A Randomized, Double-blind, Placebo-controlled Phase 3 Study to Evaluate the Immunogenicity and Safety of Ad26.RSV.preF-based Vaccine and High-dose Seasonal Influenza Vaccine, With and Without Coadministration, in Adults Aged 65 Years and Older
Phase: PHASE3
Conditions: Influenza, Human Prevention, Respiratory Syncytial Viruses Prevention
Sponsor: Janssen Vaccines & Prevention B.V.

CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,Date: 7 February 2022
Janssen Vaccines & Prevention B.V. *
Clinical Protocol
A Randomized, Double-blind, Placebo-controlled Phase 3 Study to Evaluate the
Immunogenicity and Safety of Ad26.RSV.preF-based Vaccine and High-dose Seasonal
Influenza Vaccine, With and Without Coadministration, in Adults Aged 65 Years and
Older
Protocol VAC18193RSV3005; Phase 3
Amendment 2
VAC18193 (JNJ-64400141/JNJ-64213175)
* Janssen Vaccines & Prevention B.V. is a Janssen pharmaceutical company of Johnson & Johnson and is hereafter
referred to as the sponsor of the study. The sponsor is identified on the Contact Information page that accompanies
the protocol.
Studies conducted at sites in the United States (US)will be conducted under US Food & Drug
Administration Investigational New Drug (IND) regulations (21 CFR Part 312).
Status: 
Approved
Date: 
7 February 2022
Prepared by: Janssen Vaccines & Prevention B.V.
EDMS number: 
EDMS-RIM-305812, 3.0
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.
NCT05071313

VAC18193 (JNJ-64400141/JNJ-64213175) 
Clinical Protocol VAC18193RSV3005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved,Date: 7 February 2022
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 2 
This document
Amendment 1 
1 December 2021
Original Protocol 
17 May 2021
Amendment 2 (This document)
Overall Rationale for the Amendment: The VAC18193RSV3005 study was designed to
evaluate the concomitant administration of Ad26.RSV.preF-based vaccine and a seasonal
influenza vaccine, which is routinely administered to eligible adults ahead of the peak of the
influenza season (~ mid-winter usually). At the time of this amendment, the initial target sample
size was unlikely to be achieved because the majority of adults ≥65 years in the selected areas had
already received their seasonal influenza vaccination. Therefore, the target sample size has been
reduced. The new target sample size of approximately 750 participants still affords at least 80%
power to achieve the primary objective, which is deemed acceptable.
Additionally, the name of the laboratory for the validated hemagglutination inhibition (HI) assay
has been removed to allow flexibility for laboratory selection, and a clarification regarding the
database transfer and review of participant diary entries has been made.
The changes made to the clinical protocol VAC18193RSV3005 as part of Protocol Amendment 2
are listed below, including the rationale of each change and a list of all applicable sections.
Changes made in previous protocol amendments are listed in Section 10.7 Appendix 7: Protocol
Amendment History.
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
4.1 Overall Design
9.2 Sample Size
Determination
The targeted total sample size for the
study has been revised from 880 to
approximately 750 participants.
Because of challenges with enrollment of
participants that have not yet received a
seasonal influenza vaccine during the
2021-2022 influenza season.
The new target sample size still affords at
least 80% power to achieve the primary
objective, which is deemed acceptable.
1.1 Synopsis
8.1 Immunogenicity
Assessments
The name of the laboratory for the
validated HI assay has been removed.
To allow flexibility for laboratory
selection for the HI assay.
1.3 Schedule of
Activities
8.3.2 Method of
Detecting AEs, SAEs,
and AESIs
The process and responsible parties for
transferring participant diary information
into the database and for reviewing and
grading of diary entries has been
clarified.
Clarification

VAC18193 (JNJ-64400141/JNJ-64213175) 
Clinical Protocol VAC18193RSV3005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Status: Approved,Date: 7 February 2022
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 3
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
1. 
PROTOCOL SUMMARY..................................................................................................................... 6
1.1. 
Synopsis........................................................................................................................................... 6
1.2. 
Schema.......................................................................................................................................... 13
1.3. 
Schedule of Activities..................................................................................................................... 14
2. 
INTRODUCTION................................................................................................................................ 17
2.1. 
Study Rationale.............................................................................................................................. 17
2.2. 
Background .................................................................................................................................... 18
2.3. 
Benefit-risk Assessment................................................................................................................. 19
2.3.1. 
Risks Related to Study Participation .......................................................................................... 19
2.3.2. 
Benefits of Study Participation.................................................................................................... 21
2.3.3. 
Benefit-risk Assessment of Study Participation.......................................................................... 22
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 23
4. 
STUDY DESIGN ................................................................................................................................ 25
4.1. 
Overall Design................................................................................................................................ 25
4.2. 
Scientific Rationale for Study Design............................................................................................. 26
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 27
4.3. 
Justification for Dose...................................................................................................................... 27
4.4. 
End of Study Definition................................................................................................................... 28
5. 
STUDY POPULATION ...................................................................................................................... 28
5.1. 
Inclusion Criteria............................................................................................................................ 28
5.2. 
Exclusion Criteria........................................................................................................................... 29
5.3. 
Lifestyle Considerations................................................................................................................. 32
5.4. 
Screen Failures.............................................................................................................................. 32
5.5. 
Criteria for Temporarily Delaying Study Vaccine Administration ................................................... 33
6. 
STUDY VACCINES AND CONCOMITANT THERAPY.................................................................... 33
6.1. 
Study Vaccines Administration ...................................................................................................... 33
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 34
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 36
6.4. 
Study Vaccination Compliance ...................................................................................................... 37
6.5. 
Dose Modification........................................................................................................................... 37
6.6. 
Continued Access to Study Vaccine After the End of the Study ................................................... 37
6.7. 
Treatment of Overdose .................................................................................................................. 37
6.8. 
Concomitant Therapy..................................................................................................................... 37
7. 
DISCONTINUATION OF STUDY VACCINATION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 39
7.1. 
Discontinuation of Study Vaccination............................................................................................. 39
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 39
7.2.1. 
Withdrawal From the Use of Research Samples ....................................................................... 40
7.3. 
Lost to Follow-up............................................................................................................................ 40
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 40
8.1. 
Immunogenicity Assessments ....................................................................................................... 42
8.2. 
Safety Assessments....................................................................................................................... 43
8.2.1. 
Physical Examinations................................................................................................................ 43
8.2.2. 
Vital Signs................................................................................................................................... 43

VAC18193 (JNJ-64400141/JNJ-64213175) 
Clinical Protocol VAC18193RSV3005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved,Date: 7 February 2022
8.3. 
AEs, SAEs, AESIs, and Other Safety Reporting ........................................................................... 44
8.3.1. 
Time Period and Frequency for Collecting AE, SAE, and AESI Information.............................. 44
8.3.2. 
Method of Detecting AEs, SAEs, and AESIs.............................................................................. 45
8.3.3. 
Follow-up of AEs, SAEs, and AESIs .......................................................................................... 46
8.3.4. 
Regulatory Reporting Requirements for SAEs........................................................................... 47
8.3.5. 
Pregnancy................................................................................................................................... 47
8.3.6. 
Adverse Events of Special Interest............................................................................................. 47
8.3.6.1. 
Thrombosis with Thrombocytopenia Syndrome...................................................................... 47
8.4. 
Medical Resource Utilization.......................................................................................................... 49
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 50
9.1. 
Statistical Hypotheses.................................................................................................................... 50
9.2. 
Sample Size Determination ........................................................................................................... 51
9.3. 
Populations for Analysis Sets ........................................................................................................ 51
9.4. 
Statistical Analyses ........................................................................................................................ 52
9.4.1. 
General Considerations.............................................................................................................. 52
9.4.2. 
Participant Information................................................................................................................ 52
9.4.3. 
Immunogenicity Analyses........................................................................................................... 53
9.4.3.1. 
Primary Endpoints ................................................................................................................... 53
9.4.3.2. 
Secondary Endpoints .............................................................................................................. 53
9.4.4. 
Safety Analyses.......................................................................................................................... 54
9.5. 
Planned Analyses .......................................................................................................................... 54
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 55
10.1. 
Appendix 1: Abbreviations ............................................................................................................. 55
10.2. 
Appendix 2: AEs, SAEs, AESIs, PQCs, and Other Safety Reporting: Definitions and
Procedures for Recording, Evaluating, Follow-up, and Reporting................................................. 56
10.2.1. 
AE Definitions and Classifications.............................................................................................. 56
10.2.2. 
Attribution Definitions.................................................................................................................. 57
10.2.3. 
Severity Criteria.......................................................................................................................... 58
10.2.4. 
Special Reporting Situations ...................................................................................................... 58
10.2.5. 
Procedures ................................................................................................................................. 59
10.2.6. 
PQC Handling............................................................................................................................. 60
10.2.7. 
Contacting Sponsor Regarding Safety, Including Product Quality............................................. 61
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 62
10.3.1. 
Regulatory and Ethical Considerations ...................................................................................... 62
10.3.2. 
Financial Disclosure.................................................................................................................... 65
10.3.3. 
Informed Consent Process ......................................................................................................... 65
10.3.4. 
Data Protection........................................................................................................................... 66
10.3.5. 
Long-term Retention of Samples for Additional Future Research.............................................. 67
10.3.6. 
Committees Structure................................................................................................................. 67
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data............................................................ 67
10.3.8. 
Data Quality Assurance.............................................................................................................. 68
10.3.9. 
Case Report Form Completion................................................................................................... 69
10.3.10. Source Documents ..................................................................................................................... 69
10.3.11. Monitoring ................................................................................................................................... 70
10.3.12. On-site Audits ............................................................................................................................. 70
10.3.13. Record Retention........................................................................................................................ 71
10.3.14. Study and Site Start and Closure ............................................................................................... 71
10.4. 
Appendix 4: Toxicity Grading Scale............................................................................................... 73
10.5. 
Appendix 5: Guidance on Study Conduct During a Natural Disaster............................................ 78
10.6. 
Appendix 6: Thrombotic Events to be Reported as Potential AESIs ............................................. 80
10.7. 
Appendix 7: Protocol Amendment History..................................................................................... 81
11. REFERENCES................................................................................................................................... 84
INVESTIGATOR AGREEMENT................................................................................................................. 86

VAC18193 (JNJ-64400141/JNJ-64213175) 
Clinical Protocol VAC18193RSV3005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved,Date: 7 February 2022
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Overview of the Groups, Targeted Number of Participants, and Vaccinations ........................ 25
Table 2: 
Summary of Immunogenicity Assays (Humoral)...................................................................... 43
Table 3: 
Laboratory Tests That May Be Performed Upon Sponsor Request on Immunogenicity
Samples Collected on Day 1, Day 29 and/or Day 57............................................................... 48
Table 4: 
Laboratory Tests That May Be Requested by the Sponsor to be Performed at the
Central Laboratory After Potential AESI Reporting .................................................................. 49
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 13

VAC18193 (JNJ-64400141/JNJ-64213175) 
Clinical Protocol VAC18193RSV3005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved,Date: 7 February 2022
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Randomized, Double-blind, Placebo-controlled Phase 3 Study to Evaluate the Immunogenicity and
Safety of Ad26.RSV.preF-based Vaccine and High-dose Seasonal Influenza Vaccine, With and
Without Coadministration, in Adults Aged 65 Years and Older
The respiratory syncytial virus (RSV) vaccine that will be investigated in the current study, the
Ad26/protein preF RSV vaccine (VAC18193), is a combination of 2 vaccine components, administered as
a single intramuscular (IM) injection:
 
Ad26.RSV.preF (JNJ-64400141), a replication-incompetent adenovirus serotype 26 (Ad26)
containing a DNA transgene that encodes the prefusion conformation-stabilized F protein (pre-F)
derived from the RSV A2 strain.
 
RSV preF protein (JNJ-64213175), a recombinant pre-F protein derived from the RSV A2 strain.
Influenza and respiratory syncytial viruses cause infection leading to seasonal illness, hospitalization,
morbidity, and mortality in older adults. Commercially available influenza vaccines are given yearly before
the start of the influenza season and it is possible that an RSV vaccine would be given at the same time, as
both the RSV and influenza seasons overlap.
After a first-in-human safety and immunogenicity study with Ad26.RSV.preF, the possibility to
coadminister 
Ad26.RSV.preF 
with 
a 
seasonal 
influenza 
vaccine 
was 
explored 
in
study VAC18193RSV2003. The immunogenicity and safety results of this study support the potential for
coadministration of Ad26.RSV.preF-based vaccines with seasonal influenza vaccines. The current study
will examine the immunogenicity and safety of the Ad26/protein preF RSV vaccine (containing both
Ad26.RSV.preF and RSV preF protein) coadministered with a quadrivalent high-dose seasonal influenza
vaccine (coadministration [CoAd] group) compared to administration of each vaccine separately (Control
group). The aim is to provide an indication of whether these vaccines can be administered concomitantly.
The seasonal influenza vaccine that will be used in this study is Fluzone® High-Dose Quadrivalent (Sanofi
Pasteur Inc.) (further referred to as Fluzone HD Quadrivalent).
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primarya
 
To demonstrate the non-inferiority of the 
concomitant administration of Ad26.RSV.preF- 
based vaccine and a quadrivalent high-dose 
seasonal 
influenza 
vaccine 
versus 
the 
administration of a quadrivalent high-dose
seasonal influenza vaccine alone in terms of
humoral immune response expressed by the
geometric 
mean 
titers 
(GMTs) 
of
hemagglutination inhibition (HI) antibody titers
against each of the 4 influenza vaccine strains,
using a non-inferiority margin of 1.5 for the GMT
ratio (Control group/CoAd group)
 
HI titers against each of the 4 influenza
vaccine strains at 28 days after the
administration of a quadrivalent high-dose
seasonal influenza vaccine

VAC18193 (JNJ-64400141/JNJ-64213175) 
Clinical Protocol VAC18193RSV3005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Status: Approved,Date: 7 February 2022
Objectives 
Endpoints
 
To demonstrate the non-inferiority of the
concomitant 
administration 
of
Ad26.RSV.preF-based 
vaccine 
and 
a
quadrivalent high-dose 
seasonal 
influenza
vaccine 
versus 
the 
administration 
of
Ad26.RSV.preF-based vaccine alone in terms of
humoral immune response expressed by the
GMTs of pre-F  enzyme-linked immunosorbent
assay (ELISA) antibody titers, using a non-
inferiority margin of 1.5 for the GMT ratio
(Control group/CoAd group)
 
pre-F  ELISA antibody titers at 28 days
after 
the 
administration 
of
Ad26.RSV.preF-based vaccine
Secondary
 
To assess the safety and reactogenicity of a single
dose 
of 
Ad26.RSV.preF-based 
vaccine
administered separately or concomitantly with a
quadrivalent 
high-dose 
seasonal 
influenza
vaccine
 
Solicited local (injection site)and systemic
adverse events (AEs) for 7 days after each
vaccination
 
Unsolicited AEs for 28 days after each
vaccination
 
Serious adverse events (SAEs)and adverse
events of special interest (AESIs) until
6 months 
after 
the 
second study
vaccination
 
To assess the safety and reactogenicityof a single
dose of a quadrivalent high-dose seasonal
influenza vaccine administered concomitantly
with Ad26.RSV.preF-based vaccine
 
Solicited local (injection site)and systemic
AEs for 7 days after each vaccination
 
Unsolicited AEs for 28 days after each
vaccination
 
SAEs until 6 months after the second study
vaccination
 
To compare seroconversion rates against the
4 influenza vaccine strains after the concomitant
administration of Ad26.RSV.preF-based vaccine
and a quadrivalent high-dose seasonal influenza
vaccine versus the administration of a
quadrivalent high-dose 
seasonal 
influenza
vaccine alone
 
Seroconversion is defined for each of the
4 influenza vaccine strains at 28 days after
the administration of a quadrivalent
high-dose seasonal influenza vaccine:
 HI titer ≥1:40 in participants with a
prevaccination HI titer of <1:10, or
 a ≥4-fold HI titer increase in participants
with a prevaccination HI titer of ≥1:10
 
To compare seroprotection rates against the
4 influenza vaccine strains after the concomitant
administration of Ad26.RSV.preF-based vaccine
and a quadrivalent high-dose seasonal influenza
vaccine versus the administration of a
quadrivalent high-dose 
seasonal 
influenza
vaccine alone
 
Seroprotection is defined for each of the
4 influenza vaccine strains as HI titer
≥1:40 at 28 days after the administration of
a 
quadrivalent 
high-dose 
seasonal
influenza vaccine
a These primary objectives are co-primary, ie, not hierarchical.

