly confirmed
SARS-CoV-2 infection will be removed at the analysis level from the (S)AE listings and tables
and presented separately. For each AE, the percentage of participants who experience at least
1 occurrence of the given event will be summarized by vaccine group.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue intervention 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 one solicited local (at injection site) or systemic AE
will be presented. The frequencies by vaccine group as well as frequencies according to severity
and duration will be described for solicited adverse events. Frequencies of unsolicited adverse
events, separately for all and vaccination-related only, will be presented by System Organ Class
and preferred term, while those of solicited adverse events will be presented only by preferred
term.
Clinical Laboratory Tests
Laboratory data (abnormal or graded, when available) will be listed and/or tabulated by participant
and time point.
Vital Signs
Vital signs including temperature, pulse/heart rate, respiratory rate, and blood pressure (systolic
and diastolic) will be summarized over time, using descriptive statistics and/or graphically. The
percentage of participants with values beyond clinically important limits will be summarized.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
89
Status: Approved,  Date: 16 September 2022
Physical Examinations
Physical examination findings will be summarized at baseline. Physical examination abnormal
findings will be listed.
9.4.4. 
Exploratory Endpoint(s)
The correlation between the binding antibody (ELISA) titers and neutralizing antibody (VNA)
titers to SARS-CoV-2 will be assessed in a subset of participants at selected timepoints using
Spearman's rank correlation, for example. Seronegative and seropositive participants in the sub
study will be analyzed as a subgroup and shown in graphs using different colors and symbols.
Additional details, including statistical methodology for analysis of other exploratory endpoints,
will be provided in the SAP for both the main study and sub study.
9.4.5. 
Other Analyses
An IDMC has been commissioned for the Ad26.COV2.S program. Any relevant safety
information from this study will be shared with the IDMC.
9.5. 
Planned Analyses
The sponsor may be unblinded for this study, but the blind will be maintained at the participant
and study site level up to study end.
The primary analysis, which will be performed on unblinded data, will include safety up to Day 85
and immunogenicity up to Day 71 in the main study and sub study for all groups and will be
performed when all participants have completed the visit that takes place 85 days after the first
study vaccination or discontinued earlier.
The final analysis for the main study will be performed when all included participants from the
main study have completed their last visit (at least 6 months post last vaccination) or discontinued
earlier. Results from participants in the sub study may be available with the main study. Results
from the main study and the sub study may be combined in one report.
Depending on availability of results, primary and final analysis might be combined.
Further interim analyses may be performed for safety and/or immunogenicity to facilitate decision
making with regards to planning of future studies or for regulatory submission purposes.
The IDMC set for the program will have overview on the safety of this study.
Unblinding due to availability of an authorized/licensed COVID-19 vaccine
Investigators may receive requests to unblind study participants who become eligible to receive an
authorized/licensed COVID-19 vaccine at the efficacious dose if/when these become available,
including the sponsors. 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
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
90
Status: Approved,  Date: 16 September 2022
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).
If the participant prefers another company’s vaccine, they will be informed that there are no data
on the safety of receiving two different COVID-19 vaccines. In the event of the participant
unblinding in order to receive an authorized/licensed COVID-19 vaccine, no further study
vaccination will be permitted. Unblinded participants will be asked to continue to be followed in
this study in line with the Schedule of Activities (SoA) to the extent that they permit. Safety 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, if
applicable and feasible. All data will be analyzed separately from the point of unblinding, for safety
and immunogenicity analysis, as described in the SAP.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
91
Status: Approved,  Date: 16 September 2022
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations and Definitions
Ad26 
adenovirus type 26
ADCC  
antibody-dependent cell-mediated cytotoxicity
AdVAC® 
adenoviral vaccine (vector platform)
AE 
adverse event
AESI 
adverse event of special interest
ALT  
alanine aminotransferase
AP  
antigen presentation
AST  
aspartate aminotransferase
BMI 
body mass index
BUN  
Blood Urea Nitrogen
CD  
cluster of differentiation
CDC  
Centers for Disease Control and Prevention
COPD  
chronic obstructive pulmonary disease
COVID-19 
coronavirus disease-2019
CPK  
creatine phosphokinase
CVST  
cerebral venous sinus thrombosis
eCRF  
Electronic case report form(s)
CT  
computed tomographic
DBL 
data base lock
DIC  
disseminated intravascular coagulation
DNA  
deoxyribonucleic acid
DVT  
deep vein thrombosis
eCOA  
electronic clinical outcome assessment
eCRF  
electronic case report form
eDC  
electronic data capture
ELISA  
enzyme-linked immunosorbent assay
ELISpot 
enzyme-linked immunospot
ERD  
enhanced respiratory disease
FAS  
full analysis set
Fc 
crystallizable fragment
FDA  
Food and Drug Administration
FI 
formalin-inactivated
FIH  
first-in-human
FOIA  
Freedom of Information Act
GBS  
Guillain-Barre Syndrome
GCP  
Good Clinical Practice
GLP  
good laboratory practice
GMC  
Geometric mean concentration
GMT  
Geometric mean titer
HIT  
heparin-induced thrombocytopenia
HITT  
heparin-induced thrombotic thrombocytopenia
HIV  
human immunodeficiency virus
IB  
investigator's brochure
ICF  
informed consent form
ICS  
intracellular cytokine staining
ICH  
International Conference on Harmonisation
ICMJE  
International Committee of Medical Journal Editors
ICU  
intensive care unit
IDMC  
Independent Data Monitoring Committee
IEC  
Independent Ethics Committee
IFN-γ 
interferon gamma
IL 
interleukin
IM  
intramuscular
IND  
Investigational New Drug
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
92
Status: Approved,  Date: 16 September 2022
IPPI 
Investigational Product Preparation Instructions
IRB  
Institutional Review Board
IUD  
intrauterine device
IUS  
intrauterine hormone-releasing system
IWRS  
interactive web response system
MAAE 
medically-attended adverse event
MedDRA  
Medical Dictionary for Regulatory Activities
MERS (-CoV) 
Middle East respiratory syndrome (coronavirus)
MIS  
multisystem inflammatory syndrome
N 
nucleocapsid
NHP  
Non-human primate
NI 
Non-inferiority
NIAID  
National Institute of Allergy and Infectious Diseases
PCR  
polymerase chain reaction
PI 
principal investigator
PPI 
per protocol immunogenicity
PQC  
product quality complaint
PRBC  
packed red blood cells
PSRC  
Prevention Science Review Committee
PT  
prothrombin time
PTT  
partial thromboplastin time
RNA  
ribonucleic acid
RSV  
respiratory syncytial virus
RT-PCR  
real-time 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
SoA  
Schedule of Activities
SRP/S  
study responsible physician/scientist
SUSAR  
suspected unexpected serious adverse reaction
Th 
T-helper
TNF-α 
tumor necrosis factor alpha
TTS  
thrombosis with thrombocytopenia syndrome
ULN  
upper limit ofthe normal range
US  
United States
VNA  
virus neutralization assay
vp 
virus particle
WBC  
white blood cell
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 (US
FDA 2020a, US FDA 2020b).
eCOA  
An umbrella term encompassing different types of outcomes assessments, in particular, the
Safety Diary.
Safety Diary  
The electronic technology used to record solicited signs and symptoms by the participants
in the Safety Subset.
NCT04908722

NCT04908722

NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
95
Status: Approved,  Date: 16 September 2022
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
 
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
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
96
Status: Approved,  Date: 16 September 2022
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, if applicable, 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
 
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
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
97
Status: Approved,  Date: 16 September 2022
 
