Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 64
Healthy volunteers: yes

Brief summary:
The purpose of this study is to assess a trend for the prophylactic efficacy of a single dose of 1\*10\^11 virus particles (vp) of adenovirus serotype 26 respiratory syncytial virus pre-fusion F protein (Ad26.RSV.preF) administered intramuscularly to adults aged 18-50 years in the respiratory syncytial virus (RSV) challenge model in terms of reduction of nasal wash viral load compared to placebo.

Detailed description:

Arms:
arm 1: Participants will receive single intramuscular injection of 1\*10\^11 virus particles (vp) of Ad26.RSV.preF during Day -90 to Day -28. On Day 0, intranasal challenge with respiratory syncytial virus (RSV)-A Memphis 37b virus will occur for all participants. arm 2: Participants will receive single intramuscular injection of placebo as sterile 0.9 percent (%) saline for injection during Day -90 to Day -28. On Day 0, intranasal challenge with RSV-A Memphis 37b virus will occur for all participants.

Interventions: intervention 1: Ad26.RSV.preF intervention 2: Placebo
Intervention descriptions: intervention 1: Ad26.RSV.preF will be administered as intramuscular injection at a dose of 1\*10\^11 vp in single-use vials. intervention 2: Placebo will be administered as sterile 0.9% saline for injection.

Protocol document:
Prot_000.pdf: 
1
Status: Approved, Date: 24 July 2018
Janssen Vaccines & Prevention B.V.
Clinical Protocol
An Exploratory, Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Prophylactic Efficacy of a Single Immunization of Ad26.RSV.preF Against 
Respiratory Syncytial Virus Infection in a Virus Challenge Model in Healthy 18 to 50 
Year-Old Adults
Protocol VAC18193RSV2002; Phase 2a
Amendment 3
VAC18193 (JNJ-64400141)
EudraCT NUMBER: 2017-003194-33
Status:
Approved
Date:
24 July 2018
Prepared by:
Janssen Vaccines & Prevention B.V.
EDMS number:
EDMS-ERI-146009250, 8.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
NCT03334695


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Protocol History
VAC18193RSV2002
Document Type and
File Name
Issued Date
Amendment
Type
Comments
Initial Clinical Trial Protocol
VAC18193RSV2002_Protocol (v1)
02-August-2017
-
Not submitted
Revised Protocol
VAC18193RSV2002_Protocol (v2)
22-August-2017
-
-
Protocol Amendment 1
VAC18193RSV2002_Protocol_Amend_1 
20-October-2017
Non-
substantial
For details, please refer to 
Section Amendment 1
Protocol Amendment 2
VAC18193RSV2002_Protocol_Amend_2
17-November-
2017
Non-
substantial
For details, please refer to 
Section Amendment 2
Protocol Amendment 3
VAC18193RSV2002_Protocol_Amend_3
This document
Substantial
For details, please refer to 
Section Amendment 3


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 3
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
SYNOPSIS.................................................................................................................................................. 10
TIME AND EVENTS SCHEDULE .............................................................................................................. 20
ABBREVIATIONS ...................................................................................................................................... 23
1.
INTRODUCTION................................................................................................................................ 24
1.1.
Background .................................................................................................................................... 24
1.2.
Overall Rationale for the Study...................................................................................................... 28
1.3.
Risk/Benefit Section....................................................................................................................... 29
1.3.1.
Known Benefits........................................................................................................................... 29
1.3.2.
Potential Benefits........................................................................................................................ 29
1.3.3.
Known Risks............................................................................................................................... 29
1.3.4.
Potential Risks............................................................................................................................ 30
1.3.5.
Overall Benefit/Risk Assessment ............................................................................................... 33
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 33
2.1.
Objectives and Endpoints .............................................................................................................. 33
2.1.1.
Objectives ................................................................................................................................... 33
2.1.2.
Endpoints.................................................................................................................................... 35
2.2.
Hypothesis ..................................................................................................................................... 37
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 37
3.1.
Overview of Study Design.............................................................................................................. 37
3.2.
Study Design Rationale.................................................................................................................. 42
4.
SUBJECT POPULATION.................................................................................................................. 43
4.1.
Inclusion Criteria ............................................................................................................................ 43
4.2.
Exclusion Criteria ........................................................................................................................... 45
4.3.
Viral Challenge Exclusion Criteria.................................................................................................. 48
4.4.
Prohibitions and Restrictions ......................................................................................................... 49
5.
STUDY VACCINE ALLOCATION AND BLINDING.......................................................................... 50
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 51
7.
STUDY VACCINE COMPLIANCE .................................................................................................... 52
8.
PRE-STUDY AND CONCOMITANT THERAPY ............................................................................... 52
9.
STUDY EVALUATIONS .................................................................................................................... 53
9.1.
Study Procedures........................................................................................................................... 53
9.1.1.
Overview..................................................................................................................................... 53
9.1.2.
Visit Windows ............................................................................................................................. 53
9.1.3.
Screening Phase ........................................................................................................................ 54
9.1.4.
Vaccination Phase...................................................................................................................... 55
9.1.4.1.
Vaccination .............................................................................................................................. 55
9.1.4.2.
Post-vaccination Follow-Up..................................................................................................... 56
9.1.5.
Viral Challenge Phase ................................................................................................................ 56
9.1.5.1.
Entry to the Quarantine Unit.................................................................................................... 56
9.1.5.2.
Challenge................................................................................................................................. 57


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9.1.5.3.
Post-challenge......................................................................................................................... 57
9.1.5.4.
Discharge from the Unit........................................................................................................... 57
9.1.6.
Day 28 Post-challenge................................................................................................................ 58
9.1.7.
Final Visit .................................................................................................................................... 58
9.1.8.
Early Withdrawal – Early Exit Visit.............................................................................................. 58
9.1.9.
Overflow Subjects....................................................................................................................... 58
9.2.
Study Evaluations .......................................................................................................................... 59
9.2.1.
Immunogenicity........................................................................................................................... 59
9.2.2.
Antiviral Activity Samples for Infectivity ...................................................................................... 60
9.2.3.
Mucus Weight and Tissue Count................................................................................................ 60
9.2.4.
RSV Subject Symptom Card ...................................................................................................... 61
9.2.5.
Respiratory Parameters: Spirometry .......................................................................................... 61
9.2.6.
Safety Evaluations...................................................................................................................... 62
9.2.6.1.
Adverse Events ....................................................................................................................... 62
9.2.6.2.
Clinical Laboratory Tests......................................................................................................... 64
9.2.6.3.
Electrocardiogram ................................................................................................................... 67
9.2.6.4.
Vital Signs................................................................................................................................ 67
9.2.6.5.
Physical Examination .............................................................................................................. 67
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY VACCINE/WITHDRAWAL 
FROM THE STUDY ........................................................................................................................... 68
10.1.
Completion ..................................................................................................................................... 68
10.2.
Discontinuation from Challenge Phase/Withdrawal from the Study .............................................. 68
10.3.
Contraindications to Vaccination.................................................................................................... 69
11.
STATISTICAL METHODS................................................................................................................. 70
11.1.
Analysis Sets.................................................................................................................................. 70
11.2.
Sample Size Determination ........................................................................................................... 70
11.3.
Subject Information ........................................................................................................................ 71
11.4.
Efficacy Analyses ........................................................................................................................... 71
11.5.
Immunogenicity Analyses .............................................................................................................. 73
11.6.
Efficacy versus Immunogenicity Relationship................................................................................ 73
11.7.
Safety Analyses ............................................................................................................................. 73
11.8.
Planned Analyses .......................................................................................................................... 74
11.9.
Data Review Committee ................................................................................................................ 75
11.10.
Study Vaccination Pausing Rules .................................................................................................. 75
12.
ADVERSE EVENT REPORTING ...................................................................................................... 76
12.1.
Definitions ...................................................................................................................................... 77
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 77
12.1.2.
Attribution Definitions.................................................................................................................. 78
12.1.3.
Severity Criteria .......................................................................................................................... 79
12.2.
Special Reporting Situations.......................................................................................................... 80
12.3.
Procedures..................................................................................................................................... 80
12.3.1.
All Adverse Events...................................................................................................................... 80
12.3.2.
Serious Adverse Events ............................................................................................................. 81
12.3.3.
Pregnancy................................................................................................................................... 82
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 82
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 82
13.1.
Procedures..................................................................................................................................... 83
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 83
14.
STUDY VACCINE INFORMATION ................................................................................................... 83
14.1.
Physical Description of Study Vaccine........................................................................................... 83
14.2.
Packaging and Labeling................................................................................................................. 83
14.3.
Storage and Handling .................................................................................................................... 84


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14.4.
Vaccine Accountability ................................................................................................................... 84
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 85
16.
ETHICAL ASPECTS ......................................................................................................................... 85
16.1.
Study-Specific Design Considerations........................................................................................... 85
16.2.
Regulatory Ethics Compliance....................................................................................................... 86
16.2.1.
Investigator Responsibilities ....................................................................................................... 86
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 86
16.2.3.
Informed Consent ....................................................................................................................... 87
16.2.4.
Privacy of Personal Data ............................................................................................................ 88
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 89
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 89
17.1.
Protocol Amendments.................................................................................................................... 89
17.2.
Regulatory Documentation ............................................................................................................ 89
17.2.1.
Regulatory Approval/Notification ................................................................................................ 89
17.2.2.
Required Pre-study Documentation ........................................................................................... 89
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 90
17.4.
Source Documentation................................................................................................................... 91
17.5.
Case Report Form Completion ...................................................................................................... 91
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 92
17.7.
Record Retention ........................................................................................................................... 92
17.8.
Monitoring ...................................................................................................................................... 93
17.9.
Study Completion/Termination....................................................................................................... 93
17.9.1.
Study Completion/End of Study.................................................................................................. 93
17.9.2.
Study Termination....................................................................................................................... 93
17.10.
On-Site Audits ................................................................................................................................ 94
17.11.
Use of Information and Publication................................................................................................ 94
REFERENCES............................................................................................................................................ 96
INVESTIGATOR AGREEMENT ............................................................................................................... 109
LAST PAGE.............................................................................................................................................. 109
LIST OF ATTACHMENTS
ATTACHMENT 1:
TOXICITY TABLES................................................................................................... 98
ATTACHMENT 2:
OBJECTIVES AND ENDPOINTS TABLE.............................................................. 104
ATTACHMENT 3:
SAMPLE SUBJECT SYMPTOM CARD ................................................................. 107
ATTACHMENT 4:
EXPECTED SYMPTOMS AFTER CHALLENGE WITH THE MEMPHIS RSV 
STRAIN.................................................................................................................... 108
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Study Design: Vaccination and Challenge ............................................................................... 14
Table 2:
Summary of Immunogenicity Assays (Humoral) ...................................................................... 17
Table 3:
Summary of Immunogenicity Assays (Cellular)........................................................................ 17
Table 4:
Study Design: Vaccination and Challenge ............................................................................... 38
Table 5:
Summary of Immunogenicity Assays (Humoral) ...................................................................... 59


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Table 6:
Summary of Immunogenicity Assays (Cellular)........................................................................ 59
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 42
Figure 2:
Expected Power for Several Reductions in Viral Load............................................................. 71


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PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
22 August 2017
Amendment 1
20 October 2017
Amendment 2
17 November 2017
Amendment 3
24 July 2018
Amendments below are listed beginning with the most recent amendment.
Amendment 3 (Issued date: 24 July 2018)
The overall reason for the amendment: 
The power calculations for this study were based on the AUC results observed in the placebo group in a historical 
study (53718678RSV2001; a study with an RSV-specific fusion inhibitor in the virus challenge model). The RT-
PCR assay, used to measure VL-AUC for the primary endpoint in 53718678RSV2001, is a different assay than 
the one in the current study. As the current study is an exploratory study, the statistical assumptions are 
monitored by an unblinded monitor. During this exercise it was revealed while both assays give similar results in 
the higher range of the assay, the assay of the historical study gives more granularity in the lower range compared 
to the assay in the current study. Therefore, the peak viral load is added as a secondary efficacy endpoint as this 
parameter should be less sensitive to the difference in the assays compared to the AUC.
The table below gives an overview of all affected sections
Synopsis: Objectives; Endpoints
2.1.1 Objectives
2.1.2 Endpoints
11.4 Efficacy Analyses
Attachment 2: Objectives and Endpoints Table
Amendment 2 (Issued date: 17 November 2017)
The overall reason for the amendment: 
Following feedback from the study site, the amendment is made to facilitate enrollment by clarifying that the 
smoking restriction only applies from 30 days prior to entry into the quarantine Unit through the last study-related 
activity, and to allow participation of subjects with a history of eczema only in childhood. Alignment of the AE 
severity criteria and correction of the physical description of the Ad26.RSV.preF vaccine are also made.
The table below gives an overview of the rationale for each change and all affected sections
Rationale: To clarify that the smoking restriction only applies from 30 days prior to entry into the quarantine 
Unit through the last study-related activity, and to remove requirement for a urine cotinine test during screening
and pre-vaccination on Day -28.
Time and Events Schedule
4.4 Prohibitions and Restrictions
9.1.3 Screening Phase
9.1.4.1 Vaccination
Rationale: To clarify that subjects with only a childhood history of eczema are allowed to participate in the 
study.
4.2 Exclusion Criteria
Rationale: To align the protocol-specified AE severity criteria for AEs not listed in the FDA toxicity tables in 


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Attachment 1 with the FDA severity criteria.
12.1.3 Severity Criteria
Rationale: To amend the description of the Ad26.RSV.preF vaccine.
14.1 Physical Description of Study Vaccine
Rationale: Other minor changes and corrections made throughout the protocol.
Amendment 1 (Issued date: 20 October 2017)
The overall reason for the amendment:
This amendment is made to correct inconsistencies, errors and omissions in specifications of study procedures.
The table below gives an overview of the rationale for each change and all affected sections
Rationale: To indicate that the nasopharyngeal swab/nasal wash test will only be done once during screening.
Time and Events Schedule
9.1.3 Screening Phase
Rationale: To indicate that nasopharyngeal swabs will be used for the respiratory virus screen on entry to the 
quarantine Unit.
Time and Events Schedule
9.1.5.1 Entry to the Quarantine Unit
Rationale: To indicate that the RVAT assessment on discharge from the quarantine Unit will be done on 
nasopharyngeal swabs.
Time and Events Schedule
Rationale: To add drugs of abuse screen, cotinine, and breath alcohol test on Day –28.
Time and Events Schedule
9.1.4.1 Vaccination
Rationale: To change the volume of blood for clinical laboratory assessments on Day –28, Day –21 and at the early 
exit visit to 10 mL.
Time and Events Schedule
Rationale: To add blood volumes for assessment of cardiac enzymes on entry to the challenge unit and on Days 3, 
7 and 11.
Time and Events Schedule
9.1.5.3 Post-challenge
Rationale: To add blood collection for biochemistry and hematology assessments on discharge from the quarantine 
Unit and at 28 days post-challenge.
Time and Events Schedule
3.1 Overview of Study Design
9.1.5.4 Discharge from the Unit
9.1.6 Day 28 Post-challenge
9.2.6.2 Clinical Laboratory Tests
Rationale: To include language indicating that acute myocarditis is a rare complication of viral infection.


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1.3.4 Potential Risks
Rationale: To clarify the timing of immunogenicity blood draws for overflow subjects.
9.1.9 Overflow Subjects
Rationale: To clarify that tissue and paper bag distribution for mucus weight and tissue count will start on Day –1.
9.2.3 Mucus Weight and Tissue Count
Rationale: To add appearance, color, nitrite, urobilinogen, bilirubin and leucocytes to the urinalysis parameters.
9.2.6.2 Clinical Laboratory Tests
Rationale: Other minor changes and corrections made throughout the protocol.


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SYNOPSIS
An Exploratory, Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Prophylactic Efficacy of a Single Immunization of Ad26.RSV.preF Against Respiratory Syncytial 
Virus Infection in a Virus Challenge Model in Healthy 18 to 50 Year-Old Adults
Ad26.RSV.preF (JNJ-64400141) is a replication-incompetent serotype 26 (Ad26) containing a 
deoxyribonucleic acid (DNA) transgene that encodes for the conformation-stabilized pre-fusion F protein 
(pre-F) of the respiratory syncytial virus (RSV) A2 strain.
RATIONALE
This is an exploratory human challenge study, the partial aim of which is to determine the utility of the 
RSV challenge model in RSV vaccine development by looking for a trend in efficacy of Ad26.RSV.preF, 
an RSV vaccine that has shown a high degree of efficacy in preclinical challenge models. In this 
randomized double-blind study, healthy adult subjects will be vaccinated with either a single dose of 
1x1011 vp (viral particles) of Ad26.RSV.preF or placebo and 28 days later (window between 24 to 90 
days) will be inoculated by the intranasal route with RSV-A Memphis 37b virus. The prophylactic 
antiviral effect and the prophylactic effect on clinical symptoms of RSV infection after challenge, as well 
as safety and tolerability of Ad26.RSV.preF after vaccination, will be evaluated compared with placebo. 
This is an exploratory study as an RSV vaccine has not previously been tested in this challenge model. If 
the findings in this study fail to suggest any trend toward efficacy of this highly potent vaccine, it might 
suggest that the RSV human challenge model is not appropriate for RSV vaccine development. This study 
could however provide an indication of the prophylactic efficacy of Ad26.RSV.preF to prevent and or 
modify experimentally-induced RSV infection in healthy adults aged 18-50 inclusive who have been pre-
screened for susceptibility to experimental RSV infection by measurement of RSV neutralizing antibody.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Objectives
Primary Objective
The primary objective is to assess a trend for the prophylactic efficacy of a single dose of 1x1011 vp of 
Ad26.RSV.preF administered intramuscularly to adults aged 18-50 years in the RSV challenge model in 
terms of reduction of nasal wash viral load as measured by the area under the curve (AUC) over time by 
quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) compared to placebo.
Secondary Objectives

To assess a trend for prophylactic efficacy of a single dose of Ad26.RSV.preF in the RSV challenge 
model in terms of reduction of nasal wash viral load as measured by the peak viral load of the RT-
PCR compared to placebo.

To assess the effect of a single dose of 1x1011 vp of Ad26.RSV.preF on viral load, as measured by 
RT-PCR and quantitative culture of RSV, and clinical symptoms on Day 6 and Day 7 post-challenge
compared to placebo.

To assess a trend for prophylactic efficacy of a single dose of 1x1011 vp of Ad26.RSV.preF in the 
RSV challenge model in terms of prevention of symptomatic RSV infection defined as two 
quantifiable RT-PCR measurements and one or more positive clinical symptoms of any grade from 
two different categories in the symptom scoring system (Upper Respiratory, Lower Respiratory, 
Systemic), or one Grade 2 symptom from any category compared to placebo.

To assess a trend for prophylactic efficacy of a single dose of 1x1011 vp of Ad26.RSV.preF in the 
RSV challenge model in terms of prevention of symptomatic RSV infection defined as two 


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quantifiable RT-PCR measurements and one or more positive clinical symptoms of any grade in any 
category from the symptom scoring system compared to placebo.

To assess a trend for prophylactic efficacy of a single dose of 1x1011 vp of Ad26.RSV.preF in the 
RSV challenge model in terms of the weight of mucous secretions and tissue count over time 
compared to placebo.

To assess the safety and tolerability of a single dose of 1x1011 vp of Ad26.RSV.preF administered 
intramuscularly.
Exploratory Objectives

To assess a trend for prophylactic efficacy of a single dose of 1x1011 vp of Ad26.RSV.preF in the 
RSV challenge model in terms of clinical symptoms as measured by the AUC over time of 
symptoms collected by a graded symptom scoring system compared to placebo.

To assess a trend for prophylactic efficacy of a single dose of 1x1011 vp of Ad26.RSV.preF in the 
RSV challenge model in terms of AUC for viral load (VL-AUC), as measured by quantitative culture 
of RSV from nasal wash samples, compared to placebo.

To explore the relationship of humoral (including nasal wash samples if feasible) and cellular 
immunogenicity outcomes and the VL-AUC and the AUC for clinical symptoms.

To assess a trend for prophylactic efficacy of a single dose of 1x1011 vp of Ad26.RSV.preF in the 
RSV challenge model in terms of prevention of symptomatic RSV infection defined as two 
quantifiable RT-PCR measurements and/or positive serological measurement of RSV infection in the 
context of immunization and pre-existing antibody and one or more positive clinical symptoms of 
any grade in any category compared to placebo.

To assess a trend for prophylactic efficacy of a single dose of 1x1011 vp of Ad26.RSV.preF in the 
RSV challenge model in terms of respiratory parameters measured by spirometry during the study 
compared to placebo.

To explore the relationships between clinical symptoms and viral load, as measured by RT-PCR and 
quantitative culture of RSV, in Ad26.RSV.preF subjects and placebo.

To explore other immunologic parameters in relation to the VL-AUC by RT-PCR and AUC for 
clinical symptoms and occurrence of symptomatic RSV infection defined as two quantifiable RT-
PCR measurements or more plus one clinical symptom of any grade.

To explore the immune response of a single dose of 1x1011 vp of Ad26.RSV.preF compared to 
placebo.

To explore humoral and cellular responses to challenge with RSV-A Memphis 37b in immunized 
and non-immunized subjects.

To explore the relationship between immunogenicity and pre-existing Ad26 neutralizing antibody.

To explore other potential efficacy endpoints, as defined in the statistical analysis plan (SAP), to 
determine the best efficacy endpoint to use in subsequent clinical studies investigating the vaccine’s 
efficacy.
Endpoints
Primary Endpoint: Viral Load
The primary endpoint is the VL-AUC of RSV-A Memphis 37b as determined by quantitative RT-PCR
assay of nasal wash samples.


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Nasal wash samples are taken every 12 (±1) hours beginning two days (ie, in the morning) after 
inoculation of the challenge virus. Quantitative RT-PCR is utilized to measure viral load.
Secondary Endpoints

Peak viral load of RSV-A Memphis 37b, defined as the maximum viral load as determined by 
quantitative RT-PCR assay of nasal wash samples, observed over the entire time period.

Occurrence of symptomatic RSV infection defined as two quantifiable RT-PCR measurements at
different timepoints plus symptoms of any grade from two different categories from the subject 
symptom card (SSC) or two quantifiable RT-PCR measurements plus any Grade 2 symptom from 
any category. The three SSC categories are:
o
Upper Respiratory symptoms: runny nose, stuffy nose, sneezing, sore throat, earache
o
Lower Respiratory symptoms: cough, shortness of breath, chest tightness, wheeze
o
Systemic symptoms: malaise, headache, muscle and/or joint ache, chilliness/feverishness

Occurrence of RSV infection defined as two quantifiable RT-PCR measurements plus any clinical 
symptom of any severity.

Total weight of mucus produced and tissue count.

Safety and tolerability
o
Unsolicited adverse events (AEs) from informed consent form (ICF) signature until 28 days after 
vaccination, and from the entry into the Unit until 28 days after challenge.
o
Safety data including, but not limited to, physical examinations, vital signs, 12-lead 
electrocardiograms (ECGs) and clinical laboratory results (including biochemistry, hematology, 
and urinalysis).
o
Serious adverse events (SAEs) throughout the study (from signing the ICF to the end of the study, 
6 months after vaccination).
o
Solicited local and systemic AEs for 7 days after vaccination.
Exploratory Endpoints

AUC of the total clinical symptom score. The total clinical symptom score is a composite of 13 self-
reported symptoms (on the SSC) divided into three categories (Upper Respiratory, Lower 
Respiratory, Systemic).

The VL-AUC of RSV-A Memphis 37b, as determined by quantitative culture of RSV of nasal wash
samples.

Pre-F antibody in nasal wash samples measured by pre-F enzyme-linked immunosorbent assay 
(ELISA) normalized to a standard protein or antibody to account for variability of sample volume, 
dilution and concentration in nasal wash samples.

Proportion of subjects with symptomatic RSV infection (RT-PCR or serology). Seroconversion is 
defined as a four-fold rise against the G and/or N protein by ELISA which would indicate a take of 
the virus inoculum to such extent that a systemic immunologic response against an antigen not in the 
vaccine was induced.

Neutralizing antibody against RSV-Memphis 37b (challenge strain) and RSV A2.

RSV pre-F and post-F antibodies from serum and nasal wash samplesa measured by ELISA.
                                                
a Assumes that the ELISA for nasal wash samples will be available.


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
Respiratory parameters: spirometry (FEV1, FVC, FEV1/FVC).

Vaccine immune response defined as specific pre-F levels of antibody as measured by ELISA, 
specific neutralizing antibody levels, F antigen-specific cellular responses as measured by interferon 
gamma enzyme-linked immunospot (IFNγ ELISpot) assay, flow cytometry cytokine analysis and/or 
secreted cytokines compared to placebo.
Additional exploratory analyses may be performed to investigate vaccine-elicited immune responses 
further. These may include, but are not limited to, the following assays:

RSV cross-neutralization of B and/or other A strain

Binding antibodies to RSV G and/or N

F-protein antibody specificity characterization

Adenovirus neutralization assay

Functional and molecular antibody characterization
Hypothesis
This is an exploratory human challenge study that will evaluate the effect of Ad26.RSV.preF on viral 
replication and on clinical symptoms of RSV infection after challenge. To focus interpretation, a formal 
primary hypothesis is described that will be statistically tested. The primary hypothesis is that a single 
dose of 1x1011 vp of Ad26.RSV.preF shows a trend of reduction in VL-AUC of the quantitative RT-PCR 
in healthy subjects challenged intranasally with the RSV-A Memphis 37b virus, compared with healthy 
subjects given placebo who are similarly challenged. 
As no RSV vaccine has been previously tested in a human challenge model, the statistical results of this 
hypothesis test will need to be interpreted with care as the relation between the results from this human 
challenge model and vaccine efficacy is unknown. An effect that is significant at 5% (one-sided) will be 
considered a significant effect. An effect that is significant at 20% (one-sided) will be considered as a 
trend. This trend, if observed, should be confirmed in future studies.
OVERVIEW OF STUDY DESIGN
This is a single center, randomized, placebo-controlled, double-blind Phase 2a human challenge study, to 
be conducted in approximately 44 healthy male and female subjects aged 18-50 years inclusive who have 
been pre-screened for susceptibility to RSV infection, ie, have levels of RSV neutralizing antibodies 
compatible with susceptibility to RSV infectiona.
Subjects will receive single intramuscular doses of 1x1011 vp of Ad26.RSV.preF or placebo. More than 44 
(and up to 70) subjects will be vaccinated to account for withdrawals between vaccination and challenge. 
The challenge study site, hVIVO, has the capacity to challenge and house under isolation 22 subjects at a 
time and thus the study will be conducted in several cohorts with up to 22 subjects per cohort. Within 
each cohort, subjects will be randomized 1:1 to 1x1011 vp of Ad26.RSV.preF or placebo.
                                                
a The cut-off is based on the average 25th percentile of the past 12 months screening results.