VAC18193 (JNJ-64400141/JNJ-64213175) 
Clinical Protocol VAC18193RSV3005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
8
Status: Approved,Date: 7 February 2022
Hypotheses
To demonstrate the non-inferiority of the concomitant administration of Ad26/protein preF RSV vaccine
and a seasonal influenza vaccine versus the administration of a seasonal influenza vaccine alone, 28 days
after the administration of a seasonal influenza vaccine,in terms of humoral immune response as measured
by the hemagglutination inhibition assay (HI assay),
AND
to demonstrate the non-inferiority of the concomitant administration of Ad26/protein preF RSV vaccine
and a seasonal influenza vaccine versus the administration of Ad26/protein preF RSV vaccine alone,
28 days after the administration of Ad26/protein preF RSV vaccine,in terms of humoral immune response
(pre-F ELISA),
the following hypotheses will be tested:
Null Hypothesis:
 
For at least 1 of the 4 influenza vaccine strains: the GMT of HI antibody titers against the considered
vaccine strain, 28 days after concomitant administration of Ad26/protein preF RSV vaccine and a
seasonal influenza vaccine is inferior by at least 1.5 to the GMT 28 days after the administration of a
seasonal influenza vaccine alone.
OR
 
The GMT of pre-F ELISA titers 28 days after concomitant administration of Ad26/protein preF RSV
vaccine and a seasonal influenza vaccine is inferior by at least 1.5 to the GMT 28 days after the
administration of Ad26/protein preF RSV vaccine alone.
Alternative Hypothesis:
 
For each of the 4 influenza vaccine strains: the GMT of HI antibody titers 28 days after concomitant
administration of Ad26/protein preF RSV vaccine and a seasonal influenza vaccine is non-inferior to
the GMT 28 days after the administration of a seasonal influenza vaccine alone, using a non-inferiority
margin of1.5, for the ratio GMTControl group/GMTCoAd group.
AND
 
The GMT of the pre-F ELISA titers 28 days after concomitant administration of Ad26/protein preF
RSV vaccine and a seasonal influenza vaccine is non-inferior to the GMT 28 days after the
administration of Ad26/protein preF RSV vaccine alone, using a non-inferiority margin of 1.5, for the
ratioGMTControl group/GMTCoAd group.
OVERALL DESIGN
This is a randomized, double-blind, placebo-controlled, multicenter Phase 3 study in adult participants aged
65 years and older. Approximately 750 participants will be randomized in parallel in this study in a 1:1
ratio to 1 of 2 groups. All study vaccinations will be given by the IM route.
Group  
N 
Day 1 
Day 29
1 (CoAd group) 
±375 
Ad26/protein preF RSV vaccine + Fluzone
HD Quadrivalent
Placebo
2 (Control group) 
±375 
Placebo + Fluzone HD Quadrivalent 
Ad26/protein preF RSV vaccine
N  number of participants.

VAC18193 (JNJ-64400141/JNJ-64213175) 
Clinical Protocol VAC18193RSV3005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,Date: 7 February 2022
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 unsolicited AEs,solicited local (injection site)
or systemic AEs, and vital signs (systolic and diastolic blood pressure [sitting], heart rate, respiratory rate,
and body temperature) will be documented by study-site personnel following this observation period. In
addition, participants will record solicited signs and symptoms in a participant diary beginning on the
evening of the vaccination day and on a daily basis for 7 days postvaccination.
Blood will be collected from all participants to assess humoral immune responses prevaccination, on each
vaccination day and at 28 days after the second study vaccination.
Safety issues that might arise from this study may be escalated to an independent Data Monitoring
Committee,as needed.
The end of the study is defined as the last participant’s last visit.
NUMBER OF PARTICIPANTS
Approximately 750 participants will be randomized in parallel in this study in a 1:1 ratio to 1 of 2 groups.
VACCINATION GROUPS AND DURATION
The study duration will be approximately 7 months per participant. The study comprises screening on
Day 1, vaccination for each participant on Days 1 and 29 with a 28-day follow-up period after each
vaccination, and collection of SAEs and AESIs until 6 months after the second study vaccination.
Study Vaccines Administration
The RSV vaccine to be used in this study is composed of Ad26.RSV.preF and RSV preF protein, to be
administered as a single injection (1.0 mL) in the deltoid muscle:
 
Ad26.RSV.preF (JNJ-64400141) will be used at a dose level of 1×1011 viral particles.
 
RSV preF protein (JNJ-64213175) will be used at a dose level of 150 μg.
Placebo for Ad26/protein preF RSV vaccine will be 0.9% saline (1.0 mL).
The seasonal influenza vaccine to be used in this study is Fluzone HD Quadrivalent formulated for the
2021-2022 influenza season. Fluzone HD  Quadrivalent is a suspension for IM injection supplied in a
0.7-mL single-dose prefilled syringe. Each dose of Fluzone HD  Quadrivalent contains 240 µg of
hemagglutinin (HA): 60 µg of each of 4 influenza strains (2 influenza A strains and 2 influenza B strains).
On Day 1, each participant will receive 2 IM injections, 1 in each arm; on Day 29, each participant will
receive 1 IM injection. The right arm should be used for seasonal influenza vaccination on Day 1; the left
arm should be used for Ad26/protein preF RSV vaccine or placebo on Days 1 and 29.
IMMUNOGENICITY EVALUATIONS
Venous blood samples of approximately 20 mL will be collected for the determination of humoral immune
responses.
It is assumed that all enrolled participants will have a preexisting immune response due to previous RSV
exposure as well as influenza-specific responses to 1 or more strains, either by natural exposure to influenza
or by annual influenza vaccination (not including the current influenza season).

VAC18193 (JNJ-64400141/JNJ-64213175) 
Clinical Protocol VAC18193RSV3005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,Date: 7 February 2022
Humoral immunogenicity evaluations are summarized in the table below.
Assay 
Purpose
Primary endpoints
HI assay* 
Analysis of HI to influenza vaccine strains
F-protein antibody  
(RSV-A pre-F ELISA**) 
Analysis of antibodies binding to RSV-A F protein in prefusion
form
Secondary endpoints
HI assay* 
Analysis of HI to influenza vaccine strains
* The HI antibody titers against influenza virus strains recommended by the World Health Organization (WHO)
for use in 2021-2022 in the Northern Hemisphere season will be measured using a validated HI assay
platform.
** The same assay was used for immunogenicity assessments in the VAC18193RSV2001 (Cypress) study.
SAFETY EVALUATIONS
Safety assessments will include the monitoring of AEs and vital signs.
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
informed consent form (ICF) is obtained until the end of the study/early withdrawal. Solicited AEs,
collected through a participant diary, will be recorded for each vaccination from the time of vaccination
until 7 days postvaccination. 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
postvaccination. All SAEs, AESIs, and AEs leading to discontinuation from the study/vaccination
(regardless of the causal relationship) are to be reported from the moment of first study vaccination until
completion ofthe participant’s last study-related procedure, which may include contact for safety follow-
up. All AEs will be followed until resolution or until clinically stable.
STATISTICAL METHODS
Sample Size Determination
Sample size calculations are performed under the following assumptions:
 
No effect of coadministration of Ad26/protein preF RSV vaccine and seasonal influenza vaccine on
the immune response against influenza as measured by HI antibody titers against the 4 influenza
vaccine strains at 28 days after the administration of seasonal influenza vaccine.
 
A standard deviation of 2.1 at the log2 scale for HI antibody titers against the 4 influenza vaccine
strains at 28 days after the administration of seasonal influenza vaccine (with or without Ad26/protein
preF RSV vaccine)a.
 
No effect of coadministration of Ad26/protein preF RSV vaccine and seasonal influenza vaccine on
the immune response against RSV as measured by pre-F ELISA at 28 days after the administration of
Ad26/protein preF RSV vaccine.
a 
Based on results obtained from a previous Fluzone HD Quadrivalent study (NCT03282240
[ClinicalTrials.gov 2019]).

VAC18193 (JNJ-64400141/JNJ-64213175) 
Clinical Protocol VAC18193RSV3005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,Date: 7 February 2022
 
A standard deviation of 1.1 at the log2 scale for pre-F ELISA at 28 days after the administration of
Ad26/protein preF RSV vaccine (with or without seasonal influenza vaccine)a.
 
A non-inferiority margin of 1.5b.
 
2-sided αof 5%.
A total of 330 evaluable participants per group are needed to have 94.7% power to show non-inferiority in
HI antibody titers for 1 influenza vaccine strain. With this sample size, the overall power to show
non-inferiority in HI antibody titers against each of the 4 influenza vaccine strains at 28 days after the
administration of seasonal influenza vaccine as well as non-inferiority in pre-F ELISA at 28 days after the
administration of Ad26/protein preF RSV vaccine is at least 80%.
To account for exclusions from the per protocol set (see below for definitions of analysis sets), drop-outs
and missing samples, approximately 375 participants per group should be enrolled, resulting in a total
sample size of approximately 750 participants.
Populations for Analysis Sets
Vaccination assignment will follow the as-treated principle.
The Full Analysis (FA) Set will include all participants who received at least 1 study vaccination, regardless
of the occurrence of protocol deviations and vaccine type (seasonal influenza, Ad26/protein preF RSV
vaccine, or placebo). All safety and participant information analyses will be based on the FA Set.
The Per-protocol Influenza Immunogenicity (PPII) Set will include all randomized participants who
received the first study vaccination, and for whom immunogenicity data are available for at least one of the
influenza strains in the vaccine. Samples taken after a participant experiences a major protocol deviation
expected to impact the immunogenicity outcomes will be excluded from the PPII analysis.
The Per-protocol RSV Immunogenicity (PPRI) Set will include all randomized participants who received
Ad26/protein preF RSV vaccine in combination with seasonal influenza vaccine for the CoAd group and
Ad26/protein preF RSV vaccine alone for the Control group and for whom RSV immunogenicity data are
available. Samples taken after a participant experiences a major protocol deviation expected to impact the
immunogenicity outcomes will be excluded from the PPRI analysis.
The list of major protocol deviations that would lead to elimination from the immunogenicity analysis will
be specified in the statistical analysis plan or major protocol violation criteria document, which will be
finalized before database lock and unblinding.
The primary analysis set for analyses related to influenza immunogenicity is the PPII Set, the primary
analysis set for analyses related to RSV immunogenicity is the PPRI Set. As a sensitivity analysis, key
tables may also be based on the FA Set.
a Based on Day 29 pre-F ELISA results obtained from Cohort 2, Group 14 in study VAC18193RSV1004
(IB Ad26/protein preF RSV vaccine 2021).
b Non-inferiority criteria based on FDA guidance for influenza vaccines (FDA 2007b).

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Immunogenicity Analyses
The primary immunogenicity objectives will be assessed by calculating:
 
The 2-sided 95% confidence intervals (CIs) for the difference in log-transformed HI antibody titers
against each of the 4 influenza vaccine strains at 28 days after the administration of the quadrivalent
high-dose seasonal influenza vaccine between the Control and the CoAd group.
 
The 2-sided 95% CIs for the difference in log-transformed pre-F ELISA titers at 28 days after the
administration of Ad26/protein preF RSV vaccine between the Control and the CoAd group.
For HI antibody titers against each of the 4 influenza vaccine strains and for pre-F ELISA titers, an analysis
of variance (ANOVA) model will be fitted with the respective titers as dependent variable and group
(Control or CoAd) and age category (as stratified) as independent variable. Based on these ANOVA models,
the CIs around the difference will be calculated and will be back-transformed (by exponentiation) to CIs
around a GMT ratio (GMTControl group/GMTCoAd group) and compared to the non-inferiority limit of 1.5.
Only if the upper bound of the 2-sided 95% CI for the GMT ratio (Control group/CoAd group) of the HI
antibody titer for each of the 4 vaccine strains and for pre-F  ELISA lies below 1.5, non-inferiority of
coadministration versus separate administration will be concluded for both vaccines (seasonal influenza
vaccine and Ad26/protein preF RSV vaccine). If 1 or more confidence limits for the GMT ratio exceed 1.5,
non-inferiority cannot be concluded.
As a sensitivity analysis to assess the impact of baseline titers, the primary endpoint will also be evaluated
adjusting for the respective baseline titers. For immunogenicity, baseline is considered as the last
assessment prevaccination. In a second sensitivity analysis, different variances between the groups will be
allowed. Therefore, the CIs will be calculated via Welch’s ANOVA.
Seroconversion is defined for each of the 4 influenza vaccine strains at 28 days after the administration of
a seasonal influenza vaccine as:
 
HI titer ≥1:40 in participants with a prevaccination HI titer of <1:10, or
 
a ≥4-fold HI titer increase in participants with a prevaccination HI titer of ≥1:10
Seroprotection is defined for each of the 4 influenza vaccine strains as HI titer ≥1:40 at 28 days after the
administration of a seasonal influenza vaccine.
The difference in proportions of seroconverted and seroprotected participants between the Control and the
CoAd group will be estimated together with the 2-sided 95% CIs (calculated using Wilson’s score method).
Additionally, HI antibody titers and pre-F ELISA titers will be summarized with descriptive statistics.
Safety Analyses
No formal statistical testing of safety data is planned. All safety data will be analyzed descriptively by
group. All safety analyses will be based on the FA Set.

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vaccination may be delayed up to 10 days, or the participant may be withdrawn at the discretion of the investigator. In case the administration of the second study
vaccination needs to be delayed, it can be delayed up to 10 days on top of the allowed window for Visit 3 (±5 days). On the other hand, the immunogenicity and
safety assessments of Visit 3 should still be performed on the actual Day 29 (±5 days).
i. 
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 unsolicited AEs, solicited local (injection site) or systemic AEs, and vital signs (systolic and diastolic blood pressure [sitting], heart rate,respiratory rate,and
body temperature) will be documented by study-site personnel following this observation period.
j. 
AESIs, including potential AESIs, are to be reported to the sponsor from the moment of first study vaccination until 6 months after the second study vaccination.
See Section 8.3.6.
k. 
Concomitant therapies will be collected from the time of first study vaccination, through 28 days after the second study vaccination when associated with an AE,
and from ICF signature until 6 months after the second study vaccination when associated with an SAE or AESI.
l. 
Any history of SARS-COV-2 vaccination (name/manufacturer of the vaccine and date of administration, whenever possible) prior to and during the study will be
collected in the eCRF.
m. Rulers and thermometers will be distributed at Visits 1 and 3.
n. 
Diary entries will be reviewed with the participant by a qualified and delegated study staff member (eg, investigator, sub-investigator, or study nurse). The
delegated study staff member grades any signs or symptoms using the toxicity grading scale (Appendix 4: Toxicity Grading Scale) and will complete their
assessment in the relevant sections of the eCRF. The diary review and grading of symptoms are done under the oversight of the investigator or a delegated
physician.
Participants will be contacted by telephone 2 to 4 days after each vaccination, to remind them to fill in the participant diaries and to check that they are entering
information correctly.
o. 
Screening and vaccination may be split into 2 visits in consultation with the sponsor or its delegate, for example when a criterion for temporarily delaying study
vaccine administration (see Section 5.5) is met. Every effort should be made for split visits to occur preferably within 3 to 5 days and no later than 10 days, and
pre-vaccination vital signs should be repeated on the day of vaccination if this visit is split.
p. 
Aliquots of serum samples collected for immunogenicity tests can be reconverted for participant’s safety purposes upon sponsor request. Please refer to Table 3 for
a non-exhaustive list of tests that may be requested to be performed on these samples in case of potential AESI reporting.
q. 
Includes the assessment of the severity of solicited AEs during the Visit 2 and Visit 4 phone calls.
r. 
Includes the assessment of the severity of unsolicited AEs and the occurrence of special reporting situations during all visits up to 28 days post-vaccination,
including the Visit 2 and Visit 4 phone calls.

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2. 
INTRODUCTION
The respiratory syncytial virus (RSV) vaccine that will be investigated in the current study, the
Ad26/protein preF RSV vaccine (VAC18193), is a combination of 2 vaccine components,
administered as a single intramuscular (IM) injection:
 
Ad26.RSV.preF (JNJ-64400141), a replication-incompetent adenovirus serotype 26 (Ad26)
containing a DNA transgene that encodes the prefusion conformation-stabilized F protein
(pre-F) derived from the RSV A2 strain.
 