Report of deaths of participants under the investigator's care
 
Notification if a new investigator is responsible for the study at the site
 
Development Safety Update Report and Line Listings, where applicable
 
Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct), the amendment and applicable ICF revisions
must be submitted promptly to the IEC/IRB for review and approval before implementation of the
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 sub investigators 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
Each participant must give written consent according to local requirements after the nature of the
study has been fully explained. The ICF(s) must be signed before performance of any study-related
activity. 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
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
98
Status: Approved,  Date: 16 September 2022
consent to participate at any time. They will be informed that choosing not to participate will not
affect the care the participant will receive. Finally, they will be told that the investigator will
maintain a participant identification register for the purposes of long-term follow-up if needed and
that their records may be accessed by health authorities and authorized sponsor personnel without
violating the confidentiality of the participant, to the extent permitted by the applicable law(s) or
regulations. By signing the ICF the participant is authorizing such access. It also denotes that the
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.
If the participant is unable to read or write, an impartial witness should be present for the entire
informed consent process (which includes reading and explaining all written information) and
should personally date and sign the ICF after the oral consent of the participant is obtained.
10.3.4. 
Data Protection
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality
and compliance with applicable data privacy protection laws and regulations. Appropriate
technical and organizational measures to protect the personal data against unauthorized disclosures
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place.
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity
of participants confidential.
The informed consent obtained from the participant includes explicit consent for the processing of
personal data and for the investigator/institution to allow direct access to his or her original medical
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and
regulatory inspection. This consent also addresses the transfer of the data to other entities and to
other countries.
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.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
99
Status: Approved,  Date: 16 September 2022
Exploratory 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 vaccination with Ad26 based
vaccines including Ad26.COV2.S, to understand SARS-CoV-2 infection, to understand
differential vaccine responders, and to develop tests/assays related to Ad26-based vaccines and 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. 
Safety Monitoring Committees Structure
Independent Data Monitoring Committee
An IDMC has been established to monitor safety data on an ongoing basis to ensure the continuing
safety of the participants enrolled in this study. The IDMC will consist of at least one medical
expert in the relevant therapeutic area and at least one statistician; committee membership
responsibilities, authorities, and procedures will be documented in its charter.
The IDMC will review data as indicated in Section 4.1.
Ad hoc review may be performed further to the occurrence of any AE/SAE, or at request of the
sponsor’s medical monitor or designee. The principal investigator and sponsor’s study responsible
physician will inform the IDMC of any AE of concern.
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 8.3.6). 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, including exploratory research data, generated as a result of
this study, are considered confidential and remain the sole property of the sponsor. The investigator
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
100
Status: Approved,  Date: 16 September 2022
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 exploratory
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
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 18months after the study end date, or the sponsor confirms there
will be no multicenter study publication. Authorship of publications resulting from this study will
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which
state that the named authors must have made a significant contribution to the conception or design
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the
work or revised it critically for important intellectual content; and given final approval of the
version to be published; and agreed to be accountable for all aspects of the work in ensuring that
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
101
Status: Approved,  Date: 16 September 2022
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 eCRF for accuracy and completeness during on-site monitoring visits and
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.
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 must 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
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.
All participative measurements (eg, questionnaires) will be completed by the same individual who
made the initial baseline determinations whenever possible.
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:
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
102
Status: Approved,  Date: 16 September 2022
 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 medical history and prestudy medication), and
study identification; study discussion and date of signed informed consent; dates of visits; results
of safety parameters as required by the protocol; record of all AEs and follow-up of AEs;
concomitant medication; vaccine receipt/dispensing/return records; study vaccine administration
information; and date of study completion and reason for early discontinuation of study vaccine or
withdrawal from the study, if applicable.
The author of an entry in the source documents should be identifiable.
Participant- and investigator-completed scales and assessments designated by the sponsor (ie,
diary to record solicited AEs, daily signs)will be recorded and will be considered source data. The
participant’s diary used to collect information regarding solicited signs and symptoms after
vaccination will be considered source data.
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 eCRF 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. 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 compare the data entered into the eCRF with the source documents
(eg, hospital/clinic/physician’s office medical records). 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 verification by the
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
103
Status: Approved,  Date: 16 September 2022
sponsor study site contact. If electronic records are maintained at the study site, the method of
verification must be discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying
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.
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 source documents, 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
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
104
Status: Approved,  Date: 16 September 2022
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.
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
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
105
Status: Approved,  Date: 16 September 2022
10.4. Appendix 4: Adverse Events, Medically-attended Adverse Events, Serious
Adverse Events, Adverse Events of Special Interest, 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.
Any respiratory tract infection that is not due to SARS-CoV-2 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 any 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. In general, any (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. In general, (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.
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
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
106
Status: Approved,  Date: 16 September 2022
 
Is Medically Important*
*Medical and scientific judgment 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 one 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).
At each visit the participant will be asked if they have had a private/off-study COVID-19 test. If a
participant receives a positive SARS-CoV-2 result from a private/off-study test (whether through
PCR or serological testing) during the study, and the positive result occurs within 28 days after
vaccination, the event will be reported as an AE. If it occurs after 28 days, the event will be
recorded as an SAE only if the event qualifies as serious. The participant can continue in the study
for safety follow-up if they choose to; however, this must be in accordance with local country and
site level recommendations for COVID-19, and they will not be permitted to receive further study
vaccination administrations. Any positive SARS-CoV-2 result should be recorded 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.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
107
Status: Approved,  Date: 16 September 2022
10.4.3. 
Severity Criteria
All AEs and laboratory data will be coded for severity usinga modified version of the FDA grading
table, based on version of September 2007, included in Section 10.6.
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
The severity of solicited signs and symptoms will be graded in the diary by the participant based
on the severity assessment provided in the diary and then verified by the investigator using the
toxicity grading scale in Section 10.6. (Note: severity of the measured events will be derived from
the diameter [for erythema and swelling] and the temperature measurements [for fever]).
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:
 
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)
 
Exposure to a sponsor study vaccine from breastfeeding
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 SAE page 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,
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
108
Status: Approved,  Date: 16 September 2022
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough,
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory
infection"). Investigators must record in the eCRF their opinion concerning the relationship of the
AE to study therapy. All measures required for AE management must be recorded in the source
document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be
provided with a "wallet (study) card" and instructed to carry this card with them for the duration
of the study indicating the following:
 
Study number
 
Statement, in the local language(s), that the participant is participating in a clinical study
 
Investigator's name and 24-hour contact telephone number
 
Local sponsor's name and 24-hour contact telephone number (for medical personnel only)
 
Site number
 
Participant number
 
Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon  the
participant's discontinuation from the study, must be followed until any of the following occurs:
 
The event resolves
 
The event stabilizes
 
The event returns to baseline, if a baseline value/status is available
 
The event can be attributed to agents other than the study vaccine or to factors unrelated to
study conduct
 
It becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE.
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during
participation in the study must be reported as an SAE, except hospitalizations for the following:
 