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Table 1:
Study Design: Vaccination and Challenge
Group
N
Day –28
Day 0*
1
22
Ad26.RSV.preF (1x1011 vp)
Challenge with RSV-A 
Memphis 37b**
2
22
Placebo
* ie, not less than 24 or more than 90 days after vaccination.
**Subjects will be challenged in two or more cohorts of up to 22 subjects per cohort. Within each cohort, subjects will be 
randomized 1:1 to 1x1011 vp of Ad26.RSV.preF or placebo.
Note: The infection rate (based on mucus weight, symptoms and viral shedding) in the placebo group will be followed on an 
ongoing basis by an unblinded individual who does not have any other study function to ensure a sufficient infection rate has 
occurred. If the infection rate is lower than anticipated, additional subjects may be enrolled, initially four additional subjects in 
each arm and up to 70 in total. This is to ensure that a high enough number of evaluable subjects is reached in each arm.
Initially, two sentinel subjects will be enrolled and vaccinated, and 48-hour safety will be checked by the 
investigator/study-responsible physician after vaccination. Safety data for review will include solicited 
and unsolicited AEs and SAEs. In the absence of significant findings, the rest of the subjects will be 
enrolled and vaccinated. The sentinel approach with 2 subjects (1 active and 1 placebo) is taken to ensure 
active and placebo subjects are included in the evaluations, taking into account the blinding. The 
observation at 48 hours post-dose is primarily to rule out anaphylaxis or cytokine storm.
All subjects will be closely observed for a minimum of 30 minutes post-vaccination, to monitor for the 
development of any acute reactions, or longer if deemed necessary by the investigator. Any unsolicited, 
solicited local or systemic AEs and vital signs will be documented by study-site personnel following this 
observation period. Subjects will be given a thermometer, ruler and daily assessment (subject) diary with 
instructions for the proper recording of events. Each subject will record solicited local (at injection site) 
and systemic AEs and body temperatures, beginning on the evening of the study vaccine dosing day and 
on a daily basis for the following 7 days. Body temperatures should be taken at approximately the same 
time each day, preferably in the evening.a Study-site personnel will collect and review subject diary 
information and confirm the entries at subsequent site visits.
One to two days prior to viral challenge, subjects will be admitted to the Unit to confirm eligibility for 
challenge and to orient them to the challenge Unit. At this time, assessments will include relevant medical 
information since vaccination, physical examination, ECG and clinical laboratory testing. Blood will be 
collected for immunogenicity assessments. The target day for intranasal challenge with the RSV-A 
Memphis 37b virus is Day 0, 28 days after vaccination, with a window of 24 days to 90 days after 
vaccination. The 90 day window is to account for the few “overflow” subjects that were vaccinated (to be 
available to replace any withdrawals) but may not have been challenged but might be available for a 
subsequent challenge cohort as explained in more detail below.
This range for timing of the challenge is specified for the following reason. A total of 26 subjects will be 
vaccinated for the first challenge cohort, of whom the first 22 who are vaccinated will be challenged. Any
subjects that are vaccinated but not challenged in the first cohort (overflow subjects) will be included in a 
subsequent cohort if they are still available and continue to meet all entry criteria. The withdrawal rate 
between vaccination and challenge for the first cohort will be used to assess how many extra subjects will 
need to be vaccinated for subsequent cohorts.b The durability of the humoral and cellular immune 
                                                
a The 7-day post-vaccination temperature measurements may be taken earlier to coincide with the corresponding 
clinic visit.
b Any overflow subject who is vaccinated but not challenged will be followed to the end of the study, or can be 
challenged at the discretion of the sponsor, providing study blind had not been broken. Immunogenicity blood 
draws for overflow subjects who are not challenged will occur at 28 days post-vaccination, and again 28 days 


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response after a single dose of an Ad26.RSV.FA2-vectored RSV vaccinea was demonstrated for at least 6 
months following vaccination and justifies this time window between vaccination and challenge. The 6-
month immunogenicity data for Ad26.RSV.preF from study VAC18193RSV1003 will be available prior 
to vaccination and will be reviewed to further justify this strategy.
In the Unit, subjects will live in separate isolation rooms, and all personnel having contact with the 
subjects will wear isolation clothing, including personal protective equipment, to minimize the possibility 
of cross-contamination between subjects. On Day 0, each subject will receive the contents (0.8 mL) of 1 
vial of virus inoculum.
From Day 2 to Day 11, nasal wash samples will be collected every 12 (±1) hours, abbreviated physical 
examination and vital signs measurements will be conducted daily, and SSCs will be filled out three times 
daily and reviewed by the attending physician. 24-hour tissue counts and mucus weights will be 
determined.
Nasopharyngeal samples will be taken on Day 12 and tested for the presence of virus prior to discharge 
using rapid virus antigen test (RVAT). Subjects will only be discharged on Day 12 if no detectable virus 
is present (negative RVAT). If symptoms are present, but no virus is detected (negative RVAT), 
discharge will be at the investigator’s discretion. If appropriate, subjects may reside in quarantine for an 
additional night or longer before discharge. It is unlikely that subjects will transmit RSV virus to their 
close contacts after they have been released from the quarantine Unit. After infection with RSV, 
infectious virus will be present in the subject’s nose for several days, but it is not expected to be present in 
the subject’s nose at the time of discharge from the Unit. This is because the usual duration of time that 
RSV remains infective in adults is several days shorter than the time they will spend in the Unit in 
isolation.9 Furthermore, at discharge, subjects will be negative by the RVAT assay.
To reduce any risk of passing RSV on to others, subjects will be advised to avoid contact with the 
following vulnerable groups of people for two weeks after they leave the Unit: 

any person with any known immunodeficiency

any person receiving immunosuppressant medications

any person undergoing or soon to undergo cancer chemotherapy

any person who has congestive heart failure or is in frail health

any person who has a diagnosis of emphysema or chronic obstructive pulmonary disease (COPD), is 
elderly residing in a nursing home, or has severe lung disease

any person who has received a transplant (bone marrow or solid organ)

children below the age of 1 year

elderly persons (aged 75 years or older)
Unsolicited AEs will be collected from ICF signature until 28 days after vaccination, and from the entry 
into the Unit until 28 days after challenge. SAEs will be collected from ICF signature until 6 months after 
vaccination. Any clinically significant abnormalities persisting at the end of the study/early withdrawal 
will be followed by the investigator until resolution or until a clinically stable endpoint is reached.
                                                                                                                                                            
after the date they would have originally been challenged on, to provide some vaccinated but not challenged 
controls for the study.
a See Section 1.1 for background information and clinical data on the Ad26.RSV.FA2 vaccine.


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Blood will be collected for sero-susceptibility (neutralizing antibody to RSV-A Memphis 37b) within 90
days of vaccination and on entry to the Unit. Blood and urine will be collected for laboratory safety 
assessments within 56 days of vaccination, pre-vaccination, at 7 days post-vaccination and prior to 
challenge on Day –1 or Day –2.
Blood samples for humoral and cellular immunity will be collected pre-vaccination, 1-2 days prior to 
challenge, and at 28 days after challenge. Note: blood samples for immunogenicity assessment will be 
collected from all subjects whether subjects are challenged or not (ie, including “overflow” subjects).
Blood draws for overflow subjects who are not challenged will occur at 28 days post-vaccination and 
again 28 days later. Overflow subjects who are challenged in a later cohort will also have blood draws at 
the time of challenge and 28 days after challenge.
RSV pre-F antibody will be assessed on the day before challenge and at discharge from the Unit from 
nasal wash samples.
The end of the study will be the last subject’s last visit by telephone at 6 months post-vaccination.
An internal data review committee (DRC) will be commissioned for this study, the members of which 
consist of a clinician with expertise in vaccines and infectious diseases, a medical safety officer and a 
statistician, none of whom will be part of the study team or involved in the conduct of the study. The 
DRC will meet if, in the judgment of the investigator and/or the sponsor’s study-responsible physician, a 
significant or unexpected safety event occurs.
SUBJECT POPULATION
Subjects will be healthy (on the basis of physical examination, medical history and vital signs 
measurement performed within 56 days of vaccination) male or female adults, aged ≥18 to ≤50 years on 
the day of ICF signature. All subjects will be pre-screened within 90 days of vaccination for susceptibility 
to RSV infection and will have RSV neutralizing antibody levels compatible with susceptibility to RSV 
infection.
DOSAGE AND ADMINISTRATION
Ad26.RSV.preF will be supplied at a concentration of 1x1011 vp/0.5 mL in single-use vials, with an 
extractable volume of 0.5 mL, for intramuscular injection into the deltoid of the non-dominant arm. A 
dose level of 1x1011 vp will be used.
Placebo will be supplied as sterile 0.9% saline for injection.
For each subject, every vaccination will be 0.5 mL in volume.
An unblinded pharmacist, or other qualified individual will prepare the appropriate vial and syringe and 
provide the syringe in a blinded manner to the study vaccine administrator who will perform the injection.
IMMUNOGENICITY EVALUATIONS
Humoral and cellular immunogenicity evaluations are summarized in the tables below. Sample collection 
and processing will be performed by the staff at the clinical site according to current versions of approved 
standard operating procedures.


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Table 2:
Summary of Immunogenicity Assays (Humoral)
Assay 
Purpose
Exploratory endpoints
RSV neutralization RSV-A 
Memphis 37b
Measure levels of the antibody to the challenge strain
Intranasal pre-F and post-F
antibody*
Measure levels of vaccine induced antibody at the site of infection
RSV neutralization A2 
Analysis of neutralizing antibodies to the A2 strain
RSV strain cross-neutralization 
Analysis of cross-neutralizing antibodies to B and/or a different A strain
F-protein antibody
(ELISA; pre- and/or post-fusion) 
Analysis of antibodies binding to RSV F protein in post-fusion and/or pre-
fusion form
RSV G/N ELISA
Analysis of binding antibodies to G and N proteins of RSV
Adenovirus neutralization assay
Analysis of neutralizing antibodies to adenovirus
Functional and molecular 
antibody characterization
Analysis of antibody characteristics including but not limited to ADCC, 
ADCP, avidity, Fc characteristics, Ig isotype
*From nasal wash samples, if the ELISA will be available
ADCC = antibody-dependent cell-mediated cytotoxicity; ADCP = antibody-dependent cellular phagocytosis; ELISA = enzyme-
linked immunosorbent assay; F = fusion; Ig = immunoglobulin; RSV = respiratory syncytial virus
Table 3:
Summary of Immunogenicity Assays (Cellular)
Assay 
Purpose
Exploratory endpoints
IFNγ ELISpot
T-cell IFNγ responses to RSV F-protein peptides
Flow cytometry (ICS)
Analysis of T-cell responses to RSV F-protein peptides (including, but not limited
to, CD4/CD8, IL2, IFNγ, TNFα and/or activation markers, memory, Th1/Th2 
subtyping)
Cytokine analysis
Analysis of secreted cytokines in RSV F peptide-stimulated PBMC supernatant, 
including, but not limited to, measurement of Th1/Th2 cytokine balance
ELISpot = enzyme-linked immunospot; F = fusion; ICS = intracellular cytokine staining; IFNγ = interferon gamma; IL = 
interleukin; PBMC = peripheral blood mononuclear cell; Th = T-helper (cell); RSV = respiratory syncytial virus; TNFα = tumor 
necrosis factor alpha
SAFETY EVALUATIONS
On a daily basis, for 7 days post-vaccination, subjects will be asked to record symptoms of the following 
AEs via the subject diary:

Solicited local AEs: erythema (measured using the ruler supplied), swelling/induration (measured 
using the ruler supplied, and graded using the functional scale), and pain/tenderness.

Solicited systemic AEs: fatigue, headache, myalgia, arthralgia, chills, nausea and fever (ie, body 
temperature ≥38 °C).
Body temperature (tympanic or oral) should be measured at approximately the same time each day using 
the thermometer supplied. The 7-day post-vaccination temperature measurements may be taken earlier to 
coincide with the corresponding clinic visit.
The investigator will review each subject’s diary at the subsequent in-clinic visit; diary information will 
be transcribed by the study personnel into the electronic case report form (eCRF).
The investigator or study-site staff will document any reported unsolicited AEs and perform causality 
evaluations from the time of ICF signature until 28 days after vaccination, and from the entry into the 
Unit until 28 days after challenge. SAEs will be collected from the time of ICF signature until the study 
end, 6 months after vaccination.


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From the day of challenge until discharge from the Unit, a SSC will be filled out three times a day and 
reviewed by the attending physician. Temperature, heart rate and blood pressure will be obtained on a 
daily basis.
STATISTICAL METHODS
Sample Size Determination
The sample size was based on the ability to detect trends with a high one-sided alpha (20%), given this is 
an exploratory study whose partial aim is to determine the utility of the RSV human challenge model for 
RSV vaccine development. For a one-sided alpha level of 20%, the study has at least 80% power if 
Ad26.RSV.preF induces a reduction of VL-AUC of the quantitative RT-PCR assay by 50% or more. For 
a one-sided alpha level of 5%, the study has at least 80% power if Ad26.RSV.preF induces a reduction of 
VL-AUC of the quantitative RT-PCR assay by 75% or more. These calculations assume 22 subjects per 
arm, a mean VL-AUC in the placebo group of 320 log10 h/mL, corresponding standard deviation 275, and 
an infection rate in placebo of 65%.
An effect that is significant at 5% (one-sided) will be considered a significant effect. An effect that is 
significant at 20% (one-sided) will be considered as a trend. This trend, if observed, might be confirmed 
in future studies. 
As this is an exploratory study, the statistical assumptions described above will need to be demonstrated 
to be correct for the analysis to be conducted as indicated below and as planned in further detail in the 
SAP. For example, if the infection rate from the study is considerably below 65% then the study will be 
considered to be underpowered to be able to accurately determine the stated aims.
Planned Analyses
The following analyses will be performed:

PRIMARY ANALYSIS will be performed when all subjects have completed the quarantine phase or 
discontinued earlier. The pre-challenge neutralization and pre-F ELISA, and post-challenge RT-
PCR, nasal mucous and tissue count, and clinical symptom data will be available although the 
analysis may be performed on snapshot data. All other data available at the time of primary analysis, 
including completed cellular data, will be included. Preliminary safety data, including Day 28 post-
challenge, if available, will also be included.

FINAL ANALYSIS will be performed when all subjects have completed the 6 month safety follow-
up visit or discontinued earlier.
Depending on when the data are available, both analyses might be combined.
Efficacy Analyses
For the primary efficacy endpoint (VL-AUC of RSV-A Memphis 37b as determined by quantitative RT-
PCR assay of nasal wash samples) the exact Wilcoxon Rank Sum test will be performed and the one-
sided p-value will be interpreted at the 5% and 20% significance level, specifically only analyzing the 
statistical significance of a reduction in VL-AUC in the active versus placebo groups.
Secondary endpoints will be analyzed descriptively.
Immunogenicity Analyses
No formal hypothesis on immunogenicity will be tested. Descriptive statistics (geometric mean and 95% 
confidence interval [CI] for ELISA and virus neutralization assays; median and quartiles for ELISpot and
intracellular cytokine staining [ICS]) will be calculated for continuous immunologic parameters at all 


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timepoints. For the humoral assays, geometric mean fold rises from baseline and corresponding 95% CIs 
may be calculated as well. For immunogenicity, baseline is considered as the last assessment pre-
vaccination with Ad26.RSV.preF or placebo. Graphical representations of immunologic parameters will 
be made as applicable.
Frequency tabulations will be calculated for discrete (qualitative) immunologic parameters as applicable.
Safety Analyses
No formal statistical testing of safety data is planned. For the planned analyses, safety data will be 
analyzed descriptively.


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TIME AND EVENTS SCHEDULE
Clinic Phase
Scree
-ning
d
VACCINATION
VIRAL CHALLENGE: Quarantine Unit
OUTPATIENT
Pre-viral 
Challenge
Chall a
Post-viral Challenge
Dis-
charge
Follow-up
Final 
Visit g
Visit Timing
Vacc
Vacc 
+3 d b
Vacc 
+7 d
Vacc 
+26 d
Vacc 
+27 d
Vacc 
+28 d
Chall
+1 d
Chall
+2 d to +11 d
Chall
+12 d c
Challenge
+ 28d
Vacc
+ 6 mo
Target Study Day
Days
-84 to
-31 f
Day
-28
Day
-25 g
Day
-21
Day -2 or Day -1 
Admission to 
Unit (Procedures 
on either day)
Day 0
Viral 
chall-
enge
Day 1
Day 2 onwards
Procedures to be 
executed daily
Day 12
Day 28
Day 
155
Early
Exit e
Visit Window
±1 d
±2 d
±4 d
±14 d
Written informed consent

h
Inclusion/exclusion criteria

Demographics

Medical history/pre-study meds

Medical information review

Body height 

Body weight



Complete physical examination



Abbreviated/directed phys examination i







Vital signs j incl. body temperature










12-lead ECG k



Drugs of abuse screen



Cotinine screen

Breath alcohol test



Serology (HIV-1/2, hepatitis B/C)

RSV sero-susceptibility l


Nasopharyngeal swab/nasal wash 
tolerance test

Respiratory virus screen (from 
nasopharyngeal swab)

Serum pregnancy test m



Urine pregnancy test m



Randomization

Inclusion/exclusion criteria check n

Eligibility for viral challenge check

Pre-vaccination symptoms o

Safety lab blood sample, mL
10
10
10
10
10
10
10
10
Urine sample for urinalysis





Blood sample for cellular immunity, mL
50
50
50
50
Blood sample for humoral immunity, mL
10
10
10
10
RSV pre-F antibody assessment (from 
nasal wash sample)


Vaccination

30 minute post-vaccination observation p

Subject diary distribution r

Subject diary review by site staff




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Clinic Phase
Scree
-ning
d
VACCINATION
VIRAL CHALLENGE: Quarantine Unit
OUTPATIENT
Pre-viral 
Challenge
Chall a
Post-viral Challenge
Dis-
charge
Follow-up
Final 
Visit g
Visit Timing
Vacc
Vacc 
+3 d b
Vacc 
+7 d
Vacc 
+26 d
Vacc 
+27 d
Vacc 
+28 d
Chall
+1 d
Chall
+2 d to +11 d
Chall
+12 d c
Challenge
+ 28d
Vacc
+ 6 mo
Target Study Day
Days
-84 to
-31 f
Day
-28
Day
-25 g
Day
-21
Day -2 or Day -1 
Admission to 
Unit (Procedures 
on either day)
Day 0
Viral 
chall-
enge
Day 1
Day 2 onwards
Procedures to be 
executed daily
Day 12
Day 28
Day 
155
Early
Exit e
Visit Window
±1 d
±2 d
±4 d
±14 d
Solicited AE recording
- - - - - continuous - - - - -

Unsolicited AE recording q
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - continuous - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

SAE recording
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - continuous - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

Concomitant medications s
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - continuous - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

Challenge virus inoculation

Nasal wash sample t



RVAT (from nasopharyngeal swab) c

Subject symptom card





Spirometry






24-hour tissue count and mucus weight





Approx daily blood draw, mL
10
70
–
10
70
–
–
30
10
70
–
70
Approx cumulative study blood draw, mL
10
80
80
90
160
160
160
190
200
270
270
–
AE = adverse event; d = day; chall = challenge; ECG = electrocardiogram; HIV = human immunodeficiency virus; ICF = informed consent form; mo = month; RVAT = rapid virus 
antigen test; SAE = serious adverse event; vacc = vaccination 
pre-dose; pre- and post-dose; screening laboratory tests are to be done within 56 days of randomization; blood samples for immunogenicity will only be taken if the early exit is 
≥14 days after the previous immunogenicity blood draw; if within 7 days of study vaccination; check of diary during the telephone call; three times daily; every 12 (±1)
hours; on Days 3, 7 and 11; Days 3, 7, and 11 for cardiac enzymes only. Note: cardiac enzymes will also be assessed on entry to the quarantine Unit in addition to biochemistry 
and hematology parameters.
a. Intranasal challenge with the RSV-A Memphis 37b virus will occur on Day 0, not less than 24 or more than 90 days after vaccination.
b. At 48-hours post-vaccination, a telephone call will additionally be made to two sentinel subjects to collect safety information.
c. Subjects will only be discharged if no detectable virus is present (negative RVAT) in nasopharyngeal samples taken on Day 12. If symptoms are present, but no virus is detected 
(negative RVAT), discharge will be at the investigator’s discretion. If appropriate, subjects may reside in quarantine for an additional night or longer before discharge.
d. Historical pre-screening data collected through the ethics committee-approved hVIVO screening protocol within 56 days (90 days for viral serology) to 3 days prior to vaccination.
may be used for screening procedures. Historical pre-screening data obtained prior to this window can be re-assessed any time from 40 days to 3 days prior to vaccination.
e. For those subjects who are unable to continue participation in the study, but for whom consent is not withdrawn, an exit visit will be conducted as soon as possible.
f. ie, 56 days to 3 days prior to vaccination.
g. By telephone.
h. Study-specific consent may occur on the day of vaccination, providing all required eligibility information has been collected through the ethics committee-approved hVIVO screening 
protocol.
i. Directed physical examination includes respiratory system, nose, ear, throat, and facial lymph nodes examination.
j. Supine systolic and diastolic blood pressure, heart rate and respiratory rate after at least 5 minutes rest.
k. Supine ECG after at least 5 minutes rest.
l. Neutralizing antibody to RSV-A Memphis 37b; blood will be collected within 90 days of vaccination and on entry to the Unit.


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m. For all female subjects.
n. To include exclusion criteria 1, 7, 8, 9, 10, 14 and 16.
o. The investigator must check for acute illness or body temperature ≥37.8 °C at the time of vaccination. In such cases, the subject may be re-screened (if vaccination number not 
assigned), or withdrawn at the discretion of the investigator. Note: the minimum time between vaccination and challenge is 24 days.
p. Subjects will be closely observed for a minimum of 30 minutes post-vaccination. Any unsolicited, solicited local and systemic AEs, and vital signs will be documented by study-site 
personnel following this observation period.
q. Unsolicited AEs will be collected from ICF signature until 28 days after vaccination, and from the entry into the Unit until 28 days after challenge.
r. Rulers and thermometers will be distributed at the vaccination visit.
s. Concomitant therapies will be collected and recorded in the eCRF from time of study vaccine administration until 28 days after vaccination, and from the entry into the Unit until 28 
days after challenge, and additionally outside of these periods when associated with an SAE.
t. Aliquots may be taken from nasal wash samples if more than one assay is to be assessed at a given timepoint.


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ABBREVIATIONS
Ad26
adenovirus serotype 26
Ad35
adenovirus serotype 35
AE
adverse event
AUC
area under the curve
β-hCG
β-human chorionic gonadotropin
CI
confidence interval
COPD
chronic obstructive pulmonary disease
CS
circumsporozoite
DNA
deoxyribonucleic acid
DRC
Data Review Committee
ECG
electrocardiogram
eCRF
electronic case report form 
eDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
ELISpot
enzyme-linked immunospot (assay)
ERD
enhanced respiratory disease
FA
full analysis
F protein
fusion protein
FDA
(US) Food and Drug Administration
FI
formalin-inactivated
FIH
first-in-human
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Conference on Harmonisation
ICS
intracellular cytokine staining
IEC
Independent Ethics Committee
IFNγ
interferon gamma
IRB
Institutional Review Board
ITTc
intent-to-treat-challenge
PPI
per-protocol immunogenicity
PQC
Product Quality Complaint
RVAT
rapid virus antigen test
RSV
respiratory syncytial virus
RT-PCR
reverse transcriptase-polymerase chain reaction
SAE
serious adverse event
SAP
statistical analysis plan
SOP
standard operating procedure
SRP
study-responsible physician
SSC
subject symptom card
SUSAR
suspected unexpected serious adverse reaction
Th 
T-helper (cell)
TNFα
tumor necrosis factor alpha
US
United States
VL-AUC
AUC for viral load
vp
viral particles
WBC
white blood cell


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1.
INTRODUCTION
A human adenovirus-vectored vaccine candidate which has shown promise in preclinical animal 
models of respiratory syncytial virus (RSV), and which is currently being tested in elderly 
subjects aged ≥60 years in stable health in Study VAC18193RSV1003, will be assessed in this 
study:

Ad26.RSV.preF (JNJ-64400141), a replication-incompetent adenovirus serotype 26 (Ad26) 
containing a deoxyribonucleic acid (DNA) transgene that encodes for the pre-fusion 
conformation-stabilized F protein (pre-F) derived from the RSV A2 strain.
This will be an exploratory Phase 2a study where the prophylactic efficacy of Ad26.RSV.preF in 
the human challenge model of RSV infection will be assessed, and the appropriateness of the 
RSV human challenge model for RSV vaccine development will be evaluated on the basis of its 
ability to show a trend toward prophylactic efficacy with a RSV vaccine that has shown promise 
in preclinical challenge models.
For the most comprehensive nonclinical and clinical information regarding Ad26.RSV.preF, 
refer to the latest version of the Investigator’s Brochure for Ad26.RSV.preF.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.
1.1.
Background
RSV is considered to be the most important cause of serious acute respiratory illness in infants 
and children under 5 years of age.16,34,38 Globally, in 2005, RSV was responsible for an estimated 
3.4 million hospitalizations worldwide in children under 5 years of age. Furthermore, 66,000 to 
199,000 children younger than 5 years died from RSV-associated acute lower respiratory tract 
infection (LRTI) in 2005, and 99% of these deaths occurred in developing countries.27
Nevertheless, the disease burden due to RSV in developed countries is substantial, with RSV 
infection during childhood linked to the development of wheezing, airway hyperreactivity and 
asthma.31,33,35,36,37 In the United States (US), the infection rate was 68.8% in children younger 
than 12 months of age and 82.6% during the second year of life. Virtually all children had been 
infected at least once by 24 months of age, and about one half had experienced 2 infections.14 In 
the US, RSV infection in children under 5 years of age is the cause of 57,000 to 175,000 
hospitalizations, 500,000 emergency room visits, and approximately 500 deaths each year.30,34,38
In children under 1 year of age, RSV is the most important cause of bronchiolitis, and RSV 
hospitalization is highest among children under 6 months of age.6,16
In addition to children, RSV is an important cause of respiratory infections in the elderly, 
immunocompromised, and those with underlying chronic cardiopulmonary conditions.10 In long-
term care facilities, RSV is estimated to infect 5-10% of the residents per year with significant 
rates of pneumonia (10 to 20%) and death (2 to 5%).11 In one epidemiology study of RSV 
burden, it was estimated that 11,000 elderly persons die annually of RSV in the US.39 These data 
support the importance of developing an effective vaccine for certain adult populations.