RSV preF protein (JNJ-64213175), a recombinant pre-F protein derived from the RSV A2
strain.
For the most comprehensive nonclinical and clinical information regarding the Ad26/protein preF
RSV vaccine, refer to the latest version of the Investigator’s Brochure (IB) for Ad26/protein preF
RSV vaccine (IB Ad26/protein preF RSV vaccine 2021).
The term “study vaccine” used throughout the protocol, refers to the Ad26/protein preF RSV
vaccine,placebo, and the seasonal influenza vaccine Fluzone® High-Dose Quadrivalent as defined
in Section 6.1.
The term “sponsor” used throughout this document refers to the entities listed in the Contact
Information page(s), which will be provided as a separate document.
The non-inferiority criteria used in this study are based on guidance from regulatory authorities
(for details, refer to Section 2.2).
2.1. 
Study Rationale
Influenza and respiratory syncytial viruses cause infection leading to seasonal illness,
hospitalization, morbidity, and mortality both in infants and older adults. Commercially available
influenza vaccines are recommended yearly before the start of the influenza season and it is
possible that an RSV vaccine would be given at the same time, as both the RSV and influenza
seasons overlap.
After a first-in-human safety and immunogenicity study with Ad26.RSV.preF, the possibility to
coadminister Ad26.RSV.preF with a seasonal influenza vaccine was explored in
study VAC18193RSV2003. The immunogenicity and safety results of this study support the
potential for coadministration of Ad26.RSV.preF-based vaccines with seasonal influenza vaccines
(Section 2.2). The current study will examine the immunogenicity and safety ofthe Ad26/protein
preF RSV vaccine (containing both Ad26.RSV.preF and RSV preF protein) coadministered with
a quadrivalent high-dose seasonal influenza vaccine (coadministration [CoAd] group) compared
to administration of each vaccine separately (Control group). The aim is to provide an indication
of whether these vaccines can be administered concomitantly.
The seasonal influenza vaccine that will be used in this study is Fluzone High-Dose Quadrivalent
(Sanofi Pasteur Inc.) (further referred to as Fluzone HD Quadrivalent). Fluzone HD Quadrivalent

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is indicated for active immunization for prevention of disease caused by influenza A subtype
viruses and type B viruses contained in the vaccine in adults aged 65 years and older. Fluzone HD
(trivalent vaccine) was first approved in 2009. Fluzone HD Quadrivalent containing an additional
influenza B strain was approved in 2019 and is widely used in the United Kingdom and United
States. For more details, refer to Section 6.1.
2.2. 
Background
RSV is an important cause of serious respiratory infections in adults aged 60 years and older,
immunocompromised individuals, and those with underlying chronic cardiopulmonary conditions
(Falsey 2005). Exact numbers on the burden of RSV disease in adults aged 60 years and older are
limited. In long-term care facilities, RSV is estimated to infect 5% to 10% of the residents per year
with significant rates of pneumonia (10%-20%) and death (2%-5%) as a consequence
(Falsey 2000). In the United States, approximately 177,000 hospital admissions and approximately
10,000 to 14,000 deaths per year are due to severe RSV infections in adults aged 65 years and
older (Falsey 2005). These data support the importance ofdeveloping a safe and effective vaccine
for certain adult populations, such as older adults. Currently, there are no vaccines or specific
treatments available for RSV.
Several studies have indicated that high serum neutralizing antibody levels are associated with
reduced risk of severe RSV infection in older adults (Falsey 1998; Walsh 2004). There is some
indication that decreased protection against RSV in older adults could be attributed to an age-
related decline in RSV-specific T-cell function  (de Bree 2005; Looney 2002). The
Ad26.RSV.preF vaccine component evaluated in this study is based on the AdVac® platform,
which has been shown to promote strong humoral and cellular responses (Barouch 2013;
Barouch 2018; Data on file; Milligan 2016).
Nonclinical Studies
For the most comprehensive nonclinical information regarding the Ad26/protein preF RSV
vaccine, refer to the latest version of the IB for Ad26/protein preF RSV vaccine (IB Ad26/protein
preF RSV vaccine 2021).
Clinical Studies
For the most comprehensive clinical information regarding the Ad26/protein preF RSV vaccine,
refer to the latest version of the IB for Ad26/protein preF RSV vaccine (IB Ad26/protein preF
RSV vaccine 2021).
In the completed study VAC18193RSV2003, an assessment was made whether 1x1011 vp of
Ad26.RSV.preF alone (ie, without RSV preF protein) could be coadministered with a seasonal
influenza vaccine (Fluarix  Quadrivalent 2017/2018). The study determined the 2-sided 90%
confidence limits of the geometric mean titer (GMT)ratio of the hemagglutination inhibition (HI)
antibody  GMT  against each of the 4 influenza vaccine strains (A/Michigan, A/Hong Kong,
B/Brisbane, and B/Phuket) when administered alone versus coadministered with Ad26.RSV.preF,
and compared this with a non-inferiority margin of 2. The 2-sided 90% upper confidence limits of
the GMT ratios were 1.11, 1.12, 1.34, and 1.36, respectively, and therefore did not indicate

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interference from Ad26.RSV.preF with the immune response to the seasonal influenza vaccine.
More stringent non-inferiority criteria will be used in the present study, based on guidance from
regulatory authorities (FDA 2007b).
RSV neutralization and RSV F protein enzyme-linked immunosorbent assay (ELISA) responses
were also similar between groups. The reactogenicity profile in both groups was acceptable.
Clinical Safety Experience With Ad26-based Vaccines
Thrombosis in combination with thrombocytopenia (thrombosis with thrombocytopenia syndrome
[TTS]), in some cases accompanied by internal bleeding, has been observed very rarely following
vaccination with the Janssen Coronavirus Disease 2019 (COVID-19) (Ad26.COV2.S) vaccine.
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. The associated symptoms began approximately 1 to 2 weeks after vaccination,
mostly in women under 60 years of age. Thrombosis in combination with thrombocytopenia can
be fatal. The exact pathophysiology of TTS is unclear. This event has not been observed to date
with any other Janssen Ad26-based vaccines. Participants should be instructed to seek immediate
medical attention if they develop symptoms such as shortness of breath, chest pain, leg swelling,
persistent abdominal pain, severe or persistent headaches, blurred vision, skin bruising or petechiae
beyond the site of vaccination.
2.3. 
Benefit-risk Assessment
More detailed information about the known and expected benefits and risks of the Ad26/protein
preF RSV vaccine may be found in the IB for Ad26/protein preF RSV vaccine (IB Ad26/protein
preF RSV vaccine 2021).
2.3.1. 
Risks Related to Study Participation
The following potential risks for the Ad26/protein preF RSV vaccine will be monitored during the
study:
Risks Related to Ad26/protein preF RSV Vaccine
The Ad26/protein preF RSV vaccine is being studied in 4 ongoing studies in more than
6,500 participants aged 60 years and above, including participants with comorbidities, to assess
safety and immunogenicity, and to investigate whether the vaccine prevents RSV disease. In these
studies, the most commonly reported solicited local AEs were injection site pain/tenderness and
swelling (mild to moderate). The most frequently reported solicited systemic AEs were fatigue,
muscle pain, headache, chills, joint pain, and nausea, which were mild to moderate in severity.
These solicited AEs were short-lived and resolved within a few days. Overall, available results
from these studies show the vaccine to be well-tolerated with no safety concerns.

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Risks Related to Fluzone HD Quadrivalent
Fluzone HD Quadrivalent is licensed to be used for individuals aged 65 years or above in the
countries participating to this study. Fluzone HD Quadrivalent will be administered in the study
following the approved prescribing information.
In adults, the most common (≥10%) solicited local adverse reactionafter Fluzone HD Quadrivalent
administration  was pain (41.3%), the most common solicited systemic adverse reactions were
myalgia (22.7%), headache (14.4%), and malaise (13.2%).
For further details, refer to the Fluzone HD Quadrivalent package insert.
General Risks Related to Vaccination
In general, IM injection may cause local itching, warmth, pain, tenderness, erythema/redness,
induration, swelling, arm discomfort, or bruising of the skin. Participants may exhibit general signs
and symptoms associated with IM injection of a vaccine and/or placebo, including fever, chills,
rash, myalgia, nausea/vomiting, headache, dizziness, arthralgia, general itching, and fatigue. These
side effects will be monitored, but are generally short-term and do not require treatment.
Syncope can occur in association with administration of injectable vaccines. Syncope can be
accompanied by falls. Procedures should be in place to avoid injury from falling. If syncope
develops, participants should be observed until the symptoms resolve. Fear of injection might lead
to fainting and fast breathing.
Participants may have an allergic reaction to the vaccination. An allergic reaction may cause a
rash, urticaria, or even anaphylaxis. Severe reactions are rare. Participants with a known or
suspected allergy, or history of anaphylaxis or other serious adverse reactions to vaccines or their
excipients (including specifically the excipients of the study vaccine) will be excluded from the
study.
After each vaccination, participants will remain at the study site for 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 Ad26/protein preF RSV vaccine on a fetus or nursing baby is unknown.
Participants may therefore only participate if they are postmenopausal (defined as no menses for
12 months without an alternative medical cause) and not intending to conceive by any methods.
Participants who are surgically sterile are also eligible for the study. Follow-up information
regarding the outcome of the pregnancy and any postnatal sequelae in the infant will be required.
Because the effect on sperm is unknown, participants must inform the study-site personnel if their
partner becomes pregnant during the study. Follow-up information regarding the outcome of the
pregnancy and any postnatal sequelae in the infant will be required upon the consent provided by
the partner.

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Participants with Immunosuppression/Reduced Immune Response
Participants with abnormal function of the immune system will be excluded from the study.
Limited evidence indicates that inactivated vaccines (or nonreplicating viral vaccines) generally
have the same safety profile in immunocompromised patients as in immunocompetent individuals.
However, the magnitude, breadth, and persistence of the immune response to vaccination may be
reduced or absent in immunocompromised persons.
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. Participants with
contraindications to IM injections and blood draws (eg, bleeding disorders) will be excluded.
Concomitant Vaccination
Concomitant vaccination might have an influence on both the safety profile and immunogenicity
ofthe Ad26/protein preF RSV vaccine. Likewise, the Ad26/protein preF RSV vaccine might have
an influence on both the safety profile and immunogenicity of any concomitant vaccination. As a
result, licensed live attenuated vaccines should be given at least 28 days before or after vaccination.
Other licensed (not live) vaccines (eg, tetanus, hepatitis A, hepatitis B, rabies) should be given at
least 14  days before or after vaccination to avoid potential confusion of adverse reactions and
potential immune interference. If a vaccine is indicated in a postexposure setting (eg, rabies or
tetanus), it must take priority over the study vaccine.
For severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) vaccines either licensed or
available under Emergency Use Authorization: live attenuated vaccines should be given at least
28 days before or after vaccination; non-live vaccines should be given at least 14 days before or
after vaccination. A viral-vectored SARS-COV-2 vaccine is not to be given at any time prior to
randomization or during the study period until 28 days after the last study vaccination.
Unknown Risks
There may be other risks that are not known. If any significant new risks are identified, the
investigators and participants will be informed.
2.3.2. 
Benefits of Study Participation
Participants may benefit from clinical testing.
The clinical benefits of the Ad26/protein preF RSV vaccine have yet to be established.
The Ad26/protein preF RSV vaccine is under development for prophylaxis of RSV and vaccine
efficacy is being evaluated in ongoing studies. Results from the primary analysis of study
VAC18193RSV2001 with approximately 5,800 participants showed the potential for the vaccine
to prevent lower respiratory tract disease caused by RSV in participants aged 65 years and older.

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Vaccination with a seasonal influenza vaccine may provide protection against the influenza A
subtype viruses and type B viruses contained in the vaccine during the season.
2.3.3. 
Benefit-risk Assessment of Study Participation
Based on the available data and proposed safety measures, the overall benefit-risk assessment for
this clinical study is considered acceptable for the following reasons:
 
The dose levels for Ad26.RSV.preF and RSV preF protein used in the current study were
determined from the primary analysis of Cohort 2 in study VAC18193RSV1004 and is
currently under further evaluation in studies VAC18193RSV1004 and VAC18193RSV2001.
Available safety data from all studies show the vaccine to be well-tolerated with no safety
concerns. Based on these data, the dose levels of Ad26.RSV.preF and RSV preF protein
selected for the present study are 1×1011 vp and 150 µg, respectively (Section 4.3).
 
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.
 
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 participant diary  to document solicited signs and symptoms. Details are
provided in Section 8.2.
 
The investigator or the designee will document unsolicited AEs as indicated in
Sections 8.2 and 8.3,and Appendix 2.
 
Any clinically significant abnormalities will be followed by the investigator until
resolution or until clinically stable.
 
After vaccination, participants will enter a 6-month safety follow-up period for collection
of serious adverse events (SAEs)and adverse events of special interest (AESIs).
 
All AEs, SAEs, and AESIs will be followed by the investigator until clinical resolution
or until a clinically stable condition is reached, or until the participant has been deemed
lost to follow-up after demonstration of due diligence of follow-up efforts. An early exit
visit will be conducted for those participants who are unable to continue participation in
the study and withdraw from the study before Day 211, but who do not withdraw consent.
Participants who wish to withdraw consent from participation in the study will be offered
an early exit visit (prior to formal withdrawal of consent) (Section 7.2).
 
Several safety measures are included in this protocol to minimize the potential risk to
participants, including the following:
 
Safety issues that might arise from this study may be escalated to an independent Data
Monitoring Committee (DMC),as needed.

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Study vaccinations will be discontinued in participants for the reasons described in
Section 7.
 
Temporary contraindications to study vaccination are included in Section 5.5.
3. 
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primarya
 
To demonstrate the non-inferiority of the
concomitant administration of Ad26.RSV.preF-
based vaccine and a quadrivalent high-dose
seasonal 
influenza 
vaccine 
versus 
the
administration of a quadrivalent high-dose
seasonal influenza vaccine alone in terms of
humoral immune response expressed by the
GMTs of HI antibody titers against each of the
4 influenza vaccine strains, using a non-
inferiority margin of 1.5 for the GMT ratio
(Control group/CoAd group)
 
HI titers against each of the 4 influenza
vaccine strains at 28 days after the
administration of a quadrivalent high-dose
seasonal influenza vaccine
 
To demonstrate the non-inferiority of the
concomitant administration of Ad26.RSV.preF-
based vaccine and a quadrivalent high-dose
seasonal 
influenza 
vaccine 
versus 
the
administration of Ad26.RSV.preF-based vaccine
alone in terms of humoral immune response
expressed by the GMTs of pre-F ELISA antibody
titers, using a non-inferiority margin of 1.5 for the
GMT ratio (Control group/CoAd group)
 
pre-F  ELISA  antibody titers at 28 days
after 
the 
administration 
of
Ad26.RSV.preF-based vaccine
Secondary
 
To assess the safety and reactogenicity of a single
dose 
of 
Ad26.RSV.preF-based 
vaccine
administered separately or concomitantly with a
quadrivalent high-dose seasonal 
influenza
vaccine
 
Solicitedlocal (injection site)and systemic
AEs for 7 days after each vaccination
 
Unsolicited AEs for 28 days after each
vaccination
 
SAEs and AESIs until 6 months after the
second study vaccination
 
To assess the safety and reactogenicityof a single
dose of a quadrivalent high-dose seasonal
influenza vaccine administered concomitantly
with Ad26.RSV.preF-based vaccine
 
Solicited local (injection site)and systemic
AEs for 7 days after each vaccination
 
Unsolicited AEs for 28 days after each
vaccination
 
SAEs until 6 months after the second study
vaccination

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Objectives 
Endpoints
 
To compare seroconversion rates against the
4 influenza vaccine strains after the concomitant
administration of Ad26.RSV.preF-based vaccine
and a quadrivalent high-dose seasonal influenza
vaccine versus the administration of a
quadrivalent high-dose seasonal 
influenza
vaccine alone
 Seroconversion is defined for each of the
4 influenza vaccine strains at 28 days after
the administration of a quadrivalent high-
dose seasonal influenza vaccine:
 HI titer ≥1:40 in participants with a
prevaccination HI titer of <1:10, or
 a ≥4-fold HI titer increase in participants
with a prevaccination HI titer of ≥1:10
 
To compare seroprotection rates against the
4 influenza vaccine strains after the concomitant
administration of Ad26.RSV.preF-based vaccine
and a quadrivalent high-dose seasonal influenza
vaccine versus the administration of a
quadrivalent high-dose seasonal 
influenza
vaccine alone
 
Seroprotection is defined for each of the
4 influenza vaccine strains as HI titer
≥1:40 at 28 days after the administration of
a 
quadrivalent 
high-dose 
seasonal
influenza vaccine
a These primary objectives are co-primary, ie, not hierarchical.
Refer to Section 8 for evaluations related to endpoints.
HYPOTHESES
To demonstrate the non-inferiority of the concomitant administration of Ad26/protein preF RSV
vaccine and a seasonal influenza vaccine versus the administration of a seasonal influenza vaccine
alone, 28 days after the administration of a seasonal influenza vaccine, in terms of humoral
immune response as measured by the hemagglutination inhibition assay (HI assay),
AND
to demonstrate the non-inferiority of the concomitant administration of Ad26/protein preF RSV
vaccine and a seasonal influenza vaccine versus the administration of Ad26/protein preF RSV
vaccine alone, 28 days after the administration of Ad26/protein preF RSV vaccine, in terms of
humoral immune response (pre-F ELISA),
the following hypotheses will be tested:
Null Hypothesis:
 
For at least 1 of the 4 influenza vaccine strains: the GMT of HI antibody titers against the
considered vaccine strain, 28 days after concomitant administration of Ad26/protein preF
RSV vaccine and a seasonal influenza vaccine is inferior by at least 1.5 to the GMT 28 days
after the administration of a seasonal influenza vaccine alone.
OR
 
The GMT of pre-F ELISA titers 28 days after concomitant administration of Ad26/protein
preF RSV vaccine and a seasonal influenza vaccine is inferior by at least 1.5 to the GMT
28 days after the administration of Ad26/protein preF RSV vaccine alone.