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.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
109
Status: Approved,  Date: 16 September 2022
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 an SAE.
Information regarding SAEs will be transmitted to the sponsor using an SAE reporting form and
safety report form of the eCRF, which must be completed and reviewed by a physician from the
study site, and transmitted in a secure manner to the sponsor within 24 hours. The initial and
follow-up reports of an SAE should be transmitted in a secure manner electronically or by
facsimile (fax). Telephone reporting should be the exception and the reporter should be asked to
complete the appropriate form(s) first.
Adverse Events of Special Interest
AESIs will be carefully monitored during the study by the sponsor. Suspected AESIs must be
reported to the sponsor within 24 hours of awareness irrespective of seriousness (ie, serious and
non-serious AEs) or causality assessment, following the procedure described above for SAEs and
will require enhanced data collection.
10.4.6. 
Product Quality Complaint Handling
Definition
A PQC is defined as any suspicion of a product defect related to manufacturing, labeling, or
packaging, ie, any dissatisfaction relative to the identity, quality, durability, reliability, or
performance of a distributed product, including its labeling, drug delivery system, or package
integrity. A PQC may have an impact on the safety and efficacy of the product. In addition, it
includes any technical complaints, defined as any complaint that indicates a potential quality issue
during manufacturing, packaging, release testing, stability monitoring, dose preparation, storage
or distribution of the product or the drug delivery system.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after
being made aware of the event.
A sample of the suspected product should be maintained under the correct storage conditions until
a shipment request is received from the sponsor.
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.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
110
Status: Approved,  Date: 16 September 2022
10.5. Appendix 5: Contraceptive Guidance and Collection of Pregnancy
Information
Participants must follow contraceptive measures as outlined in Section 5.1. Pregnancy information
will be collected and reported as noted in Section 8.3.5 and Section 10.4.
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 one 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 total hysterectomy, bilateral tubal ligation/clip, 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.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
111
Status: Approved,  Date: 16 September 2022
10.6. Appendix 6: 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)
(US DHHS 2007).
A: Tables for Clinical Abnormalities
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 judgment when characterizing
bradycardia among some healthy participant populations, for example, conditioned athletes.
# Revised by the sponsor.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
112
Status: Approved,  Date: 16 September 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.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
113
Status: Approved,  Date: 16 September 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 
No interference with  
activity  
Some interference 
with activity not 
requiring medical 
intervention  
Prevents daily  
activity and
requires medical
intervention
Hospitalization#
# Revised by the sponsor.
B: Tables for Laboratory Abnormalities
Laboratory tests may be performed during routine medical care and assessment of AEs or other
medical events based on the investigator’s judgment.
The laboratory values provided in the tables below serve as guidelines and are dependent upon
institutional normal parameters. Institutional normal reference ranges should be provided to
demonstrate that they are appropriate.
Serum * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life
Threatening
(Grade 4)**
Sodium –Hyponatremia mEq/L 
132 –134 
130 –131 
125 –129 
< 125
Sodium –Hypernatremia mEq/L 
144 –145 
146 –147 
148 –150 
> 150
Potassium –Hyperkalemia mEq/L 
5.1 –5.2 
5.3 –5.4 
5.5 –5.6 
> 5.6
Potassium –Hypokalemia mEq/L 
3.5 –3.6 
3.3 –3.4 
3.1 –3.2 
< 3.1
Glucose –Hypoglycemia mg/dL 
65 –69 
55 –64 
45 –54 
< 45
Glucose –Hyperglycemia 
  Fasting mg/dL 
  Random –mg/dL 
100 –110 
110 –125 
111 –125 
126 –200 
>125 
>200 
Insulin
requirements or
hyperosmolar
coma
Blood Urea Nitrogen  
(BUN) mg/dL
23 –26 
27 –31 
> 31 
Requires dialysis
Creatinine –mg/dL 
1.5 –1.7 
1.8 –2.0 
2.1 –2.5 
> 2.5 or requires
dialysis
Calcium –hypocalcemia mg/dL 
8.0 –8.4 
7.5 –7.9 
7.0 –7.4 
< 7.0
Calcium –hypercalcemia mg/dL 
10.5 –11.0 
11.1 –11.5 
11.6 –12.0 
> 12.0
Magnesium –hypomagnesemia mg/dL 
1.3 –1.5 
1.1 –1.2 
0.9 –1.0 
< 0.9
Phosphorous –hypophosphatemia mg/dL 2.3 –2.5 
2.0 –2.2 
1.6 –1.9 
< 1.6
Creatine phosphokinase 
(CPK) –mg/dL 
1.25 –1.5 x  
ULN***
1.6 –3.0 x ULN  3.1 –10 x ULN  
> 10 x ULN
Albumin –Hypoalbuminemia g/dL 
2.8 –3.1 
2.5 –2.7 
< 2.5 
--
Total Protein –Hypoproteinemia g/dL 
5.5 –6.0 
5.0 –5.4 
< 5.0 
--
Alkaline phosphate – 
increase by factor
1.1 –2.0 x ULN  2.1 –3.0 x ULN  3.1 –10 x ULN  > 10 x ULN
Liver Function Tests –ALT, AST  
increase by factor
1.1 –2.5 x ULN  2.6 –5.0 x ULN  5.1 –10 x ULN  > 10 x ULN
Bilirubin –when accompanied 
by any increase in Liver Function Test 
increase by factor
1.1 –1.25 x 
ULN  
1.26 –1.5 x 
ULN  
1.51 –1.75 x 
ULN
> 1.75 x ULN
Bilirubin –when Liver Function Test 
is normal; increase by factor
1.1 –1.5 x ULN  1.6 –2.0 x ULN  2.0 –3.0 x ULN  > 3.0 x ULN
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
114
Status: Approved,  Date: 16 September 2022
Serum * 
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life
Threatening
(Grade 4)**
Cholesterol 
201 –210 
211 –225 
> 226 
---
Pancreatic enzymes –amylase, lipase 
1.1 –1.5 x ULN 1.6 –2.0 x ULN 2.1 –5.0 x ULN > 5.0 x ULN
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the
laboratory abnormalities as potentially life-threatening (Grade 4). For example. a low sodium value that falls
within a Grade 3 parameter (125-129 mEq/L) should be recorded as a Grade 4 hyponatremia event ifthe
participant had a new seizure associated with the low sodium value.
***ULN is the upper limit ofthe normal range.
Hematology * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life
Threatening
(Grade 4)
Hemoglobin (Female)- gm/dL 
11.0 –12.0 
9.5 –10.9 
8.0 –9.4 
< 8.0
Hemoglobin (Female) 
change from baseline value - gm/dL
Any decrease –1.5 1.6 –2.0 
2.1 –5.0 
> 5.0
Hemoglobin (Male) - gm/dL 
12.5 –13.5 
10.5 –12.4 
8.5 –10.4 
< 8.5
Hemoglobin (Male) 
change from baseline value –gm/dL
Any decrease –1.5 1.6 –2.0 
2.1 –5.0 
> 5.0
WBC Increase - cell/mm3 
10,800 –15,000 
15,001 –20,000 20,001 –25, 000 > 25,000
WBC Decrease - cell/mm3 
2,500 –3,500 
1,500 –2,499 
1,000 –1,499 
< 1,000
Lymphocytes Decrease - cell/mm3 
750 –1,000 
500 –749 
250 –499 
< 250
Neutrophils Decrease - cell/mm3 
1,500 –2,000 
1,000 –1,499 
500 –999 
< 500
Eosinophils - cell/mm3 
650 –1500 
1501 - 5000 
> 5000 
Hypereosinophilic
Platelets Decreased - cell/mm3 
125,000 –140,000 100,000 – 
124,000
25,000 –99,000 
< 25,000
PT –increase by factor 
(prothrombin time) 
1.0 –1.10 x  
ULN** 
1.11 –1.20 x 
ULN
1.21 –1.25 x ULN  > 1.25 ULN
PTT –increase by factor 
(partial thromboplastin time) 
1.0 –1.2 x ULN  
1.21 –1.4 x 
ULN
1.41 –1.5 x ULN  > 1.5 x ULN
Fibrinogen increase - mg/dL 
400 –500 
501 –600 
> 600 
--
Fibrinogen decrease - mg/dL 
150 –200 
125 –149 
100 –124 
< 100 or associated
with gross bleeding
or disseminated
intravascular
coagulation (DIC)
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.
** ULN is the upper limit ofthe normal range.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
115
Status: Approved,  Date: 16 September 2022
Urine * 
Mild  
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life-Threatening
(Grade 4)
Protein  
Trace 
1+  
2+ 
Hospitalization or
dialysis
Glucose 
Trace 
1+  
2+ 
Hospitalization for hyperglycemia
Blood (microscopic) – 
red blood cells per 
high power field (rbc/hpf) 
1 - 10 
11 –50 
> 50 and/or 
gross 
blood 
Hospitalization or
packed red blood cells (PRBC)
transfusion
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
116
Status: Approved,  Date: 16 September 2022
10.7. Appendix 7: Summary of Guidance from CDC Websitea on Underlying
Medical Conditions That Lead or Might Lead to Increased Risk for Severe
Illness From COVID-19
Adults of any age with certain underlying medical conditions are at increased risk for severe
illness from COVID-19: Severe illness from COVID-19 is defined as hospitalization, admission
to the ICU, intubation or mechanical ventilation, or death.
Adults of any age with the following conditions are at increased risk of severe illness from the
virus that causes COVID-19b::
 Cancer
 Chronic kidney disease
 COPD
 Heart conditions, such as heart failure, coronary artery disease or cardiomyopathies
 Immunocompromised state (weakened immune system) from solid organ transplant
 Obesity (BMI of 35 kg/m2 or higher but < 40 kg/m2)
 Severe Obesity (BMI ≥ 40 kg/m2)
 Pregnancy
 Sickle cell disease
 Smoking
 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, adults of any age 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
aSource: 
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. Updated 02 November 2020.
b The list of underlying medical conditions is not exhaustive and only includes conditions with sufficient evidence to
draw conclusions.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
117
Status: Approved,  Date: 16 September 2022
 Overweight (BMI > 25 kg/m2, but < 30 kg/m2)
 Pulmonary fibrosis (having damaged or scarred lung tissues)
 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.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
118
Status: Approved,  Date: 16 September 2022
10.8. Appendix 8: TTS AESI Form
The form below represents the type of information that may be collected in case of a suspected
AESI in order to help adjudicate whether the event is a case of TTS. Additional data may be
requested by the sponsor for investigation of the event.
Adverse Event of Special Interest Questionnaire (AESIQ) for Thromboembolism with
Thrombocytopenia Syndrome
Date of Report: 
[dd-MMM-yyyy]
1. Adverse Event Description
Participant’s clinical signs and symptoms
Leg/Calf Oedema 
Pain in Leg/Calf 
Haemoptysis
Dyspnoea 
Chest Pain/Discomfort 
Syncope
Tachypnoea 
Tachycardia  
Cough
Loss of consciousness 
Headache  
Seizure
Visual impairment 
Weakness 
Impaired speech
Confusional state 
Paresthesia 
Gait disturbance
Other symptoms:
Was patient on VTE prophylaxis? 
No 
Yes, details:
2. Medical History and Concurrent Conditions
Provide details:
Is the participant overweight or have obesity? 
No 
Yes
    If available, please provide: 
    