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Despite the high disease burden, no licensed vaccine is available for RSV. The first vaccine 
candidate for young children, which consisted of formalin-inactivated RSV (FI-RSV), was 
associated with enhanced respiratory disease (ERD) upon infection with RSV.19 Although the 
mechanisms for ERD are not fully understood, it is thought that FI-RSV failed to induce 
adequate neutralizing antibody titers and CD8 priming, and induced a T-helper (Th) 2 skewed 
response.26
Adenoviral-vectored Vaccines
It is thought that an efficacious RSV vaccine should induce high levels of neutralizing 
antibodies, antigen-specific CD8+ T-cell responses, and Th1-type CD4+ T cells.3 The candidate 
RSV vaccine being evaluated in this protocol is based on the AdVac® platform which has been 
shown to promote a strong antibody response, as well as CD8+ T cell and Th1-type CD4+ T-cell 
responses.
The immunogenicity profile of adenoviral vectors, with particular emphasis on Th1 responses, is 
illustrated by data obtained from immunization of adults with Ad26-vectored human 
immunodeficiency virus (HIV) vaccine (Ad26.ENVA.01), and of adults and infants with an 
adenovirus serotype 35 (Ad35)-vectored tuberculosis (TB) vaccine (Ad35.TB-S). These data 
show predominantly interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα) 
production in CD4+ and CD8+ T cells.2,5,29 Furthermore, in mice, Ad26- and Ad35-vectored 
vaccines with malaria circumsporozoite (CS) transgene inserts (Ad26.CS.01 and Ad35.CS.01), 
when administered as single immunizations or in combination as a heterologous prime-boost 
regimen at dose levels ranging from 1x108 viral particles (vp) to 1x1010 vp, induce 
predominantly CD8+ T-cell responses, as well as mainly immunoglobulin (Ig) G2a antibody 
responses, indicative of a Th1-biased response.32
Ad26.RSV.FA2 Clinical Data
Ad26 encoding for the wild-type RSV FA2, Ad26.RSV.FA2, has been evaluated in studies 
VAC18192RSV1001 and VAC18192RSV1003 (N = 48 and 32, respectively, of which 35 and 
24 subjects, respectively, received Ad26.RSV.FA2) in adults at doses of 5x1010 vp. All subject 
visits have been completed in both studies.
Results indicate that there have been no safety concerns following vaccination in either study. 
After vaccination with Ad26.RSV.FA2, local reactogenicity comprised almost exclusively mild 
to moderate pain of median duration 1 to 3 days. The most commonly experienced solicited 
systemic adverse events (AEs; headache, fatigue, chills and myalgia) were also mostly mild to 
moderate in severity and of median duration 1 to 3 days; most unsolicited AEs and most 
laboratory abnormalities were mild to moderate in severity. No serious adverse events (SAEs) 
were reported and no AEs led to withdrawal from study vaccine.
Single vaccination with 5x1010 vp Ad26.RSV.FA2 raised humoral and cellular immunity; 
humoral and cellular immune responses were maintained for at least 6 months following 


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vaccination. An increase in RSV neutralizing antibody titers was observed; RSV-specific T-cell 
responses were also increased.
FA2 and preF RSV Vaccines
The candidate vaccine assessed in this study is Ad26.RSV.preF, ie, a replication-incompetent 
Ad26-containing a DNA transgene that encodes for the pre-fusion conformation-stabilized 
F protein derived from the RSV A2 strain.
First-in-human (FIH) clinical studies (VAC18192RSV1001 [FIH for Ad35.RSV.FA2] and 
VAC18192RSV1003 [FIH for Ad26.RSV.FA2]) have been completed with vaccines 
Ad26.RSV.FA2 and Ad35.RSV.FA2 (ie, a similar recombinant, replication-incompetent vaccine 
using an Ad35 vector), in which Ad26 and Ad35, respectively, encode for a wild-type RSV 
F protein of the RSV A2 strain.
The adenoviral vectors Ad26 and Ad35 are derived from Group B and D serotype adenoviruses 
and have been similarly modified to be replication-incompetent; expression of the antigen is 
controlled by the same promotor. An Ad26-based RSV vaccine was chosen for further clinical 
development over the Ad35-based counterpart based on a better immunogenicity profile from 
nonclinical data, a similar safety and immunogenicity profile but at half the Ad35 dose from 
clinical data, and a better manufacturing profile.
The F protein of RSV F undergoes a conformational transition from a metastable pre-fusion 
conformation to a stable post-fusion conformation. Neutralizing sensitive epitopes reside on both 
proteins, but recent evidence indicates that those epitopes specific to the pre-F protein seem to be 
more potent than those previously identified and present on the post-F protein.13,15 This evidence 
in the design of the candidate RSV vaccine (Ad26.RSV.preF) in which the adenoviral vector 
encodes for a full length RSV F protein stabilized in the pre-F protein conformation. 
 
 
22 This change 
in the transgene confers more stability to the pre-fusion form of the protein.22 This change also 
induces higher immune responses against pre-fusion epitopes because the majority of 
neutralizing antibodies target the pre-fusion protein conformation.23,28 For these reasons, it is 
anticipated that the Ad26.RSV.preF vaccine candidate will generate more neutralizing antibodies 
relative to the Ad26.RSV.FA2 vaccine.42
Ad26.RSV.preF Preclinical Data
Ad26.RSV.preF is immunogenic in mice and cotton rats, with humoral responses that include the 
induction of RSV neutralizing antibodies. In addition, in mice it was shown that Ad26.RSV.preF 
elicits cellular responses, characterized by the induction of RSV F-specific CD8+ IFNγ+ T cells. 
The immune response after Ad26.RSV.preF immunization was Th1 biased. In cotton rats, single 
immunization with Ad26.RSV.preF protects the upper and lower respiratory tract from challenge 
with RSV A2 and RSV B strains, without induction of any histopathological signs of ERD.42
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Ad26.RSV.preF Clinical Data
Ad26.RSV.preF is under evaluation in the ongoing FIH Phase 1 study VAC18193RSV1003 in 
elderly subjects aged ≥60 years in stable health. In this randomized, placebo-controlled, double-
blind study, 72 elderly male and female subjects have been randomized in parallel to one of five 
study groups and have received the first (Day 1) of two intramuscular injections as follows:

Group 1 – 5x1010 vp Ad26.RSV.preF on Day 1 and 1 year later;

Group 2 – 5x1010 vp Ad26.RSV.preF on Day 1 and placebo 1 year later;

Group 3 – 1x1011 vp Ad26.RSV.preF on Day 1 and 1 year later;

Group 4 – 1x1011 vp Ad26.RSV.preF on Day 1 and placebo 1 year later;

Group 5 – placebo on Day 1 and 1 year later.
Safety and immunogenicity data from the unblinded interim analysis 28 days post-Dose 1 from 
all 72 subjects who received Ad26.RSV.preF (5x1010 vp or 1x1011 vp) or placebo confirmed the 
immunogenicity of the vaccine; the 1x1011 vp dose of Ad26.RSV.preF was more immunogenic
than the 5x1010 vp dose. No safety concerns were revealed; the reactogenicity of both doses was 
comparable.
For study VAC18193RSV1003, Ad26.RSV.preF was provided in a different buffer (Formulation 
Buffer 1a) from the one to be used in the current study (Formulation Buffer 2b). The formulation 
buffer was changed to enhance the Ad26.RSV.preF drug product stability at 2 to 8 °C for storage 
purposes in future studies. The new formulation buffer was considered well-tolerated when 
tested in a nonclinical single-dose intramuscular safety study in rabbits.42
Safety Data Supporting Dose Selection from Other Ad26-based Vaccines
In addition to the two completed studies with Ad26.RSV.FA2 and one ongoing study with 
Ad26.RSV.preF, the dose level for Ad26.RSV.preF used in this study is supported by experience 
in adults with other Ad26 vaccines encoding for different antigens (EnvA [in Ad26.ENVA.01 
against HIV];4,5 CS protein [in Ad26.CS.01 against malaria];7,29 and Ebola glycoprotein [in 
Ad26.ZEBOV against Ebola virus]25). Note that, in general, at a given dose level, no significant 
changes in the safety profiles of Ad26-based vaccines have been seen when the transgene has 
been changed.
In completed clinical studies,c the safety of Ad26.ENVA.01, Ad26.CS.01 and Ad26.RSV.FA2 
has previously been evaluated in at least 293 adult subjects, of whom 243 have received 
                                                
a
b
c Safety data from these studies are summarized in a separate report (Adenoviral Vaccine Safety Database V2.0, December 2016) 
which is available on request.
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5x1010 vp, and found to be well-tolerated. In addition, four Phase 1 studies with Ad26.ZEBOV 
have been completed in adults: 291 subjects have received Ad26.ZEBOV at 5x1010 vp and 
1x1011 vp without significant safety issues: 15 subjects have received 1x1011 vp (25 doses 
administered), and 276 subjects have received 5x1010 vp. The safety data from these Ebola 
studies showed no safety concerns at 5x1010 vp and 1x1011 vp. Overall, these clinical data are 
supportive of dosing Ad26.RSV.preF at 1x1011 vp in the current study.
1.2.
Overall Rationale for the Study
This is an exploratory, double-blind, randomized, placebo-controlled human challenge study in 
which healthy adult subjects will receive single intramuscular doses of 1x1011 vp of 
Ad26.RSV.preF or placebo and 28 days later (window between 24 to 90 days) will undergo 
intranasal challenge with RSV-A Memphis 37b virus. This is an exploratory study as an RSV 
vaccine has not previously been tested in this challenge model. The prophylactic antiviral effect, 
prevention of clinical symptoms of RSV infection, and prevention of RSV infection will be 
evaluated. The study will also explore the relationship between immunogenicity and efficacy 
outcomes.
The study is considered to be exploratory because no RSV vaccine has been previously tested in 
the human challenge model of RSV infection. The RSV vaccine developed by the sponsor is 
mainly intended to protect against moderate-severe low respiratory tract RSV infection. The 
RSV symptoms seen in this challenge model are mild and mainly limited to the upper respiratory 
tract compared to those which would be observed in a clinical efficacy trial of naturally-
occurring infection where more severe symptoms, plus RT-PCR-confirmed RSV infection, 
would be measured (see Attachment 4). Although it might be expected that a vaccine would be 
better able to protect against mild disease than severe disease, it might also be that mild upper 
respiratory disease could be more difficult for a vaccine to protect against, for the reason that a 
parenteral vaccine would induce lower levels of antibody and cellular responses in the 
nasopharynx compared to levels induced in the blood and lower respiratory tract. Preclinical data 
indicates this might be the case: when the dose of vaccine is reduced, protection against virus 
infection in the nasopharynx is lost before protection in the lung. It is not known whether the 
vaccine in this study, which is to be dosed at the highest dose already given safely to humans, 
will induce a sufficient immune response to give protection in the nasopharynx, or at least to 
give an indication of some protection. Therefore this study is considered highly exploratory, and 
is as much a test of whether this model will prove to be useful in vaccine studies, as it is a study 
of the effectiveness the RSV vaccine under development. 
Since preclinical models have suggested some level of protection by the vaccine against
nasopharyngeal infection, the study includes a formal primary objective of lowering area under 
the curve of viral load (VL-AUC), despite the exploratory nature of this study. This VL-AUC 
has been found in previous studies to be the most sensitive and least variable parameter for 
efficacy measurement in this model. If the vaccine can prevent infection completely in some 
subjects, a powerful effect on the AUC would be seen since in those subjects the AUC would be 
0. There are also a small number of secondary objectives related to reduction of symptoms 


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occurring at a specific time, reduction of overall mucous secretion and incidence of infection 
utilizing more severe or very mild symptoms as alternative definitions, coupled in both cases 
with two quantifiable RT-PCR measurements to confirm the symptoms are due to RSV. 
The statistical approach to this exploratory study is to have an alpha of 20% to indicate a trend 
and 5% as a significant result for the primary endpoint. If positive results or a trend in the 
primary or secondary objectives are found, this would suggest that the challenge model may be a 
reasonable approach to examine vaccine efficacy and would provide evidence to perform more 
extensive studies. If this study fails its primary endpoint, and does not show any trends in the 
other endpoints, it would suggest that the human RSV challenge model is not an appropriate 
model to evaluate potential efficacy of RSV vaccines directed against more serious disease that 
has more of a lower respiratory component.
Therefore this study will serve as a pilot to explore the value of evaluating RSV vaccines in the 
human challenge model in RSV vaccine development, with the possibility that, if the model is 
appropriate, a trend toward efficacy with Ad26.RSV.preF could be detected.
1.3.
Risk/Benefit Section
1.3.1.
Known Benefits
The clinical benefits of vaccination with Ad26.RSV.preF have yet to be established. For the 
subjects in this study the vaccine may have no direct benefit.
1.3.2.
Potential Benefits
Results from clinical studies with Ad26.RSV.preF may be useful in developing a new vaccine to 
prevent RSV infection. The vaccination may provide some protection against subsequent RSV 
infection in adults participating in the study who have been screened for susceptibility to RSV 
infection.
1.3.3.
Known Risks
All vaccines have the potential to cause adverse experiences. To date, limited clinical data with 
Ad26.RSV.preF are available from the Phase 1 VAC18193RSV1003 study in elderly subjects 
aged ≥60 years in stable health. Safety data from an unblinded interim analysis at 28 days post-
Dose 1 from all subjects who received Ad26.RSV.preF (5x1010 vp or 1x1011 vp) or placebo did 
not reveal any safety concerns.
No specific safety concerns were identified based on the currently available clinical data.


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1.3.4.
Potential Risks
The following potential risks for Ad26.RSV.preF will be monitored during the study. 
Risks Related to Vaccines
Subjects may exhibit local signs and symptoms associated with vaccination, including erythema, 
swelling/induration, and pain/tenderness. These local reactions will be monitored, but are 
generally short-term and do not require treatment.
Subjects may exhibit general signs and symptoms associated with administration of a vaccine, or 
vaccination with placebo, including fatigue, headache, myalgia, arthralgia, chills and nausea. 
These side effects will be monitored, but are generally short-term and do not require treatment.
Subjects may have an allergic reaction to the vaccination. An allergic reaction may cause a rash, 
hives or even difficulty breathing. Severe reactions, including anaphylaxis, are rare but can occur 
with any vaccine. Medications will be available in the clinic to treat serious allergic reactions 
promptly. Subjects with a known allergy, or history of anaphylaxis or other serious adverse 
reactions to vaccines or vaccine components (including any of the constituents of the study 
vaccine) will be excluded from the study. The study site should have medical treatment available 
in case of severe allergic reactions following vaccine administration.
Risks Related to Adenoviral-vectored Vaccines
Safety data available from 10 completed clinical studies in adults with other Ad26-vectored 
vaccine candidates, in which Ad26 with different inserts has been evaluated at dose levels 
ranging from 1x109 vp to 1x1011 vp, indicate that no safety concerns would be anticipated from 
vaccination with Ad26.RSV.preF at doses of 5x1010 vp and 1x1011 vp.
Local AEs (moderate injection site pain and tenderness, and moderate to severe redness at the 
injection site) and systemic AEs (headache, chills, joint pain, muscle pain, tiredness/generally 
not feeling well/fatigue and fever) have been reported after vaccination with Ad26-vectored 
vaccines. In a few subjects, transient laboratory abnormalities have been seen, including changes 
in neutrophils (neutropenia/neutrophil count decreased). Laboratory changes including decreased 
hemoglobin, decreased platelets, and moderate elevations in liver transaminases were observed 
that were not associated with any clinical findings and appear to be transient based on no 
reported persistent abnormalities in any of the subjects.
For further details on the safety profiles of other Ad26-vectored vaccine candidates, see the 
Ad26.RSV.preF Investigator’s Brochure.1
Risks from Collection of Nasal Wash Samples/Nasopharyngeal Swabs
Collection of nasal wash samples or nasopharyngeal swabs may cause a nosebleed.


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Risks from Blood Draws
Blood drawing may cause pain/tenderness, bruising, bleeding, lightheadedness, dizziness, 
vasovagal response, and, rarely, infection at the site where the blood is taken.
Pregnancy and Birth Control
The effect of the study vaccine on a fetus or nursing baby is unknown so women of childbearing 
potential are required to agree to practice effective birth control measures for sexual intercourse 
from signing the informed consent form (ICF) until at least 4 months after vaccination (see 
Section 4.1). Use of hormonal contraception should start at least 28 days before vaccination. 
Women who are pregnant or breast-feeding, or are planning to become pregnant while enrolled 
in the study until 6 months after study vaccination, will be excluded from the study. Men having 
sexual intercourse with women or men are required to agree to use effective contraception for 
sexual intercourse starting from entry to the quarantine Unit and continuing until 3 months after 
the date of viral challenge (see Section 4.3).
Subjects with Immuno-suppression/Reduced Immune Response
Limited evidence indicates that inactivated vaccines (or non-replicating 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. Subjects with abnormal 
function of the immune system will be excluded from the study.
Concomitant Vaccination 
Concomitant vaccination might have an influence on both safety profile and immunogenicity of 
Ad26.RSV.preF. Likewise, Ad26.RSV.preF might have an influence on both safety profile and 
immunogenicity of any concomitant vaccination. As a result, vaccination with live attenuated 
vaccines within 28 days of a study vaccination (ie, before and after) is prohibited. Other vaccines 
(eg, influenza, tetanus, hepatitis A, hepatitis B, rabies) should be given at least 14 days before (or 
at least 14 days after) administration of study vaccine. If a vaccine is indicated in a post-exposure 
setting (eg, rabies or tetanus), it must take priority over the study vaccine.
Risks Associated with the Human Challenge Model
Healthy adult subjects will be recruited as they are best suited to tolerate inoculation of the virus. 
Severe complications tend to occur almost exclusively in infants, the elderly, and persons of any 
age with chronic co-morbidities or who are significantly immune-compromised. Qualified 
doctors and nurses in the quarantine Unit will manage any symptoms.
As a consequence of the RSV-A Memphis 37b inoculation, AEs (serious or non-serious) related 
to RSV infection commonly occur. These anticipated AEs are related to, but not limited to, 
rhinitis, rhinorrhea, nasal congestion, sneezing, nasopharyngitis, ear ache, malaise (tiredness), 
cough, shortness of breath, muscle and/or joint pain, headache, fever, nasal blood spotting, and 


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upper respiratory tract infection. In addition, laboratory abnormalities related to RSV viral 
infection may occur such as, but not limited to, hematologic changes (increases in white blood 
cell [WBC] count and changes in differential values) and increased levels of inflammatory 
markers (eg. C-reactive protein).
The study virus, like many viruses, can cause more substantial health issues such as myocarditis. 
However, the chance of this resulting in permanent changes is rare as most cases are minor and 
resolve without sequelae. In over 500 subjects inoculated with the study virus by hVIVO, clinical 
laboratory tests in 2 subjects have shown changes suggestive of myocardial inflammation: both 
cases returned to normal without treatment and were not associated with specific symptoms or 
ECG changes.
It is unlikely that subjects will transmit RSV virus to their close contacts after they have been 
released from the quarantine Unit. After infection with RSV, infectious virus will be present in 
the subject’s nose for several days, but it is not expected to be present in the subject’s nose at the 
time of discharge from the Unit. This is because the usual duration of time that RSV remains 
infective in adults is several days shorter than the time they will spend in the Unit in isolation.9
All subjects will stay in the quarantine Unit from 1 or 2 days prior to RSV inoculation until 12
days after challenge. Nasopharyngeal swabs will be tested for the presence of virus prior to 
discharge using rapid virus antigen test (RVAT). Subjects will only be discharged when no 
detectable virus is present (negative RVAT). If symptoms are present, but no virus is detected 
(negative RVAT), discharge will be at the investigator’s discretion. If appropriate, subjects may 
reside in quarantine for an additional night or longer before discharge.
To reduce the risk of passing RSV on to others, the subject will be advised to avoid contact with 
the following vulnerable groups of people for two weeks after they leave the quarantine Unit:

any person with any known immunodeficiency

any person receiving immunosuppressant medications

any person undergoing or soon to undergo cancer chemotherapy

any person who has congestive heart failure or is in frail health

any person who has a diagnosis of emphysema or chronic obstructive pulmonary disease 
(COPD), is elderly residing in a nursing home, or has severe lung disease

any person who has received a transplant (bone marrow or solid organ)

children below the age of 1 year

elderly persons (aged 75 years or older).
Unknown Risks
There may be other serious risks that are not known.


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1.3.5.
Overall Benefit/Risk Assessment
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 of Ad26.RSV.preF to be used in this study will be 1x1011 vp. There were no safety 
concerns with this dose in study VAC18193RSV1003 in elderly subjects aged ≥60 years in 
stable health. This dose was found to be safe and well-tolerated in other Ad26-vectored 
vaccines against HIV and Ebola.

The study will be paused prior to challenge if one or more subjects experience any vaccine-
related SAEs, or two or more subjects experience severe AEs considered to be at least 
possibly related to Ad26.RSV.preF after discussion between sponsor and investigator (see 
Section 17.9.2). In these situations, the pausing rules will apply (see Section 11.10).

The study will be terminated if one or more subjects experience any severe or clinically 
significant illness from RSV challenge, after discussion with the investigator, hVIVO, and 
the sponsor’s study-responsible physician (SRP) (see Section 17.9.2).

Several safety measures have been proposed to minimize potential risk to subjects, 
including:
o
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria (as 
specified in the protocol) will be allowed to participate in this study. The selection 
criteria include adequate provisions to minimize the risk and protect the well-being of 
subjects in the study.
o
Utilization of sentinel subjects (see Section 3.1).
o
Utilization of withdrawal criteria (see Section 10.2).
o
Close monitoring of subjects throughout the study as described in Section 9.
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
2.1.1.
Objectives
Primary Objective
The primary objective is to assess a trend for the prophylactic efficacy of a single dose of 
1x1011 vp of Ad26.RSV.preF administered intramuscularly to adults aged 18-50 years in the 
RSV challenge model in terms of reduction of nasal wash viral load as measured by the area 
under the curve (AUC) over time by quantitative reverse transcriptase-polymerase chain reaction 
(RT-PCR) compared to placebo.


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Secondary Objectives

To assess a trend for prophylactic efficacy of a single dose of Ad26.RSV.preF in the RSV 
challenge model in terms of reduction of nasal wash viral load as measured by the peak viral 
load of the RT-PCR compared to placebo.

To assess the effect of a single dose of 1x1011 vp of Ad26.RSV.preF on viral load, as 
measured by RT-PCR and quantitative culture of RSV, and clinical symptoms on Day 6 and 
Day 7 post-challenge compared to placebo.

To assess a trend for prophylactic efficacy of a single dose of 1x1011 vp of Ad26.RSV.preF 
in the RSV challenge model in terms of prevention of symptomatic RSV infection defined as 
two quantifiable RT-PCR measurements and one or more positive clinical symptoms of any 
grade from two different categories in the symptom scoring system (Upper Respiratory, 
Lower Respiratory, Systemic), or one Grade 2 symptom from any category compared to 
placebo.

To assess a trend for prophylactic efficacy of a single dose of 1x1011 vp of Ad26.RSV.preF 
in the RSV challenge model in terms of prevention of symptomatic RSV infection defined as 
two quantifiable RT-PCR measurements and one or more positive clinical symptoms of any 
grade in any category from the symptom scoring system compared to placebo.

To assess a trend for prophylactic efficacy of a single dose of 1x1011 vp of Ad26.RSV.preF 
in the RSV challenge model in terms of the weight of mucous secretions and tissue count 
over time compared to placebo.

To assess the safety and tolerability of a single dose of 1x1011 vp of Ad26.RSV.preF 
administered intramuscularly.
Exploratory Objectives

To assess a trend for prophylactic efficacy of a single dose of 1x1011 vp of Ad26.RSV.preF 
in the RSV challenge model in terms of clinical symptoms as measured by the AUC over 
time of symptoms collected by a graded symptom scoring system compared to placebo.

To assess a trend for prophylactic efficacy of a single dose of 1x1011 vp of Ad26.RSV.preF 
in the RSV challenge model in terms of AUC for viral load (VL-AUC), as measured by 
quantitative culture of RSV from nasal wash samples, compared to placebo.

To explore the relationship of humoral (including nasal wash samples if feasible) and 
cellular immunogenicity outcomes and the VL-AUC and the AUC for clinical symptoms.

To assess a trend for prophylactic efficacy of a single dose of 1x1011 vp of Ad26.RSV.preF 
in the RSV challenge model in terms of prevention of symptomatic RSV infection defined as 
two quantifiable RT-PCR measurements and/or positive serological measurement of RSV 
infection in the context of immunization and pre-existing antibody and one or more positive 
clinical symptoms of any grade in any category compared to placebo.


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
To assess a trend for prophylactic efficacy of a single dose of 1x1011 vp of Ad26.RSV.preF 
in the RSV challenge model in terms of respiratory parameters measured by spirometry 
during the study compared to placebo.

To explore the relationships between clinical symptoms and viral load, as measured by RT-
PCR and quantitative culture of RSV, in Ad26.RSV.preF subjects and placebo.