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Alternative Hypothesis:
 
For each of the 4 influenza vaccine strains: the GMT of HI antibody titers 28 days after
concomitant administration of Ad26/protein  preF RSV vaccine and a seasonal influenza
vaccine is non-inferior to the GMT 28 days after the administration of a seasonal influenza
vaccine 
alone, 
using 
a 
non-inferiority 
margin 
of 
1.5, for 
the 
ratio
GMTControl group/GMTCoAd group.
AND
 
The GMT of the pre-F ELISA titers 28 days after concomitant administration of Ad26/protein
preF RSV vaccine and a seasonal influenza vaccine is non-inferior to the GMT 28 days after
the administration of Ad26/protein preF RSV vaccine alone, using a non-inferiority margin of
1.5, for the ratio GMTControl group/GMTCoAd group.
4. 
STUDY DESIGN
4.1. 
Overall Design
This is a randomized, double-blind, placebo-controlled, multicenter Phase 3 study  in adult
participants aged 65 years and older.
Approximately 750 participants will be randomized in parallel in this study in a 1:1 ratio to 1 of
2 groups (Table 1).
Group 1 will receive Ad26/protein preF RSV vaccine on Day 1 administered at the same time as
Fluzone HD  Quadrivalent, and placebo on Day 29. Group 2 will receive placebo on Day 1
administered at the same time as Fluzone HD Quadrivalent, and Ad26/protein preF RSV vaccine
on Day 29. All study vaccinations will be given by the IM route.
Table 1: 
Overview of the Groups, Targeted Number of Participants, and Vaccinations
Group  
N 
Day 1 
Day 29
1 (CoAd group) 
±375 
Ad26/protein preF RSV vaccine + Fluzone
HD Quadrivalent
Placebo
2 (Control group) 
±375 
Placebo + Fluzone HD Quadrivalent 
Ad26/protein preF RSV vaccine
N = number of participants.
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 unsolicited AEs,solicited
local (injection site)or systemic AEs, and vital signs (systolic and diastolic blood pressure [sitting],
heart rate, respiratory rate, and body temperature) will be documented by study-site personnel
following this observation period. In addition, participants will record solicited signs and
symptoms in a participant diary beginning on the evening of the vaccination day and on a daily
basis for 7 days postvaccination (Section 8).
The reporting periods of AEs,SAEs, and AESIs are detailed in Section 8.3. Reporting periods for
concomitant therapy are outlined in Section 6.8.
Blood will be collected from all participants to assess humoral immune responses prevaccination,
on each vaccination day and at 28 days after the second study vaccination.

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Safety issues that might arise from this study may be escalated to an independent DMC,as needed.
The study duration will be approximately 7 months per participant. The study comprises screening
on Day 1, vaccination for each participant on Days 1 and 29 with a 28-day follow-up period after
each vaccination, and collection of SAEs and AESIs until 6 months after the second study
vaccination. The end of the study is defined as the last participant’s last visit.
Over the entire study, the total blood volume to be collected from each participant will be
approximately 60 mL.
Unscheduled study visits may be performed based on investigator’s clinical judgment and may
include further evaluations, as needed.
A diagram of the study design is provided in Section 1.2 (Figure 1). Further details are provided
in the Schedule of Activities.
4.2. 
Scientific Rationale for Study Design
For the rationale for performing this study, refer to Section 2.1.
Blinding, Control, Vaccination Groups
A placebo control will be used for the Ad26/protein preF RSV vaccine to establish the frequency
and magnitude of changes in clinical endpoints that may occur in the absence of active study
vaccine. Randomization will be used to minimize bias in the assignment of participants to
vaccination groups, to increase the likelihood that known and unknown participant attributes
(eg,demographic and baseline characteristics) are evenly balanced across vaccination groups, and
to enhance the validity of statistical comparisons across vaccination groups. Blinded vaccine will
be used to reduce potential bias during data collection and evaluation of clinical endpoints.
Vaccine Component Selection
The rationale behind the selection of the Ad26/protein preF RSV vaccine is described in
Section 2.2 and in the IB for Ad26/protein preF RSV vaccine (IB Ad26/protein  preF
RSV vaccine 2021).
Dose Level Selection
The rationale behind the dose level selection for the Ad26/protein preF RSV vaccine is described
in Section 4.3.
Vaccine Regimen Selection
The single-dose regimen of the Ad26/protein preF RSV vaccine was selected based on the results
from the primary analysis of study VAC18193RSV1004 (Section 4.3). The single-dose regimen
of Fluzone HD Quadrivalent is based on its licensed posology, as described in the Fluzone HD
Quadrivalent package insert.

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Selection of Primary Immunogenicity Timepoint
The timepoint of 28 days after study vaccination was selected for evaluation of the
immunogenicity of both Ad26/protein preF RSV vaccine and Fluzone HD  Quadrivalent. This
timepoint was used for the evaluation of immunogenicity in previous studies of the
Ad26.RSV.preF component of the RSV vaccine, including the previous coadministration study
VAC18193RSV2003 with Fluarix Quadrivalent (Section 2.2), and in a previous study of Fluzone
HD Quadrivalent (Chang 2019). Selection  of a single timepoint for both vaccines reduces the
burden of study visits and invasive procedures. The assumed standard deviation of 2.1 at the log2
scale for HI antibody titers against the 4 influenza vaccine strains at 28 days after the
administration of seasonal influenza vaccine (Section 9.2) is based on what was observed in a
previous Fluzone HD Quadrivalent study (NCT03282240)(ClinicalTrials.gov 2019).
4.2.1. 
Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during
the study, participants will be given any new information that may affect their decision to continue
participation. They will be told that their consent to participate in the study is voluntary and may be
withdrawn at any time with no reason given and without penalty or loss of benefits to which they
would otherwise be entitled. Only participants who are fully able to understand the risks, benefits,
and potential AEs of the study, and provide their consent voluntarily will be enrolled.
The primary ethical concern is that this study will be performed in adult participants who will
receive no benefit from participation  in the study, except for compensation for the time and
inconveniences that may arise from participation in the study.
Vaccination with a seasonal influenza vaccine may provide protection against the influenza A
subtype viruses and type B viruses contained in the vaccine. Note, interference of the Ad26/protein
preF RSV vaccine on the immunogenicity of seasonal influenza vaccine cannot be ruled out.
See Section 2.3 for Benefit-Risk Assessment.
The total blood volume to be collected is considered to be an acceptable amount of blood to be
collected over this time period from the population in this study based upon the standard of the
United States (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 (OHRP 1998; FDA 1998).
4.3. 
Justification for Dose
The dose level for the Ad26/protein preF RSV vaccine used in the current study was determined
from the primary analysis of Cohort 2 in study VAC18193RSV1004. From the primary analysis,
a significant increase in humoral immune responses including virus neutralizing antibodies (virus
neutralization assay) and pre-F  antibody titers were observed in the groups combining
Ad26.RSV.preF  (5×1010 or 1×1011 vp) and RSV preF protein  (50 or 150 µg) compared to
Ad26.RSV.preF 1×1011 vp alone. No relevant differences between the combination groups and

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Ad26.RSV.preF alone were noted for cellular immune responses. All regimens had acceptable
safety and reactogenicity profiles, which were similar across groups. Additionally, in the primary
analysis of study VAC18193RSV2001, vaccine efficacy was demonstrated for these dose levels.
Based on these data, the dose levels of Ad26.RSV.preF and RSV preF protein selected for the
present study are 1×1011 vp and 150 µg, respectively.
4.4. 
End of Study Definition
End of Study Definition
The end of study is considered as the last visit (on Day 211) for the last participant in the study.
The final data from the 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.
Participant Study Completion Definition
A participant will be considered to have completed the study if the participant has completed
assessments at the Day 211 visit.
Participants who prematurely discontinue study vaccination for any reason before completion of
the double-blind phase will not be considered to have completed the study.
5. 
STUDY POPULATION
Screening for eligible participants will be performed prevaccination on Day 1. Screening and
vaccination may be split into 2 visits in consultation with the sponsor or its delegate. Refer to
Section 5.4 for conditions under which the repeat of any screening procedures are allowed.
The inclusion and exclusion criteria for enrolling participants in this study are described below. 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.
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. 
must sign an informed consent form (ICF) indicating that the participant understands the
purpose, procedures and potential risks and benefits of the study, and is willing to
participate in the study.
2. 
willing and able to adhere to the prohibitions and restrictions specified in this protocol.
3. 
65 years of age and older on the day of signing the ICF and expected to be available for
the duration of the study.

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4. 
before randomization, a participant must be:
 
postmenopausal (postmenopausal state is defined as no menses for 12 months
without an alternative medical cause); and
 
not intending to conceive by any methods.
Note: Surgically sterile participantsare also eligible for the study.
5. 
in the investigator’s clinical judgment, participant must be in stable health at the time of
vaccination. Participants may have underlying illnesses such as hypertension, type 2
diabetes, hyperlipoproteinemia, or hypothyroidism, as long as their symptoms and signs
are stable at the time of vaccination, and these conditions receive routine follow-up by
the participant’s healthcare provider. Participants will be included on the basis of medical
history and vital signsa performed between ICF signature and vaccination.
6. 
from the time of vaccination through 3 months after vaccination, agrees not to donate
blood.
7. 
must be able to read, understand, and complete questionnaires in the e-diary.
8. 
must be willing to provide verifiable identification, has means to be contacted and to
contact the investigator during the study.
9. 
must be able to work with smartphones/tablets/computers.
5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
1. 
Criterion modified per Amendment 1
1.1 history of malignancy within 5 years before screening not in the following
categories:
a. Participants with squamous and basal cell carcinomas of the skin and
carcinoma in situ of the cervix may be enrolled at the discretion of the
investigator.
b. Participants with a history of malignancy within 5 years before screening, with
minimal risk of recurrence per investigator’s judgement, can be enrolled.
2. 
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)(IB Ad26/protein preF RSV vaccine 2021).
a Participants can be enrolled with Grade 1 or Grade 2 values for vital signs measurements (refer to Appendix 4:
Toxicity Grading Scale).

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3. 
history of severe allergic reactions (eg, anaphylaxis) to any component of the Fluzone
HD Quadrivalent vaccine, including egg protein, or following a previous dose of any
influenza vaccine.
4. 
abnormal function of the immune system resulting from:
a. Clinical conditions (eg, autoimmune disease or immunodeficiency) expected to
have an impact on the immune response elicited by the study vaccine. Participants
with autoimmune disease (eg, autoimmune-mediated thyroid disease, autoimmune
inflammatory rheumatic disease such as rheumatoid arthritis, and type 1 diabetes)
that is stable and inactive without the use of systemic immunomodulators and
glucocorticoids may be enrolled at the discretion of the investigator.
b. Use of systemic corticosteroids within 2 months before administration of the first
study vaccine until 28 days after the second study vaccination.
Note: Ocular, topical, or inhaled steroids are allowed
c. Administration of antineoplastic and immunomodulating agents, eg, cancer
chemotherapeutic agents,or radiotherapy within 6 months before administration of
the first study vaccine until 28 days after the second study vaccination.
5. 
per medical history, participant has chronic active hepatitis B or hepatitis C infection.
6. 
per medical history, participant has human immunodeficiency virus type 1 or type 2
infection.
7. 
history of acute polyneuropathy (eg, Guillain-Barré syndrome) or chronic idiopathic
demyelinating polyneuropathy.
8. 
Criterion modified per Amendment 1
8.1 
received hematopoietic stem cell transplant in medical history, treatment with
immunoglobulins expected to impact the vaccine-induced immune response
(including monoclonal antibodies for chronic underlying conditions) in the 2
months, immunoglobulins specific to RSV, human metapneumovirus, or
parainfluenza viruses in the 12 months, apheresis therapies in the 4 months, or
blood products in the 4 months before the planned administration of the first
study vaccine or has any plans to receive such treatment during the study.
Note: The investigator is encouraged to contact the sponsor to discuss
eligibility of participants on immunoglobulin treatment.
9. 
history of TTS or heparin-induced thrombocytopenia and thrombosis (HITT).
10. 
received or plans to receive:
a. Licensed live attenuated vaccines within 28 days before or after planned
administration of the first or subsequent study vaccines.
b. Other licensed (not live) vaccines within 14 days before or after planned
administration of the first or subsequent study vaccines.

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11. 
Criterion modified per Amendment 1
11.1 received or plans to receive a SARS-COV-2 vaccine:
a. Live attenuated SARS-COV-2 vaccine within 28 days before or after planned
administration of the first or subsequent study vaccines.
b. Non-live SARS-COV-2 vaccine within 14 days before or after planned
administration of the first or subsequent study vaccines.
c. A viral-vectored SARS-COV-2 vaccine at within 6 months prior to
randomization or during the study period until 28 days after the last study
vaccination.
12. 
received vaccination with seasonal influenza vaccine for the current influenza season
in the Northern Hemisphere.
13. 
received an RSV vaccine in a previous RSV vaccine study.
14. 
received or plans to receive an Ad26-vectored vaccine at any time prior to
randomization until 28 days after each study vaccination (for exclusion criteria related
to SARS-COV-2 vaccines,please refer to Exclusion Criterion 11).
15. 
Criterion modified per Amendment 1
15.1 received an investigational drug or used an invasive investigational medical
device within 30 days or received an investigational vaccine within 6 months
before the planned administration of the first study vaccination or is currently
enrolled or plans to participate in another investigational study during this study.
Note: Participation in an observational clinical study (ie, without intervention)
or in the observational phase of interventional studiesis allowed upon approval
of the sponsor or its delegate.
16. 
has a serious chronic disorder, eg, chronic obstructive pulmonary disease or congestive
heart failure, end-stage renal disease with or without dialysis, clinically unstable cardiac
disease, Alzheimer’s disease, or has any condition, including conditions placing the
participant at high risk for severe influenza,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.
17. 
has had major surgery (per the investigator’s judgment) within 4 weeks before
administration of the first study vaccine or will not have recovered from surgery per the
investigator’s judgment at time of vaccination.
18. 
contraindication to IM injections and blood draws (eg, bleeding disorders).
19. 
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.

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20. 
has had major psychiatric illness and/or drug or alcohol abuse which in the
investigator’s opinion would compromise the participant’s safety and/or compliance
with the study procedures.
21. 
cannot communicate reliably with the investigator.
22. 
who, in the opinion of the investigator, is unlikely to adhere to the requirements of the
study, or unlikely to complete the full course of vaccination and observation.
23. 
who has significant scarring, tattoos, abrasions, cuts, or infections over the deltoid
region of both arms that, in the investigator’s opinion, could interfere with evaluation
of injection site local reactions.
NOTE: Investigators should ensure that all study enrollment criteria have been met prior to the
first study vaccination. If a participant’s clinical status changes (including any available laboratory
results or receipt of additional medical records) after screening but before the first dose of study
vaccine is given such that the participant no longer meets all eligibility criteria, then the participant
should be excluded from participation in the study. Section 5.4 describes options for rescreening.
The required documentation to support meeting the enrollment criteria is described under Source
Documents in Appendix 3.
5.3. 
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions
during the study to be eligible for participation:
1. 
refer to Section 6.8,Concomitant Therapyfor 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.
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.
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.