       Height 
Weight 
BMI
Does the participant have a sedentary lifestylea? 
No 
Yes – details:
Has the participant been in a sitting position for long 
periods of time prior to the event?
No 
Yes – details:
Is there a current history of smoking (active or passive)? 
No 
Yes – details:
Is there a prior history of smoking (active or passive)? 
No 
Yes – details:
Does the participant have a prior history of:
Cancer 
No 
Yes – details:
Autoimmune disease (i.e., collagen-vascular disease, 
inflammatory bowel disease) or myeloproliferative
disease?
No 
Yes – details:
Clotting disorder or a hypercoagulable state 
No 
Yes – details:
Varicose veins 
No 
Yes – details:
Trauma to the involved leg or pelvis 
No 
Yes – details:
DVT/PE or other VTE  
No 
Yes – details:
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
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
119
Status: Approved,  Date: 16 September 2022
Blood transfusion  
No 
Yes – details:
Cardiovascular disease 
No 
Yes – details:
If the participant has experienced a previous thrombotic
event, address the following:
    1.  Date (or estimate) 2.  Provide brief description of the
nature of the event 3.  Provide brief description of the
treatment of the event 4.  Note any residual manifestations
of the event.
 
If the patient has experienced more than one previous
thrombotic event, please list other events.
Was the (female) participant pregnant at the time of 
event?
No 
Yes – details:
Does the participant has any of genetic risk factors:
Dysfibrinogenemia 
Antiphospholipid syndrome  
Factor V Leiden mutation
Protein C or S deficiency  
Elevated factor VIII levels 
Anti-thrombin deficiency
Hyperhomocysteinemia 
Prothrombin gene mutation  
Blood-clotting disorder
Thrombophilia
Does the participant have any acquired risk factors:
Reduced mobility (paralysis, paresis, travel etc.) 
Recent surgery
Indwelling central venous catheters                       
Recent trauma
Recent discontinuation of anticoagulants (e.g., heparin, warfarin, DOACs)
Hormone replacement therapy (including contraceptives)
Phlebitis 
Lupus
Inflammatory bowel disease 
Myeloproliferative disorders
Diabetes mellitus 
Hyperlipidemia
Hypertension                                                                       
Dehydration
Other significant medical co-morbidities or risk factors for DVT, specify:
If yes to any of the above, provide details:
Provide Well’s score, if calculated:
3. Relevant results of diagnostic tests including laboratory tests, imaging, biopsies, etc.
(Note the levels/conclusion, date performed, normal ranges as well as any other details.
Alternatively, attach full reports of the diagnostic tests.)
Diagnostic Test 
Results at baseline or prior 
to use of product (Include 
date and value/details) 
Test results after use of
product (Include date
and value/details)
CBC with smear (microscopic
evaluation)
ESR
Platelet count
Antibodies to platelet factor 4
(PF4)
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
120
Status: Approved,  Date: 16 September 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)
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
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
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
121
Status: Approved,  Date: 16 September 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)
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:
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
122
Status: Approved,  Date: 16 September 2022
10.9. Appendix 9: Thrombotic Events to be Reported as Suspected AESIs
The list of thrombotic events to be reported to the sponsor as 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
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
123
Status: Approved,  Date: 16 September 2022
10.10. Appendix 10: Protocol Amendment History
Amendment 6 (01 June 2022)
Overall Rationale for the Amendment: The overall reason for this amendment is to allow
flexibility to stop enrollment in the sub-study of seronegative participants earlier due to the
increasing challenges of recruiting seronegative participants into the sub study. The amendment
also removes the interim analysis after the first vaccination at 28 days post dose 1 of the main
study. The primary analysis will now include both post dose 1 and post dose 2 data together as the
primary analysis. In alignment with other VAC31518 protocols an exclusion criterion was added
for TTS and HITT.
Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
4.1 Overall Design  
4.2 Scientific Rationale for the 
Study Design  
5.2 Exclusion Criteria 
9.2 Sample Size Determination  
Modify language regarding
enrollment targets for seropositive
and seronegative participants to
allow flexibility to stop enrollment
early for seronegative participants
in the sub study.
There are increasing challenges in
the ability to recruit seronegative
participants.
5.2 Exclusion Criteria 
A history of TTS or HITT have
been added to the exclusion criteria.
To align with other Ad26. COV2.S
protocols.
1.1 Synopsis 
3 Objectives and Endpoints 
Removed the seroconversion
objective from the main study and
included responder information in
the humoral response endpoint for
the main study and sub study.
Simplification and clarification of
the humoral response objective and
endpoint.
1.1 Synopsis 
4.1 Overall Design  
6.3 Measures to Minimize Bias: 
Randomization and Blinding 
9.5 Planned Analyses 
The interim analysis at 28 days post
dose 1 has been removed from the
protocol, and language to allow
additional interim analyses was
added.
This interim analysis at 28 days
post dose 1 will no longer be
performed, but instead the primary
analysis will include post dose 1
and post dose 2 data. However,
additional analyses may be
performed to help facilitate decision
making for future studies or
regulatory submissions; therefore,
language to allow for these
additional analyses has been added.
2.3.1 Risks Related to Study
Participation
Text has on the relationship of
Heparin-induced 
Immune
Thrombotic Thrombocytopenia and
TTS has been added.
New updated IB issued with new
risk language around TTS.
1.1 Synopsis
8.1 Immunogenicity Assessments
The last sentence in the footnotes of
the immunogenicity assessment
table was removed.
This footnote was added in
Amendment 3 to cover the
circumstance of a participant
becoming unblinded due to testing
outside the protocol.
9.4.1 General Considerations 
Added text stating that samples
obtained after SARS-CoV-2
infection will not be included in the
per protocol immunogenicity
analysis set.
Clarification
10.2 Appendix 2: Clinical 
Laboratory Tests 
Combined the columns for serology
testing.
Remove redundancy.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
124
Status: Approved,  Date: 16 September 2022
Section number 
and Name
Description of Change 
Brief Rationale
11 REFERENCES  
Updated IB reference to Edition 6 
(2022) and throughout the protocol.
New updated IB issued.
Throughout the protocol 
Minor grammatical, formatting, 
spelling changes or clarifications 
were made.
Minor errors and clarifications were
noted.
Amendment 5 (30 November 2021)
Overall Rationale for the Amendment: The overall reason for this amendment is to clarify that
hematology assessment will be assessed pre- and post-vaccination in all of the participants in both
the main and sub study. In addition, exploratory endpoints have been updated or added in both the
main and sub study to include analysis against emerging variants due to the evolving nature of the
COVID-19 virus.
Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
3 OBJECTIVES AND 
ENDPOINTS  
Included neutralization and S-
ELISA or equivalent assay analysis
of emerging variants in the
exploratory objectives for the main
and sub study.
An additional exploratory endpoint
has been added to the main and sub
study to access hematology
laboratory parameters pre- and
post-vaccination.
Due to the evolving nature of the
COVID-19 virus.
The exploratory objective was
missing in the previous version of
the protocol.
1.1 Synopsis 
8.1 Immunogenicity Assessments 
Added ELISA as an additional
exploratory assay to the
immunogenicity assessments.
Also added analysis of emerging
variants to SARS-COV-2 VNA.
To align with the addition of the
exploratory objective of binding
antibody assessment against
emerging variants and addition of
analysis of emerging variants via
VNA.
2 INTRODUCTION  
Wording about collaboration with
Operation Warp Speed has been
removed.
BARDA is not funding the
COV3003 study.
8STUDY ASSESSMENTS AND 
PROCEDURES  
Nasal swab kit has been removed