To explore other immunologic parameters in relation to the VL-AUC by RT-PCR and AUC 
for clinical symptoms and occurrence of symptomatic RSV infection defined as two 
quantifiable RT-PCR measurements or more plus one clinical symptom of any grade.

To explore the immune response of a single dose of 1x1011 vp of Ad26.RSV.preF compared 
to placebo.

To explore humoral and cellular responses to challenge with RSV-A Memphis 37b in 
immunized and non-immunized subjects.

To explore the relationship between immunogenicity and pre-existing Ad26 neutralizing 
antibody.

To explore other potential efficacy endpoints, as defined in the statistical analysis plan 
(SAP), to determine the best efficacy endpoint to use in subsequent clinical studies 
investigating the vaccine’s efficacy.
Objectives and endpoints are tabulated in Attachment 2.
2.1.2.
Endpoints
Primary Endpoint: Viral Load
The primary endpoint is the VL-AUC of RSV-A Memphis 37b as determined by quantitative 
RT-PCR assay of nasal wash samples.
Nasal wash samples are taken every 12 (±1) hours beginning two days (ie, in the morning) after 
inoculation of the challenge virus. Quantitative RT-PCR is utilized to measure viral load.
Secondary Endpoints

Peak viral load of RSV-A Memphis 37b, defined as the maximum viral load as determined 
by quantitative RT-PCR assay of nasal wash samples, observed over the entire time period.

Occurrence of symptomatic RSV infection defined as two quantifiable RT-PCR 
measurements at different timepoints plus symptoms of any grade from two different 
categories from the subject symptom card (SSC)a
or two quantifiable
RT-PCR 
measurements plus any Grade 2 symptom from any category. The three SSC categories are:
o
Upper Respiratory symptoms: runny nose, stuffy nose, sneezing, sore throat, earache
                                                
a See Attachment 3.


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o
Lower Respiratory symptoms: cough, shortness of breath, chest tightness, wheeze
o
Systemic symptoms: malaise, headache, muscle and/or joint ache, chilliness/ 
feverishness

Occurrence of RSV infection defined as two quantifiable RT-PCR measurements plus any 
clinical symptom of any severity.

Total weight of mucus produced and tissue count.

Safety and tolerability
o
Unsolicited adverse events (AEs) from ICF signature until 28 days after vaccination, 
and from the entry into the Unit until 28 days after challenge.
o
Safety data including, but not limited to, physical examinations, vital signs, 12-lead 
electrocardiograms (ECGs) and clinical laboratory results (including biochemistry, 
hematology, and urinalysis).
o
Serious adverse events (SAEs) throughout the study (from signing the ICF to the end of 
the study, 6 months after vaccination).
o
Solicited local and systemic AEs for 7 days after vaccination.
Exploratory Endpoints

AUC of the total clinical symptom score. The total clinical symptom score is a composite of 
13 self-reported symptoms (on the SSC) divided into three categories (Upper Respiratory, 
Lower Respiratory, Systemic).

The VL-AUC of RSV-A Memphis 37b, as determined by quantitative culture of RSV of 
nasal wash samples.

Pre-F antibody in nasal wash samples measured by pre-F enzyme-linked immunosorbent 
assay (ELISA) normalized to a standard protein or antibody to account for variability of 
sample volume, dilution and concentration in nasal wash samples.

Proportion of subjects with symptomatic RSV infection (RT-PCR or serology). 
Seroconversion is defined as a four-fold rise against the G and/or N protein by ELISA which 
would indicate a take of the virus inoculum to such extent that a systemic immunologic 
response against an antigen not in the vaccine was induced.

Neutralizing antibody against RSV-Memphis 37b (challenge strain) and RSV A2.

RSV pre-F and post-F antibodies from serum and nasal wash samplesa measured by ELISA.

Respiratory parameters: spirometry (FEV1, FVC, FEV1/FVC).
                                                
a Assumes that the ELISA for nasal wash samples will be available.


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
Vaccine immune response defined as specific pre-F levels of antibody as measured by 
ELISA, specific neutralizing antibody levels, F antigen-specific cellular responses as 
measured by interferon gamma enzyme-linked immunospot (IFNγ ELISpot) assay, flow 
cytometry cytokine analysis and/or secreted cytokines compared to placebo.
Additional exploratory analyses may be performed to investigate vaccine-elicited immune 
responses further. These may include, but are not limited to, the following assays:

RSV cross-neutralization of B and/or other A strain

Binding antibodies to RSV G and/or N

F-protein antibody specificity characterization

Adenovirus neutralization assay

Functional and molecular antibody characterization
Refer to Section 9.2 for evaluations related to endpoints.
Objectives and endpoints are tabulated in Attachment 2.
2.2.
Hypothesis
This is an exploratory human challenge study that will evaluate the effect of Ad26.RSV.preF on 
viral replication and on clinical symptoms of RSV infection after challenge. To focus 
interpretation, a formal primary hypothesis is described that will be statistically tested. The 
primary hypothesis is that a single dose of 1x1011 vp of Ad26.RSV.preF shows a trend of 
reduction in VL-AUC of the quantitative RT-PCR in healthy subjects challenged intranasally 
with the RSV-A Memphis 37b virus, compared with healthy subjects given placebo who are 
similarly challenged. 
As no RSV vaccine has been previously tested in a human challenge model, the statistical results 
of this hypothesis test will need to be interpreted with care as the relation between the results 
from this human challenge model and vaccine efficacy is unknown. An effect that is significant 
at 5% (one-sided) will be considered a significant effect. An effect that is significant at 20% 
(one-sided) will be considered as a trend. This trend, if observed, should be confirmed in future 
studies.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a single center, randomized, placebo-controlled, double-blind Phase 2a human challenge 
study, to be conducted in approximately 44 healthy male and female subjects aged 18-50 years 


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who have been pre-screened for susceptibility to RSV infection, ie, have levels of RSV 
neutralizing antibodies compatible with susceptibility to RSV infection.a
Subjects will receive single intramuscular doses of 1x1011 vp of Ad26.RSV.preF or placebo. 
More than 44 (and up to 70) subjects will be vaccinated to account for withdrawals between 
vaccination and challenge. The challenge study site, hVIVO, has the capacity to challenge and 
house under isolation 22 subjects at a time and thus the study will be conducted in several 
cohorts with up to 22 subjects per cohort. Within each cohort, subjects will be randomized 1:1 to 
1x1011 vp of Ad26.RSV.preF or placebo.
Table 4:
Study Design: Vaccination and Challenge
Group
N
Day –28
Day 0*
1
22
Ad26.RSV.preF (1x1011 vp)
Challenge with RSV-A 
Memphis 37b**
2
22
Placebo
* ie, not less than 24 or more than 90 days after vaccination.
**Subjects will be challenged in two or more cohorts of up to 22 subjects per cohort. Within each cohort, subjects will be 
randomized 1:1 to 1x1011 vp of Ad26.RSV.preF or placebo.
Note: The infection rate (based on mucus weight, symptoms and viral shedding) in the placebo group will be followed on an 
ongoing basis by an unblinded individual who does not have any other study function to ensure a sufficient infection rate has 
occurred. If the infection rate is lower than anticipated, additional subjects may be enrolled, initially four additional subjects in 
each arm and up to 70 in total. This is to ensure that a high enough number of evaluable subjects is reached in each arm.
Initially, two sentinel subjects will be enrolled and vaccinated, and 48-hour safety will be 
checked by the investigator/SRP after vaccination. Safety data for review will include solicited 
and unsolicited AEs and SAEs. In the absence of significant findings, the rest of the subjects will 
be enrolled and vaccinated. The sentinel approach with 2 subjects (1 active and 1 placebo) is 
taken to ensure active and placebo subjects are included in the evaluations, taking into account 
the blinding. The observation at 48 hours post-dose is primarily to rule out anaphylaxis or 
cytokine storm.
All subjects will be closely observed for a minimum of 30 minutes post-vaccination, to monitor 
for the development of any acute reactions, or longer if deemed necessary by the investigator. 
Any unsolicited, solicited local or systemic AEs and vital signs will be documented by study-site 
personnel following this observation period. Subjects will be given a thermometer, ruler and 
daily assessment (subject) diary with instructions for the proper recording of events. Each subject 
will record solicited local (at injection site) and systemic AEs and body temperatures, beginning
on the evening of the study vaccine dosing day and on a daily basis for the following 7 days. 
Body temperatures should be taken at approximately the same time each day, preferably in the 
                                                
a The cut-off is based on the average 25th percentile of the past 12 months screening results.


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evening.a Study-site personnel will collect and review subject diary information and confirm the 
entries at subsequent site visits.
One to two days prior to viral challenge, subjects will be admitted to the Unit to confirm 
eligibility for challenge and to orient them to the challenge Unit. At this time, assessments will 
include relevant medical information since vaccination, physical examination, ECG and clinical 
laboratory testing. Blood will be collected for immunogenicity assessments. The target day for 
intranasal challenge with the RSV-A Memphis 37b virus is Day 0, 28 days after vaccination, 
with a window of 24 days to 90 days after vaccination. The 90 day window is to account for the 
few “overflow” subjects that were vaccinated (to be available to replace any withdrawals) but 
may not have been challenged but might be available for a subsequent challenge cohort as 
explained in more detail below.
This range for timing of the challenge is specified for the following reason. A total of 26 subjects 
will be vaccinated for the first challenge cohort, of whom the first 22 who are vaccinated will be 
challenged. Any subjects that are vaccinated but not challenged in the first cohort (“overflow” 
subjects) will be included in a subsequent cohort if they are still available and continue to meet 
all entry criteria. The withdrawal rate between vaccination and challenge for the first cohort will 
be used to assess how many extra subjects will need to be vaccinated for subsequent cohorts.b
The durability of the humoral and cellular immune response after a single dose of an 
Ad26.RSV.FA2-vectored RSV vaccine was demonstrated for at least 6 months following 
vaccination and justifies this time window between vaccination and challenge. The 6-month 
immunogenicity data for Ad26.RSV.preF from study VAC18193RSV1003 will be available 
prior to vaccination and will be reviewed to further justify this strategy.
In the Unit, subjects will live in separate isolation rooms, and all personnel having contact with 
the subjects will wear isolation clothing, including personal protective equipment, to minimize 
the possibility of cross-contamination between subjects. On Day 0, each subject will receive the 
contents (0.8 mL) of 1 vial of virus inoculum.
From Day 2 to Day 11, nasal wash samples will be collected every 12 (±1) hours, abbreviated 
physical examination and vital signs measurements will be conducted daily, and SSCs will be 
filled out three times daily and reviewed by the attending physician. 24-hour tissue counts and 
mucus weights will be determined.
                                                
a The 7-day post-vaccination temperature measurements may be taken earlier to coincide with the corresponding 
clinic visit.
b Any overflow subject who is vaccinated but not challenged will be followed to the end of the study, or can be 
challenged at the discretion of the sponsor, providing study blind had not been broken. Immunogenicity blood 
draws for overflow subjects who are not challenged will occur at 28 days post-vaccination, and again 28 days 
after the date they would have originally been challenged on, to provide some vaccinated but not challenged 
controls for the study.


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Nasopharyngeal samples will be taken on Day 12 and tested for the presence of virus prior to 
discharge using rapid virus antigen test (RVAT). Subjects will only be discharged on Day 12 if 
no detectable virus is present (negative RVAT). If symptoms are present, but no virus is detected 
(negative RVAT), discharge will be at the investigator’s discretion. If appropriate, subjects may 
reside in quarantine for an additional night or longer before discharge. It is unlikely that subjects 
will transmit RSV virus to their close contacts after they have been released from the quarantine 
Unit. After infection with RSV, infectious virus will be present in the subject’s nose for several 
days, but it is not expected to be present in the subject’s nose at the time of discharge from the 
Unit. This is because the usual duration of time that RSV remains infective in adults is several 
days shorter than the time they will spend in the Unit in isolation.9 Furthermore, at discharge, 
subjects will be negative by the RVAT assay.
To reduce any risk of passing RSV on to others, subjects will be advised to avoid contact with 
the following vulnerable groups of people for two weeks after they leave the Unit: 

any person with any known immunodeficiency

any person receiving immunosuppressant medications

any person undergoing or soon to undergo cancer chemotherapy

any person who has congestive heart failure or is in frail health

any person who has a diagnosis of emphysema or COPD, is elderly residing in a nursing 
home, or has severe lung disease

any person who has received a transplant (bone marrow or solid organ)

children below the age of 1 year

elderly persons (aged 75 years or older)
Unsolicited AEs will be collected from ICF signature until 28 days after vaccination, and from 
the entry into the Unit until 28 days after challenge. SAEs will be collected from ICF signature 
until 6 months after vaccination. Any clinically significant abnormalities persisting at the end of 
the study/early withdrawal will be followed by the investigator until resolution or until a 
clinically stable endpoint is reached.
Blood will be collected for sero-susceptibility (neutralizing antibody to RSV-A Memphis 37b) 
within 90 days of vaccination and on entry to the Unit. Blood and urine will be collected for 
laboratory safety assessments within 56 days of vaccination, pre-vaccination, at 7 days post-
vaccination and prior to challenge on Day –1 or Day –2. Blood will additionally be collected for 
biochemistry and hematology assessments at discharge from the quarantine Unit and at 28 days 
post-challenge. Blood for assessment of cardiac enzymes will also collected on Days 3, 7, and 
11. 
Blood samples for humoral and cellular immunity will be collected pre-vaccination, 1-2 days 
prior to challenge, and at 28 days after challenge. Note: blood samples for immunogenicity 


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assessment will be collected from all subjects whether subjects are challenged or not (ie, 
including “overflow” subjects). Blood draws for overflow subjects who are not challenged will 
occur at 28 days post-vaccination and again 28 days later. Overflow subjects who are challenged 
in a later cohort will also have blood draws at the time of challenge and 28 days after challenge.
RSV pre-F antibody will be assessed on the day before challenge and at discharge from the Unit
from nasal wash samples.
An internal data review committee (DRC) will be commissioned for this study, the members of 
which consist of a clinician with expertise in vaccines and infectious diseases, a medical safety 
officer and a statistician, none of whom will be part of the study team or involved in the conduct 
of the study. The DRC will meet if, in the judgment of the investigator and/or the sponsor’s SRP, 
a significant or unexpected safety event occurs.
The end of the study will be the last subject’s last visit by telephone at 6 months after 
vaccination.
A diagram of the study design is provided in Figure 1.


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Figure 1:
Schematic Overview of the Study
* Historical pre-screening data collected through the ethics committee-approved hVIVO screening protocol within 56 days to 3 
days prior to vaccination (90 days for viral serology) may be used for screening procedures. Historical pre-screening data 
obtained prior to this window can be re-assessed any time from 40 days to 3 days prior to vaccination.
RVAT = rapid virus antigen test
3.2.
Study Design Rationale
Dose Selection
The rationale behind selection of the Ad26 vector and dose selection is described in Section 1.1.
Availability of Safety Data Prior to Dosing
Two initial FIH studies (VAC18192RSV1001, N = 48; VAC18192RSV1003, N = 32) in healthy 
adults examining homologous and heterologous regimens of 5x1010 vp of Ad26.RSV.FA2 and 
Safety: 7 (±2) days post-vaccination
Screening: 56 days 
to 3 days before 
vaccination*
Vaccination: Day -28
Admission to the Unit: 1-2 days pre-challenge
Safety: 3 (±1) days post-vaccination
SCREENING PHASE
VACCINATION PHASE
Challenge: Day 0
(window: 24-90 days post-vaccination)
Day 2 onwards: each day vital signs (once daily), 
nasal wash samples (every 12 [±1] hours), signs 
and symptoms post-challenge (subject symptom 
card three times daily)
Day 1: signs and symptoms post-challenge
Discharge from the Unit: Day 12
Nasopharyngeal samples to be RSV virus-free 
by RVAT and subjects to be symptom-free
PRE-VIRAL CHALLENGE
RSV-A MEMPHIS 37b CHALLENGE
POST-VIRAL CHALLENGE
Safety/immuno: 28 (±4) days post-challenge
OUTPATIENT PHASE
FINAL VISIT: SAE follow-up by telephone
6 months (±14 days) post-vaccination


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5x1010 vp of Ad35.RSV.FA2 have been completed. Both Ad26.RSV.FA2 and Ad35.RSV.FA2 
were shown to be safe and immunogenic.
One subsequent FIH study (VAC18193RSV1003, N = 72) in elderly adults in stable health 
examining homologous regimens of 5x1010 vp and 1x1011 vp of Ad26.RSV.preF is ongoing. All 
72 subjects have been randomized and have received the first dose. Safety data from the 
unblinded interim analysis 28 days post-Dose 1 from all 72 subjects who received 
Ad26.RSV.preF (5x1010 vp or 1x1011 vp) or placebo did not reveal any safety concerns.
4.
SUBJECT POPULATION
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following two subsections. If there is a question about the inclusion or exclusion criteria below, 
the investigator must consult with the appropriate sponsor representative and resolve any issues 
before enrolling a subject in the study. Waivers are not allowed.
Screening for eligible subjects will be performed between 56 days to 3 days before vaccination.
Historical pre-screening data collected through the ethics committee-approved hVIVO screening 
protocol within 56 days (90 days for viral serology) to 3 days prior to vaccination may be used 
for screening procedures. Historical pre-screening data obtained prior to this window can be re-
assessed any time from 40 days to 3 days prior to vaccination.
Each potential subject must satisfy all of the following criteria to be enrolled in the study.
4.1.
Inclusion Criteria
1
Each subject must sign an ICF indicating that he or she understands the purpose of and 
procedures required for the study, is willing to participate in the study and attend all 
scheduled visits, is willing to be isolated and stay in the clinic for the quarantine phase, and 
is willing and able to comply with all study procedures and adhere to the prohibitions and 
restrictions specified in this protocol.
2
Subject is a man or woman, ≥18 to ≤50 years old on the day of ICF signature.
3
Subjects must be in good health, without significant medical illness, on the basis of a 
medical evaluation that reveals the absence of any clinically relevant abnormality and 
includes a physical examination (including height and weight), skin examination, medical 
history, vital signs (systolic and diastolic blood pressure and heart rate, respiratory rate, and 
body temperature), and the results of clinical laboratory tests performed within 56 days of 
vaccination. If there are abnormalities, the subject may be included only if the investigator 
judges the abnormalities or deviations from normal to be not clinically significant. This 
determination must be recorded in the subject’s source documents and initialed by the 
investigator.
4
Subjects must have a non-clinically significant 12-lead ECG within 56 days of vaccination
including: 


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a) normal sinus rhythm (heart rate between 50 and 100 beats per minute [bpm], extremes 
included)
b) QT interval corrected for heart rate according to Fridericia (QTcF) interval ≤450 ms
c) QT interval corrected for heart rate according to Bazett (QTcB) interval ≤450 ms
d) QRS interval <120 ms
e) PR interval ≤210 ms.
Note: Retesting of abnormal ECG values that may lead to exclusion will be allowed once 
without prior approval from the sponsor. Repeat ECG due to equipment failure will not 
count as a retest. Subjects with a normal value at retest may be included.
5
Subjects must be sero-suitable for RSV within 90 days of vaccination (low immunity to the 
RSV-A Memphis 37b virus using a virus neutralization assay).
6
Subject must be healthy on the basis of clinical laboratory tests performed within 56 days 
of vaccination. If the results of the laboratory screening tests are outside the local 
laboratory normal reference ranges and additionally within the limits of toxicity Grade 1 
according to the US Food and Drug Administration (FDA) toxicity tables (ie, for tests in 
the FDA tablea), the subject may be included only if the investigator judges the 
abnormalities or deviations from normal to be not clinically significant and appropriate and 
reasonable for the population under study. This determination must be recorded in the 
subject’s source documents and initialed by the investigator.
Note: If laboratory screening tests are out of local laboratory normal ranges and deemed 
clinically significant, repeat of screening tests is permitted once using an unscheduled visit 
during the screening period to assess eligibility.
7
Contraceptive use by men or women should be consistent with local regulations regarding 
the use of contraceptive methods for subject participating in clinical studies.
Before randomization, a woman must be either:
a.
Not of childbearing potential defined as:
i. Premenarchal: a premenarchal state is one in which menarche has not yet 
occurred.
ii. postmenopausal: amenorrhea for at least 12 months without an alternative 
medical cause.
iii. permanently sterile: permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, bilateral tubal occlusion/ligation procedures, and 
bilateral oophorectomy.
b. Of childbearing potential and
                                                
a For the FDA toxicity grading tables, see Attachment 1: FDA Guidance document “Toxicity Grading Scale for Healthy Adult 
and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” (September 2007).


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i. practicing an acceptable effective method of contraception. Acceptable methods 
for this study include:

hormonal contraception;

intrauterine device;

intrauterine hormone-releasing system;

male or female condom with or without spermicide;

cap, diaphragm or sponge with a vaginal spermicide;

vasectomized partner (the vasectomized partner should be the sole partner for 
that subject);

sexual abstinence*.
*Sexual abstinence is considered an effective method only if defined as refraining 
from heterosexual intercourse from signing the informed consent until 4 months after 
study vaccination. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the subject.
ii. agrees to remain on an effective method of contraception from signing the 
informed consent until 4 months after study vaccination. Use of hormonal 
contraception should start at least 28 days before the administration of study 
vaccine.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal 
woman experiences menarche) or the risk of pregnancy changes (eg, a woman who is not 
heterosexually active becomes active), a woman must begin an acceptable effective method 
of contraception, as described above.
8
All female subjects must:
a. Have a negative highly sensitive serum β-human chorionic gonadotropin (β-hCG) 
pregnancy test within 56 days of vaccination
b. Have a negative urine β-hCG pregnancy test immediately prior to study vaccine 
administration
9
From the time of vaccination through 3 months after completion of the study, subject agrees 
not to donate blood.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study.
1.
Subject has acute illness (this does not include minor illnesses such as diarrhea) or 
temperature ≥37.8 ºC within 24 hours prior to study vaccination.
2.
Subject has a history of an underlying clinically significant acute or chronic medical 
condition or physical examination findings for which, in the opinion of the investigator, 
participation would not be in the best interest of the subject (eg, compromise the well-
being) or that could prevent, limit, or confound the protocol-specified assessments.


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3.
Subject has history of malignancy (exceptions are basal cell carcinomas of the skin treated 
over 5 years prior to vaccination considered cured with minimal risk of recurrence).
4.
Subject has had major surgery (per the investigator’s judgment), within 12 weeks before 
dosing, or will not have fully recovered from surgery, or has surgery planned during the 
time the subject is expected to participate in the study or within 6 months after study 
vaccination. Note: Subjects with planned surgical procedures to be conducted under local 
or locoregional anesthesia and not judged as major by the investigator may participate.
5.
Subject has chronic active hepatitis B or hepatitis C infection, documented by hepatitis B 
surface antigen and hepatitis C antibody, respectively.
6.
Subjects with current human immunodeficiency virus type 1 (HIV-1) or HIV-2 infection.
7.
Subject is in receipt of, or planning to receive, licensed live attenuated vaccine within 
28 days of study vaccination and the viral challenge (ie, before and after); other licensed 
vaccines (ie, not live: eg, influenza, tetanus, hepatitis A, hepatitis B or rabies) should be 
given at least 14 days before or 14 days after study vaccination and the viral challenge.
8.
Subject has received an investigational drug or used an invasive investigational medical 
device within 3 months or received an investigational vaccine within 6 months before the 
planned administration of study vaccine or is currently enrolled or plans to participate in 
another investigational study during the course of this study. Note: Participation in an 
observational clinical study (ie, with no intervention) is allowed upon approval of the 
sponsor.
9.
Subject has previously participated in, or is currently participating in an RSV vaccine 
study.
10.
Subject has previously received treatment with immunoglobulin. Subject has received 
treatment with blood products in the 4 months before the planned administration of study 
vaccine or has any plans to receive such treatment during the study.
11.
Subject has a known allergy, or history of anaphylaxis or other serious adverse reactions to 
vaccines or vaccine components (including any of the constituents of the study vaccine).
12.
Criterion modified per Amendment 2:
12.1 Subject has a history of chronic urticaria (recurrent hives), eczema and/or atopic 
dermatitis. Note: Subjects with a history of eczema only in childhood are allowed.
13.
Subject has a history of acute polyneuropathy (eg, Guillain-Barré syndrome).
14.
Subject has abnormal function of the immune system resulting from:

Clinical conditions (eg, autoimmune disease or immunodeficiency)

Chronic (longer than 10 days) or recurrent use of systemic corticosteroids during the 
study and within 6 months before administration of study vaccine (Note: ocular, 
topical or inhaled steroids are allowed)


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
Administration of antineoplastic and immunomodulating agents or radiotherapy during 
the study and within 9 months before administration of study vaccine
15.
Subject has a contraindication to intramuscular injections and blood draws, eg, bleeding 
disorders.
16.
Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant 
while enrolled in this study or within 6 months after study vaccination.
17.
Subject is an employee of the investigator or study site, with direct involvement in the 
proposed study or other studies under the direction of that investigator or study site, as well 
as family members of the employees or the investigator, or an employee of the sponsor.
18.
Subject cannot communicate reliably with the investigator.
19.
Subject who, in the opinion of the investigator, is unlikely to adhere to the requirements of 
the study, or are unlikely to complete the full course of vaccination, challenge and 
observation.
20.
Subjects with a past history of heart arrhythmias (extrasystoli, tachycardia at rest) or of risk 
factors for Torsade de Pointes syndrome (eg, hypokalemia, family history of long QT 
syndrome). 
21.
Subjects with a history or evidence of abuse of alcohol, barbiturates, amphetamines, 
recreational or narcotic drug use within 3 months prior to ICF signature, which in the 
investigator’s opinion would compromise subject’s safety and/or compliance with the 
study procedures.
22.
Subjects with a positive urine drug test at screening. Urine will be tested for the presence 
of amphetamines, benzodiazepines, cocaine, cannabinoids, opioids, methadone, and 
barbiturates. Note: A positive urine drug test may be repeated once in the same sample, as 
soon as possible, to exclude a technical error. Subjects with a negative urine drug test at 
retest may be included.
23.
Subject has a history of any illness that, in the opinion of the investigator, might confound 
the results of the study or that could prevent, limit or confound the protocol-specified 
assessments. This may include, but is not limited to, significant cardiac, vascular, 
pulmonary, gastrointestinal (such as significant diarrhea, gastric stasis, or constipation) that 
in the investigator’s opinion could confound the challenge protocol assessments.
Note: A history of childhood asthma before the age of 12 years is acceptable provided the 
subject is asymptomatic without treatment. Subjects with a single episode of wheezing 
after age 12 years (lasting less than eight weeks) can be included at the investigator’s 
discretion provided the episode was more than four years ago and did not require a hospital 
admission and/or oral steroids.
24.
Subjects having been previously experimentally inoculated with a virus from the same 
virus-family (Paramyxoviridae).