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Rescreening is allowed only for resolution of an acute condition or meeting a time window (eg,for
a prohibited medication). Only 1 rescreening per participant is permitted. Rescreened participants
will be assigned a new participant number, undergo the informed consent process, and then restart
a new screening phase.
5.5. 
Criteria for Temporarily Delaying Study Vaccine Administration
The following events constitute a temporary contraindication to study vaccination:
 
Clinically significant acute illness at the time of vaccination. This does not include minor
illnesses, such as diarrhea or mild upper respiratory tract infection.
 
Fever (body temperature ≥38.0°C [≥100.4°F]) within 24 hours prior to the planned time of
vaccination.
 
Medically indicated vaccinations, including SARS-COV-2 vaccine boosters
If any of these events occur at the scheduled time for the first vaccination, randomization at a later
date within the screening window (allowed window up to 10 days) is permitted at the discretion
of the investigator and after consultation with the sponsor. In this case, screening and vaccination
can be split over 2 visits. If randomization cannot occur within the screening window, rescreening
is required.
If any of these events occur at the scheduled time for the second vaccination, Visit 3 (Day 29)
would need to be split into two visits. The administration of the second study vaccination can be
delayed up to 10 days on top of the allowed time window of Visit 3 (±5 days). On the other hand,
the immunogenicity and safety assessments of Visit 3 should still be performed on the actual Day
29 (±5 days).
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 VACCINES AND CONCOMITANT THERAPY
6.1. 
Study Vaccines Administration
The investigational medicinal products to be administered to participants in this study are
Ad26.RSV.preF, RSV preF protein, Fluzone HD Quadrivalent,and placebo.
The Ad26/protein preF RSV vaccine to be used in this study is composed of Ad26.RSV.preF and
RSV preF protein, to be administered as a single injection (1.0 mL) in the deltoid muscle:
 
Ad26.RSV.preF (JNJ-64400141) will be used at a dose level of 1×1011 vp.
 
RSV preF protein (JNJ-64213175) will be used at a dose level of 150 μg.
Ad26.RSV.preF and RSV preF protein will be manufactured and provided under the responsibility
of the sponsor. Labels will contain information to meet the applicable regulatory requirements.
Note that RSV preF protein clinical trial material will be labelled as “RSV-F Vaccine”. Refer to

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the IB for Ad26/protein preF RSV vaccine for details of the components and a list of excipients
(IB Ad26/protein preF RSV vaccine 2021).
Placebo for Ad26/protein preF RSV vaccine will be 0.9% saline (1.0 mL).
The seasonal influenza vaccine to be used in this study is Fluzone HD Quadrivalent formulated
for the 2021-2022 influenza season. Fluzone HD Quadrivalent is a suspension for IM injection
supplied in a 0.7-mL single-dose prefilled syringe. Each dose of Fluzone HD  Quadrivalent
contains 240 µg of hemagglutinin (HA): 60 µg of each of 4 influenza strains (2 influenza A strains
and 2 influenza B strains). For details, refer to the Fluzone HD  Quadrivalent package insert.
Fluzone HD Quadrivalent will be administered open-label (unblinded). There is no placebo control
to be used for Fluzone HD Quadrivalent.
Participants will be vaccinated at the study site according to the schedule shown in Table 1. On
Day 1, each participant will receive 2 IM injections, 1 in each arm; on Day 29, each participant
will receive 1 IM injection. The right arm should be used for seasonal influenza vaccination on
Day 1; the left arm should be used for Ad26/protein preF RSV vaccine or placebo on Days 1 and 29.
For information on the window for the second study vaccination, see Section 8. If a participant
cannot be vaccinated within the allowed window, the decision regarding vaccination will be
assessed on a case-by-case basis, upon discussion between sponsor and investigator.
Study vaccine administration must be captured in the source documents and the electronic case
report form (eCRF).
For a definition of study vaccine overdose, refer to Section 6.7.
6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage of Ad26/protein preF RSV vaccine and Placebo
Vials must be stored in a secured location under controlled temperature with no access for
unauthorized personnel. The study refrigerator/freezer must be equipped with a continuous
temperature monitor and alarm and should be equipped with back-up power systems. Ifthe study
vaccine components are exposed to temperatures outside the specified temperature range, all
relevant data will be sent to the sponsor to determine if the affected study vaccine components can
be used or will be replaced. The affected study vaccine components must be quarantined and not
used until further instruction from the sponsor is received.
Administration of study vaccine (Ad26/protein preF RSV vaccine or placebo) on Days 1 and 29
will be blinded. An unblinded study-site pharmacist, or other qualified individual will prepare the
appropriate vials and syringes, labeled with the participant’s identification number, and provide
the syringes for Ad26/protein preF RSV vaccine and placebo in a blinded manner to the blinded
vaccine administrator who will perform the injection.

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Refer to the Investigational Product Preparation Instructions and Study Site Investigational
Product and Procedures Manual for additional guidance on study vaccine preparation, handling,
and storage.
Preparation/Handling/Storage of Fluzone HD Quadrivalent
Fluzone HD Quadrivalent should be stored, handled, and administered according to the
instructions on the package insert. Administration of Fluzone HD Quadrivalent on Day 1 will not
be blinded. The disposal of the vaccine will be according to local prescribing information. The
study refrigerator/freezer must be equipped with a continuous temperature monitor and alarm and
should be equipped with back-up power systems. If the study vaccine components are exposed to
temperatures outside the specified temperature range, all relevant data will be sent to the sponsor
to determine if the affected study vaccine components can be used or will be replaced. The affected
study vaccine components must be quarantined and not used until further instruction from the
sponsor is received.
Accountability
The investigator is responsible for ensuring that all study vaccine received at the site is inventoried
and accounted for throughout the study. The study vaccine administered to the participant must be
documented on the vaccine accountability form. All study vaccine will be stored and disposed of
according to the sponsor’s instructions.
Study 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 return 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 return form.
Potentially hazardous materials containing hazardous liquids, such as used ampules, needles,
syringes, and vials, should be disposed of immediately in a safe manner and therefore will not be
retained for vaccine accountability purposes.
Study vaccine should be dispensed under the supervision of the investigator or a qualified member
of the study-site personnel. Study vaccine will be supplied only to participants participating in the
study. 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.
Refer to the Investigational Product Preparation Instructions and Study Site Investigational
Product and Procedures Manual for additional guidance on the final disposition of unused study
vaccines.

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6.3. 
Measures to Minimize Bias: Randomization and Blinding
Study Vaccine Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Participants will be randomly assigned
to 1 of 2 vaccination groups based on a computer-generated randomization schedule prepared
before the study by or under the supervision of the sponsor. The randomization will be balanced
by using randomly permuted blocks and will be stratified by age categories (65-74 years,
75-84 years, ≥85 years). The interactive web response system (IWRS) will assign a unique study
vaccine allocation code, which will dictate the study vaccine assignment and matching study
vaccine kit for the participant. The requestor must use their own user identification and personal
identification number when contacting the IWRS, and will then give the relevant participant details
to uniquely identify the participant.
Blinding
The investigator will not be provided with randomization codes until database lock of the final
analysis. The participants remain blinded until database lock of the final analysis. The codes will
be maintained within the IWRS, which has the functionality to allow the investigator to break the
blind for an individual participant.
For the sponsor, unblinding (at the participant level) will occur at the time of the primary analysis
(Section 9.5). From the primary analysis onwards, group level results may be shared as needed;
however, efforts will be made to preserve the blinding to the individual participant allocation.
Data that may potentially unblind the study vaccine assignment (eg,immunogenicity data, study
vaccine preparation/accountability data, study vaccine allocation) will be handled with special care
to ensure that the integrity of the blind is maintained and the potential for bias is minimized. This
can include making special provisions, such as segregating the data in question from view by the
investigators, clinical team, or others as appropriate until the time of database lock and unblinding.
The investigator may, in an emergency, determine the identity of the study vaccine by contacting
the IWRS. While the responsibility to break the study vaccine allocation code in emergency
situations resides solely with the investigator, it is recommended that the investigator contacts 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 by the IWRS, in the appropriate section
of the eCRF, and in the source document. The documentation received from the IWRS indicating
the code break must be retained with the participant’s source documents in a secure manner.
The study-site pharmacist or qualified individual with primary responsibility for study vaccine
preparation and dispensing will be unblinded to study vaccine allocation.
Note: administration of Fluzone HD Quadrivalent will not be blinded.

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Participants who have had their study vaccine assignment unblinded should continue to return for
scheduled evaluations.
Participants who withdraw will not be replaced.
6.4. 
Study Vaccination Compliance
Ad26/protein preF RSV vaccine or placebo will be administered IM 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, and site of administration). For blinding procedures, see
Section 6.3.
6.5. 
Dose Modification
Not applicable.
6.6. 
Continued Access to Study Vaccine After the End of the Study
According to the study design, all participants in this study will receive Ad26/protein preF RSV
vaccine and Fluzone HD  Quadrivalent, irrespective of the study group to which they are
randomized. Therefore, there is no need to offer active study vaccine to placebo recipients after
the end of the study.
Participants will be instructed that study vaccine will not be made available to them after they have
completed/discontinued study vaccination.
6.7. 
Treatment of Overdose
For this study, any dose of the Ad26/protein preF RSV vaccine or Fluzone HD Quadrivalent
greater than the protocol-specified dose 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.
 
Evaluate the participant to determine, in consultation with the Medical Monitor, whether study
vaccine should be interrupted.
 
Closely monitor the participant for AEs/SAEs/AESIs until resolution.
 
Document the quantity of the excess dose as well as the duration of the overdosing in the
eCRF.
 
Report as a special reporting situation.
6.8. 
Concomitant Therapy
Prestudy therapies administered within the 30 days before administration of the first study vaccine
must be recorded on Day 1. Additionally, any history of SARS-COV-2 vaccination
(name/manufacturer of the vaccine and date of administration, whenever possible) prior to and
during the study will be collected in the eCRF.

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Concomitant therapies associated with solicited AEs will be collected by the participants in the
participant diary  from the time of study vaccination through 7 days after each vaccination.
Concomitant therapies associated with unsolicited AEs will be collected and recorded in the eCRF
from the time of study vaccination through 28 days after each vaccination. Concomitant therapies
associated with SAEs or AESIs will be collected and recorded in the eCRF from ICF signature
until 6 months after the second study vaccination.
Analgesic/antipyretic medications and non-steroidal anti-inflammatory drugs may be used
postvaccination only in cases of medical need (eg, fever or pain) and their use must be documented.
Use of these medications as routine prophylaxis prior to study vaccination is discouraged.
Information on concomitant use of herbal supplements or vitamins will not be collected.
Use of any experimental medication (including experimental vaccines other than the study
vaccine) during the study is not allowed.
Vaccination with licensed live attenuated vaccines within 28 days of a study vaccination (ie, before
or after) is prohibited. 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. If a vaccine is indicated in a postexposure setting (eg,rabies or tetanus), it must take
priority over the study vaccine.
For SARS-COV-2 vaccines either licensed or available under Emergency Use Authorization: live
attenuated vaccines should be given at least 28 days before or after vaccination; non-live vaccines
should be given at least 14 days before or after vaccination. A viral-vectored SARS-COV-2
vaccine is not to be given within 6 months prior to randomization or during the study period until
28 days after the last study vaccination.
Use of systemic corticosteroidsa must be documented until 28 days after the second study
vaccination. Antineoplastic and immunomodulating agents, eg, cancer chemotherapeutic agents or
systemic corticosteroids, or radiotherapy are prohibited until 28 days after the second study
vaccination. If the use of systemic corticosteroids, antineoplastic or immunomodulating agents or
any therapy described in exclusion criterion 8 becomes medically indicated during the study for
any participant, the sponsor should be notified.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
a Note: Ocular, topical, or inhaled steroids are allowed.

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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 safety  follow-up.
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
 
Unblinding on the participant level that, in the opinion of the sponsor, would compromise the
integrity of the data
 
Anaphylactic reaction following vaccination
 
SAE, AESI, or other potentially life-threatening (Grade 4) event that is determined to be
related to study vaccine
 
Use ofsystemic corticosteroids, antineoplastic or immunomodulating agents,or radiotherapy
(after discussion with the sponsor). See also Section 6.8.
 
Withdrawal of consent
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
 
Death
 
AnyAE that requires discontinuation from the study
 
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.
An early exit visit will be conducted for those participants who are unable to continue participation
in the study and withdraw from the study before Day 211, but who do not withdraw consent (see
Schedule of Activities). Participants who wish to withdraw consent from participation in the study
will be offered an early exit visit (prior to formal withdrawal of consent). They have the right to
refuse.
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 ICF apply

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(eg, consult with family members, contacting the participant’s other physicians, medical records,
database searches, use of locator agencies at study completion) 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 future research (refer to Long-Term
Retention of Samples for Additional Future Research in Appendix 3). In such a case, samples will
be destroyed after they are no longer needed for the clinical study. Details of the sample retention
for research are presented in the main ICF.
7.3. 
Lost to Follow-up
A participant will be considered lost to follow-up if the participant 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,
emails, fax, and, if necessary, a certified letter to the participant’s last known mailing address,
or local equivalent methods. 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 summarizes the frequency and timing of study visits and of
immunogenicity and safety measurements applicable to this study.
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures
be performed in the following sequence: vital signs, other safety assessments, 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/or in the eCRF.

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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
(injection site) and systemic signs and symptoms.
The participant diary includes instructions on how to capture the data and grading scales to assess
severity of the signs and symptoms. The study staff is responsible for providing appropriate
training to the participant to avoid missing or incorrect data. The participant diary will be reviewed
by the study-site personnel at visits indicated in the Schedule of Activities. If the participant diary
review is missed, the participant diary will be reviewed during the following visit. If a participant
misses a vaccination, the participant diary covering the period after the missed vaccination does
not have to be completed.
The total blood volume to be collected from each participant will be approximately 60 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples.
Visit Windows
For the following visits, windows will be allowed as indicated:
Study Visit # 
Day  
Visit Window  Primary Purpose
2 
8 
±2 days 
7 days after first study vaccination, Safety visit, by telephone
3 
29 
±5 days 
Second study vaccination, Immunogenicity and Safety visit
4 
36 
±2 days 
7 days after second study vaccination, Safety visit, by telephone
5 
57 
±7 days
28 days after second study vaccination, Immunogenicity and
Safety visit
6 
211 
±14 days
6 months after second study vaccination, Safety visit, by
telephone
Note: In case any of the criteria for temporarily delaying study vaccine administration (see Section
5.5) are met at Visit 3 (Day 29), this visit would need to be split into two visits. The administration
of the second study vaccination can be delayed up to 10 days on top of the allowed time window
of Visit 3 (±5 days). On the other hand, the immunogenicity and safety assessments of Visit 3
should still be performed on the actual Day 29 (±5 days).
The timings of the postvaccination visits will be determined relative to the actual day of the
corresponding vaccination. If a participant misses a vaccination, the postvaccination visits will be
calculated from the imputative vaccination date according to protocol.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF  or laboratory
requisition form.
Refer to the Schedule of Activities for the timing and frequency of all sample collections.

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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/protein preF RSV vaccine (IB Ad26/protein preF RSV vaccine 2021)
 
Fluzone HD Quadrivalent package insert
 
Study Site Investigational Product and Procedures Manual
 
laboratory manual
 
Investigational Product Preparation Instructions
 
participant diary and instructions for use
 
thermometer
 
ruler (to measure diameter of any erythema and swelling)
 
laboratory kits
 
Contact Information page(s)
 
study protocol
 
IWRS manual
 
electronic data capture (eDC) Manual/eCRF completion guidelines
 
wallet card
 
sample ICF
8.1. 
Immunogenicity Assessments
Venous blood samples of approximately 20 mL will be collected for the determination of humoral
immune responses at the time points indicated in the Schedule of Activities. Sample collection and
processing will be performed by study-site personnel according to current versions of approved
standard operating procedures.
It is assumed that all enrolled participants will have a preexisting immune response due to previous
RSV exposure as well as influenza-specific responses to 1 or more strains, either by natural
exposure to influenza or by annual influenza vaccination (not including the current influenza
season).
Humoral immunogenicity evaluations are summarized in Table 2.