from the list of supplies provided to
the investigator.
Nasal swab kits are not provided to
the investigator in this study.
10.2 Appendix 2: Clinical 
Laboratory Tests 
Included the timepoints when
serum/plasma samples are being
collected for coagulation studies
and clarified that all participants in
the main and sub-study will be
assessed for these hematology
parameters.
Clarification
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
125
Status: Approved,  Date: 16 September 2022
Section number 
and Name
Description of Change 
Brief Rationale
1.4.3 Participant with a Suspected 
AESI 
8.3.6.1 Thrombosis and 
Thrombocytopenia Syndrome 
Removed the requirement for 
laboratory assessments for 
diagnosis for suspected thrombotic 
event or TTS.
This allows the sites flexibility to
make treatment decisions prior to
any laboratory assessments.
Throughout the protocol 
Minor grammatical, formatting, 
spelling changes or clarifications 
were made.
Minor errors and unclarities were
noted.
Amendment 4 (3 August 2021)
Overall Rationale for the Amendment: The mechanism for the rare thrombosis with
thrombocytopenia syndrome (TTS) events that have been reported after vaccination with Johnson
& Johnson’s Ad26.COV2.S vaccine is not known. Examining gene expression in blood cells may
inform on the inflammation signals and pro-thrombotic signaling pathways triggered by
Ad26.COV2.S that can predispose for TTS. Gene expression profiles will be generated from blood
obtained from clinical trials to provide insights into putative signaling pathways that may
predispose for TTS and that are triggered by Ad26.COV2.S. Whole blood RNA will be sampled
on early timepoints after vaccination with Ad26.COV2.S at different dose levels, examining if the
innate gene expression patterns are dose dependent. In addition, serum samples collected at early
timepoints can inform on systemic cytokines and chemokines and lipid mediators of innate
activation to complement the transcriptome analysis. To further characterize the innate, pro-
inflammatory and other relevant (eg, pro-thrombotic) responses to the Ad26.COV2.S vector to
better understand a possible risk to TTS events, an additional sub study consisting of
40 seronegative and 20 seropositive participants to Groups 1, 3, 5 and 6 has been added to the
study. This sub study will obtain blood samples at additional timepoints for additional analyses of
transcriptome and serum innate responses as outlined above to further explore the mechanism of
these TTS events.
Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
1.3 Schema for Participants in the 
Sub Study  
1.4.2 2-dose Vaccination Schedule 
for Participants in the Sub Study  
3 OBJECTIVES AND
ENDPOINTS
4.1 Overall Study Design
4.2 Scientific Rationale for Study
Design
8STUDY ASSESSMENTS AND
PROCEDURES
8.1 Immunogenicity Assessments
9.2 Sample Size Determination
9.4 Statistical Analyses
9.4.4 Exploratory Endpoint(s)
9.5 Planned Analyses
10.2 Appendix 2: Clinical
Laboratory Assessments
A sub study has been added which 
will include an additional 40 
participants per group to investigate
the mechanism of action leading to
the possible risk to TTS events.
To gain insight into the potential
mechanism of TTS.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
126
Status: Approved,  Date: 16 September 2022
Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
3 OBJECTIVES AND 
ENDPOINTS  
Updated the endpoint text in the 
main study objectives from
“examining immune response in
vaccinated individuals after natural
infection” to individuals after
“breakthrough infection”.
Clarification
5.2 Exclusion Criteria 
Exclusion criterion 20 has been 
updated with a note that 
seropositive participants are not 
excluded from entering into the sub
study.
Both seronegative and seropositive
subjects will be enrolled in the sub
study.
2.3.1 Risks Related to Study 
Participation  
7.1 Discontinuation of Study 
Vaccination  
8.2.1 Physical Examinations 
10.1 Abbreviations and Definitions 
Text has been added regarding the 
increased risk of Guillain-Barre 
Syndrome (GBS) following use of 
the Ad26.COV2.S vaccine. GBS 
has also been added to the list of 
reasons for the discontinuation of
the Ad26.COV2.S vaccine.
Based on the emerging data
following use of the Ad26.COV2.S
vaccine, GBS has been identified as
an adverse drug reaction for the use
of Ad26.COV2.S vaccine.
1.1 Synopsis 
9.5 Planned Analyses 
Clarified up to what day the 
primary safety and immunogenicity
analyses will be performed.
Clarification
Throughout the protocol 
Minor grammatical, formatting, 
spelling changes or clarifications 
were made.
Minor errors and unclarities were
noted.
Amendment 3 (23 June 2021)
Overall Rationale for the Amendment:The main purpose of this amendment is to move the Day
85 sampling timepoint (28 days post-dose 2) to Day 71 (14 days post-dose 2) in order to align
across VAC31518COVID studies. This amendment also updates the amount of blood volume
needed (from 12 mL to 15 mL) to be collected at baseline and for AESI evaluations due to the
increased volume of blood needed to isolate serum/plasma for the coagulation related assays in the
study. An additional exclusion criterion for participants with a history of capillary leak syndrome
has also been added.
Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
1.2 Schema
1.4.1 2-dose Vaccination Schedule
3 OBJECTIVES AND
ENDPOINTS
4.1 Overall Study Design
9.1 Statistical Hypotheses
9.2.1 Immunogenicity
9.5 Planned Analyses
10.2 Appendix 2: Clinical
Laboratory Assessments
Move the sampling timepoint from
85 days post first vaccination (28
days post-dose 2) to 71 days post
first vaccination (14 days post-dose
2).
To align the post-dose 2
immunological assessment across
studies, to occur 14 days post-dose
2.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
127
Status: Approved,  Date: 16 September 2022
Section number 
and Name
Description of Change 
Brief Rationale
1.4.1 2-dose Vaccination Schedule 
1.4.3 Participants with a Suspected 
AESI 
8STUDY ASSESSMENTS AND 
PROCEDURES
The blood volume collected for 
clinical lab blood samples collected 
at baseline and for AESIs has been 
increased from 12 mL to 15 mL.
Clarification on the blood volume
to be collected in the event of a
suspected AESI.
5.2 Exclusion Criteria 
7.1 Discontinuation of Study 
Vaccination  
Additional exclusion criterion and 
reason for discontinuation of study 
vaccination have been added that
excludes/discontinues participants
from the study or further
vaccination who have a history of
capillary leak syndrome or
experience this event after the first
study vaccination.
Based on emerging postmarketing
safety data.
1.1 Synopsis 
8.1 Immunogenicity Assessments 
A footnote has been added to the 
serology table in the synopsis and 
Table 4 describing the risks to 
participants who seek serological 
testing outside the study.
Due to a risk of a participant
becoming unblinded through
antibody testing outside the
protocol.
Throughout the protocol 
Minor grammatical, formatting, 
spelling changes or clarifications 
were made.
Minor errors and unclarities were
noted.
Amendment 2 (10 May 2021)
Overall Rationale for the Amendment: This amendment has been created to include additional
safety measures due to reports of adverse events following use of the Ad26.COV2.S vaccine under
emergency use authorization in the US, suggesting an increased risk of thrombosis combined with
thrombocytopenia. Based on this, thrombosis with thrombocytopenia syndrome (TTS), which is a
very rare event, will be followed in this protocol as adverse event of special interest (AESI) that
needs to be reported to the sponsor within 24 hours of awareness. In addition, the protocol has
been adjusted to align with the latest vaccine risk language.
In addition, the blood volume for SARS.CoV.2 serology has been reduced and the exclusion
criterion excluding employees and family members from participating in the study has been added
back into the protocol per health authority request.
Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
1.4.1 2-dose Vaccination Schedule 
1.4.3 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 Study Design  
6.8Prestudy and Concomitant 
TTS will be considered an AESI. 
Follow-up assessments will be 
performed in the event of a 
suspected AESI. In addition, blood 
samples will be collected for a 
baseline assessments of platelet 
count and storage for future 
coagulation-related testing. 
Emerging data following use of the
Ad26.COV2.S vaccine under
emergency use authorization in the