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25.
Subjects who have previously participated in another human viral challenge study with a 
respiratory virus in the preceding 12 months taken from the date of viral challenge in the 
previous study to the date of expected viral challenge in this study (subjects inoculated 
with influenza virus could participate in the current RSV study).
26.
Vulnerable subjects (eg, incarcerated individuals).
27.
Subjects with a lack of good/reasonable venous access.
Note: The investigator should ensure that all study enrollment criteria have been met prior to 
vaccination. If a subject’s clinical status changes (including any available laboratory results or 
receipt of additional medical records) after ICF signature but before study vaccine is given such 
that he or she no longer meets all eligibility criteria, then the subject should be excluded from 
participation in the study. Section 17.4, Source Documentation, describes the required 
documentation to support meeting the enrollment criteria.
4.3.
Viral Challenge Exclusion Criteria
Any potential subject who meets any of the following criteria on entry to the quarantine Unit on 
Day –2 or –1 will be excluded from participating in the viral challenge.
1. Subject has acute illness within 7 days of admission (this does not include minor illnesses 
such as diarrhea). Subjects can be rescheduled for another viral challenge admission day if 
possible and the protocol window permitting.
2. Subject has a temperature ≥37.8 ºC on Day 0, the day of viral challenge. Subjects can be 
rescheduled for another viral challenge admission day if possible and the protocol window 
permitting.
3. Subjects having donated or lost more than 1 unit of blood (470 mL) within 60 days or more 
than one unit of plasma within 7 days.
4. Subjects with active acute respiratory infection.
5. Subject has any clinically significant abnormalities (ECG, vital signs).
6. Subjects having received an investigational agent (small molecule) or vaccine (other than 
study vaccine) within 30 days, or having received a biological product other than a vaccine 
within 3 months or 5 half-lives (whichever is longer) prior to entry to the quarantine Unit.
7. All female subjects must have a negative highly sensitive serum β-hCG pregnancy test on 
admission.
8. Subjects with a positive urine drug test. On admission, urine will be tested for the presence of 
amphetamines, 
benzodiazepines, 
cocaine, 
cannabinoids, 
opioids, 
methadone, 
and 
barbiturates. Note: A positive urine drug test may be repeated once in the same sample, as 
soon as possible, to exclude a technical error. Subjects with a negative urine drug test at 
retest may be included.


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9. Male subjects must agree to the contraceptive requirements below at entry to the quarantine 
Unit, and continuing until 3 months after the date of viral challenge:

Use a condom and spermicide (for all partners)

Male sterilization with the appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate (note that the use of condom with spermicide will still be required 
to prevent partner exposure)

In addition, for female partners of childbearing potential, that partner must use another 
form of contraception such as:
Established (a minimum of 2 weeks prior to admission) use of oral, injected or 
implanted hormonal methods of contraception
Placement of an intrauterine device (IUD) or intrauterine system (IUS)
Barrier methods of contraception or occlusive cap (diaphragm or cervical/vault 
caps), both with one of the following: spermicidal foam/gel/film/cream/suppository
Bilateral tubal ligation

True abstinence – when this is in line with the preferred and usual lifestyle of the 
subject
In addition to the contraceptive requirements above, male subjects must agree not to donate 
sperm following discharge from quarantine until 90 days after the date of viral challenge.
4.4.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:
1
Agree to follow all requirements that must be met during the study as noted in the inclusion 
and exclusion criteria (Section 4.1 and Section 4.2, respectively).
2
Vaccination with live attenuated vaccines within 28 days of a study vaccination and the viral 
challenge (ie, before and after) is prohibited. Other vaccines (eg, influenza, tetanus, hepatitis 
A, hepatitis B, rabies) should be given at least 14 days before (or at least 14 days after) 
administration of study vaccine and the viral challenge in order to avoid potential confusion 
of adverse reactions and potential immune interference. If a vaccine is indicated in a post-
exposure setting (eg, rabies or tetanus), it must take priority over the study vaccine.
3
Subjects may not use drugs such as amphetamines, benzodiazepines, cocaine, cannabinoids, 
barbiturates, opiates, and methadone from 3 months prior to ICF signature until completion 
of the last study-related activity. Refer to Section 8, for details regarding prohibited and 
restricted therapy during the study.
4
Subjects must not donate blood for 3 months after completion of the study.


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5
Subjects must not consume any food containing poppy seeds or any codeine containing 
formulation starting 72 hours before screening and before admission to the quarantine Unit 
(in order to avoid false-positive urine drug screen).
6
Subjects must not smoke or otherwise use tobacco products from 30 days prior to entry to 
the quarantine Unit and must continue to abstain from smoking until the completion of the 
last study-related activity.
7
To reduce the risk of passing RSV on to others, subjects will be advised to avoid contact 
with the following vulnerable groups of people for two weeks after leaving the quarantine 
Unit: 

any person with any known immunodeficiency

any person receiving immunosuppressant medications

any person undergoing or soon to undergo cancer chemotherapy

any person who has congestive heart failure or is in frail health

any person who has a diagnosis of emphysema or COPD, is elderly residing in a nursing 
home, or has severe lung disease

any person who has received a transplant (bone marrow or solid organ)

children below the age of 1 year

elderly persons (aged 75 years or older).
5.
STUDY VACCINE ALLOCATION AND BLINDING
Study Vaccine Allocation
Within each cohort, subjects will be randomized 1:1 to one of the two groups (Ad26.RSV.preF 
or placebo). Randomizations will be based on computer-generated schedules prepared before the 
study by or under the supervision of the sponsor. The randomizations will be balanced by using 
randomly permuted blocks.
A unique code will dictate the study vaccine assignment for the subject.
Withdrawal of randomized subjects from vaccination before vaccination: Additional 
subjects will be recruited and immunized to replace these withdrawn subjects at the discretion of 
the sponsor. The replacement subject will be assigned to the same group as the original 
(discontinued) subject. The replacement subject’s randomization number will equal the 
randomization number of the discontinued subject +100 (for example subject 0001 would be 
replaced by subject 0101).
As approximately 44 subjects need to be challenged, initially 4 more subjects in the first cohort 
will be randomized (overflow subjects). If subjects withdraw between vaccination and challenge, 
the unblinded pharmacist will make every effort to replace this subject with an overflow subject 


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of the same group as the withdrawn subject if possible. The withdrawal rate between vaccination 
and challenge for the first cohort will be used to assess how many extra subjects will need to be 
vaccinated for subsequent cohorts. Any subject who experiences an SAE before admission to the 
Unit will not be challenged and will be replaced.
Blinding
The investigator will be provided with a sealed randomization code for each subject, containing 
coded details of study vaccine allocation. All randomization codes, whether opened or sealed, 
will be collected after the end of the subject’s participation in the study.
Under normal circumstances, the blind should not be broken until all subjects have completed 
the study and the database is finalized. 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 an emergency situation, the investigator may 
determine the identity of the study vaccine by opening the sealed code. In the event the blind is 
broken, the sponsor must be informed as soon as possible. The date, time and reason for the 
unblinding must be documented in the appropriate section of the electronic case report form 
(eCRF). The investigator is advised not to reveal the study vaccine assignment to the study-site 
personnel or sponsor personnel. If the code is broken by the investigator or the study-site 
personnel, the subject must be withdrawn from the study and must be followed as appropriate. If 
the code is broken by the sponsor for safety reporting purposes, the subject may remain in the 
study.
The subjects, study-site personnel (including the vaccine administrator), and investigator will be 
blinded to study vaccine allocation throughout the study, except for the unblinded pharmacist or 
qualified staff member with primary responsibility for study vaccine preparation and dispensing.
At the end of the quarantine phase for the final cohort, the sponsor will request the treatment 
codes for the primary analysis. However, treatment codes will not be disclosed to the investigator 
and subject(s).
6.
DOSAGE AND ADMINISTRATION
Ad26.RSV.preF will be supplied at a concentration of 1x1011 vp/0.5 mL in single-use vials, with 
an extractable volume of 0.5 mL, for intramuscular injection into the deltoid of the non-dominant 
arm. A dose level of 1x1011 vp will be used.
Placebo will be supplied as sterile 0.9% saline for injection.
For each subject, every vaccination will be 0.5 mL in volume.


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An unblinded pharmacist, or other qualified individual will prepare the appropriate vial and 
syringe and provide the syringe in a blinded manner to the study vaccine administrator who will 
perform the injection. 
Note: the unblinded pharmacist, or other qualified individual, may also perform the 
administration, but will have no other study function. 
Further details on study vaccine preparation will be provided in the Investigational Product 
Preparation Instructions.
7.
STUDY VACCINE COMPLIANCE
Study vaccine will be administered intramuscularly by a study vaccine administrator – a trained 
and qualified study nurse, medical doctor, or otherwise qualified health care professional. The 
date and time of study vaccine administration will be recorded in the eCRF.
8.
PRE-STUDY AND CONCOMITANT THERAPY
Pre-study therapies administered up to 90 days before vaccination must be recorded in the eCRF 
at vaccination.
Concomitant therapies will be collected and recorded in the eCRF from time of study vaccine 
administration until 28 days after vaccination, and from the entry into the Unit until 28 days after 
challenge, and additionally outside of these periods when associated with an SAE meeting the 
criteria outlined in Section 12.3.2. 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.
Subjects can receive medications such as acetaminophen, non-steroidal anti-inflammatory drugs 
(NSAIDs), or antihistamines as needed, although their use must be documented and use of these 
medications as routine prophylaxis prior to study vaccination is discouraged, unless if specified 
by the sponsor. All other concomitant therapies should also be recorded if administered in 
conjunction with new or worsening AEs reported per protocol requirements outlined in Section 
12.3.1).
Chronic (longer than 10 days) or recurrent use of systemic corticosteroids is prohibited during 
the study and within 6 months before administration of study vaccine (Note: ocular, topical or 
inhaled steroids are allowed). Antineoplastic and immunomodulating agents or radiotherapy are 
prohibited in the 9 months prior to vaccination and during the study.
After the viral challenge, paracetamol, oral contraception and thyroxin, if already prescribed 
before entry to the Unit, are allowed concomitant medications.
If chronic use of prohibited therapies becomes medically indicated during the course of the study 
for any subject, the sponsor should be contacted.


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Vaccination with live attenuated vaccines within 28 days of a study vaccination and the viral 
challenge (ie, before and after) is prohibited. Other licensed vaccines (ie, not live) should be 
given at least 14 days before or at least 14 days after administration of study vaccine and the 
viral challenge in order to avoid potential confusion of adverse reactions and potential immune 
interference. If a vaccine is indicated in a post-exposure setting (eg, rabies or tetanus), it must 
take priority over the study vaccine.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
Evaluation of the safety/tolerability of the vaccine regimen will include vital signs, physical 
assessment by study-site personnel, ECGs, clinical laboratory test data and subject reports on 
signs and symptoms following vaccinations. Additional visits may be required if, in the 
investigator’s opinion, further clinical or laboratory evaluation is needed.
Each subject will be provided with a thermometer, ruler and subject diary to measure and record 
body temperature (tympanic or oral) and solicited local (at injection site) and systemic events. 
The diary includes instructions on how to capture the data and grading scales to assess severity 
of the symptoms. Study staff are responsible for providing appropriate training for diary 
completion to avoid missing or incorrect data. The subject diary will be reviewed by the study 
personnel at visits indicated in the Time and Events Schedule.
The Time and Events Schedule summarizes the frequency and timing of safety and 
immunogenicity measurements applicable to this study.
The total blood volume to be collected from each subject over the entire study will not exceed 
470 mL unless additional blood samples are required for safety reasons. The maximum volume 
of blood to be drawn at any given visit will be 70 mL.
9.1.2.
Visit Windows
For the following visits, windows will be allowed as indicated:
Visit Day
Window
Primary Purpose
Day –25
± 1 day
3-day post-vaccination, telephone call for safety
Day –21
± 2 days
7-day post-vaccination safety only visit
Challenge
24-90 days
Time between vaccination and viral challenge
28 days post-challenge
± 4 days
Safety and immunogenicity
6 months post-
vaccination
± 14 days
Final visit (SAE follow-up)


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9.1.3.
Screening Phase
Screening for eligible subjects will be performed between 56 days to 3 days prior to vaccination. 
Historical pre-screening data from hVIVO’s ethics committee-approved screening protocol can 
be used to confirm eligibility if performed within this time frame.
Only healthy subjects without acute illness or fever and complying with the inclusion and 
exclusion criteria specified in Section 4 will be included in the study. The investigator will 
provide detailed information on the study to the subjects and will obtain written informed 
consent prior to each subject’s participation in the study.
The following evaluations will be performed to determine eligibility requirements as specified in 
the inclusion and exclusion criteria:

Physical examination including vital signs measurement (respiratory rate, heart rate, supine 
systolic and diastolic blood pressure and body temperature) and height and weight

Demographic information

Medical history, including smoking habits

Review of pre-study medications

Review of inclusion/exclusion criteria

12-lead ECG

Sero-susceptibility for RSV (neutralization assay)

Serology testing (HIV type 1 or type 2, hepatitis B, hepatitis C)

Blood sampling for hematology and biochemistry laboratory testing (laboratory tests at 
screening are to be done within 56 days of randomization)

Urine sample for urinalysis

Nasopharyngeal swab tolerability testing

Nasal wash tolerability testing

Spirometry

All female subjects: serum β-hCG pregnancy testing

A urine screen for drugs of abuse and an alcohol breath test

Overall eligibility
Historical pre-screening data collected through the ethics committee-approved hVIVO screening 
protocol within 56 days (90 days for viral serology) to 3 days prior to vaccination may be used
for screening procedures. Historical pre-screening data obtained prior to this window can be re-
assessed any time from 40 days to 3 days prior to vaccination. 


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General eligibility for this clinical study will be dependent on results of laboratory tests and the
medical assessment. Study subjects who qualify for inclusion based on the medical history, 
physical examination, and laboratory results will be contacted and scheduled for enrollment and 
vaccination. If necessary, the screening visit may be split into several visits. Screening should 
occur between 56 days to 3 days before vaccination.
Subjects with laboratory values not meeting eligibility criteria at the screening visit may have 
one repeat testing at the discretion of the investigator if the abnormality is not clinically 
significant and may be a testing aberrancy. Enrollment of a subject with laboratory values 
representing toxicity Grade 1 is allowed if the investigator considers the values not to be 
clinically significant and reasonable for the population under study. Details on toxicity grade 
assessment are provided in Section 12.1.3.
After laboratory data, medical history, physical examination, ECG and nasopharyngeal 
swab/nasal wash tolerance data have been reviewed for completeness and adherence to inclusion 
and exclusion criteria, the subject can be deemed eligible for the study.
Unsolicited AEs will be recorded on the AE page of the eCRF from ICF signature until 28 days 
after vaccination, and from the entry into the Unit until 28 days after challenge. SAEs will be 
collected from ICF signature until 6 months after vaccination (ie, the end of the study).
9.1.4.
Vaccination Phase
9.1.4.1.
Vaccination
Randomization/Vaccination
After re-check of inclusion and exclusion criteriaa, a urine screen for drugs of abuse, an alcohol 
breath test, abbreviated physical examination (at the discretion of the investigator) and 
measurement of vital signs, eligible subjects will be randomized as described in Section 5. If 
medical status and/or physical examination suggest significant changes have occurred since 
screening, the laboratory tests will be repeated and the vaccination visit rescheduled, or the 
subject excluded from the study if he/she fails to meet the inclusion and exclusion criteria. Pre-
dose samples for baseline immunogenicity assessments and for clinical laboratory testing will be 
collected. All women must have a negative urine pregnancy test pre-dose. Before vaccination, 
the investigator must check for any symptoms of an acute illness or body temperature ≥37.8 °C. 
In such a situation, the subject may be re-screened (if vaccination number not assigned), or 
withdrawn at the discretion of the investigator. Note: the minimum time between vaccination and 
challenge is 24 days.
Administration of study vaccine. Vaccination will occur 28 days before challenge (window is not 
less than 24 or more than 90 days).
                                                
a To include exclusion criteria 1, 7, 8, 9, 10, 14 and 16.


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Subjects will be closely observed for a minimum of 30 minutes post-vaccination to monitor for 
the development of any acute reactions, or longer if deemed necessary by the investigator. Any 
unsolicited, solicited local or systemic AEs and vital signs will be documented in the eCRF by 
study-site personnel following this observation period.
Subjects will be provided with a subject diary, thermometer, and ruler to measure and record 
body temperature, solicited local and systemic AEs for 7 days post-vaccination.
9.1.4.2.
Post-vaccination Follow-Up
Sentinel Subjects: 48 Hours Post-first Vaccination
At 48 hours after the first vaccination, a telephone call will be made to the two sentinel subjects 
only to collect safety information (solicited and unsolicited AEs, SAEs and concomitant 
medications).
3 and 7 days post-vaccination
The visit at 3 days post-vaccination will be a telephone call to check subject diaries and to collect 
safety information (solicited and unsolicited AEs, SAEs and concomitant medications).
The visit at 7 days post-vaccination will include an abbreviated physical examination (at the 
discretion of the investigator), vital signs measurement, and recording of any AEs/SAEs and 
concomitant medications. Samples for clinical laboratory testing will be collected. Subject 
diaries will be reviewed and collected. If this visit occurs before the end of the post-vaccination 
diary period, review of the diaries will still take place, but diaries will be returned by subjects at 
the next visit (ie, on admission to the Unit for the challenge phase).
9.1.5.
Viral Challenge Phase
9.1.5.1.
Entry to the Quarantine Unit
Subjects will enter the quarantine Unit either one or two days before the viral challenge, to 
acclimatize and perform entry assessments. The following assessments can take place on either 
day: complete physical examination, including body weight, relevant medical information since 
vaccination, vital signs and spirometry, samples for clinical laboratory tests (including cardiac 
enzymes), ECG, blood samples for immunogenicity assessments, spirometry, and recording of 
any unsolicited AEs/SAEs and concomitant medications. Nasopharyngeal swabs and nasal wash 
samples will be collected to screen for respiratory virus and for RSV pre-F antibody assessment, 
respectively, and blood samples will be taken to determine sero-susceptibility for RSV for post-
hoc reconfirmation (neutralization assay).
The SSC will be filled out by the subject and reviewed by the attending physician. Tissues for 
tissue counts and mucus weight will be distributed on Day –1. The first 24-hour collection will 
start on Day –1; tissue counts and mucus weights will be determined on Day 0.


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A serum pregnancy test (β-hCG) will be performed for all female subjects. A urine drug screen, a 
urine cotinine test, and an alcohol breath test will be performed.
Throughout the challenge phase of the study from entry to the Unit until discharge, subjects will 
stay in individual isolation rooms to minimize cross-contamination between subjects.
Before challenge inoculation on Day 0, the subject’s clinical status will be checked, including 
any available laboratory results or receipt of additional medical records.
9.1.5.2.
Challenge
On Day 0, intranasal challenge with RSV-A Memphis 37b virus will occur for all subjects. The 
site physician, or inoculation-trained member of the site medical team, will inoculate each 
subject intranasally with 0.8 mL of virus, delivered by pipetting 2x200 µL of virus per nostril.
The target day for challenge is 28 days after vaccination (window is not less than 24 or more 
than 90 days). The longer window will be for the few overflow subjects that are available for 
challenge in a subsequent cohort.
Additionally, all post-challenge procedures per Section 9.1.5.3 will be carried out apart from 
collection of a nasal wash sample and ECG. 
The inoculum virus titer is determined in an infectivity (plaque) assay, the titer is reported in 
plaque forming units per mL (PFU/mL). The challenge dose is approximately 4log10 PFU. One 
vial of challenge virus will be provided for each subject. Full details of inoculation procedures 
will be provided in the Analytical Plan.
9.1.5.3.
Post-challenge
On each of the 11 days after the challenge, procedures will include a directed physical 
examination, spirometry and monitoring of vital signs. Nasal wash samples will be taken every 
12 (±1) hours from the second day after challenge until discharge. The SSC will be filled out 
three times a day by the subject and reviewed by the attending physician. Tissue counts and 
mucus weight will be determined for each 24-hour interval. ECGs will be carried out, and blood 
samples collected for clinical laboratory tests (cardiac enzymes only) on Days 3, 7 and 11. Any 
unsolicited AEs/SAEs and concomitant medications will be recorded.
9.1.5.4.
Discharge from the Unit
On Day 12, subjects will only be discharged when no detectable virus is present (negative 
RVAT). If symptoms are present, but no virus is detected (negative RVAT), discharge will be at 
the investigator’s discretion. If appropriate, subjects may reside in quarantine for an additional 
night or longer before discharge.
Procedures will include a complete physical examination including body weight, vital signs and 
spirometry, collection of nasopharyngeal swabs, and completion of the SSC by the subject and 
review by the attending physician. Tissue counts and mucus weight will be determined for the 
final 24-hour interval, and nasal wash samples will be collected for RSV pre-F antibody 


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assessment. A urine pregnancy test will be performed for all female subjects. Any unsolicited 
AEs/SAEs and concomitant medications will be recorded, and blood samples collected for 
clinical laboratory tests (hematology and biochemistry only).
9.1.6.
Day 28 Post-challenge
The visit at 28 days post-challenge will include an abbreviated physical examination (at the 
discretion of the investigator), and vital signs measurement. Blood samples for immunogenicity 
assessments will be collected. Any unsolicited AEs/SAEs and concomitant medications will be 
recorded, and blood samples collected for clinical laboratory tests (hematology and biochemistry 
only). A urine pregnancy test will be performed for all female subjects.
9.1.7.
Final Visit
The final visit at 6 months post-challenge will be a telephone call to record SAEs and 
concomitant medications associated with any SAE.
9.1.8.
Early Withdrawal – Early Exit Visit
For those subjects who are unable to continue participation in the study, but who do not 
withdraw consent, an early exit visit will be conducted as soon as possible. In the event of early 
withdrawal from the study, all procedures required at the Day 28 visit (Section 9.1.6) will be 
performed. Samples for immunogenicity assessments will only be collected if the early exit is at 
least 14 days after the previous blood draw for immunogenicity. Samples for safety laboratory 
testing will only be collected if the early exit is within 7 days of the vaccination. Solicited AEs 
will be recorded if the early exit visit occurs within 7 days of vaccination. Any unsolicited 
AEs/SAEs and concomitant medications will be recorded. At the early exit visit, a serum 
pregnancy test (β-hCG), not a urine test, will be performed for all female subjects.
Precautions for any subject leaving the challenge Unit are listed in Section 4.4.
9.1.9.
Overflow Subjects
The timing of immunogenicity blood draws for overflow subjects will be as follows:

Any overflow subject who is challenged in a later cohort: blood draws at the time of 
challenge and 28 days after challenge.

Any overflow subject who is not challenged: blood draws at 28 days post-vaccination, and 
again 28 days after the date they would have originally been challenged on.
Any overflow subject who is vaccinated but not challenged will be followed to the end of the 
study. Unsolicited AEs will be collected until 28 days after vaccination; SAEs will be collected 
until the end of the study.
Alternatively, these subjects can be challenged at the discretion of the sponsor, providing the 
study blind has not been broken.


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9.2.
Study Evaluations
9.2.1.
Immunogenicity
Venous blood samples of approximately 10 mL and 50 mL will be collected for the 
determination of humoral and cellular responses, respectively, pre-vaccination, one or two days 
before viral challenge, and at 28 days post-challenge, or at the early exit visit if the subject 
prematurely terminates the study, without withdrawing consent.
All sample collection and processing will be performed by the staff at the clinical site according 
to current versions of approved standard operating procedures.
Humoral and cellular immunogenicity evaluations are summarized in Table 5 and Table 6, 
respectively.
Table 5:
Summary of Immunogenicity Assays (Humoral)
Assay 
Purpose
Exploratory endpoints
RSV neutralization RSV-A 
Memphis 37b 
Measure levels of the antibody to the challenge strain
Intranasal pre-F and post-F 
antibody*
Measure levels of vaccine induced antibody at the site of infection
RSV neutralization A2 
Analysis of neutralizing antibodies to the A2 strain
RSV strain cross-neutralization 
Analysis of cross-neutralizing antibodies to B and/or a different A strain
F-protein antibody
(ELISA; pre- and/or post-fusion) 
Analysis of antibodies binding to RSV F protein in post-fusion and/or pre-
fusion form
RSV G/N ELISA
Analysis of binding antibodies to G and N proteins of RSV
Adenovirus neutralization assay
Analysis of neutralizing antibodies to adenovirus
Functional and molecular 
antibody characterization
Analysis of antibody characteristics including but not limited to ADCC, 
ADCP, avidity, Fc characteristics, Ig isotype
*From nasal wash samples, if the ELISA will be available
ADCC = antibody-dependent cell-mediated cytotoxicity; ADCP = antibody-dependent cellular phagocytosis; ELISA = enzyme-
linked immunosorbent assay; F = fusion; Ig = immunoglobulin; RSV = respiratory syncytial virus
Table 6:
Summary of Immunogenicity Assays (Cellular)
Assay 
Purpose
Exploratory endpoints
IFNγ ELISpot
T-cell IFNγ responses to RSV F-protein peptides
Flow cytometry (ICS)
Analysis of T-cell responses to RSV F-protein peptides (including, but not limited
to, CD4/CD8, IL2, IFNγ, TNFα and/or activation markers, memory, Th1/Th2 
subtyping)
Cytokine analysis
Analysis of secreted cytokines in RSV F peptide-stimulated PBMC supernatant, 
including, but not limited to, measurement of Th1/Th2 cytokine balance
ELISpot = enzyme-linked immunospot; F = fusion; ICS = intracellular cytokine staining; IFNγ = interferon gamma; IL = 
interleukin; PBMC = peripheral blood mononuclear cell; Th = T-helper (cell); RSV = respiratory syncytial virus; TNFα = tumor 
necrosis factor alpha
In addition to RT-PCR performed on nasal wash samples collected from Day 2 following 
challenge, any immunogenicity blood sample collected from a subject who subsequently 
undergoes challenge may also be assayed by a serological assay (eg, ELISA specific to RSV 


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protein G and/or N) to confirm RSV infection and evaluate the relationship between these assays 
and virological and clinical findings.
Nasal wash samples collected pre- and post-challenge and at discharge from the Unit will be 
used to assess any immunoglobulin or cellular immune component and its possible relation to 
viral load and clinical findings.
Instructions for the collection, handling, storage, and shipment of blood and nasal wash samples 
for immunogenicity assay are found in the Laboratory Manual that will be provided. Collection, 
handling, storage, and shipment of blood and nasal wash samples to the central laboratory must 
be under the specified, and where applicable, controlled temperature conditions as indicated in 
the Laboratory Manual.
9.2.2.
Antiviral Activity Samples for Infectivity
Respiratory syncytial virus viral load will be measured in nasal washes (in both nostrils), using 
quantitative RT-PCR and a cell-based infectivity assay. Samples for the determination of RSV 
levels will be taken at several timepoints during the study, as indicated in the Time and Events 
Schedule. The procedures for sample processing and storage will be provided in the hVIVO 
Analytical Plan. The changes in RSV viral load will not be reported as AEs or SAEs.