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Table 2: 
Summary of Immunogenicity Assays (Humoral)
Assay 
Purpose
Primary endpoints
HI assay* 
Analysis of HI to influenza vaccine strains
F-protein antibody  
(RSV-A pre-F ELISA**) 
Analysis of antibodies binding to RSV-A F protein in prefusion
form
Secondary endpoints
HI assay* 
Analysis of HI to influenza vaccine strains
* The HI antibody titers against influenza virus strains recommended by the World Health Organization (WHO)
for use in 2021-2022 in the Northern Hemisphere season will be measured using a validated HI assay
platform.
** The same assay was used for immunogenicity assessments in the VAC18193RSV2001 (Cypress) study.
8.2. 
Safety Assessments
Safety assessments will include the monitoring of AEs and vital signs.
AEs will be reported and followed by the investigator as specified in Section 8.3 and Appendix 2.
Any clinically significant abnormalities will be followed by the investigator until clinical
resolution (return to baseline) or until a clinically stable condition  is reached, or until the
participant has been deemed lost to follow-up after demonstration of due diligence of follow-up
efforts.
The study will include the following evaluations of safety and reactogenicity according to the time
points provided in the Schedule of Activities.
8.2.1. 
Physical Examinations
At any clinic visit, an abbreviated, symptom-directed examination may be performed if deemed
necessary by the investigator based on any clinically relevant issues, clinically relevant symptoms,
and medical history.
Physical examinations will be performed by the investigator or appropriately trained delegate. Any
clinically relevant abnormalities or changes in severity noted during the review of body systems
should be documented in the eCRF as an AE or SAE if it meets the criteria for an AE or SAE
according to the protocol reporting requirements.
8.2.2. 
Vital Signs
Vital signs will be measured pre- and postdose on Days 1 and 29. At non-vaccination visits, vital
signs will be measured if deemed necessary by the investigator. Body temperature (oral route
preferred), heart rate (beats per minute), respiratory rate (breaths per minute), and systolic and
diastolic blood pressure (mmHg) will be assessed. Height and weight will be measured during
screening.
Blood pressure and heart rate measurements will be assessed, if possible, with a completely
automated device. Manual techniques will be used only if an automated device is not available.

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Sitting systolic and diastolic blood pressure and heart and respiratory rate measurements should
be preceded by at least 5 minutes of rest in a quiet setting without distractions (eg, television, cell
phones).
Confirmatory vital signs measurement can be performed if inconsistent with a prior measurement.
Any abnormalities or changes in severity noted during the review of vital signs should be
documented in the eCRF.
8.3. 
AEs, SAEs, AESIs, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including AEs, SAEs,
AESIs (including potential AESIs, refer to Section 8.3.6), and Product Quality Complaints (PQCs),
from clinical studies are crucial for the protection of participants, investigators, and the sponsor,
and are mandated by regulatory agencies worldwide. The sponsor has established standard
operating procedures in conformity with regulatory requirements worldwide to ensure appropriate
reporting of safety information; all clinical studies conducted by the sponsor or its affiliates will
be conducted in accordance with those procedures.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the
participant’s legally acceptable representative) for the duration of the study.
Further details on AEs,SAEs, AESIs, and PQCs can be found in Appendix 2.
8.3.1. 
Time Period and Frequency for Collecting AE, SAE, and AESI
Information
All AEs
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.
Clinically relevant medical events not meeting the above criteria and occurring between signing
of ICF and moment of first study vaccination will be collected on the Medical History eCRF page
as preexisting conditions.
Solicited AEs, collected through a participant diary, will be recorded for each vaccination from
the time of vaccination until 7 days postvaccination.
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 postvaccination.
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.
All SAEs and AEs leading to discontinuation from the study/vaccination (regardless of the causal
relationship) are to be reported from the moment of first study vaccination until completion of the

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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.
See Section 7.2 for procedures associated with withdrawal of consent.
All AEs will be followed until resolution or until clinically stable.
SAEs
All SAEs occurring during the study must be reported to the appropriate sponsor contact person
by study-site personnel immediately, but no later than 24 hours of their knowledge of the event.
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 immediately, but no later than 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.
AESIs
TTS is considered to be an AESI. Thrombotic events and/or symptomatic thrombocytopenia
(defined as platelet count below the lower limit of normal [LLN] range for the testing lab) are
considered to be potential AESIs. All AESIs, including potential AESIs, will be reported to the
sponsor from the moment of first study vaccination until 6 months after the second study
vaccination (see Section 8.3.6).
8.3.2. 
Method of Detecting AEs, SAEs, and AESIs
Care will be taken not to introduce bias when detecting AEs, SAEs, or AESIs. Open-ended and
nonleading verbal questioning of the participant is the preferred method to inquire about AE
occurrence.
Solicited AEs
Solicited AEs are used to assess the reactogenicity of the study vaccine and are predefined local
(injection site) and systemic events for which the participant is specifically questioned and which
are noted by participants in their participant diary.
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.
In addition, participants will record solicited signs and symptoms in a participant diary for 7 days
postvaccination. All participants will be provided with a participant diary and instructions on how
to complete the participant diary (see Overview in Section 8). The study is primarily using an e-
diary and the data collected in the e-diary will be transferred to the sponsor. If a paper diary is
used, the e-diary vendor will transcribe the information provided by the participant in the paper
diary into the relevant sections of the e-diary database. The review of diary entries with participants

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may be done by a qualified and delegated study staff member including investigator, sub-
investigator,or study nurse. The delegated study staff membergrades any signs or symptoms using
the toxicity grading scale (Appendix 4: Toxicity Grading Scale)and will complete their assessment
in the relevant sections of the eCRF. The diary review and grading of symptoms are done under
the oversight of the investigator or a delegated physician. Once a solicited sign or symptom from
a participant diaryis considered to be of severity Grade 1 or above, it will be recorded as a solicited
AE.
Solicited Local (Injection Site)AEs
Participants will be asked to note in the participant diary  occurrences of injection site
pain/tenderness, erythema and swelling at the study vaccine injection sites (as detailed in the
participant diary) daily for 7 days postvaccination (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).
Solicited Systemic AEs
Participants will be instructed on how to record daily temperature using a thermometer provided
for home use. Participants should record the temperature (oral route preferred) in the participant
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 ≥38.0°C (≥100.4°F), as recorded in
at least 1 measurement (Marcy 2004).
Participants will also be instructed on how to note signs and symptoms in the participant diary on
a daily basis for 7 days postvaccination (day of vaccination and the subsequent 7 days), for the
following events: fatigue, headache, nausea, and myalgia.
Unsolicited AEs
Unsolicited AEs are all AEs for which the participant is not specifically questioned in the
participant diary.
For details regarding AESIs, refer to Section 8.3.6.
8.3.3. 
Follow-up of AEs, SAEs, and AESIs
The investigator is obligated to perform or arrange for the conduct of supplemental measurements
and evaluations as medically indicated to elucidate the nature and causality of the AE, SAE, AESI,
or PQCs as fully as possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other health care professionals.
AEs and the special reporting situation of pregnancy will be followed by the investigator as
specified in Appendix 2.

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8.3.4. 
Regulatory Reporting Requirements for SAEs
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
(IEC)/ Institutional Review Board (IRB)that approved the protocol unless otherwise required and
documented by the IEC/IRB. A SUSAR will be reported to regulatory authorities unblinded.
Participating investigators and IEC/IRB will receive a blinded SUSAR summary, unless otherwise
specified.
8.3.5. 
Pregnancy
All initial reports of pregnancy in participants or partners of male participants must be reported to
the sponsor by the study-site personnel within 24 hours of their knowledge of the event using the
appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and
must be reported using an SAE reporting form. If a participant becomes pregnant during the study,
a determination regarding study vaccination discontinuation must be made by the investigator in
consultation with the sponsor. Follow-up information regarding the outcome of the pregnancy and
any postnatal sequelae in the infant will be required. If the partner of a male participant becomes
pregnant during the study, follow-up information regarding the outcome of the pregnancy and any
postnatal sequelae in the infant will be required upon the consent provided by the partner.
8.3.6. 
Adverse Events of Special Interest
AESIs (including potential 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.
AESIs and potential AESIs will be carefully monitored during the study by the sponsor.
AESIs and potential AESIs must be reported to the sponsor within 24 hours of awareness
irrespective of seriousness (ie, serious and nonserious AEs) or causality following the procedure
described above for SAEs.
AESIs must be reported using the AESI form in the eCRF using the eCRF completion guidelines.
Specific requirements for the AESI are described below.
8.3.6.1. 
Thrombosis with Thrombocytopenia Syndrome
As described in Section 2.2, TTS has been observed very rarely following vaccination with Janssen
COVID vaccine 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 2021)
Because this syndrome is rare and not completely understood, all cases of thrombosis and/or
symptomatic thrombocytopenia will be considered a potential case of TTS and should be reported

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to the sponsor within 24 hours of awareness using the AESI form. Each potential AESI will be
reviewed to identify a TTS case. A potential TTS case is defined as:
 
Thrombotic events: suspected deep vessel venous or arterial thrombotic events as detailed in
Section 10.6, Appendix 6,
and/or
 
Symptomatic thrombocytopenia, defined as platelet count below LLN for the testing lab
Symptoms, signs, or conditions suggestive of a thrombotic event or symptomatic
thrombocytopenia should be recorded and reported as a potential 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 symptomatic 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 symptomatic thrombocytopenia, complete blood count including
platelet count and a coagulation profile available from participant’s medical records should be
entered in the eCRF. In case these results are not available at the time of the event report in the
eCRF, the study site is recommended to obtain a complete blood count including platelet count
and a coagulation profile (to be performed at the local laboratory). Repeat testing at the local
laboratory may be requested for confirmation upon sponsor discretion.
Aliquots of serum samples collected for immunogenicity tests can be reconverted for participant’s
safety purposes upon sponsor request (Table 3).
Table 3 provides non-exhaustive list(s) of laboratory tests that may be performed (upon sponsor
request).
In addition, the sponsor may request additional laboratory tests on additional blood samples
obtained as soon as possible after the potential AESI onset, either during an ad hoc unscheduled
visit or the next scheduled visit, whichever comes first. Table 4 provides a non-exhaustive list of
laboratory tests that may be requested by the sponsor in case of potential AESI reporting, for which
additional samples may be needed.
Table 3: 
Laboratory Tests That May Be Performed Upon Sponsor Request on Immunogenicity Samples
Collected on Day 1, Day 29 and/or Day 57
Parameters 
Timepoints
 Serum samples for assay such as but not limited to:
o Heparin Induced Thrombocytopenia (HIT)/PF4 Ab, IgG·(HIT assay)
If the above test is positive, also consider:
 Anti-cardiolipin antibody
 Beta-2 glycoprotein
 Days 1, 29 and 57 visits
(aliquots of serum samples
collected for immunogenicity
test can be reconverted for
participant’s safety purposes).
Ab = antibody, IgG = immunoglobulin G, PF4 = platelet factor 4.
Note: results of the test should be reported in the narrative of the event and/or in the TTS AESI pages of the eCRF.

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Table 4: 
Laboratory Tests That May Be Requested by the Sponsor to be Performed at the Central
Laboratory After Potential AESI Reporting
Parameters 
Timepoints
 Serum/plasma/whole blood samples for coagulation-related assays such as 
but not limited to: 
o Fibrinogen 
o D-dimer· 
o Lupus anticoagulant· 
o Anti-cardiolipin antibody 
o Beta-2 glycoprotein·
o Heparin Induced Thrombocytopenia (HIT)/PF4 Ab, IgG·(HIT assay)
o Platelet activation assay (if HIT/PF4 is positive)
o Homocysteine·
o COVID-19 serological test
 As soon as possible after the
potential AESI onset upon
sponsor request (during an ad
hoc unscheduled visit or the
next scheduled visit, whichever
comes first).
Ab = antibody, AESI = adverse event of special interest; COVID-19 = Coronavirus Disease 2019, IgG =
immunoglobulin G, PF4 = platelet factor 4.
Note: results of the test should be reported in the narrative of the event and/or in the TTS AESI pages of the eCRF.
Irrespective on samples for central laboratory tests collection, relevant data for TTS assessment reported in the
medical records of the participant should be reported in eCRF narrative of the event and/or in the TTS AESI pages
of the eCRF.
AESIs, including potential AESIs, will require enhanced data collection and evaluation. Every
effort should be made to report as much information as possible about the event to the sponsor in
a reasonable timeframe. Relevant laboratory results can be entered on the AESI form in the eCRF,
using the eCRF completion guidelines.
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.
If an event meets the criteria for an SAE (Section 10.2.1), it should be reported using the same
process as for other SAEs.
Treatment and Follow-up Recommendation
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, American
Society of Hematology 2021; British Society for Haematology 2021; CDC 2021). The use of
heparin may be harmful and alternative treatments may be needed. Consultation with a
hematologist is strongly recommended.
8.4. 
Medical Resource Utilization
Medical Resource Utilization parameters are not evaluated in this study.

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9. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the immunogenicity and safety data is
outlined below. Specific details will be provided in the statistical analysis plan (SAP).
9.1. 
Statistical Hypotheses
For a description of the hypotheses, see Section 3.
The study is successful if both below objectives are demonstrated:
 non-inferiority of the concomitant administration of Ad26/protein preF RSV vaccine and
a seasonal influenza vaccine versus the administration of a seasonal influenza vaccine
alone, 28 days after the administration of a seasonal influenza vaccine,in terms of humoral
immune response as measured by the HI assay,
AND
 non-inferiority of the concomitant administration of Ad26/protein preF RSV vaccine and
a seasonal influenza vaccine versus the administration of Ad26/protein preF RSV vaccine
alone, 28 days after the administration of Ad26/protein preF RSV vaccine, in terms of
humoral immune response (pre-F ELISA)
Therefore,the following confidence intervals (CIs)will be calculated:
 the 2-sided 95% CIs for the difference in log-transformed HI antibody titers against each
of the 4 seasonal influenza vaccine strains at 28 days after the administration  of the
quadrivalent high-dose seasonal influenza vaccine between the Control and the CoAd
group, and
 the 2-sided 95% CIs for the difference in log-transformed pre-F ELISA titers at 28 days
after the administration of Ad26/protein preF RSV vaccine between the Control and the
CoAd group
Only if the upper bound of the 2-sided 95% CI for the GMT ratio (Control group/CoAd group) of
the HI antibody titer for each of the 4 vaccine strains and for pre-F ELISA lies below 1.5, non-
inferiority of coadministration versus separate administration will be concluded for both vaccines
(seasonal influenza vaccine and Ad26/protein preF RSV vaccine). If 1 or more confidence limits
for the GMT ratio exceed 1.5, non-inferiority cannot be concluded.
As both non-inferiority objectives should be demonstrated to have a successful study, no
multiplicity adjustment is needed.

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9.2. 
Sample Size Determination
Sample size calculations are performed under the following assumptions:
 
no effect of coadministration of Ad26/protein preF RSV vaccine and seasonal influenza
vaccine on the immune response against influenza as measured by HI antibody titers against
the 4 influenza vaccine strains at 28 days after the administration of seasonal influenza vaccine
 
a standard deviation of 2.1 at the log2 scale for HI antibody titers against the 4 influenza
vaccine strains at 28 days after the administration of seasonal influenza vaccine (with or
without Ad26/protein preF RSV vaccine)a
 
no effect of coadministration of Ad26/protein preF RSV vaccine and seasonal influenza
vaccine on the immune response against RSV as measured by pre-F ELISA at 28 days after
the administration of Ad26/protein preF RSV vaccine
 
a standard deviation of 1.1 at the log2 scale for pre-F ELISA at 28 days after the administration
of Ad26/protein preF RSV vaccine (with or without seasonal influenza vaccine)b
 
a non-inferiority margin of 1.5c
 
2-sided αof 5%
A total of 330 evaluable participants per group are needed to have 94.7% power to show
non-inferiority in HI antibody titers for 1 influenza vaccine strain. With this sample size, the
overall power to show non-inferiority in HI antibody titers against each of the 4 influenza vaccine
strains at 28 days after the administration of seasonal influenza vaccine as well as non-inferiority
in pre-F ELISA at 28 days after the administration of Ad26/protein preF RSV vaccine is at least
80%.
To account for exclusions from the per protocol set (see Section 9.3), drop-outs and missing
samples, approximately 375 participants per group should be enrolled, resulting in a total sample
size of approximately 750 participants.
9.3. 
Populations for Analysis Sets
Vaccination assignment will follow the as-treated principle.
The Full Analysis (FA)Set will include all participants who received at least 1 study vaccination,
regardless of the occurrence of protocol deviations and vaccine type (seasonal influenza,
Ad26/protein preF RSV vaccine, or placebo). All safety and participant information analyses will
be based on the FA Set.
a 
Based on results obtained from a previous Fluzone HD Quadrivalent study  (NCT03282240
[ClinicalTrials.gov 2019]).
b 
Based on Day 29 pre-F  ELISA results obtained from Cohort 2, Group 14 in study VAC18193RSV1004
(IB Ad26/protein preF RSV vaccine 2021).
c 
Non-inferiority criteria based on FDA guidance for influenza vaccines (FDA 2007b).