US suggest an increased risk of
thrombosis combined with
thrombocytopenia, with onset of
symptoms approximately 1-2 weeks
after vaccination. Therefore,
additional reporting and data
collection procedures are
implemented to follow-up
thrombotic events and
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
128
Status: Approved,  Date: 16 September 2022
Section number 
and Name
Description of Change 
Brief Rationale
Therapy  
7.1 Discontinuation of Study 
Vaccination
8STUDY ASSESSMENTS AND
PROCEDURES
8.2.4 Clinical Laboratory
Assessments
8.3 Adverse Events, Serious
Adverse Events, Medically-
attended Adverse Events, Adverse
Events of Special Interest, and
Other Safety Reporting
8.3.1 Time Period and Frequency
for Collecting Adverse Event,
Medically-attended Adverse Event,
Adverse Event of Special Interest,
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
8.3.6 Adverse Events of Special
Interest
8.3.6.1 Thrombosis with
Thrombocytopenia Syndrome
9.4.3 Secondary Endpoint(s)
10.2 Clinical Laboratory Tests
10.3.6 Safety Monitoring
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
10.8Appendix 8: TTS AESI Form
10.9 Appendix 9: Thrombotic
Events to be Reported as AESIs
thrombocytopenia and identify
cases of TTS.
1.4.1 2-dose Vaccination Schedule 
The volume of blood taken for 
SARS.CoV.2 serology has been 
reduced from 3.5mL to 2.5mL.
For consistency across COVID
protocols.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
129
Status: Approved,  Date: 16 September 2022
Section number 
and Name
Description of Change 
Brief Rationale
5.2 Exclusion Criteria 
Exclusion criterion excluding 
employees and family members of
the investigator or sponsor from the
study has been reintroduced.
Per health authority request.
10.2 Clinical Laboratory Tests 
Added a clinical laboratory test 
table to the appendix. 
For consistency across COVID
protocols.
Throughout the protocol 
Minor grammatical, formatting, 
spelling changes or clarifications 
were made.
Minor errors and unclarities were
noted.
Amendment 1 (8 March 2021)
Overall Rationale for the Amendment: The main purpose of this amendment is the removal of
the Placebo arms of the study, as placebo control is considered not required for end-of shelf-life
investigation. Furthermore, after consideration of additional COV2001 study results, dose groups
of9×1010 vp, 7×1010 vp, and 3.5×1010 vp Ad26.COV2.S were added and the 1-dose regimen was
removed, resulting in 6 dose-groups, each receiving 2 doses.
Section Number 
and Name
Description of Change 
Brief Rationale
Protocol Title
1.1 Synopsis
2 INTRODUCTION
4.1 Overall Design
4.2 Scientific Rationale for
Study Design
6.1 Study Vaccines
Administered
6.6 Continued Access to
Study Vaccine After the End
of the Study
9.2.1 Immunogenicity
Placebo arms have been removed. 
Placebo control is considered
not required for end-of shelf-
life investigation
1.1 Synopsis
2.1 Study Rationale
3 OBJECTIVES AND
ENDPOINTS
4.1 Overall Design
4.3 Justification for Dose
6.1 Study Vaccines
Administered
9.1 Statistical Hypotheses
9.2 Sample Size
Determination
9.2.1 Immunogenicity
9.4.2 Primary Endpoint(s)
Dose groups of 9×1010 vp, 7×1010 vp and
3.5×1010 vp Ad26.COV2.S were added and the
1-dose regimen was removed, resulting in 6
dose-groups, each receiving 2 doses.
New insights after
consideration of additional
COV2001 study results.
1.1 Synopsis
6.6 Continued Access to
Study Vaccine After the End
of the Study
Added language that allows participants in
groups not meeting non-inferiority to receive a
booster dose.
To ensure that participants in
groups who received a dose
level that did not meet non-
inferiority would be eligible to
receive a licensed/authorized
dose.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
130
Status: Approved,  Date: 16 September 2022
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
6.3 Measures to Minimize 
Bias: Randomization and 
Blinding 
6.6 Continued Access to 
Study Vaccine After the End 
of the Study  
7.1 Discontinuation of Study 
Vaccination  
9.5 Planned Analyses
Clarification ofprocedures 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 on
receiving two different
COVID-19 vaccines.
1.1 Synopsis 
4.1 Overall Design  
9.4.5 Other Analyses 
Updated the type of safety information that 
should be shared with the IDMC from 
“ongoing” to “significant” safety information. 
To clarify type of safety data
that will be shared with the
IDMC.
1.4.1 2-dose Vaccination 
Schedule 
Clarified in footnote r that the site should report 
the 2nd vaccination date in the eCOA portal at
Visit 4 to ensure that the appropriate diary is
visible in the electronic diary.
Added to footnote 6 that a valid SARS-CoV-2
test within 28 days of screening was
acceptable.
Clarified in footnote j that if the participant has
acute illness or body temperature
≥38.0°C/100.4°F 24 hours prior to planned
vaccination, the vaccination can be rescheduled
Clarifications
1.4.1 2-dose Vaccination 
Schedule 
4.1 Overall Design
Additional blood draw added pre-vaccination at 
Day 57. 
Added SARS-Cov-2 serology as a separate 
sample collection. 
Evaluates a longer timepoint
after 1 dose.
Aliquots for this testing cannot
be taken from samples
planned for humoral immunity
analyses.
5.1 Inclusion Criteria 
Redundant text in Criterion 5 stating 
participants with comorbidities increasing their 
risk for severe COVID-19 except for smoking
was removed.
Added the word “female” to Criterion 7 for 
clarification. 
Added footnote to inclusion Criterion 6 about 
the use of condoms as an acceptable 
contraceptive barrier.
Adjusted inclusion Criterion 4 to BMI <35 
Mentioned twice in the
Criterion.
Alignment with other Phase 3
protocols.
Alignment with other Phase 3
protocols.
To allow less restrictions for
enrollment.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
131
Status: Approved,  Date: 16 September 2022
Section Number 
and Name
Description of Change 
Brief Rationale
5.2 Exclusion Criteria 
6.8 Prestudy and 
Concomitant Therapy  
7.1 Discontinuation of Study 
Vaccination  
Added to Criterion 4 that a substantial 
immunosuppressive steroid dose is defined as 
≥2 weeks of daily receipt of 20 mg of
prednisone or equivalent. Therefore, the
specification of ‘(>10 days)’ when referring to
the chronic use of systemic corticosteroids has
been removed from the exclusion criterion 4
and aligned throughout.
Alignment with other Phase 3
protocols.
5.2 Exclusion Criteria 
6.8Prestudy and 
Concomitant Therapy  
Clarified in Criterion 9 that investigational drug 
includes drugs for prophylaxis of COVID-19. 
Also clarified that the use of investigational
immunoglobulin (Ig) and monoclonal
antibodies or convalescent serum are not
allowed during the study.
Alignment with other Phase 3
protocols.
5.2 Exclusion Criteria 
Updated text to be more specific about the type 
of blood products used for treatment in 
Criterion 7.
Exclusion criterion 14 deleted: There is no
restriction on enrollment of participants that are
employees of the investigator or study site, as
well as family members of the employees or
the investigator, or an employee of the sponsor.
Clarification on definition of diabetes in 
Criterion 20.
Alignment with other Phase 3
protocols.
Clarification
7.2 Participant 
Discontinuation/Withdrawal 
From the Study
Clarified that a participant that withdrawals 
consent will be offered an optional safety visit.
Clarification
8STUDY ASSESSMENTS 
AND PROCEDURES  
Removed reference to home visits 
Removed reference to molecular testing for the
presence of SARS-CoV-2 infection within 4
days before vaccination,
The study is not operationally
set up for home visits
9.4.3 Secondary Endpoint(s) 
Removal of the text that SAEs and MAAEs are 
collected on the full FAS. 
Redundant with the previous
paragraph.
10.5 Appendix 5: 
Contraceptive Guidance and 
Collection of Pregnancy
Information
Adjusted wording regarding ‘permanently 
sterile’ 
Alignment with ICF risk
language
Throughout the protocol 
Minor editorial adjustments for clarification, 
grammatical, formatting, or spelling changes 
were made. 
Clarification, grammatical,
formatting, or spelling
correction
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
132
Status: Approved,  Date: 16 September 2022
11. 
REFERENCES
1. 
Agrawal AS (2016), Tao X, Algaissi A, et al. Immunization with inactivated Middle East Respiratory
Syndrome coronavirus vaccine leads to lung immunopathology on challenge with live virus. Hum Vaccin
Immunother. 2016;12(9):2351-2356.
2. 
American Society of Hematology. COVID-19 resources (2021). Thrombosis with Thrombocytopenia