RSV neutralization assay
To be eligible for the study a subject must be ‘sero-suitable’. Each subject will be initially 
screened for eligibility based on low immunity to the RSV-A Memphis 37b virus using a 
virus neutralization assay. This assay will be performed within 90 days of vaccination and 
on admission to the Unit (for post-hoc confirmation of RSV sero-susceptibility).

Cell-based infectivity assay
Details will be provided in the Laboratory Manual.

PCR for viral load: quantitative RT-PCR
The viral ribonucleic acid (RNA) will be extracted from the nasal wash, complementary 
deoxyribonucleic acid (cDNA) will be generated and quantitative RT-PCR of the N gene of 
the RSV strain will be performed. The quantitative RT-PCR will inform on the presence or 
absence of the RSV in the nasal wash and if the RSV is present the quantitative RT-PCR 
will provide the amount of virus (plaque forming unit equivalents [PFUe] per mL).
9.2.3.
Mucus Weight and Tissue Count
At several timepoints during the study, as is indicated in the Time and Events Schedule, the 
mucus weight (nasal) will be assessed.
Subjects will be given pre-weighed packets of paper tissues (handkerchiefs). After each tissue is 
used for nose blowing or sneezing, the subjects should store them in an airtight plastic bag. 


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Paper tissue and bag distribution first takes place on Study Day –1 at 08:00 a.m. (± 30 minutes). 
Paper tissue collection starts from Study Day 1 through the day of discharge at approximately the 
same time.
Subjects will be instructed to place used single tissues into a specified bag which will be 
collected the following morning. A daily 24-hour collection will take place and new bags will be 
distributed.
All paper tissues used by each subject will be collected for each 24-hour period throughout the 
quarantine phase, to determine daily mucus weight and number of tissues used.
Used and unused tissues will be counted. In case of missing tissues, they will be replaced by new 
dry tissues, and the subjects will be re-educated about proper tissue use and collection.
Collection time of the plastic bags, daily mucus weight, and number of tissues used should be 
recorded on the eCRF.
Tissues will not be stored after the mucus weight is determined. 
9.2.4.
RSV Subject Symptom Card
At several timepoints during the study, as indicated in the Time and Events Schedule, all subjects 
will complete the SSC in order to assess the clinical symptoms of acute RSV infection (see 
Attachment 3).8 For each timepoint the results will be transcribed onto the eCRF by a member of 
the study-site personnel, and will be summarized according to the instructions.
The duration and severity of self-reported symptoms, clinical symptoms, respiratory tract illness, 
and systemic illnesses will be assessed and compared between treatment groups.
The investigator will review the subject’s SSC entries on a daily basis after the administration of 
challenge virus. Subject symptom scores (self-assessment form), including body temperatures, 
and AEs will be conducted and daily during quarantine.
From challenge until discharge from the Unit, SSC findings greater than Grade 0 will be 
presumed to represent virus infection consequent to challenge, and will not additionally be 
captured as an AE, unless they meet the criteria for an SAE. The changes in RSV viral load will 
not be reported as AEs or SAEs.
9.2.5.
Respiratory Parameters: Spirometry
Spirometry (FEV1, FVC, FEV1/FVC) will be performed at several timepoints as specified in the 
Time and Events Schedule. Spirometry may also be investigated at any time following 
respiratory signs or symptoms (repeated coughing, bradypnea, tachypnea, rales and rhonchi) of 
respiratory difficulties. Spirometry will be performed as per hVIVO’s Operating Instruction. In 
case of respiratory difficulties, the investigator may decide to perform additional lung function 
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Spirometry will be done for each subject at approximately the same timepoint on each day from 
Day 0.
At each timepoint, three technically acceptable measurements will be recorded using a 
spirometer. The best reading from each assessment (as provided by the spirometry machine) will 
be used for analysis.
The following data will be automatically calculated:

FEV1 % predicted;

FEV1/FVC ratio (absolute, not predicted);
Any clinically relevant changes in pulmonary function occurring during the study will be 
recorded on the Adverse Event Section of the eCRF.
9.2.6.
Safety Evaluations
Any clinically relevant changes occurring from ICF signature until discharge from the Unit must 
be recorded on the eCRF. Any clinically significant abnormalities, including those persisting at 
the end of the study/early withdrawal, will be followed by the investigator until resolution or 
until a clinically stable endpoint is reached.
Adverse events occurring form ICF signature until 28 days after vaccination will be examined 
for relationship to study vaccine. Adverse events occurring from admission to the quarantine 
Unit until 28 days after challenge will be evaluated for relationship to the challenge.
The study will include the evaluations of safety and tolerability outlined in the following sections 
according to the timepoints provided in the Time and Events Schedule.
9.2.6.1.
Adverse Events
Unsolicited AEs will be reported by the subject from ICF signature until 28 days after 
vaccination, and from the entry into the Unit until 28 days after challenge. Solicited AEs will be 
reported by the subject for 7 days after vaccination via the subject diary. Adverse events will be 
followed by the investigator as specified in Section 12.3.
For solicited AEs, the following applies:

Solicited Adverse Events
Information related to solicited events as defined in Section 12.1.1, will be recorded by subjects 
in a diary for 7 days after vaccination. Each subject will be provided with a diary and instructions 
on how to complete the diary (Section 9.1.1). There will be a minimum 30-minute post-
vaccination assessment of solicited events at the site. Diary information will be transcribed by 
the study personnel in the appropriate eCRF pages.


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Subjects will be asked to note in the diary occurrences of pain/tenderness, erythema and 
induration/swelling at the study vaccine injection site daily for 7 days post-vaccination. The 
extent (largest diameter) of any erythema, and induration/swelling should be measured (using the 
ruler supplied) and recorded daily. Induration/swelling should also be graded using the 
functional scale.
o
Injection Site Pain/Tenderness
Injection site pain (eg, stinging, burning) is an unpleasant sensory and emotional 
experience associated with actual or potential tissue damage and occurring at the 
immunization site (with or without involvement of surrounding tissue). Injection site 
tenderness is a painful sensation localized at the injection site upon palpation and/or 
movement of the limb. Due to subjective nature of the reaction, the severity assessment 
of pain/tenderness is self-reported (if a subject is unable to provide self-report, other 
reporters include family member/caregiver or health care provider).12
o
Injection Site Erythema
Injection site erythema is a redness of the skin caused by dilatation and congestion of the 
capillaries localized at the injection site. It can best be described by looking and 
measuring.
o
Injection Site Swelling/Induration
Injection site swelling is a visible enlargement of an injected limb. It may be either soft 
(typically) or firm (less typical). Injection site induration is a palpable thickening, 
firmness, or hardening of soft tissue, usually has well-demarcated palpable borders, can 
be visible (raised or sunken compared to surrounding skin), is often ‘woody’ to touch 
and has a flat shape. As differentiation between swelling and induration may be difficult 
without health care professional’s assessment, both symptoms have been combined to 
allow self-assessment by the subjects. Both swelling and induration can best be 
described by looking and measuring.
Note: any other injection site events not meeting the above case definitions should be 
reported separately as unsolicited AEs.20,21
Systemic Adverse Events
Subjects will be instructed on how to record daily temperature using a thermometer provided 
for home use. Subjects should record body temperatures in the diary in the evening of the 
day of vaccination, and then daily for the next 7 days approximately at the same time each 
day.a If more than one measurement is made on any given day, the highest temperature of 
that day will be used in the eCRF.
                                                
a The 7-day post-vaccination temperature measurements may be taken earlier to coincide with the corresponding
clinic visit.


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Fever is defined as endogenous elevation of body temperature ≥38° C, as recorded in at least 
one measurement.24
Subjects will also be instructed on how to note daily in the diary for 7 days after vaccination 
symptoms of the following events: fatigue, headache, myalgia, arthralgia, chills, nausea, and 
fever (ie, body temperature ≥38 °C).
The severity of these solicited systemic AEs will be graded by the investigator according to 
the criteria presented in Section 12.1.3.
If a solicited local or systemic AE is not resolved by 7 days after vaccination, the follow-up will 
be captured on the diary. The subject will be instructed to record the date of last symptoms and 
maximum severity in the diary after resolution.
9.2.6.2.
Clinical Laboratory Tests
Blood and urine samples for laboratory safety assessments will be collected for screening up to 
56 days prior to vaccination, pre-vaccination, 7 days post-vaccination, and prior to challenge on 
Day –1 or Day –2. Blood samples will additionally be collected at discharge from the quarantine 
Unit and at 28 days post-challenge. The following tests will be performed by a local laboratory 
(*parameters only measured at screening):

Hematology Panel
platelet count. 
white blood cell (WBC) count (absolute) 
WBC differential 
neutrophils 
lymphocyte 
monocytes 
eosinophils 
basophils 
red blood cell (RBC) count 
reticulocyte count (% and absolute) 
hemoglobin
hematocrit
mean corpuscular volume (MCV) 
mean corpuscular hemoglobin (MCH) 
MCH concentration (MCHC) 

Biochemistry Panel
sodium 
potassium 
glucose (random) 
albumin 


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chloride 
bicarbonate 
calcium 
uric acid 
total protein 
creatinine 
total, direct, and indirect bilirubin 
inorganic phosphate 
blood urea nitrogen 
C-reactive protein 
gamma glutamyl transferase 
alkaline phosphatase 
alanine transaminase 
lactate dehydrogenase 
aspartate transaminase 
urea 

Cardiac Enzymes (done together with ECGs on admission, and on Days 3, 7 and 11)
Troponin T
creatinine kinase

Urinalysis – dipstick for:
specific gravity
pH
glucose
protein
blood
ketones
appearance
color
nitrite
urobilinogen
bilirubin
leucocytes
A repeat urinalysis will be performed in the event of a positive dipstick test. Microscopic reflex 
testing will be carried out if the repeat urinalysis dipstick test is also positive.
Review and Grading of Laboratory Data
The investigator must review each laboratory result, document this review and assess 
systematically any clinical significance. The laboratory reports must be filed with the source 
documents.


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Laboratory values will be initially evaluated by the investigator according to local laboratory 
criteria. Abnormal values outside the local laboratory range of normal will be graded according 
to the FDA Guidance document “Toxicity Grading Scale from Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials” (see Attachment 1). Laboratory 
values within local laboratory normal limits will not be FDA graded and will be considered as 
normal.
Reporting Laboratory Abnormalities as AEs
Any clinically significant abnormal laboratory value within 28 days post-vaccination that falls 
outside of the local laboratory normal range and that requires follow-up will be captured as an 
AE. Laboratory values outside normal ranges that are not clinically significant in the judgment of 
the investigator, should not be recorded as AEs.
Any laboratory value falling within the local laboratory normal range will not be severity graded 
or recorded as an AE, regardless of whether the value falls within FDA ranges for Grade 1 or 
higher.
Note: Values for parameters falling within the local laboratory normal range should not be 
reported as AEs.
Repeat of Clinically Significant Laboratory Tests
For any clinically significant abnormal laboratory value that has increased in grade over baseline, 
the test must be repeated at the next scheduled visit or sooner based on the investigator’s 
judgment, however Grade 3 abnormalities should be retested within 48 hours. Any clinically 
significant abnormalities (including those persisting at the end of the study or at early 
withdrawal) will be followed by the investigator until resolution or until a clinically stable 
endpoint is reached (see Section 12.3).
Screening Procedures
For entry into the study, each subject must be healthy on the basis of clinical laboratory tests 
performed within 56 days of vaccination. Enrollment of a subject with laboratory values outside 
of the local laboratory normal range representing FDA toxicity Grade 1 is allowed if the 
investigator considers the values reasonable for the population under study and not clinically 
significant.
Additional Clinical Laboratory Assessments
Additional clinical laboratory assessments to be performed are as follows:

Serology testing (HIV type 1 or type 2, hepatitis B, hepatitis C) within 56 days of 
vaccination

Serum pregnancy testing (-hCG) for all female subjects within 56 days of vaccination and 
at entry to the quarantine Unit


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
Urine pregnancy testing for all female subjects pre-vaccination

Urine drug screen at screening and at entry to the quarantine Unit
9.2.6.3.
Electrocardiogram
Supine 12-lead ECGs will be performed within 56 days of vaccination and on Day –1 or Day –2
prior to challenge; ECGs will only be performed at other times during the study if clinically 
indicated based on signs and symptoms. ECGs will be interpreted locally.
For 30 minutes prior to the ECG, subjects should refrain from meals, hot or cold beverages and 
strenuous exercise, and should remain in a room with a comfortable temperature. Each ECG 
should be obtained after the subject has been at rest for at least 5 minutes.
Enrollment of a subject with abnormal ECG results is allowed as long as the investigator feels 
that these are not clinically significant and appropriate for the population.
9.2.6.4.
Vital Signs
Supine blood pressure and pulse/heart rate measurements should be preceded by at least 5 
minutes of rest in a quiet setting without distractions (eg, television, cell phones).
The following measurements will be performed:

Heart rate (beats per minutes, bpm), respiratory rate (breaths per minute), systolic blood 
pressure (mmHg) and diastolic blood pressure (mmHg)

Body temperature (tympanic or oral route)
Confirmatory vital signs measurement can be performed if inconsistent with a prior 
measurement. If any clinically significant changes in vital signs are noted, they will be reported 
as AEs and followed to resolution, or until reaching a clinically stable endpoint.
9.2.6.5.
Physical Examination
A full physical examination will be carried out within 56 days of vaccination, on admission to 
the Unit, and on discharge from the Unit. At all other visits, an abbreviated, symptom-directed 
examination will be performed by the investigator based on any clinically relevant issues, 
clinically relevant symptoms and medical history. Symptom-directed physical examination may 
be repeated if deemed necessary by the investigator.
Physical examinations will be performed by the investigator or appropriately trained delegate. 
Any abnormalities or changes in severity noted during the review of body systems should be 
documented in the eCRF.


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10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY VACCINE/ 
WITHDRAWAL FROM THE STUDY
10.1.
Completion
A subject will be considered to have completed the study challenge if he or she has been 
challenged in the quarantine Unit and remained until meeting the requirements for discharge 
from the Unit. A subject will be considered to have completed the study if he or she has 
completed assessments at the final visit at 6 months post-vaccination. 
10.2.
Discontinuation from Challenge Phase/Withdrawal from the Study
Discontinuation from Challenge Phase
Subjects will be discontinued prior to the viral challenge phase (ie, pre-inoculation) for the 
reasons listed below. These subjects must not receive the viral challenge but should continue 
other study procedures, eg, safety follow-up:

Pregnancy

Any SAE

Any related AE, worsening of health status or intercurrent illness that, in the opinion of the 
investigator, precludes the subject from viral challenge

The randomization code is broken by the investigator or the study-site personnel
Overflow subjects from the first cohort will be challenged in subsequent cohorts. Any subject
who is vaccinated in subsequent cohorts but not challenged will be followed to the end of the 
study.
Withdrawal from the Study
Each subject has the right to withdraw from the study at any time for any reason without 
affecting the right to treatment by the investigator. Although the subject is not obliged to give a 
reason for withdrawing prematurely, the investigator should make a reasonable effort to ascertain 
the reason(s) while fully respecting the subject’s rights.
A subject will be withdrawn from the study for any of the following reasons:

Repeated failure to comply with protocol requirements

Decision by the sponsor or the investigator to stop or cancel the study

Decision by local regulatory authorities and Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) to stop or cancel the study

Lost to follow-up

Withdrawal of consent


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
Death
Any unnecessary study discontinuation should be avoided. Should a subject be withdrawn, all 
efforts should be made to complete and report the observations as thoroughly as possible. 
Whenever a subject is withdrawn from the study, independent of the reason, a final evaluation 
should be completed for that subject and the major reason for which the subject was withdrawn 
must be stated. If a subject is lost to follow-up, every reasonable effort must be made by the 
study-site personnel to contact the subject and determine the reason for withdrawal. The 
measures taken to follow-up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Study vaccine assigned to the withdrawn 
subject may not be assigned to another subject. In general, subjects who withdraw will not be 
replaced, unless that subject was randomized but did not receive any study vaccine. Any subject
who withdraws from the study after vaccination but before challenge will be replaced in the 
challenge by an overflow subject.
For those subjects who are unable to continue participation in the study, but for whom consent is 
not withdrawn, an exit visit will be conducted as soon as possible (see Section 9.1.8).
Subjects who wish to withdraw consent from participation in the study will be offered a single 
exit visit for safety follow-up (prior to formal withdrawal of consent). They have the right to 
refuse.
Precautions for any subject leaving the challenge Unit are listed in Section 4.3.
Withdrawal from the Use of Samples in Future Research
The subject may withdraw consent for use of samples for future research (refer to Section
16.2.5). In such a case, samples will be destroyed after they are no longer needed for the clinical 
study. Details of the sample retention for research are presented in the main ICF.
10.3.
Contraindications to Vaccination
The following events constitute a contraindication to vaccination at that point in time. If any of 
these events occur at the scheduled time for vaccination, the subject may be re-screened (if 
vaccination number not assigned), or withdrawn at the discretion of the investigator and after 
consultation with the sponsor. Note: the minimum time between vaccination and challenge is 24 
days:

Severe acute illness at the time of vaccination. This does not include minor illnesses such as 
diarrhea.

Fever (body temperature ≥37.8 °C) at the time of vaccination.
Note: medically indicated vaccines should be given at least 14 days before or 14 days after study 
vaccine administration and the viral challenge (see Section 4.3).


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11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the immunogenicity and safety data is 
outlined below. Specific details will be provided in the SAP. 
Planned analyses are described in Section 11.8.
11.1.
Analysis Sets
The Full Analysis (FA) Set includes all subjects who were randomized and received study 
vaccine, regardless of the occurrence of protocol deviations. Vaccination assignment will follow 
the as-treated principle. All safety and subject information analyses will be based on the FA set. 
As a sensitivity analysis, key immunogenicity tables will also be based on the FA set.
The Intent-to-Treat-Challenge (ITTc) population is a subset of the FA set that includes all 
randomized, vaccinated and challenged subjects. All efficacy analyses will be performed on the 
ITTc population. Important subject information tables might be repeated based on the ITTc 
population as well.
The Per-protocol Immunogenicity (PPI) Set will include all randomized and vaccinated 
subjects for whom immunogenicity data are available, excluding subjects with major protocol 
deviations expecting to impact the immunogenicity outcomes.
In addition, for subjects who experience a natural RSV infection (based on RT-PCR, or other
sources), samples taken after the natural infection will not be included in the PPI set.
The analysis of immunogenicity will be based on the PPI set.
11.2.
Sample Size Determination
A sample size of 44 challenged subjects (22 vaccinated and 22 placebo subjects) was chosen as 
this would provide sufficient evidence to assess if the challenge model is a reasonable approach 
to examine vaccine efficacy. A multiple of 22 subjects was selected given the capacity of the 
quarantine Unit.
The sample size was based on the ability to detect trends with a high one-sided alpha (20%), 
given this is an exploratory study whose partial aim is to determine the utility of the RSV human 
challenge model for RSV vaccine development. Figure 2 shows the expected power for several 
reductions in VL-AUC of the quantitative RT-PCR assay, with this selected sample size, a mean 
VL-AUC in the placebo group of 320 log10 h/mL with corresponding standard deviation 275, an 
infection rate in placebo of 65% and a one-sided alpha of 5% and 20% based on a Wilcoxon 
Rank Sum test. This graph suggests that for a one-sided alpha level of 20%, the study has at least 
80% power if Ad26.RSV.preF induces a reduction of VL-AUC of the quantitative RT-PCR 
assay by 50% or more. For a one-sided alpha level of 5%, the study has at least 80% power if 
Ad26.RSV.preF induces a reduction of VL-AUC of the quantitative RT-PCR assay by 75% or 
more.


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An effect that is significant at 5% (one-sided) will be considered a significant effect. An effect 
that is significant at 20% (one-sided) will be considered as a trend. This trend, if observed, might 
be confirmed in future studies. 
As this is an exploratory study, the statistical assumptions described above will need to be 
demonstrated to be correct for the analysis to be conducted as indicated below and as planned in 
further detail in the SAP. For example, if the infection rate from the study is considerably below 
65% then the study will be considered to be underpowered to be able to accurately determine the 
stated aims. The infection rate in the placebo group will be followed on an ongoing basis by an 
unblinded individual who does not have any other study function to ensure a sufficient infection 
rate has occurred. If the infection rate is lower than anticipated, additional subjects may be 
enrolled, initially four additional subjects in each arm and up to 70 in total. This is to ensure that 
a high enough number of evaluable subjects is reached in each arm.
Figure 2:
Expected Power for Several Reductions in Viral Load
11.3.
Subject Information
For all subjects, demographic characteristics (eg, age, height, weight, body mass index [BMI], 
race, and gender), and other baseline characteristics (eg, physical examination, medical history, 
and concomitant diseases) will be tabulated and summarized with descriptive statistics.
11.4.
Efficacy Analyses
For efficacy, baseline is defined as the last assessment challenge with the virus.


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The primary efficacy endpoint is the VL-AUC of RSV-A Memphis 37b as determined by 
quantitative RT-PCR assay of nasal wash samples. The VL-AUC is calculated based on the viral 
load values measured twice daily, starting with the baseline value, and ending with the last 
available value before discharge.
For this primary efficacy endpoint the exact Wilcoxon Rank Sum test will be performed and the 
one-sided p-value will be interpreted at the 5% and 20% significance level, specifically only 
analysing the statistical significance of a reduction in VL-AUC in the active versus placebo 
groups.
The secondary efficacy endpoints are:

The peak viral load of RSV-A Memphis 37b, defined as the maximum viral load as 
determined by quantitative RT-PCR assay of nasal wash samples, observed over the entire 
time period

The effect of vaccination on viral load and symptoms on Day 6 and Day 7

The viral load of RSV-A Memphis 37b as determined by quantitative RT-PCR assay of 
nasal wash samples over time

The VL-AUC of RSV-A Memphis 37b as determined by quantitative culture of RSV of 
nasal wash samples and the corresponding AUC

Weight of mucus produced over time and the corresponding AUC, tissue count

Proportion of subjects with symptomatic RSV infection. Symptomatic RSV infection is 
defined in two ways:
o
Conservative: the subject has two or more quantifiable RT-PCR measurements on 
different samples and the subject has one of the following
symptoms from two different categories (Upper Respiratory, Lower Respiratory, 
Systemic) from the SSC, regardless of grade and assessment timepoint.
any Grade 2 symptom from any category.
o
Liberal: two or more quantifiable RT-PCR measurements plus any clinical symptom of 
any severity.
Note: the quantifiable RT-PCR assessment and the symptoms should not necessarily occur 
at the same day.
Exploratory efficacy endpoints are:

Proportion of subjects with symptomatic RSV infection (RT-PCR or serology). 
Symptomatic RSV infection is defined as having two or more quantifiable RT-PCR 
measurements or serology confirmation of RSV, and any clinical symptom of any severity.

Total clinical symptom score (using a composite of 10 and 13 self-reported symptoms on the 
SSC) over time and the corresponding AUC.