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The Per-protocol Influenza Immunogenicity (PPII) Set will include all randomized participants
who received the first study vaccination, and for whom immunogenicity data are available for at
least one of the influenza strains in the vaccine. Samples taken after a participant experiences a
major protocol deviation expected to impact the immunogenicity outcomes will be excluded from
the PPII analysis.
The Per-protocol RSV Immunogenicity (PPRI) Set will include all randomized participants who
received Ad26/protein preF RSV vaccine in combination with seasonal influenza vaccine for the
CoAd group and Ad26/protein preF RSV vaccine alone for the Control group and for whom RSV
immunogenicity data are available. Samples taken after a participant experiences a major protocol
deviation expected to impact the immunogenicity outcomes will be excluded from the PPRI
analysis.
The list of major protocol deviations that would lead to elimination from the immunogenicity
analysis will be specified in the SAP or major protocol violation criteria document, which will be
finalized before database lock and unblinding.
The primary analysis set for analyses related to influenza immunogenicity is the PPII Set, the
primary analysis set for analyses related to RSV immunogenicity is the PPRI Set. As a sensitivity
analysis, key tables may also be based on the FA Set.
9.4. 
Statistical Analyses
The SAP will be finalized prior to database lock of the primary analysis and it will include a more
technical and detailed description of the statistical analyses described in this section. This section
is a summary of the planned statistical analyses of the most important endpoints including primary
and key secondary endpoints.
9.4.1. 
General Considerations
The primary analysis will be performed when all participants have completed the visit 28 days
after the second study vaccination or discontinued earlier.
The significance level (α) is 5% (2-sided). As both non-inferiority objectives should be
demonstrated to have a successful study and as no interim analyses before the primary analysis are
planned, no multiplicity adjustments are needed.
Refer to Section 9.3 for the choice of populations for the different analyses.
9.4.2. 
Participant Information
For all participants, demographic characteristics (eg, age, height, body weight, BMI, race, and
gender) and other baseline characteristics will be tabulated and summarized descriptively  by
group.

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9.4.3. 
Immunogenicity Analyses
9.4.3.1. 
Primary Endpoints
The primary immunogenicity objectives will be assessed by calculating:
 
the 2-sided 95% CIs for the difference in log-transformed HI antibody titers against each of
the 4 influenza vaccine strains at 28 days after the administration of the quadrivalent high-
dose seasonal influenza vaccine between the Control and the CoAd group.
 
the 2-sided 95% CIs for the difference in log-transformed pre-F ELISA titers at 28 days after
the administration of Ad26/protein preF RSV vaccine between the Control and the CoAd
group.
For HI antibody titers against each of the 4 influenza vaccine strains and for pre-F ELISA titers,
an analysis of variance (ANOVA) model will be fitted with the respective titers as dependent
variable and group (Control or CoAd) and age category (as stratified) as independent variable.
Based on these ANOVA models, the CIs around the difference will be calculated and will be back-
transformed (by exponentiation) to CIs around a GMT ratio (GMTControl group/GMTCoAd group) and
compared to the non-inferiority margin of 1.5.
Only if the upper bound of the 2-sided 95% CI for the GMT ratio (Control group/CoAd group) of
the HI antibody titer for each of the 4 vaccine strains and for pre-F  ELISA lies below 1.5,
non-inferiority of coadministration versus separate administration will be concluded for both
vaccines (seasonal influenza vaccine and Ad26/protein preF RSV vaccine). If 1 or more
confidence limits for the GMT ratio exceed 1.5, non-inferiority cannot be concluded.
As a sensitivity analysis to assess the impact of baseline titers, the primary endpoint will also be
evaluated adjusting for the respective baseline titers. For immunogenicity, baseline is considered
as the last assessment prevaccination. In a second sensitivity analysis, different variances between
the groups will be allowed. Therefore,the CIs will be calculated via Welch’s ANOVA.
9.4.3.2. 
Secondary Endpoints
Seroconversion is defined for each of the 4 influenza vaccine strains at 28 days after the
administration of a seasonal influenza vaccine:
 
HI titer ≥1:40 in participants with a prevaccination HI titer of <1:10, or
 
a ≥4-fold HI titer increase in participants with a prevaccination HI titer of ≥1:10
Seroprotection is defined for each of the 4 influenza vaccine strains as HI titer ≥1:40 at 28 days
after the administration of a seasonal influenza vaccine.
The difference in proportions of seroconverted and seroprotected participants between the Control
and the CoAd group will be estimated together with the 2-sided 95% CIs (calculated using
Wilson’s score method).
Additionally, HI antibody titers and pre-F  ELISA titers will be summarized with descriptive
statistics. Descriptive statistics (geometric mean and 95% CI) of the actual values will be

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calculated for continuous immunogenicity  parameters at all timepoints. Geometric mean fold
increases from baseline and corresponding 95% CIs might additionally be calculated. Graphical
representations of immunogenicity parameters will be created as applicable.
For categorical variables, frequency tables will be presented. Difference in proportions and
corresponding CIs may be calculated where appropriate.
9.4.4. 
Safety Analyses
No formal statistical testing of safety data is planned. All safety data will be analyzed descriptively
by group. All safety analyses will be based on the FA Set.
AEs
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 phase (ie, AEs occurring after each vaccination up to 28 days postvaccination) and all SAEs
and AESIs will be included in the analysis. For each AE, the number and percentage of participants
who experience at least 1 occurrence of the given event will be summarized by group.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue study vaccination due to an AE, or who experience a severe
AE, an SAE, or an AESI.
Summaries and/or listings may be provided separately for AEs with onset outside the above
defined timeframe (ie, beyond 28 days postvaccination) and that were reported prevaccination at
the time of the subsequent vaccination.
Solicited local (injection site) and systemic AEs will be summarized descriptively. The overall
frequencies by group as well as frequencies according to severity and duration will be calculated
for solicited AEs. In addition, the number and percentages of participants with at least 1 solicited
local (injection site) or systemic AE will be presented. Frequencies of unsolicited AEs, separately
for all and vaccination-related only, will be presented by System Organ Class and preferred term.
Vital Signs
Baseline and emerging vital signs abnormalities will be listed.
9.5. 
Planned Analyses
The following analyses are planned:
 
Primary analysis: safety and immunogenicity analysis at 28 days after the second study
vaccination. This analysis will be performed based on sponsor unblinded data (study-site
personnel and participants will remain blinded until the end of the study).
 
Final analysis: including SAE data up to study end. This analysis will be performed on
unblinded data.

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations
Ad26 
adenovirus serotype 26
AE 
adverse event
AESI 
adverse event of special interest
ANOVA  
analysis of variance
CI 
confidence interval
CoAd 
coadministration
COVID-19 
Coronavirus Disease 2019
CVST  
cerebral venous sinus thrombosis
DMC  
Data Monitoring Committee
eCRF  
electronic case report form
eDC  
electronic data capture
ELISA  
enzyme-linked immunosorbent assay
FA 
Full Analysis
FDA  
(United States) Food and Drug Administration
FOIA  
Freedom of Information Act
GCP  
Good Clinical Practice
GMT  
geometric mean titer
HA  
hemagglutinin
HI 
hemagglutination inhibition
HI assay  
hemagglutination inhibition assay
HITT  
heparin-induced thrombocytopenia and thrombosis
IB  
Investigator’s Brochure
ICF  
informed consent form
ICH  
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use
ICMJE 
International Committee of Medical Journal Editors
IEC  
Independent Ethics Committee
IM  
intramuscular(ly)
IRB  
Institutional Review Board
IWRS  
interactive web response system
MedDRA  
Medical Dictionary for Regulatory Activities
PCC  
protocol clarification communication
PPII 
Per-protocol Influenza Immunogenicity
PPRI 
Per-protocol RSV Immunogenicity
PQC  
Product Quality Complaint
pre-F 
prefusion conformation-stabilized F protein
PT  
preferred term
RSV  
respiratory syncytial virus
SAE 
serious adverse event
SAP  
statistical analysis plan
SARS-COV-2 
severe acute respiratory syndrome coronavirus 2
SUSAR  
suspected unexpected serious adverse reaction
TTS  
thrombosis with thrombocytopenia syndrome
US  
United States
vp 
viral particles
WHO  
World Health Organization

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10.2. Appendix 2: AEs, SAEs, AESIs, PQCs, and Other Safety Reporting:
Definitions and Procedures for Recording, Evaluating, Follow-up, and
Reporting
10.2.1. 
AE Definitions and Classifications
AE
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 study 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 International
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [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.
Note: For time period of sponsor’s AE collection, see All AEs under Section 8.3.1, Time Period
and Frequency for Collecting AE and SAE Information.
SAE
An SAE based on ICH and European Union Guidelines on Pharmacovigilance for Medicinal
Products for Human Use is any untoward medical occurrence that at any dose:
 
Results in death.
 
Is life-threatening.
(The participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.)
 
Requires inpatient hospitalization or prolongation of existing hospitalization.
 
Results in persistent or significant disability/incapacity.
 
Is a congenital anomaly/birth defect.
 
Is a suspected transmission of any infectious agent via a medicinal product.
 
Is Medically Important*.
*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.

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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 by the sponsor to health authorities and by the investigator to the IEC/IRB according
to regulatory and local requirements.
Unlisted (Unexpected) AE/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product
reference safety information. For the Ad26/protein preF RSV vaccine, the expectedness of an AE
will be determined by whether or not it is listed in the IB (IB Ad26/protein preF RSV vaccine
2021).
For Fluzone HD Quadrivalent with a marketing authorization, the expectedness of an AE will be
determined by whether or not it is listed in the package insert.
10.2.2. 
Attribution Definitions
Assessment of Causality
The causal relationship to study vaccine is determined by the investigator. The following selection
should be used to assess all AEs.
Related
There is a reasonable causal relationship between study vaccine administration and the AE.
Not Related
There is not a reasonable causal relationship between study vaccine administration and the AE.
The term “reasonable causal relationship” means there is evidence to support a causal relationship.
By definition, all solicited AEs at the injection site (local) will be considered related to the study
vaccine administration.

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10.2.3. 
Severity Criteria
All AEs will be coded for severity using a modified version of the FDA grading table, based on
version of September 2007 (FDA 2007a), included in Appendix 4, Toxicity Grading Scale.
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 requiring 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 emergency room
visit or hospitalization
The severity of solicited signs and symptoms will be graded in the participant diary  by the
participant based on the severity assessment provided in the participant diary and then verified by
the investigator using the toxicity grading scale in Appendix 4. (Note: severity of the measured
events will be derived from the diameter [for erythema and swelling] and the temperature
measurements [for fever])
10.2.4. 
Special Reporting Situations
Safety events of interest for 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
 
Reporting of participant pregnancy or participant partner(s) pregnancy
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.

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10.2.5. 
Procedures
All AEs
All AEs, regardless of seriousness, severity, or presumed relationship to study vaccine, must be
recorded using medical terminology in the source document and the eCRF. Whenever possible,
diagnoses should be given when signs and symptoms are due to a common etiology (eg,cough,
runny nose, sneezing, sore throat, and head congestion should be reported as “upper respiratory
infection”). Investigators must record in the eCRF their opinion concerning the relationship of the
AE to study vaccine. 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
SAEs
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).

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Any event requiring hospitalization (or prolongation of hospitalization) that occurs during
participation in the study must be reported as an SAE, except hospitalizations for the following:
 
Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending
placement in long-term care facility).
 
Surgery or procedure planned before entry into the study (must be documented in the eCRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not be
considered SAEs. Any AE that results in a prolongation of the originally planned
hospitalization is to be reported as a new SAE.
The cause of death of a participant in a study during the entire study period, whether or not the
event is expected or associated with the study vaccine, is considered an SAE and must be reported.
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, including potential AESIs, will be carefully monitored during the study by the sponsor and
must be reported to the sponsor within 24 hours of awareness irrespective of seriousness (ie,
serious and nonserious AEs) or causality assessment, following the procedure described above for
SAEs and will require enhanced data collection.
10.2.6. 
PQC 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.
All complaints related to ANY part of the Ad26/protein preF RSV vaccine must be reported within
1 business day. In the event of public holiday, measures must be taken to ensure reporting no later
than calendar day 3.
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.

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A sample of the suspected product should be maintained under the correct storage conditions until
a shipment request is received from the sponsor.
10.2.7. 
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues, PQCs, or questions regarding the study are listed in the Contact
Information page(s), which will be provided as a separate document.

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10.3. Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
10.3.1. 
Regulatory and Ethical Considerations
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and
country-specific requirements.
GCPis an international ethical and scientific quality standard for designing, conducting, recording,
and reporting studies that involve the participation of human participants. Compliance with this
standard provides public assurance that the rights, safety, and well-being of study participants are
protected, consistent with the principles that originated in the Declaration of Helsinki, and that the
study data are credible.
Protocol Clarification Communications
If text within a final approved protocol requires clarification (eg, current wording is unclear or
ambiguous) that does not change any aspect of the current study conduct, a protocol clarification
communication (PCC) may be prepared. The PCC Document will be communicated to the
Investigational Site, Site Monitors, Local Trial Managers, Clinical Trial Managers, and/or Contract
Research Organizations who will ensure that the PCC explanations are followed by the
investigators.
The PCC Document may be shared by the sites with IECs/IRBs per local regulations.
The PCC Documents must NOT be used in place of protocol amendments, but the content ofthe
PCC Document must be included in any future protocol amendments.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or
when the relevant competent authority has raised any grounds for non-acceptance, except when
necessary to eliminate immediate hazards to the participants, in which case the amendment must
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where
required) only needs to be notified.
In situations where a departure from the protocol is unavoidable during the study, the investigator
or other physician in attendance will contact the appropriate sponsor representative listed in the
Contact Information page(s), which will be provided as a separate document. Except in emergency
situations, this contact should be made before implementing any departure from the protocol. In
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and
agree on an appropriate course of action. The data recorded in the eCRF and source documents

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will reflect any departure from the protocol, and the source documents will describe this departure
and the circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country, if applicable. A study may not be initiated until all local regulatory
requirements are met.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study vaccine to the
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator.

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.

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IEC or IRB
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 ofthe 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.

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
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, Study-Specific Ethical Design
Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
10.3.2. 
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial
information in accordance with local regulations to allow the sponsor to submit complete and
accurate financial certification or disclosure statements to the appropriate regulatory authorities.
Investigators are responsible for providing information on financial interests during the 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.

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Participants will be informed that their participation is voluntary and that they may withdraw
consent to participate at any time. They will be informed that choosing not to participate will not
affect the care the participant will receive. Finally, they will be told that the investigator will
maintain a participant identification register for the purposes of long-term follow-up if needed and
that their records may be accessed by health authorities and authorized sponsor personnel without
violating the confidentiality of the participant, to the extent permitted by the applicable law(s) or
regulations. By signing the ICF the participant is authorizing such access. It also denotes that the
participant agrees to allow their 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 their 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 their 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.