Syndrome (also termed Vaccine-induced Thrombotic Thrombocytopenia). https://www.hematology.org/covid-
19/vaccine-induced-immune-thrombotic-thrombocytopenia. Accessed: 27 April 2021.
3. 
Anywaine Z (2019), Whitworth H, Kaleebu P, et al. Safety and Immunogenicity of a 2-Dose Heterologous
Vaccination Regimen With Ad26.ZEBOV and MVA-BN-Filo Ebola Vaccines: 12-Month Data From a Phase 1
Randomized Clinical Trial in Uganda and Tanzania. J Infect Dis. 2019;220(1):46-56.
4. 
Arepally GM, Padmanabhan, A. Heparin-induced thrombocytopenia: a focus on thrombosis. Arterioscler
Thromb Vasc Biol. 2021;41:141–152.
5. 
Barouch DH (2013), Liu J, Peter L, et al. Characterization of humoral and cellular immune responses elicited
by a recombinant adenovirus serotype 26 HIV-1 Env vaccine in healthy adults (IPCAVD 001). J Infect Dis.
2013:207(2);248-256.
6. 
Barouch DH (2018), Tomaka FL, Wegmann F, et al. Evaluation of a mosaic HIV-1 vaccine in a multicentre,
randomised, double-blind, placebo-controlled, phase 1/2a clinical trial (APPROACH) and in rhesus monkeys
(NHP 13-19). Lancet. 2018;392(10143):232-243.
7. 
Berry JD (2004), Jones S, Drebot MA, et al. Development and characterisation of neutralising monoclonal
antibody to the SARS-coronavirus. J Virol Methods. 2004;120(1):87-96.
8. 
Bisht H (2004), Roberts A, Vogel L, et al. Severe acute respiratory syndrome coronavirus spike protein
expressed by attenuated vaccinia virus protectively immunizes mice. Proc Natl Acad Sci USA.
2004;101(17):6641-6646.
9. 
Bolles M (2011), Deming D, Long K, et al. A double-inactivated severe acute respiratory syndrome
coronavirus vaccine provides incomplete protection in mice and induces increased eosinophilic
proinflammatory pulmonary response upon challenge. J Virol. 2011;85(23):12201-12215.
10. Brighton Collaboration. Interim Case Definition of Thrombosis with Thrombocytopenia Syndrome (TTS)
(2021). 21 April 2021. https://brightoncollaboration.us/thrombosis-with-thrombocytopenia-syndrome-interim-
case-definition/. Accessed: 29 April 2021.
11. British Society for Haematology. Guidance produced from the Expert Haematology Panel (EHP) focussed on
Covid-19 Vaccine induced Thrombosis and Thrombocytopenia (VITT)(2021). https://b-s-
h.org.uk/media/19530/guidance-version-13-on-mngmt-of-thrombosis-with-thrombocytopenia-occurring-after-
c-19-vaccine 20210407.pdf. Version 1.3; 7 April 2021.  Accessed: 27 April 2021.
12. Buchholz UJ (2004), Bukreyev A, Yang L, et al. Contributions of the structural proteins of severe acute
respiratory syndrome coronavirus to protective immunity. Proc Natl Acad Sci USA. 2004;101(26):9804-9809.
13. Bukreyev A (2004), Lamirande EW, Buchholz UJ, et al. Mucosal immunisation of African green monkeys
(Cercopithecus aethiops) with an attenuated parainfluenza virus expressing the SARS coronavirus spike protein
for the prevention of SARS. Lancet. 2004;363(9427):2122-2127.
14. Centers for Disease Control and Prevention (2021e). Cases of cerebral venous sinus thrombosis with
thrombocytopenia after receipt of the Johnson & Johnson COVID-19 Vaccine. 13 April 2021.
https://emergency.cdc.gov/han/2021/han00442.asp. Accessed: 27 April 2021.
15. Center for Disease Control and Prevention (2020b). Coronavirus Disease 2019 (COVID-19) Symptoms of
Coronavirus. Available at: https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html.
Accessed: 18 September 2020.
16. Centers for Disease Control and Prevention (2020c). Coronavirus disease 2019 (COVID-19). Groups at higher
risk for severe illness. https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-
medical-conditions.html?CDC AA refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-
ncov%2Fneed-extra-precautions%2Fgroups-at-higher-risk.htmlAccessed 19 Jul 2020.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
133
Status: Approved,  Date: 16 September 2022
17. Centers for Disease Control and Prevention (2021I). Reproductive Health: Contraception.
https://www.cdc.gov/reproductivehealth/contraception Accessed 1 March 2021.
18. Chan JF (2015), Lau SK, To KK, Cheng VC, Woo PC, Yuen KY. Middle East respiratory syndrome
coronavirus: another zoonotic betacoronavirus causing SARS-like disease. Clin. Microbiol. Rev.
2015;28(2):465–522.
19. Chen N (2020), Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel
coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-513.
20. Chen Z (2005), Zhang L, Qin C, et al. Recombinant modified vaccinia virus Ankara expressing the spike
glycoprotein of severe acute respiratory syndrome coronavirus induces protective neutralizing antibodies
primarily targeting the receptor binding region. J Virol. 2005;79(5):2678-2688.
21. Chin J (1969), Magoffin RL, Shearer LA, Schieble JH, Lennette EH. Field evaluation of a respiratory syncytial
virus vaccine and a trivalent parainfluenza virus vaccine in a pediatric population. Am J Epidemiol.
1969;89(4);449-463.
22. Colby DJ (2020), Sarnecki M, Barouch DH, et al. Safety and immunogenicity of Ad26 and MVA vaccines in
acutely treated HIV and effect on viral rebound after antiretroviral therapy interruption. Nat Med.
2020;26(4):498-501.
23. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses (2020). The species
Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2.
Nat Microbiol. 2020;5(4):536-544.
24. Cyranoski D (2020). The biggest mystery: what it will take to trace the coronavirus source. Nature News 2020;
doi: 10.1038/d41586-020-01541-z.
25. Deming D (2006), Sheahan T, Heise M, et al. Vaccine efficacy in senescent mice challenged with recombinant
SARS-CoV bearing epidemic and zoonotic spike variants. PLoS Med. 2006;3(12):e525.
26. Dong Y (2020), Mo X, Hu Y, et al. Epidemiological Characteristics of 2143 Pediatric Patients With 2019
Coronavirus Disease in China. Pediatrics. 2020 Mar 16. pii: e20200702. [Epub ahead of print]
27. European Centre for Disease Prevention and Control (2020b). Factsheet for health professionals on
coronaviruses. https://www.ecdc.europa.eu/en/factsheet-health-professionals-coronaviruses.
Accessed 21 September 2020.
28. European Commission (1998) 98/463/EC: Council Recommendation of 29 June 1998 on the suitability of
blood and plasma donors and the screening of donated blood in the European Community.
29. Faber M (2005), Lamirande EW, Roberts A, et al. A single immunization with a rhabdovirus-based vector
expressing severe acute respiratory syndrome coronavirus (SARS-CoV) S protein results in the production of
high levels of SARS-CoV-neutralizing antibodies. J Gen Virol. 2005;86(Pt 5):1435-1440.
30. Fulginiti VA (1969), Eller JJ, Sieber OF, Joyner JW, Minamitani M, Meiklejohn G. Respiratory virus
immunization. I. A field trial of two inactivated respiratory virus vaccines; an aqueous trivalent parainfluenza
virus vaccine and an alum-precipitated respiratory syncytial virus vaccine. Am J Epidemiol.
1969:89(4);435-448.
31. Gidudu JF (2012), Walco GA, Taddio A, et al./The Brighton Immunization Site Pain Working Group.
Immunization site pain: Case definition and guidelines for collection, analysis, and presentation of
immunization safety data. Vaccine. 2012:30(30);4558-4577.
32. Honda-okubo Y (2015), Barnard D, Ong CH, Peng BH, Tseng CT, Petrovsky N. Severe acute respiratory
syndrome-associated coronavirus vaccines formulated with delta inulin adjuvants provide enhanced protection
while ameliorating lung eosinophilic immunopathology. J Virol. 2015;89(6):2995-3007.
33. Houser KV (2017), Broadbent AJ, Gretebeck L, et al. Enhanced inflammation in New Zealand white rabbits
when MERS-CoV reinfection occurs in the absence of neutralizing antibody. PLoS Pathog.
2017;13(8):e1006565.
34. Investigator's Brochure (2022): Ad26.COV2.S (VAC31518), Edition 6.0. Janssen Vaccines & Prevention B.V
(May 2022).Janssen Vaccines & Prevention B.V. Data on file.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
134
Status: Approved,  Date: 16 September 2022
35. Johns Hopkins CSSE (2020). Coronavirus COVID-19 Global Cases.
https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6.
Accessed 19 July 2020.
36. Kapikian AZ (1969), Mitchell RH, Chanock RM, Shvedoff RA, Stewart CE. An epidemiologic study of altered
clinical reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated with an
inactivated RS virus vaccine. Am J Epidemiol. 1969:89(4);405-421.
37. Kim HW (1969), Canchola JG, Brandt CD, et al. Respiratory syncytial virus disease in infants despite prior
administration of antigenic inactivated vaccine. Am J Epidemiol. 1969:89(4);422-434.
38. Kohl KS (2007), Walop W, Gidudu J, et al./The Brighton Collaboration Local Reaction Working Group for