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
To determine the most effective efficacy endpoint, additional exploratory efficacy endpoints 
will be described in the SAP.
Continuous variables will be summarized with descriptive statistics of the actual values and the 
changes from baseline where appropriate. For categorical variables, frequency tables will be 
presented. Difference in proportions and corresponding confidence intervals (CIs) may be 
calculated where appropriate. 
The relation between viral load and clinical symptoms will be graphically explored.
Spirometry 
Descriptive statistics of values and changes from baseline for FEV1, FVC, and FEV1/FVC will 
be summarized at each scheduled timepoint. The percentage of subjects with values beyond 
clinically important limits will be summarized.
11.5.
Immunogenicity Analyses
No formal hypothesis on immunogenicity will be tested. Descriptive statistics (geometric mean 
and 95% CI for ELISA and virus neutralization assays; median and quartiles for ELISpot and 
intracellular cytokine staining [ICS]) will be calculated for continuous immunologic parameters 
at all timepoints. For the humoral assays, geometric mean fold rises from baseline and 
corresponding 95% CIs may be calculated as well. For immunogenicity, baseline is considered 
as the last assessment pre-vaccination with Ad26.RSV.preF or placebo. Graphical 
representations of immunologic parameters will be made as applicable.
Frequency tabulations will be calculated for discrete (qualitative) immunologic parameters as 
applicable.
The primary analysis set for immunogenicity is the PPI set. As a sensitivity analysis, key tables 
will also be based on the FA set. Depending on their occurrence, the effect of missed doses or 
natural infections might be further explored. Note that they will be included in the tables 
showing the FA set.
11.6.
Efficacy versus Immunogenicity Relationship
The relationship between immunogenicity parameters and the VL-AUC as measured by RT-PCR
and the AUC for clinical symptoms will be graphically explored.
11.7.
Safety Analyses
No formal statistical testing of safety data is planned. All safety data will be analyzed 
descriptively by regimen.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). All reported AEs with onset during the 


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active phases (ie, AEs emerging after vaccination up to 28 days post-vaccination or during the 
quarantine phase), and all SAEs, will be included in the analysis. For each AE, the percentage of 
subjects who experience at least one occurrence of the given event will be summarized by group 
separately for the vaccination phase and challenge phase.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue study vaccine due to an AE, or who experience a severe AE or 
an SAE.
Summaries and/or listings may be provided separately for AEs with onset outside the active 
phases.
Solicited local (at injection site) and systemic AEs will be summarized descriptively. The overall 
frequencies per vaccine group as well as frequencies according to severity and duration will be 
calculated for solicited AEs. In addition, the number and percentages of subjects with at least one 
solicited local (at 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. Unsolicited AEs will be presented separately for vaccination phase and 
quarantine phase.
Clinical Laboratory Tests
Laboratory abnormalities will be determined according to the FDA Guidance document (see 
Attachment 1), or in accordance with the normal ranges for the clinical laboratory parameter if 
no grades are available. If a laboratory value falls within the grading as specified in the FDA 
table, but also within the laboratory normal limits, the value is considered as normal. Emerging 
abnormalities will be tabulated.
Vital Signs
A tabulation of the distribution of temperatures per half-degree intervals will be provided. For 
systolic and diastolic blood pressures, heart rate and respiratory rate, the percentage of subjects 
with values beyond clinically relevant limits will be summarized.
Electrocardiogram
Any abnormalities in ECG parameters (at screening and on admission to the Unit) will be listed.
Physical Examination
Any abnormality in physical examination considered to be clinically significant will be captured 
as an AE and shown in the AE outputs. Therefore, no separate analysis will be done.
11.8.
Planned Analyses
The following analyses will be performed:


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
PRIMARY ANALYSIS will be performed when all subjects have completed the quarantine 
phase or discontinued earlier. The pre-challenge neutralization and pre-F ELISA, and post-
challenge RT-PCR, nasal mucous and tissue count, and clinical symptom data will be 
available although the analysis may be performed on snapshot data. All other data available 
at the time of primary analysis, including completed cellular data, will be included. 
Preliminary safety data, including Day 28 post-challenge, if available, will also be included.

FINAL ANALYSIS will be performed when all subjects have completed the 6 month safety 
follow-up visit or discontinued earlier.
Depending on when the data are available, both analyses might be combined.
Additional interim analyses (blinded or unblinded) may be performed during the study for the 
purpose of informing future vaccine-related decisions in a timely manner, or upon health 
authority request. The results will not influence the conduct of the study in terms of early 
termination or later safety, efficacy or immunogenicity endpoint assessments, and will only be 
available to a selected group of sponsor personnel, excluding personnel involved in data 
management and data collection.
11.9.
Data Review Committee
Data Review Committee
An internal DRC will be commissioned for this study, comprised of sponsor personnel not 
directly involved in the conduct of the study, who have expertise in clinical study conduct and 
vaccines. It will consist of at least one medical expert in the relevant therapeutic area and at least 
one statistician. 
There are no planned DRC reviews. The DRC will only convene to discuss any significant or 
unexpected safety issues. The investigator and SRP will inform the DRC of any AE of concern.
After such a review, the DRC will make recommendations regarding the continuation of the 
study. The conclusions of the DRC will be communicated to the investigators, the IRB/IEC and 
the national regulatory authorities as appropriate. Details will be provided in a separate DRC 
charter.
If deemed necessary for safety review, the DRC may request the randomization codes and 
review unblinded data, if applicable.
11.10. Study Vaccination Pausing Rules
The investigator and the SRP will monitor the study vaccination pausing rules. If study 
vaccination is considered to raise significant safety concerns, further vaccination of subjects will 
be suspended until DRC review is carried out and subsequent communication between the 
sponsor and the investigators takes place.


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The occurrence of any of the following events will lead to suspension of further study 
vaccination, and trigger a meeting of the DRC to discuss study suspension, adaptation or 
discontinuation of further vaccination:
1. One or more subject experience an SAE or other potentially life-threatening (Grade 4) event 
that is determined to be related to study vaccine; OR
2. One or more subjects experience anaphylaxis clearly not attributable to other causes than 
vaccination with study vaccine; OR
3. Two or more subjects experience a Grade 3 or 4 unsolicited AE of the same type, 
determined to be related to study vaccine, that persists for 72 hours or longer; OR
4. Two or more subjects experience a Grade 3 or 4 solicited systemic AE of the same type, 
determined to be related to study vaccine, that persists for 72 hours or longer; OR
5. Two or more subjects experience a persistent (upon repeat testing) Grade 3 or 4 laboratory 
abnormality related to the same laboratory parameter and considered related to study 
vaccine, that persists for 72 hours or longer; OR
6. Death of any subject, regardless of causality.
If any of the above specific pausing rules are met, the DRC will make recommendations 
regarding the continuation of the study to the sponsor. Study suspensions or terminations will 
occur within 5 working days after the decision is made, unless local regulations specify a shorter 
timeframe. Local regulatory authorities including IECs/IRBs will be informed within the 
appropriate regulatory-mandated timeframes. A study may be resumed only upon approval of a 
substantial amendment to the initial study application by the local regulatory authorities and 
IECs/IRBs. The sponsor will communicate conclusions regarding study continuation to the 
investigators, the IECs/IRBs and the national regulatory authorities as appropriate.
The investigator may ask for a review meeting to be held for any single event or combination of 
multiple events which, in his/her professional opinion, jeopardize the safety of the subjects or the 
reliability of the data.
Vaccinations for the study may be suspended for safety concerns other than those described 
above or before pausing rules are met if, in the judgment of investigator, subject safety may be 
threatened. The sponsor should be notified that the DRC will need to be convened.
This is a single site study so stopping rules will automatically apply to the entire study. Sponsor 
activities and responsibilities related to temporary study suspension and restart are described in 
the sponsor’s applicable standard operating procedures (SOPs).17,18
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established SOPs in conformity with regulatory 


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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.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and non-
leading verbal questioning of the subject is the preferred method to inquire about AE occurrence. 
For some studies, subjects are not always able to provide valid verbal responses to open-ended 
questions. In these circumstances, another method of detecting these events is specified.
Solicited Adverse Events
Solicited AEs are pre-defined local (ie, at the injection site) and systemic events for which 
subjects are specifically questioned and which are noted by subjects in their diaries (see Section
9.1.1).
Unsolicited Adverse Events
Unsolicited AEs are all AEs for which subjects are specifically not questioned in the subject 
diary.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with 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 
Conference on Harmonisation [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: In this study, the sponsor will collect unsolicited AEs from ICF signature until 28 days 
after vaccination, and from the entry into the Unit until 28 days after challenge, and solicited 
AEs from the time of vaccination for 7 days post-vaccination (refer to Section 12.3.1). SAEs will 
be collected from ICF signature for the duration of the study.
Serious Adverse Event
An SAE based on ICH and European Union (EU) Guidelines on Pharmacovigilance for 
Medicinal Products for Human Use is any untoward medical occurrence that at any dose:


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
Results in death

Is life-threatening
(The subject 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 subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
If a serious and unexpected AE occurs for which there is evidence suggesting a causal 
relationship between the study vaccine and the event (eg, death from anaphylaxis), the event 
must be reported as a suspected unexpected serious adverse reaction (SUSAR) by the sponsor to 
health authorities and by the investigator to the IRB/IEC according to regulatory and local 
requirements.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For Ad26.RSV.preF, the expectedness of an AE will be 
determined by whether or not it is listed in the Investigator’s Brochure.1
Adverse Event Associated With the Use of the Vaccine
An AE is considered associated with the use of the vaccine if the attribution is related by the 
definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Every effort should be made by the investigator to explain any AE and assess its potential causal 
relationship, ie, to administration of the study vaccine, to viral challenge or to alternative causes 
(eg, natural history of the underlying diseases, concomitant therapy). This applies to all AEs, 
whether serious or non-serious.
Note: AEs occurring form ICF signature until 28 days after vaccination will be examined for 
relationship to study vaccine. AEs occurring from admission to the quarantine Unit until 28 days 
after challenge will be evaluated for relationship to the challenge.


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Causality of AEs should be assessed by the investigator based on the following:
Related: there is suspicion that there is a relationship between the study vaccine (or viral 
challenge) and the AE (without determining the extent of probability); there is a reasonable 
possibility that the study vaccine (or viral challenge) contributed to the AE.
Unrelated: there is no suspicion that there is a relationship between the study vaccine (or viral 
challenge) and the AE; there are other more likely causes and administration of the study vaccine 
(or viral challenge) is not suspected to have contributed to the AE.
By definition, all solicited AEs at the injection site (local) will be considered related to the study 
vaccine administration.
12.1.3.
Severity Criteria
All AEs and laboratory data will be coded for severity using the toxicity grading table in 
Attachment 1. Note: Laboratory values within local laboratory normal ranges (even if within a 
toxicity grade range), or laboratory values outside normal ranges that are not clinically 
significant in the judgment of the investigator, should not be recorded as AEs. For AEs not 
identified in the grading table, the following guidelines will be applied:
Mild (Grade 1): No interference with activity.
Moderate (Grade 2): Some interference with activity not requiring medical intervention.
Severe (Grade 3): Prevents daily activity and requires medical intervention.
Potentially life-threatening (Grade 4): Symptoms causing inability to perform basic self-care 
functions OR medical or operative intervention indicated to prevent permanent impairment, 
persistent disability.
The toxicity grading scale used for laboratory assessments is based on the FDA toxicity grading 
table, consistent with the assessment grading used throughout the protocol. If a laboratory value 
falls within the grading as specified in the FDA table, but also within the laboratory normal 
limits, the value is considered as normal. For hemoglobin, both the actual value and the change 
from reference will be graded.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
The severity of solicited AEs will be graded in the diary by the subject based on the severity 
assessment provided in the diary and then verified by the investigator using the FDA toxicity 
grading table (see Attachment 1).


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12.2.
Special Reporting Situations
Safety events of interest on a sponsor study vaccine that may require expedited reporting and/or 
safety evaluation include, but are not limited to:

Suspected abuse/misuse of a sponsor study vaccine

Accidental or occupational exposure to a sponsor study vaccine

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study vaccine, eg, name confusion)

Exposure to a sponsor study vaccine from breast-feeding
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 serious adverse event page of the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
Unsolicited AEs and special reporting situations will be reported from ICF signature until 28 
days after vaccination, and from the entry into the Unit until 28 days after challenge.
From challenge until discharge from the Unit, SSC findings greater than Grade 0 will be 
presumed to represent virus infection consequent to challenge, and will not additionally be 
captured as an AE, unless they meet the criteria for an SAE. The changes in RSV viral load will 
not be reported as AEs or SAEs.
Solicited AEs will be recorded by each subject in the subject diary for 7 days after dosing. The 
investigator will review each subject’s diary at the subsequent in-clinic visit; diary information 
will be transcribed by the study personnel in the on-site assessment forms in the eCRF.
The sponsor will evaluate any safety information that is spontaneously reported by an 
investigator beyond the time frame specified in the protocol.
The investigator will monitor and check the study data including all AE and any clinical 
laboratory data as they become available and will make determinations regarding the severity of 
the adverse experiences and their relation to study vaccine. All AEs will be deemed related to 
study vaccine or not related to study vaccine, or related to the viral challenge or not related to 
viral challenge, according to Section 12.1.2.
The investigator must review both post-injection reactogenicity and other AEs to insure the 
prompt and complete identification of all events that require expedited reporting as SAEs, invoke 
pausing rules or are other serious and unexpected events.
All AEs, regardless of seriousness, severity, or presumed relationship to study vaccine, must be 
recorded using medical terminology in the source document and the eCRF. Whenever possible, 
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough, 


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runny nose, sneezing, sore throat, and head congestion should be reported as “upper respiratory 
infection”). The investigator 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.
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 SUSARs. The investigator (or sponsor where required) must report SUSARs 
to the appropriate IEC/IRB that approved the protocol unless otherwise required and documented 
by the IEC/IRB. A SUSAR will be reported to regulatory authorities unblinded. Participating 
investigators and IEC/IRB will receive a blinded SUSAR summary, unless otherwise specified.
Each subject will 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 subject 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 staff only)

Site number

Subject number

Any other information that is required to do an emergency breaking of the blind
12.3.2.
Serious Adverse Events
All SAEs occurring from ICF signature until the end of the study must be reported to the 
appropriate sponsor contact person by study-site personnel within 24 hours of their knowledge of 
the event.
Information regarding SAEs will be transmitted to the sponsor using the sponsor’s Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site, 
and transmitted to the sponsor within 24 hours. The initial and follow-up reports of an SAE 
should be made by facsimile (fax).
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject’s participation in 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


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
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 (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a subject’s participation in a study must be reported as an SAE, except hospitalizations 
for the following:

Hospitalizations not intended to treat an acute illness or an 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 as 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 subject 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.
12.3.3.
Pregnancy
All initial reports of pregnancy in female subjects or partners of male subjects must be reported 
to the sponsor by the study-site personnel within 24 hours of their knowledge of the event using 
the sponsor’s appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, 
spontaneous abortion, fetal death, stillbirth, congenital anomalies and ectopic pregnancy) are 
considered SAEs and must be reported using the SAE Form.
Because the effect of the study vaccine on sperm is unknown, pregnancies in partners of male 
subjects included in the study will be reported as noted above.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 


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durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
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.
If the defect is combined with an SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 12.3.2). A sample of the 
suspected product should be maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY VACCINE INFORMATION
14.1.
Physical Description of Study Vaccine
A human replication-incompetent adenovirus-vectored vaccine candidate, manufactured and 
provided under the responsibility of the sponsor, will be assessed in this study:
Ad26.RSV.preF (JNJ-64400141)
Ad26.RSV.preF is a replication-incompetent Ad26 containing a DNA transgene that encodes for 
the pre-fusion conformation-stabilized F protein derived from the RSV A2 strain.
For this study, Ad26.RSV.preF will be formulated as a solution for intramuscular injection. 
Ad26.RSV.preF will be supplied as a frozen liquid to be thawed prior to use. Ad26.RSV.preF 
will be filled in stoppered and sealed 2 mL single-use glass vials in a volume of 0.75 mL to allow 
an extractable volume of at least 0.5 mL (1x1011 vp). Refer to the Investigator’s Brochure for 
details of the components of Ad26.RSV.preF and a list of excipients.1
Placebo
Placebo will be supplied as sterile 0.9% saline for injection in 2 mL ampules.
14.2.
Packaging and Labeling
All study vaccines were manufactured and packaged in accordance with Current Good 
Manufacturing Practice. All study vaccines will be packaged and labeled under the responsibility 


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of the sponsor. Study vaccine labels will contain information to meet the applicable regulatory 
requirements.
No study vaccine can be repacked or relabeled without prior approval from the sponsor.
Further details for study vaccine packaging and labeling can be found in the Investigational 
Product Preparation Instructions.
14.3.
Storage and Handling
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. Study refrigerators/freezers should be equipped with back-up 
power systems. In the event that study vaccine is exposed to temperatures outside the specified 
temperature range, all relevant data will be sent to the sponsor to determine if the affected study 
vaccine can be used or will be replaced. The affected study vaccine must be quarantined and not 
used until further instruction from the sponsor is received.
Injections should be administered in the non-dominant deltoid.a No local or topical anesthetic will 
be used prior to the injection. The study vaccine will be prepared by the unblinded site pharmacist, 
or other qualified individual who will have no other study function and administered by a blinded 
vaccine administrator.
Note: the unblinded pharmacist, or other qualified individual, may also perform the 
administration, but will have no other study function.
Further details for study vaccine storage, preparation, handling and stability can be found in the 
Investigational Product Preparation Instructions.
14.4.
Vaccine 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 
subject 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 
                                                
a For each subject, study vaccine on Day 57 will be administered in the deltoid muscle of the same (non-dominant) 
arm used for study vaccine administration on Day 1.


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authorized destruction unit and study vaccine supplies are destroyed on-site, this must also be 
documented on the vaccine return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for vaccine accountability purposes. 
Study vaccine should be dispensed under the supervision of the investigator or a qualified 
member of the study-site personnel, or by a hospital/clinic pharmacist. Study vaccine will be 
supplied only to subjects participating in the study. Study vaccine may not be relabeled or 
reassigned for use by other subjects. The investigator agrees neither to dispense the study 
vaccine from, nor store it at, any site other than the study site agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator’s Brochure for Ad26.RSV.preF

Investigational Product Preparation Instructions/Investigational Product Procedures Manual

Laboratory Manual

Trial Center File

Electronic Data Capture (eDC) Manual/eCRF completion guidelines and randomization 
instructions

Sample ICF

Subject diary

Subject symptom card

Ruler

Thermometers

Contact information page(s)
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects 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 subjects who are fully able to understand the risks, benefits, and 
potential AEs of the study, and provide their consent voluntarily will be enrolled.


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The total blood volume drawn from each adult subject will not exceed the US Department of 
Health and Human Services (HHS) Office for Human Research Protections (OHRP), and FDA 
guidelines of 550 mL in any eight-week period.40,41
See Section 1.3 for the benefit-risk assessment.
16.2.
Regulatory Ethics Compliance
16.2.1.
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.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator’s Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects 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 subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct, unless required locally), the ICF, applicable 
recruiting materials, and subject compensation programs, and the sponsor has received a copy of 


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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 subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator’s Brochure 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 subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects 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 subjects, 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.
16.2.3.
Informed Consent
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. 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 subject can read and understand. The 


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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 subjects the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects 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 subject will receive. Finally, they will be told that the investigator will 
maintain a subject 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 subject, to the extent permitted by the applicable 
law(s) or regulations. By signing the ICF the subject is authorizing such access. It also denotes 
that the subject agrees to allow his or her study physician to recontact the subject for the purpose 
of obtaining consent for additional safety evaluations, if needed.
The subject 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 subject’s personally dated signature. After having obtained the consent, a copy 
of the ICF must be given to the subject.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects 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 subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original 
medical records (source data/documents) for study-related monitoring, audit, IEC/IRB review, 
and regulatory inspection. This consent also addresses the transfer of the data to other entities 
and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.


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16.2.5.
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, to 
understand RSV, and to develop tests/assays related to Ad26.RSV.preF and RSV. The research 
may begin at any time during the study or the post-study storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.2).
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
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 subjects, 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) involves only logistic or administrative aspects of the study, the 
IEC/IRB (where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative listed in the Contact Information page(s), which will be provided as a separate 
document. Except in emergency situations, this contact should be made before implementing any 
departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the eCRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
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.
17.2.2.
Required Pre-study 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 investigator.


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
A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject 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 investigator, where required.

Signed and dated Clinical Trial Agreement, which includes the financial agreement.

Any other documentation required by local regulations.

Genetically modified organism (GMO) and/or Institutional Biosafety Committee (IBC) 
approval, if applicable.
The following documents must be provided to the sponsor before enrollment of the first subject:

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.
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification 


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and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
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: 
subject 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 vaccine or withdrawal from the study, if 
applicable.
The author of an entry in the source documents should be identifiable.
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).
The subject diary used to collect information regarding solicited events after vaccination will be 
considered source data. At the visit at 7 days after vaccination, information from the subject 
diary will be reviewed by the investigator; diary information will be transcribed by study 
personnel into the eCRF as described in the eCRF Completion Guidelines.
An eSource system may be utilized, which contains data traditionally maintained in an 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.
17.5.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject 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.


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Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject’s source documents. Data must be entered into 
eCRF in English. The eCRF must be completed as soon as possible after a subject 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.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor. Written 
instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review eCRF for accuracy and completeness during 
on-site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved 
with the investigator or designee, as appropriate. After upload of the data into the study database 
they will be verified for accuracy and consistency with the data sources.
17.7.
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 subject, 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 


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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.
17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study-site visit log that will be kept at the study site. The first 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data entered into the eCRF with the source documents 
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 
eCRF are known to the sponsor and study-site personnel and are accessible for verification by 
the 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.
17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
The end of the study will be the last subject’s last visit by telephone at 6 months post-
vaccination. The study is considered completed with the last visit for the last subject 
participating in the study. The final data from the study site will be sent to the sponsor (or 
designee) after completion of the final subject visit at that study site, in the time frame specified 
in the Clinical Trial Agreement.
17.9.2.
Study 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. The study site 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 subjects by the investigator

Discontinuation of further study vaccine development
The study will be terminated if one or more subjects experience any severe or clinically 
significant illness from RSV challenge, after discussion with the investigator, hVIVO, and the 
sponsor’s SRP.
17.10. 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. Subject privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and 
available for consultation during routinely scheduled study-site audit visits conducted by the 
sponsor or its designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding Ad26.RSV.preF or the 
sponsor’s operations (eg, patent application, formulas, manufacturing processes, basic scientific 
data, prior clinical data, formulation information) supplied by the sponsor to the investigator and 
not previously published, and any data generated as a result of this study, are considered 
confidential and remain the sole property of the sponsor. The investigator agrees to maintain this 
information in confidence and use this information only to accomplish this study, and will not 
use it for other purposes without the sponsor’s prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of Ad26.RSV.preF, 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 


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performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. 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 subject identifiers will not be used in 
publication of results. Any work created in connection with performance of the study and 
contained in the data that can benefit from copyright protection (except any publication by the 
investigator as provided for below) shall be the property of the sponsor as author and owner of 
copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multi-center) 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 multi-center study designs and substudy 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 multi-center 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 12 months of the availability of the 
final data (tables, listings, graphs), or the sponsor confirms there will be no multi-center study 
publication. Authorship of publications resulting from this study will be based on the guidelines 
on authorship, such as those described in the Uniform Requirements for Manuscripts Submitted 
to Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
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.


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Radosevic K, Rodriguez A, Lemckert AA, et al. The Th1 immune response to Plasmodium falciparum 
circumsporozoite protein is boosted by adenovirus vectors 35 and 26 with a homologous insert. Clin Vaccine 
Immunol. 2010:17;1687-1694.
33.
Regnier SA, Huels J. Association between respiratory syncytial virus hospitalizations in infants and respiratory 
sequelae: systematic review and meta-analysis. Pediatr Infect Dis J. 2013:32;820-826.
34.
Shay DK, Holman RC, Newman RD, et al. Bronchiolitis-associated hospitalizations among US children, 1980-
1996. JAMA. 1999:282;1440-1446.
35.
Sigurs N, Gustafsson PM, Bjarnason R, et al. Severe respiratory syncytial virus bronchiolitis in infancy and 
asthma and allergy at age 13. Am J Respir Crit Care Med. 2005:171;137-141.
36.
Simoes EA, Carbonell-Estrany X, Rieger CH, et al. The effect of respiratory syncytial virus on subsequent 
recurrent wheezing in atopic and nonatopic children. J Allergy Clin Immunol. 2010:126;256-262.
37.
Simoes EA, Groothuis JR, Carbonell-Estrany X, et al. Palivizumab prophylaxis, respiratory syncytial virus, 
and subsequent recurrent wheezing. J Pediatr. 2007:151;34-42, 42 e31.
38.
Stockman LJ, Curns AT, Anderson LJ, Fischer-Langley G. Respiratory syncytial virus-associated 
hospitalizations among infants and young children in the United States, 1997-2006. Pediatr Infect Dis J. 
2012:31;5-9.
39.
Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial 
virus in the United States. JAMA. 2003:289;179-186.
40.
US Department of Health and Human Services. Office for Human Research Protections - OHRP Expedited 
Review Categories (1998). Available at: http://www.hhs.gov/ohrp/regulations-and-policy/guidance/categories-
of-research-expedited-review-procedure-1998/index.html (last accessed 05 January 2017).
41.
US Food and Drug Administration. Conditions for IRB Use of Expedited Review. Available at: 
http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/GuidancesInformationSheetsandNo
tices/ucm118099.htm (last accessed 05 January 2017).
42.
Data on file.


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Attachment 1: Toxicity Tables
Adapted From the FDA Guidance document “Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” (September 2007)


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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
Does not interfere
with activity
Repeated use of 
non-narcotic
pain reliever
> 24 hours or
interferes with
activity
Any use of
narcotic pain
reliever or
prevents daily
activity
Emergency room
(ER) visit or
hospitalization
Tenderness
Mild discomfort 
to
Touch
Discomfort with
Movement
Significant
discomfort at rest
ER visit or
Hospitalization
Erythema/redness*
2.5 – 5 cm
5.1 – 10 cm
> 10 cm
Necrosis or
exfoliative
dermatitis
Induration/swelling**
2.5 – 5 cm and
does not interfere
with activity
5.1 – 10 cm or
interferes with
activity
> 10 cm or
prevents daily
activity
Necrosis
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a 
continuous variable.
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement.
Vital Signs *
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life-threatening
(Grade 4)
Fever** (°C)
Fever** (°F)
37.8 – 38.4
100.4 – 101.1
38.5 – 38.9
101.2 – 102.0
39.0 – 40
102.1 – 104
>40
>104
Tachycardia - beats per 
minute
101 – 115
116 – 130
>130
ER visit or hospitalization for 
arrhythmia
Bradycardia - beats per 
minute***
50 – 54
45 – 49
< 45
ER visit or hospitalization for 
arrhythmia
Hypertension (systolic) 
- mm Hg
141 – 150
151 – 155
>155
ER visit or hospitalization for 
malignant hypertension
Hypertension 
(diastolic) - mm Hg
91 – 95
96 – 100
>100
ER visit or hospitalization for 
malignant hypertension
Hypotension (systolic) 
- mm Hg
85 – 89
80 – 84
< 80
ER visit or hospitalization for 
hypotensive shock
Respiratory Rate -
breaths per minute
17 – 20
21 – 25
>25
Intubation
* 
Subject should be at rest for all vital sign measurements.
** 
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 subject populations, for example, conditioned athletes.