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10.3.5. 
Long-term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local regulations)
for additional research. Samples will only be used to understand Ad26.RSV.preF and RSV preF
protein, to understand RSV and other respiratory pathogens, and to develop tests/assays related to
Ad26.RSV.preF, RSV preF protein, and RSV disease. The research may begin at any time during
the study or the poststudy storage period. Included are samples from participants who were
screened but not randomized, and which may also be used to develop tests/assays related to
Ad26.RSV.preF, RSV preF protein, and RSV disease.
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, Withdrawal From the Use of Research Samples).
10.3.6. 
Committees Structure
Safety issues that might arise from this study may be escalated to an independent DMC,as needed.
All potential AESI cases will be reviewed to determine if they meet the definition of TTS (see
Section 8.3.6.1). A Charter will be developed to describe the roles and responsibilities of the
Committee appointed to perform this review.
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data
All information, including but not limited to information regarding the Ad26/protein preF RSV
vaccine or the sponsor’s operations (eg,patent application, formulas, manufacturing processes,
basic scientific data, prior clinical data, formulation information) supplied by the sponsor to the
investigator and not previously published, and any data, generated as a result of this study, are
considered confidential and remain the sole property of the sponsor. The investigator agrees to
maintain this information in confidence and use this information only to accomplish this study and
will not use it for other purposes without the sponsor’s prior written consent.
The investigator understands that the information developed in the study will be used by the
sponsor in connection with the continued development ofthe Ad26/protein preF RSV vaccine, and
thus may be disclosed as required to other clinical investigators or regulatory agencies. To permit
the information derived from the clinical studies to be used, the investigator is obligated to provide
the sponsor with all data obtained in the study.
The results of the study will be reported in a clinical study report generated by the sponsor and
will contain data from all study sites that participated in the study as per protocol. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the
study will be used to determine a coordinating investigator for the study. Results of analyses
performed after the clinical study report has been issued will be reported in a separate report and
will not require a revision of the clinical study report.
Study participant identifiers will not be used in publication of results. Any work created in
connection with performance of the study and contained in the data that can benefit from copyright

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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 18 months after the study end date,or the sponsor confirms there
will be no multicenter study publication. Authorship of publications resulting from this study will
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which
state that the named authors must have made a significant contribution to the conception or design
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the
work or revised it critically for important intellectual content; and given final approval of the
version to be published; and agreed to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work are appropriately investigated
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law. The disclosure of the final study results will be performed after the end of study in order
to ensure the statistical analyses are relevant.
10.3.8. 
Data Quality Assurance
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study-site personnel before the study, and periodic monitoring visits by the sponsor. Written
instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before
the start of the study. The sponsor may review the eCRF for accuracy and completeness during

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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 eCRF  entries, corrections, and alterations must be made by the investigator or
authorized study-site personnel. The investigator must verify that all data entries in the eCRF are
accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an
eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any
such worksheets will become part of the participant’s source documents. Data must be entered into
the eCRF in English. The eCRF must be completed as soon as possible after a participant visit and
the forms should be available for review at the next scheduled monitoring visit.
If necessary, queries will be generated in the eDC tool. If corrections to an eCRF are needed after
the initial entry into the eCRF, this can be done in either of the following ways:
 Investigator and study-site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
 Sponsor or sponsor delegate can generate a query for resolution by the investigator and
study-site personnel.
10.3.10. 
Source Documents
At a minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study site as a basis for standard medical care must be available for the following:
participant identification, eligibility, and study identification; study discussion and date of signed
informed consent; dates of visits; results of safety and immunogenicity 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 vaccination or withdrawal from the study,
if applicable.
The author of an entry in the source documents should be identifiable.
The participant 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).

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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. Data in the eSource system may be considered source documentation.
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
postinitiation visit will be made as soon as possible after enrollment has begun. At these visits, the
monitor may  compare the data entered into the eCRF  with the source documents (eg,
hospital/clinic/physician’s office medical records); a sample may be reviewed. 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 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. 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.

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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 they have been
contacted by a regulatory agency concerning an upcoming inspection.
10.3.13. 
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF
and all source documents that support the data collected from each participant, as well as all study
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical
Trial, and all study documents as specified by the applicable regulatory requirement(s). The
investigator/institution will take measures to prevent accidental or premature destruction of these
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing applications
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents will be retained for a longer period
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when these documents no
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custody must be transferred to a person who will accept
the responsibility. The sponsor must be notified in writing of the name and address of the new
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator/institution must permit access to such reports.
10.3.14. 
Study and Site Start and Closure
First Act of Recruitment
The first participant screened 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.

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Reasons for the early closure of a study site by the sponsor or investigator may include but are not
limited to:
 Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local health authorities, the sponsor’s procedures, or GCP guidelines.
 Inadequate recruitment of participants by the investigator.
 Discontinuation of further study vaccine development.

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10.4. Appendix 4: 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)
(FDA 2007a)
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 –160# 
> 160# 
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.

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

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

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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 mE/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.

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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.

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10.5. Appendix 5: Guidance on Study Conduct During a Natural Disaster
GUIDANCE ON STUDY CONDUCT DURING THE CORONAVIRUS DISEASE 2019
PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on
the conduct of this clinical study due to, for example, isolation or quarantine of participants and
study-site personnel; travel restrictions/limited access to public places, including hospitals;
study-site personnel being reassigned to critical tasks.
The sponsor is providing options for study related participant management in the event of
disruption to the conduct of the study. This guidance does not supersede any local or government
requirements or the clinical judgement of the investigator to protect the health and well-being of
participants and site staff. If, at any time, a participant’s travel to the study site is considered to be
dangerous, study participation may be interrupted, and study follow-up conducted. If it becomes
necessary to discontinue participation in the study, the procedures outlined in the protocol for
discontinuing study intervention will be followed.
If, as a result of the COVID-19 pandemic, scheduled visits cannot be conducted in person at the
study site, they will be performed to the extent possible remotely/virtually or delayed until such
time that on-site visits can be resumed. At each contact, participants will be interviewed to collect
safety data. Key immunogenicity endpoint assessments should be performed if required and as
feasible. Participants will also be questioned regarding general health status to fulfill any physical
examination requirement.
Every effort should be made to adhere to protocol-specified assessments for participants on study
intervention, including follow-up. Modifications to protocol-required assessments may be
permitted after consultation with the participant, investigator, and the sponsor. Missed
assessments/visits will be captured in the clinical trial management system for protocol deviations.
Discontinuations of study interventions and withdrawal from the study should be documented with
the prefix “COVID-19-related” in the eCRF.
If a participant has tested positive for COVID-19, the investigator should contact the sponsor’s
responsible medical officer to discuss plans for administration of study intervention, performing
study assessments, and follow-up. Modifications made to the study conduct as a result of the
COVID-19 pandemic should be summarized in the clinical study report.

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GUIDANCE SPECIFIC TO THIS PROTOCOL:
Screening and Randomization
 Enrollment of new participants may continue based on the investigator’s assessment of risks
versus benefits, depending on the situation at a particular site, and the ability to monitor
participant safety.
Site Visits
 
When site visits are not possible due to local/national guidelines, sites should collect the
assessments via telephone visits or home-based visits, if the participant allows. The actual
visit date and the type of visit (ie, telephone or home-based visit) should be captured in the
eCRF according to the eCRF completion guidelines. Procedures that cannot be performed
during a home-based visit (eg, blood samples) should be excluded.
Vaccine Administration
 
When planning for vaccination visits, local/national or institutional guidelines will be
followed. The study vaccine must be administered by a blinded qualified individual at the
study site. If this is not possible, a solution may be considered in consultation with the sponsor
and taking into consideration participant safety.
Informed Consent Form
 
Consenting and re-consenting of participants for the measures taken (including also remote
consenting by phone or video consultation) will be performed as applicable and according to
local guidance for informed consent applicable during the COVID-19 pandemic. The process
is to be documented in the source documents.
Source Data Verification/Monitoring
 
In case on-site monitoring visits are not possible, the site monitor may contact the investigator
to arrange monitoring visits and activities remotely (in accordance with site and local
requirements). Additional on-site monitoring visits may be needed in the future to catch up on
source data verification.
Site Audits
During the COVID-19 pandemic and at the impacted sites, study site GCP audits with direct
impact/engagement from the investigator and study-site personnel would not be conducted in order
to comply with national, local, and/or organizational social distancing restrictions. Additional
quality assurance activities such as remote audits or focused review of study related documents
may take place with limited impact/engagement if possible.

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10.6. Appendix 6: Thrombotic Events to be Reported as Potential AESIs
At the time of protocol writing, the list of thrombotic events to be reported to the sponsor as
potential AESIs is provided below. Further guidance may become available on thrombotic events
of interest.
 
MedDRA preferred terms (PTs)for large vessel thrombosis and embolism
 
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
 
Axillary vein thrombosis, deep vein thrombosis, pulmonary embolism, MedDRA PTs for
acute myocardial infarction*, MedDRA PTs for stroke*
Source: Shimabukuro T. CDC COVID-19 Vaccine Task Force. Thrombosis with thrombocytopenia syndrome (TTS)
following Janssen COVID-19 vaccine. Advisory Committee on Immunization Practices (ACIP). April 23, 2021.
https://www.cdc.gov/vaccines/acip/meetings/slides-2021-04-23.html.
*Vaccine Adverse Event Reporting System (VAERS) Standard Operating Procedures for COVID-19 (as of 29 January
2021) https://www.cdc.gov/vaccinesafety/pdf/VAERS-v2-SOP.pdf

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10.7. Appendix 7: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents (TOC).
Amendment 1 (1 December 2021)
Overall Rationale for the Amendment: In view of the slow rate of enrollment in the current
study, the following changes were made to the exclusion criteria to facilitate enrollment: a prior
vaccination with a viral-vectored SARS-COV-2 vaccine will be allowed if administered at least 6
months prior to randomization; and it was clarified that co-participation in the observational phase
of interventional studies can be allowed upon sponsor approval.
Clinical studies with Janssen's Ad26-vectored vaccines have not shown an impact of baseline pre-
existing Ad26 neutralizing antibodies on measured vaccine-induced immune responses. Based on
the data available to date, the Sponsor considers a prior vaccination with a viral-vectored
SARS-COV-2 vaccine acceptable if administered at least 6 months prior to randomization. This
time window may be adjusted for future Janssen immunogenicity trials when data of consecutive
administration of Ad26-based vaccines with different inserts using shorter interval become
available.
Participants who participate in the observational phase of an interventional study at screening may
also be eligible for the current study since participation in the observational phase without product
administration will not adversely impact safety of the participants or have an impact on the
vaccine-induced immune response.
Additionally, a medically indicated vaccination was added as one of the reasons to temporarily
delay study vaccination  to clarify that participants receiving such vaccinations, including
SARS-COV-2 vaccine boosters, would still be eligible to receive the study vaccination at a later
time (allowed window up to 10 days). This applies to both the first study vaccination at Visit 1
(Day 1) and the second study vaccination at Visit 3 (Day 29), thus providing the possibility to split
both Visit 1 and Visit 3 into two visits with the approval of the Sponsor or its delegate. In case the
administration of the second study vaccination (Visit 3) needs to be delayed (up to a max of 10
days on top of the allowed time window of Visit 3 [±5 days]), this visit would need to be split into
two visits as the immunogenicity and safety assessments of Visit 3 should still be performed on
the actual Day 29 (±5 days).
Furthermore, additional language referring to laboratory diagnostic tests that may be performed
for the follow-up and assessment of potential adverse events of special interest (AESIs) was added.
Clarifications were made with regards to some exclusion criteria, the recording of medical history,
and the solicited and unsolicited AE assessments to be performed during phone call visits.
Additionally, a few minor updates were made in alignment with the latest Janssen protocol
template.
The changes made to the clinical protocol VAC18193RSV3005 as part of Protocol Amendment 1
are listed below, including the rationale of each change and a list of all applicable sections.

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Section Number 
and Name
Description of Change 
Brief Rationale
5.2 Exclusion Criteria 
6.8 Concomitant 
Therapy  
Exclusion Criterion 11 was amended to 
allow the use of viral-vectored SARS-
COV-2 vaccines if administered at least
6 months prior to randomization.
To facilitate enrollment
5.2 Exclusion Criteria 
Note for Exclusion Criterion 15 was 
updated to allow participants who
participate in the observational phase of
interventional studies to be enrolled in
the study, if approved by the sponsor or
its delegate.
To facilitate enrollment
1.3 Schedule of 
Activities 
5.5 Criteria for 
Temporarily Delaying 
Study Vaccine 
Administration  
A medically indicated vaccination was 
added as one of the reasons to 
temporarily delay study vaccination. 
To clarify that participants receiving
medically indicated vaccinations,
including SARS-COV-2 vaccine boosters,
remain eligible to receive study
vaccinations. For example, this will
facilitate participants to receive non-viral
vectored SARS-COV-2 vaccine boosters
(including the mRNA-based SARS-COV-
2 vaccines) during the course of this study,
while adhering to the 14 days window
described in Exclusion Criterion 11b.
1.2 Schema 
1.3 Schedule of 
Activities 
5.5 Criteria for 
Temporarily Delaying 
Study Vaccine 
Administration  
8 STUDY 
ASSESSMENTS AND 
PROCEDURES  
It was clarified that in case any of the 
criteria for temporarily delaying study
vaccine administration are met at Visit 3
(Day 29), this visit would need to be split
into two visits. The administration of the
second study vaccination can be delayed
up to 10 days on top of the allowed time
window of Visit 3 (±5 days). On the
other hand, the immunogenicity and
safety assessments of Visit 3 should still
be performed on the actual Day 29 (±5
days).
Clarification
1.2 Schema 
1.3 Schedule of 
Activities 
5 STUDY 
POPULATION
5.5 Criteria for
Temporarily Delaying
Study Vaccine
Administration
It was clarified that screening and 
vaccination may be split into 2 visits in  
consultation with the Sponsor or its 
delegate.
To allow more flexibility in timing of
screening and vaccination in the best
interest of participants.
1.3 Schedule of 
Activities 
8.3.6.1 Thrombosis 
with 
Thrombocytopenia
Syndrome
Additional language referring to 
laboratory diagnostic tests for the 
assessment of potential AESIs was 
added.
To facilitate and simplify the local site
management of follow-up testings in the
event of potential AESIs.
5.2 Exclusion Criteria 
A textual change was made to Exclusion 
Criterion 1 to clarify that participants
with a history of malignancy within
5 years before screening, which is
considered to have minimal risk of
recurrence per investigator’s judgement,
can be enrolled.
Clarification

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Status: Approved,Date: 7 February 2022
Section Number 
and Name
Description of Change 
Brief Rationale
5.2 Exclusion Criteria 
It was clarified in Exclusion Criterion 8 
that the exclusion oftreatment with
immunoglobulins applies to those
immunoglobulins expected to impact the
vaccine-induced immune response.
Clarification
1.3 Schedule of 
Activities 
It was clarified that risk factors for blood 
clotting events and thrombocytopenia are
to be collected and documented as part of
the medical history at screening.
Clarification
1.3 Schedule of 
Activities 
It was clarified that the severity of 
solicited and unsolicited AEs and the
occurrence of special reporting situations
are to be assessed also during the phone
call visits at 7 days post first and second
study vaccination.
Clarification
Title page 
4.4 End of Study 
Definition  
8.3.1 Time Period and
Frequency for
Collecting AE, SAE,
and AESI Information
8.3.3 Follow-up of
AEs, SAEs, and AESIs
10.2.4 Special
Reporting Situations
10.2.6 PQC Handling
10.3.14 Study and Site
Start and Closure
10.5 Appendix 5:
Guidance on Study
Conduct During a
Natural Disaster
A few minor updates were made in 
alignment with the latest Janssen 
protocol template.
To align with the most recent Janssen
protocol template.
Throughout the 
protocol 
Minor grammatical, formatting, or 
spelling changes were made.
Minor errors were noted

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11. 
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termed 
Vaccine-induced 
Thrombotic 
Thrombocytopenia). 
Updated 
6 
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2021. 
Available 
at:
https://www.hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia.
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Brighton Collaboration (2021). Interim Case Definition of Thrombosis with Thrombocytopenia Syndrome (TTS).
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case-definition/. Accessed 29 April 2021.
British Society for Haematology (2021). Guidance produced from the Expert Haematology Panel (EHP) focused on
Covid-19 
Vaccine 
induced Thrombosis 
and Thrombocytopenia 
(VITT). 
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vaccine 20210407.pdf. Version 1.3; 7 April 2021. Accessed 27 April 2021.
Centers for Disease Control and Prevention  (CDC) (2021). Cases of cerebral venous sinus thrombosis with
thrombocytopenia after receipt of the Johnson & Johnson COVID-19 Vaccine. 13 April 2021. Available at:
https://emergency.cdc.gov/han/2021/han00442.asp. Accessed 27 April 2021.
Chang LJ (2019), Meng Y, Janosczyk H, Landolfi V, Talbot HK, QHD00013 Study Group. Safety and
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ClinicalTrials.gov (2019). US National Library of Medicine (NLM). Safety and Immunogenicity of High-Dose
Quadrivalent Influenza Vaccine in Participants ≥65 Years in the US. Available at:
https://clinicaltrials.gov/ct2/show/results/NCT03282240. Accessed 08 January 2021.
de Bree GJ (2005), Heidema J, van Leeuwen EM, et al. Respiratory syncytial virus-specific CD8+ memory T cell
responses in elderly persons. J Infect Dis. 2005;191(10):1710-1718.
Falsey AR (1998), Walsh EE. Relationship of serum antibody to risk of respiratory syncytial virus infection in
elderly adults. J Infect Dis. 1998;177(2):463-466.
Falsey AR (2000), Walsh EE. Respiratory syncytial virus infection in adults. Clin Microbiol Rev. 2000;13(3):371-
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Clinical Protocol VAC18193RSV3005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,Date: 7 February 2022
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VAC18193 (JNJ-64400141/JNJ-64213175) 
Clinical Protocol VAC18193RSV3005 Amendment 2
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
86
Status: Approved,Date: 7 February 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 vaccine, 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

Signature
User 
Date 
Reason
 
07-Feb-2022 
16:26:07
(GMT)
Document Approval
PPD