Swelling at or near Injection Site. Swelling at or near injection site: Case definition and guidelines for
collection, analysis and presentation of immunization safety data. Vaccine 2007:25(31);5858-5874.
39. Letko M (2020), Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2
and other lineage B betacoronaviruses. Nat Microbiol. 2020;5:562–569.
40. Li Q (2020), Guan X, Wu P, et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-
Infected Pneumonia. N Engl J Med. 2020;382:119-1207.
41. Lu R (2020), Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus:
implications for virus origins and receptor binding. Lancet. 2020;395(10224):565-574.
42. Marcy (2004)SM, Kohl KS, Dagan R, et al./The Brighton Collaboration Fever Working Group. Fever as an
adverse event following immunization: case definition and guidelines of data collection, analysis, and
presentation. Vaccine 2004:22(5-6);551-556.
43. Milligan ID (2016), Gibani MM, Sewell R, et al. Safety and immunogenicity of novel adenovirus type 26- and
modified vaccinia ankara-vectored ebola vaccines: a randomized clinical trial. JAMA.
2016:315(15);1610-1623.
44. Modjarrad K (2019), Roberts CC, Mills KT, et al. Safety and immunogenicity of an anti-Middle East
respiratory syndrome coronavirus DNA vaccine: a phase 1, open-label, single-arm, dose-escalation trial.
Lancet Infect Dis. 2019;19(9):1013-1022.
45. Moghaddam A (2006), Olszewska W, Wang B, et al. A potential molecular mechanism for hypersensitivity
caused by formalin-inactivated vaccines. Nat Med. 2006:12(8);905-907.
46. Mutua G (2019), Anzala O, Luhn K, et al. Safety and Immunogenicity of a 2-Dose Heterologous Vaccine
Regimen With Ad26.ZEBOV and MVA-BN-Filo Ebola Vaccines: 12-Month Data From a Phase 1
Randomized Clinical Trial in Nairobi, Kenya. J Infect Dis. 2019;220(1):57-67.
47. Sadoff J (2020), Le Gars M, Shukarev G, et al. Safety and immunogenicity of the Ad26.COV2.S COVID-19
vaccine candidate: interim results of a phase 1/2a, double-blind, randomized, placebo-controlled trial. medRxiv
2020; doi: https://doi.org/10.1101/2020.09.23.20199604.
48. Salisch NC (2019), Izquierdo gil A, Czapska-casey DN, et al. Adenovectors encoding RSV-F protein induce
durable and mucosal immunity in macaques after two intramuscular administrations. NPJ Vaccines. 2019;4:54.
49. Smatti MK (2018), Al Thani AA, Yassine HM. Viral-Induced Enhanced Disease Illness. Front Microbiol.
2018;9:2991.
50. Stephenson KE (2020), Wegmann F, Tomaka F, et al. Comparison of shortened mosaic HIV-1 vaccine
schedules: a randomised, double-blind, placebo-controlled phase 1 trial (IPCAVD010/HPX1002) and a
preclinical study in rhesus monkeys (NHP 17-22). Lancet HIV. 2020; doi: 10.1016/S2352-3018(20)30001-1.
Erratum in: Lancet HIV. 2020 Feb 28.
51. Streiff MB. Pathogenesis and Management of Thrombosis with Thrombocytopenia Syndrome (TTS). Centers
for Disease Control & Prevention Advisory Committee on Immunization Practices (ACIP) meeting
23 April 2021. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-04-23/02-COVID-Strieff-
508.pdf. (accessed 18 May 2021).
52. Subbarao K (2004), McAuliffe J, Vogel L, et al. Prior infection and passive transfer of neutralizing antibody
prevent replication of severe acute respiratory syndrome coronavirus in the respiratory tract of mice. J Virol.
2004;78(7):3572-3577.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
135
Status: Approved,  Date: 16 September 2022
53. Sui J (2005), Li W, Roberts A, et al. Evaluation of human monoclonal antibody 80R for immunoprophylaxis of
severe acute respiratory syndrome by an animal study, epitope mapping, and analysis of spike variants. J Virol.
2005;79(10):5900-5906.
54. U.S. Department of Health and Human Services (2007), Food and Drug Administration, Center for Biologics
Evaluation and Research. September 2007. Guidance for Industry. Toxicity Grading Scale for Healthy Adult
and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials.
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidan
ces/Vaccines/ucm091977.pdf. Accessed 19 February 2020.
55. US Department of Health and Human Services (1998). Office for Human Research Protections - OHRP
Expedited Review Categories. 1998. https://www.hhs.gov/ohrp/regulations-and-policy/guidance/categoriesof-
research-expedited-review-procedure-1998/index.html. Accessed 18 September 2020.
56. US Food and Drug Administration (1998). Conditions for IRB Use of Expedited Review. Federal Register:
November 9, 1998 (Volume 63, Number 216). https://www.fda.gov/science-research/guidance-
documentsincluding-information-sheets-and-notices/conditions-irb-use-expedited-review. Accessed
24 February 2020.
57. US Food and Drug Administration (2020a). COVID-19: Developing Drug and Biological Products for
Treatment or Prevention. Guidance for Industry. May 2020.
https://www.fda.gov/media/137926/downloadAccessed 13 November 2020.
58. US Food and Drug Administration (2020b). Development and Licensure of Vaccines to Prevent COVID-19.
Guidance for Industry. June 2020. https://www.fda.gov/media/139638/download. Accessed 13 November
2020.
59. van der Fits L (2020), Bolder R, Heemskerk-van der Meer M, et al. Adenovector 26 encoded prefusion
conformation stabilized RSV-F protein induces long-lasting Th1-biased immunity in neonatal mice. NPJ
Vaccines. 2020 [provisionally accepted for publication]
60. Widjojoatmodjo MN (2015), Bogaert L, Meek B, et al. Recombinant low-seroprevalent adenoviral vectors
Ad26 and Ad35 expressing the respiratory syncytial virus (RSV) fusion protein induce protective immunity
against RSV infection in cotton rats. Vaccine. 2015;33(41):5406-5414.
61. World Health Organization (2005a). Statement on the second meeting of the International Health Regulations
(2005) Emergency Committee regarding the outbreak of novel coronavirus (2019-nCoV).
https://www.who.int/news-room/detail/30-01-2020-statement-on-the-second-meeting-of-the-international-
health-regulations-(2005)-emergency-committee-regarding-the-outbreak-of-novel-coronavirus-(2019-ncov).
Accessed 21 September 2020.
62. World Health Organization (2020c). WHO Director-General's opening remarks at the media briefing on
COVID-19 - 11 March 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-
at-the-media-briefing-on-covid-19---11-march-2020. Accessed 06 October 2020.
63. World Health Organization (2004). WHO guidelines for the global surveillance of severe acute respiratory
syndrome (SARS). Updated recommendations, October 2004.
https://www.who.int/csr/resources/publications/WHO CDS CSR ARO 2004 1/en/. Accessed 21 September
2020..
64. Wu F (2020), Zhao S, Yu B, et al. A new coronavirus associated with human respiratory disease in China.
Nature. 2020;579(7798):265-269.
65. Yang ZY (2004), Kong WP, Huang Y, et al. A DNA vaccine induces SARS coronavirus neutralization and
protective immunity in mice. Nature. 2004;428(6982):561-564.
66. Zahn R (2012), Gillisen G, Roos A, et al. Ad35 and Ad26 vaccine vectors induce potent and cross-reactive
antibody and T-cell responses to multiple filovirus species. PLoS ONE. 2012;7(12):e44115.
67. Zhang H (2004), Wang G, Li J, et al. Identification of an antigenic determinant on the S2 domain of the severe
acute respiratory syndrome coronavirus spike glycoprotein capable of inducing neutralizing antibodies. J Virol.
2004;78(13):6938-6945.
68. Zhao J (2017), Alshukairi AN, Baharoon SA, et al. Recovery from the Middle East respiratory syndrome is
associated with antibody and T-cell responses. Sci Immunol. 2017;2(14). pii: eaan5393.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
136
Status: Approved,  Date: 16 September 2022
69. Zhou P (2020), Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of
probable bat origin. Nature. 2020;579(7798):270-273.
70. Zhou T (2004), Wang H, Luo D, et al. An exposed domain in the severe acute respiratory syndrome
coronavirus spike protein induces neutralizing antibodies. J Virol. 2004;78(13):7217-7226.
71. Zumla A (2016), Chan JF, Azhar EI, Hui DS, Yuen KY. Coronaviruses - drug discovery and therapeutic
options. Nat Rev Drug Discov. 2016;15(5):327-347.
NCT04908722

VAC31518 (JNJ-78436735) 
Clinical Protocol VAC31518COV3003 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
137
Status: Approved,  Date: 16 September 2022
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Vaccines & Prevention B.V.
Signature: electronic signature appended at the end of the protocol 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the study, written notification will be
provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD
NCT04908722

Signature
User 
Date 
Reason
 
19-Sep-2022
07:49:10
(GMT)
Document Approval
PPD
NCT04908722