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Systemic
(General)
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life-threatening 
(Grade 4)
Nausea/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
ER visit or hospitalization for 
hypotensive shock
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 
>800gms/24 
hours or requires 
outpatient IV 
hydration
ER visit or hospitalization
Headache
No interference 
with activity
Repeated use of 
non-narcotic pain 
reliever >24 hours 
or some 
interference with 
activity
Significant; any 
use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or hospitalization
Fatigue
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ER visit or hospitalization
Myalgia
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ER visit or hospitalization
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
ER visit or hospitalization


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B: Tables for Laboratory Abnormalities
The grading scale used for laboratory assessments is based on the FDA Guidance document “Toxicity 
Grading Scale from Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials”. Any laboratory value shown as a “graded” value in the table that is within the local laboratory
normal ranges will not be graded for severity or recorded as AE. For hemoglobin, both the actual value
and the change from reference will be graded. For the change from reference, the corresponding actual 
value should also be at least Grade 1.
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
100 – 110
111 – 125
> 125
Insulin requirements 
or hyperosmolar 
coma
Random Glucose -
mg/dL
110 – 125
126 – 200
>200
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
--


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Serum *
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life-
threatening
(Grade 4) **
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
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 local laboratory normal parameters.
Central laboratory 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 if the subject had a new seizure associated with the low 
sodium value.
***ULN is the upper limit of the normal range.


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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 local laboratory normal parameters. 
Central laboratory normal reference ranges should be provided to demonstrate that they are appropriate.
** ULN is the upper limit of the normal range.


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Attachment 2: Objectives and Endpoints Table
Objectives
Endpoints
PRIMARY

The primary objective is to assess a trend for the 
prophylactic efficacy of a single dose of 
1x1011 vp of Ad26.RSV.preF administered 
intramuscularly to adults aged 18-50 years in the 
RSV challenge model in terms of reduction of 
nasal wash viral load as measured by the AUC 
over time by quantitative RT-PCR compared to 
placebo.

VL-AUC of RSV-A Memphis 37b, determined by 
quantitative RT-PCR assay of nasal wash 
samples.
SECONDARY

To assess a trend for prophylactic efficacy of a 
single dose of Ad26.RSV.preF in the RSV 
challenge model in terms of reduction of nasal 
wash viral load as measured by the peak viral 
load of the RT-PCR compared to placebo.

Peak viral load of RSV-A Memphis 37b, defined 
as the maximum viral load as determined by 
quantitative RT-PCR assay of nasal wash 
samples, observed over the entire time period.

To assess the effect of a single dose of 1x1011 vp 
of Ad26.RSV.preF on viral load and clinical 
symptoms on Day 6 and Day 7 post-challenge 
compared to placebo.

Viral load, measured by RT-PCR and quantitative 
culture of RSV, and clinical symptoms on Day 6 
and Day 7.

To assess a trend for prophylactic efficacy of a 
single dose of 1x1011 vp of Ad26.RSV.preF in the 
RSV challenge model in terms of prevention of 
symptomatic RSV infection and one or more 
positive clinical symptoms of any grade from two 
different categories in the symptom scoring 
system, or one Grade 2 symptom from any 
category compared to placebo.

Occurrence of symptomatic RSV infection plus 
symptoms of any grade from two different 
categories from the SSC or two quantifiable RT-
PCR measurements plus any Grade 2 symptom 
from any category.
The three SSC categories are:
o
Upper Respiratory symptoms: runny nose, 
stuffy nose, sneezing, sore throat, earache
o
Lower Respiratory symptoms: cough, 
shortness of breath, chest tightness, wheeze
o
Systemic symptoms: malaise, headache, 
muscle and/or joint ache, 
chilliness/feverishness.

To assess a trend for prophylactic efficacy of a 
single dose of 1x1011 vp of Ad26.RSV.preF in the 
RSV challenge model in terms of prevention of 
symptomatic RSV infection and one or more 
positive clinical symptoms of any grade in any 
category from the symptom scoring system 
compared to placebo.

Occurrence of RSV infection plus any clinical 
symptom of any severity.

To assess a trend for prophylactic efficacy of a 
single dose of 1x1011 vp of Ad26.RSV.preF in the 
RSV challenge model in terms of the weight of 
mucous secretions and tissue count over time 
compared to placebo.

Total weight of mucus produced and tissue count.

To assess the safety and tolerability of a single 
dose of 1x1011 vp of Ad26.RSV.preF 
administered intramuscularly.

SAEs throughout the study (from signing the ICF 
to the end of the study, 6 months after 
vaccination).


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Objectives
Endpoints

Solicited local and systemic AEs for 7 days after 
vaccination.

Unsolicited AEs from ICF signature until 28 days 
after vaccination, and from the entry into the Unit 
until 28 days after challenge.

Safety data including, but not limited to, physical 
examinations, vital signs, 12-lead ECGs and 
clinical laboratory results (including 
biochemistry, hematology, and urinalysis).
EXPLORATORY

To assess a trend for prophylactic efficacy of a 
single dose of 1x1011 vp of Ad26.RSV.preF in the 
RSV challenge model in terms of clinical 
symptoms as measured by the AUC over time of 
symptoms collected by a graded symptom scoring 
system compared to placebo.

AUC of the total clinical symptom score.
The total clinical symptom score is a composite of 
13 self-reported symptoms (on the SSC) divided 
into three categories (Upper Respiratory, Lower 
Respiratory, Systemic).

To assess a trend for prophylactic efficacy of a 
single dose of 1x1011 vp of Ad26.RSV.preF in the 
RSV challenge model in terms of VL-AUC 
compared to placebo.

VL-AUC of RSV-A Memphis 37b, determined by 
quantitative culture of RSV of nasal wash 
samples.

To explore the relationship of humoral and 
cellular immunogenicity outcomes (including 
nasal wash if feasible) and the VL-AUC and the 
AUC for clinical symptoms.

AUC of the total clinical symptom score.

VL-AUC of RSV-A Memphis 37b.

RSV pre-F and post-F antibodies from serum and 
nasal wash samplesa measured by ELISA.

Cellular immunity measured by IFNγ ELISpot 
assay, flow cytometry cytokine analysis and/or 
secreted cytokines.

To assess a trend for prophylactic efficacy of a 
single dose of 1x1011 vp of Ad26.RSV.preF in the 
RSV challenge model in terms of prevention of 
symptomatic RSV infection and/or positive 
serological measurement of RSV infection in the 
context of immunization and pre-existing 
antibody and one or more positive clinical 
symptoms of any grade in any category compared 
to placebo.

Symptoms of any grade from any categories of the 
SSC.

Proportion of subjects with symptomatic RSV 
infection (RT-PCR or serology).

Neutralizing antibody against RSV-Memphis 37b 
(challenge strain) and RSV A2.

To assess a trend for prophylactic efficacy of a 
single dose of 1x1011 vp of Ad26.RSV.preF in the 
RSV challenge model in terms of respiratory 
parameters measured by spirometry during the 
study compared to placebo.

Respiratory parameters: spirometry (FEV1, FVC, 
FEV1/FVC).

To explore the relationships between clinical 
symptoms and viral load, as measured by RT-
PCR and quantitative culture of RSV, in 

RT-PCR and quantitative culture of RSV.

Symptoms of any grade from any categories of 
the SSC.
                                                
a Assumes that the ELISA for nasal wash samples will be available.


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Objectives
Endpoints
Ad26.RSV.preF subjects and placebo.

To explore other immunologic parameters in 
relation to the VL-AUC by RT-PCR and AUC for 
clinical symptoms and occurrence of 
symptomatic RSV infection or more plus one 
clinical symptom of any grade.

RT-PCR and quantitative culture of RSV.

VL-AUC of RSV-A Memphis 37b.

Symptoms of any grade from any categories of 
the SSC.

AUC of the total clinical symptom score.

To explore the immune response of a single dose 
of 1x1011 vp of Ad26.RSV.preF compared to 
placebo.

Evaluation of vaccine-specific responses before 
challenge by F-protein specific humoral responses 
measured by binding and/or VNA, and increase in 
cellular responses as measured by ELISpot and/or 
ICS.

To explore humoral and cellular responses to 
challenge with RSV-A Memphis 37b in 
immunized and non-immunized subjects.

ELISA (pre-F, total), neutralization, cellular (IFN 
ELISpot, flow cytometry.

Additional exploratory analyses may be 
performed to investigate vaccine-elicited immune 
responses further.

RSV cross-neutralization of B and/or other A 
strain.

F-protein antibody specificity characterization.

Adenovirus neutralization assay.

Functional and molecular antibody 
characterization.

To explore other potential efficacy endpoints, as 
defined in the SAP, to determine the best efficacy 
endpoint to use in subsequent clinical studies 
investigating the vaccine’s efficacy.
Note: Symptomatic RSV infection is defined as two quantifiable RT-PCR measurements at different timepoints


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Attachment 3: Sample Subject Symptom Card
CCI


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Attachment 4: Expected Symptoms after Challenge with the Memphis RSV Strain
The following are expected symptoms after viral challenge and should not be classified as AEs:
Runny nose, stuffy nose, sneezing, sore throat, ear ache, malaise, headache, muscle and/or joint 
ache, chilliness/feverishness, cough, chest tightness, shortness of breath and wheeze.
Any symptom not in the above list would be an unusual observation and should be recorded as 
an AE at the discretion of the PI.


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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully 
informed regarding the study 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):
ADRIAN CAPLANUSI, MD
Institution:
Janssen Vaccines & Prevention B.V.
Signature:
electronic signature appended at the end of the protocol
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
LAST PAGE


 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adrian Caplanusi
24Jul2018, 13:51:52 PM, UTC
Document Approval

SAP_001.pdf: 
Approved, Date: 30 July 2018
1
Janssen Vaccines & Prevention B.V.
Statistical Analysis Plan
An Exploratory, Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Prophylactic Efficacy of a Single Immunization of Ad26.RSV.preF Against 
Respiratory Syncytial Virus Infection in a Virus Challenge Model in Healthy 18 to 50
Year-Old Adults
Protocol VAC18193RSV2002; Phase 2a
VAC18193  (JNJ-64400141)
Status:
Approved
Date:
30 July 2018
Prepared by:
Janssen Vaccines & Prevention B.V.
Document No.: EDMS-ERI-151399729
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
NCT03334695


VAC18193  (JNJ-64400141)
Statistical Analysis Plan VAC18193RSV2002
Approved, Date: 30 July 2018
2
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES.......................................................................................................................... 3
ABBREVIATIONS ........................................................................................................................................ 4
DEFINITION OF TERMS .............................................................................................................................. 4
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Trial Objectives ................................................................................................................................ 5
1.2.
Trial Design ...................................................................................................................................... 7
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 7
1.4.
Sample Size Justification ................................................................................................................. 7
1.5.
Randomization and Blinding ............................................................................................................ 8
2.
CHANGES TO PLANNED ANALYSES.............................................................................................. 8
3.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 8
3.1.
Study phases ................................................................................................................................... 8
3.1.1.
Phase definitions .......................................................................................................................... 9
3.2.
Pooling Algorithm for Analysis Centers.......................................................................................... 10
3.3.
Analysis Sets.................................................................................................................................. 10
3.3.1.
Full Analysis Set (FA) ................................................................................................................. 10
3.3.2.
Intent -to-Treat-Challenge Set (ITTc) ......................................................................................... 10
3.3.3.
Immunogenicity Analysis Set...................................................................................................... 10
4.
DATA MONITORING COMMITTEE REVIEW................................................................................... 10
5.
SUBJECT INFORMATION................................................................................................................ 11
5.1.
Demographics and Baseline Characteristics ................................................................................. 11
5.2.
Disposition Information................................................................................................................... 11
5.3.
Protocol Deviations ........................................................................................................................ 11
5.4.
Concomitant Medications............................................................................................................... 12
6.
EFFICACY ......................................................................................................................................... 12
6.1.
Primary Efficacy Endpoint.............................................................................................................. 12
6.1.1.
Primary Efficacy Analysis ........................................................................................................... 13
6.2.
Secondary and Exploratory Efficacy Endpoints............................................................................. 14
6.2.1.
Secondary and Exploratory Efficacy Endpoint Analysis............................................................. 16
7.
SAFETY............................................................................................................................................. 17
7.1.
Adverse Events (AE)...................................................................................................................... 17
7.1.1.
Definitions ................................................................................................................................... 17
7.1.2.
Analysis of Adverse Events ........................................................................................................ 17
7.1.3.
Phase allocation of Adverse Events........................................................................................... 18
7.1.4.
Missing Data ............................................................................................................................... 19
7.1.5.
Solicited Local (Injection Site) Reactions ................................................................................... 19
7.1.6.
Solicited Systemic Adverse Events ............................................................................................ 19
7.2.
Clinical Laboratory Tests................................................................................................................ 20
7.3.
Vital Signs and Physical Examination Findings ............................................................................. 21
7.4.
Electrocardiograms ........................................................................................................................ 22
8.
IMMUNOGENICITY ........................................................................................................................... 24
8.1.
Exploratory Parameters ................................................................................................................. 24
8.2.
Handling of Missing and/or Unquantifiable Immune Response Data ............................................ 25
8.3.
Immune Response Analysis .......................................................................................................... 26
8.3.1.
Immunogenicity against the insert:............................................................................................. 26


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Statistical Analysis Plan VAC18193RSV2002
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8.3.1.1.
Humoral assays....................................................................................................................... 26
8.3.1.2.
Cellular assays ........................................................................................................................ 26
8.3.2.
Immunogenicity against the vector ............................................................................................. 27
9.
EFFICACY VERSUS IMMUNOGENICITY ........................................................................................ 27
ATTACHMENTS......................................................................................................................................... 28
Attachment 1: Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials ............................................................. 28
Attachment 2: Transforming the on-site assessments and diaries of solicited AEs into analysis 
format ............................................................................................................................................. 31
LIST OF IN-TEXT TABLES 
Table 1:
Study Design............................................................................................................................... 7
Table 2:
Phase Definitions........................................................................................................................ 9
Table 3:
Spirometry Clinical Important Limits ......................................................................................... 16
Table 4:
Vital Signs Toxicity.................................................................................................................... 21


VAC18193  (JNJ-64400141)
Statistical Analysis Plan VAC18193RSV2002
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ABBREVIATIONS
AE
adverse event
AUC
Area under the curve
CI
confidence interval
CRF
case report form
CSR
Clinical Study Report
DMC
Data Monitoring Committee
DPS
Data Presentation Specifications
eCRF
ELISA
ELISpot
GMT
FA
electronic case report form
Enzyme-linked immunosorbent assay
enzyme-linked immunospot 
Geometric mean titers
Full Analysis Set
FDA
Food and Drug Administration
ICH
International Conference on Harmonization
ITTc
ICS
Intent-to-Treat-Challenge
Intracellular Cytokine Staining
LLOD
Lower limit of detection
LLOQ
lower limit of quantification
LRTI
lower respiratory tract infection
MedDRA
NA
Medical Dictionary for Regulatory Activities
Not Applicable
PI
principal investigator
PPI
Per-protocol Immunogenicity
RSV
Respiratory syncytial virus
RTI
Respiratory tract infection
SAE
serious adverse event
SAP
Statistical Analysis Plan
SE
TLF
standard error
Tables, Listings and Figures 
ULOQ
Upper limit of quantification 
DEFINITION OF TERMS
Active vaccine
Ad26.RSV.preF
Study vaccine
Ad26.RSV.preF or Placebo


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Statistical Analysis Plan VAC18193RSV2002
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1.
INTRODUCTION
This is the Statistical Analysis Plan (SAP) applicable for the VAC18193RSV2002 trial. This 
SAP is applicable for the following analysis: 

Primary analysis will be performed when all subjects have completed the quarantine phase 
or discontinued earlier. The pre-challenge neutralization and pre-F ELISA, and post 
challenge RT-PCR, nasal mucous and tissue count, and clinical symptom data will be 
available although the analysis may be performed on snapshot data. All other data available 
at the time of primary analysis, including completed cellular data, will be included. 
Preliminary safety data, including Day 28 post-challenge, if available, will also be included.

Final analysis will be performed when all subjects have completed the 6-month safety 
follow-up visit or discontinued earlier.
Depending on when the data are available, the primary and final analysis might be combined.
Additional interim analyses (blinded or unblinded) may be performed during the study for the 
purpose of informing future vaccine-related decisions in a timely manner, or upon health 
authority request.
This document contains all information needed for performing a full efficacy, safety and 
immunogenicity analysis. Which tables, listing and figures (TLF) need to be generated for each 
analysis will be described in separate data presentation specifications (DPS) documents.
1.1.
Trial Objectives
Primary Objective
The primary objective is to assess a trend for the prophylactic efficacy of a single dose of 1x1011
vp of Ad26.RSV.preF administered intramuscularly to adults aged 18-50 years in the RSV 
challenge model in terms of reduction of nasal wash viral load as measured by the area under the 
curve (AUC) over time by quantitative reverse transcriptase-polymerase chain reaction (RT-
PCR) compared to placebo.
Secondary Objectives

To assess a trend for prophylactic efficacy of a single dose of Ad26.RSV.preF in the RSV 
challenge model in terms of reduction of nasal wash viral load as measured by the peak viral 
load of the RT-PCR compared to placebo.

To assess the effect of a single dose of 1x1011 vp of Ad26.RSV.preF on viral load, as 
measured by RT-PCR and quantitative culture of RSV, and clinical symptoms on Day 6 and 
Day 7 post-challenge compared to placebo.

To assess a trend for prophylactic efficacy of a single dose of 1x1011 vp of Ad26.RSV.preF 
in the RSV challenge model in terms of prevention of symptomatic RSV infection defined 
as two quantifiable RT-PCR measurements and one or more positive clinical symptoms of 
any grade from two different categories in the symptom scoring system (Upper Respiratory, 
Lower Respiratory, Systemic), or one Grade 2 symptom from any category compared to 
placebo.


VAC18193  (JNJ-64400141)
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
To assess a trend for prophylactic efficacy of a single dose of 1x1011 vp of Ad26.RSV.preF
in the RSV challenge model in terms of prevention of symptomatic RSV infection defined 
as two quantifiable RT-PCR measurements and one or more positive clinical symptoms of 
any grade in any category from the symptom scoring system compared to placebo.

To assess a trend for prophylactic efficacy of a single dose of 1x1011 vp of Ad26.RSV.preF 
in the RSV challenge model in terms of the weight of mucous secretions and tissue count 
over time compared to placebo.

To assess the safety and tolerability of a single dose of 1x1011 vp of Ad26.RSV.preF 
administered intramuscularly.
Exploratory Objectives

To assess a trend for prophylactic efficacy of a single dose of 1x1011 vp of Ad26.RSV.preF
in the RSV challenge model in terms of clinical symptoms as measured by the AUC over
time of symptoms collected by a graded symptom scoring system compared to placebo.

To assess a trend for prophylactic efficacy of a single dose of 1x1011 vp of Ad26.RSV.preF
in the RSV challenge model in terms of AUC for viral load (VL-AUC), as measured by
quantitative culture of RSV from nasal wash samples, compared to placebo.

To explore the relationship of humoral (including nasal wash samples if feasible) and
cellular immunogenicity outcomes and the VL-AUC and the AUC for clinical symptoms.

To assess a trend for prophylactic efficacy of a single dose of 1x1011 vp of Ad26.RSV.preF
in the RSV challenge model in terms of prevention of symptomatic RSV infection defined 
as two quantifiable RT-PCR measurements and/or positive serological measurement of RSV
infection in the context of immunization and pre-existing antibody and one or more positive
clinical symptoms of any grade in any category compared to placebo.

To assess a trend for prophylactic efficacy of a single dose of 1x1011 vp of Ad26.RSV.preF 
in the RSV challenge model in terms of respiratory parameters measured by spirometry 
during the study compared to placebo.

To explore the relationships between clinical symptoms and viral load, as measured by RT-
PCR and quantitative culture of RSV, in Ad26.RSV.preF subjects and placebo.

To explore other immunologic parameters in relation to the VL-AUC by RT-PCR and AUC 
for clinical symptoms and occurrence of symptomatic RSV infection defined as two 
quantifiable RT-PCR measurements or more plus one clinical symptom of any grade.

To explore the immune response of a single dose of 1x1011 vp of Ad26.RSV.preF compared 
to placebo.

To explore humoral and cellular responses to challenge with RSV-A Memphis 37b in 
immunized and non-immunized subjects.

To explore the relationship between immunogenicity and pre-existing Ad26 neutralizing 
antibody.

To explore other potential efficacy endpoints, as defined in the statistical analysis plan 
(SAP), to determine the best efficacy endpoint to use in subsequent clinical studies 
investigating the vaccine’s efficacy.


VAC18193  (JNJ-64400141)
Statistical Analysis Plan VAC18193RSV2002
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1.2.
Trial Design
This is a single center, randomized, placebo-controlled, double-blind Phase 2a human challenge 
study, to be conducted in approximately 44 healthy male and female subjects aged 18-50 years 
who have been pre-screened for susceptibility to RSV infection, ie, have levels of RSV 
neutralizing antibodies compatible with susceptibility to RSV infection.
Subjects will receive single intramuscular doses of 1x1011 vp of Ad26.RSV.preF or placebo. 
More than 44 subjects will be vaccinated to account for withdrawals between vaccination and 
challenge. The challenge study site, hVIVO, has the capacity to challenge and house under 
isolation 22 subjects at a time and thus the study will be conducted in several cohorts with up to
22 subjects per cohort. Within each cohort, subjects will be randomized 1:1 to 1x1011 vp of 
Ad26.RSV.preF or placebo. A schematic overview of the study design and groups is depicted in 
Table 1.
Table 1:
Study Design
Group
N
Day -28
Day 0*
Group 1
22
Ad26.RSV.preF (1x1011 vp)
Challenge with RSV-A
Memphis 37b**
Group 2
22
Placebo
* ie, not less than 24 or more than 90 days after vaccination.
**Subjects will be challenged in two or more cohorts of up to 22 subjects per cohort. Within each cohort, subjects will be 
randomized 1:1 to 1x1011 vp of Ad26.RSV.preF or placebo.
Note: The infection rate (based on mucus weight, symptoms and viral shedding) in the placebo group will be followed on an 
ongoing basis by an unblinded individual who does not have any other study function to ensure a sufficient infection rate has
occurred. If the infection rate is lower than anticipated, additional subjects may be enrolled, initially four additional subjects in 
each arm and up to 70 in total. This is to ensure that a high enough number of evaluable subjects is reached in each arm.
For further information related to the design of the study refer to CTP, Section 3.1. 
1.3.
Statistical Hypotheses for Trial Objectives
The primary hypothesis is that a single dose of 1x1011 vp of Ad26.RSV.preF shows a trend of 
reduction in VL-AUC of the quantitative RT-PCR in healthy subjects challenged intranasally 
with the RSV-A Memphis 37b virus, compared with healthy subjects given placebo who are 
similarly challenged. For further information refer to CTP, Section 2.2. 
1.4.
Sample Size Justification
A sample size of 44 challenged subjects (22 vaccinated and 22 placebo subjects) was chosen as 
this would provide sufficient evidence to assess if the challenge model is a reasonable approach 
to examine vaccine efficacy. 
As this is an exploratory study, the statistical assumptions taken for the calculation of the sample 
size will need to be demonstrated to be correct for the analysis to be conducted as planned. For 
example, if the infection rate, from the study is considerably below 65% then the study will be 
considered to be underpowered to be able to accurately determine the stated aims. The 65% 
infection rate used for the sample size calculations is referring to 65% of the placebo subjects 
having detectable viral loads. The infection rate in the placebo group will be followed on an 
ongoing basis by an unblinded individual who does not have any other study function to ensure a 


VAC18193  (JNJ-64400141)
Statistical Analysis Plan VAC18193RSV2002
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sufficient infection rate has occurred. More details regarding the infection rate monitoring are 
outlined in the monitoring plan. For further information related to the sample size justification of 
the study refer to CTP, Section 11.2. 
1.5.
Randomization and Blinding
Please refer to CTP, Section 5.
2.
CHANGES TO PLANNED ANALYSES
The CTP states that only abnormality in ECG parameters will be listed. Moreover, all ECG 
parameters collected during the quarantine period will also be summarized in tables as described 
in the Section 7.4
In addition, a sensitivity analysis of the primary endpoint is added.  At the time of the final 
analysis the quantitative RT-PCR assay values under the lower limit of quantification (LLOQ) 
will be distinguished between ‘Detected’ (values between the lower limit of quantification and 
the limit of detection) and ‘Not detected’ (values bellow the limit of detection) values, and the 
primary end point will be recalculated as indicated in Section 6.1.1.
3.
GENERAL ANALYSIS DEFINITIONS
3.1.
Study phases
The baseline (or reference) value for safety and immunogenicity analysis will be defined as the 
value of the last available assessment prior to vaccination (Day -28). For ECG values the 
baseline (or reference) value will be defined as the value of the last available assessment prior to 
challenge on Day 0, since ECGs for safety assessment are performed only during the challenge 
period.
The baseline (or reference) value for the efficacy analysis will be defined as the value of the last 
available assessment prior to challenge on Day 0.
The safety analysis will present all results by period, based on the phase definition in 
Section 3.1.1.
The immunogenicity analysis will summarize all results in the following immunogenicity 
timepoints:

Baseline (vaccination)

28 days post-vaccination*

28 days post-challenge 
*Includes all assessments taken between 22 and 33 days after vaccination.
In case there are subjects for which samples were taken later than 33 days after vaccination, the 
results will appear in listings. 


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Statistical Analysis Plan VAC18193RSV2002
Approved, Date: 30 July 2018
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Moreover, 
Study Day = visit date - date of Vaccination
Listings will be shown per phase and time point. 
3.1.1.
Phase definitions
The phases in the study will be constructed as follows:
Table 2:
Phase Definitions
Phase
Phase #
Period
Period 
#
Interval
From
To
Screening
1
Date and time of signing 
the 
informed 
consent 
forma
One minute prior to start of post-
dose period
Vaccination
2
Post-Dose 
1
Date and time of 
vaccination 
Minimum of: 
a)
23:59 on 32 days after the 
vaccination (23:59 of day of 
vaccination + 32 days)
b)
23:59 
at 
the 
date 
of 
database cut-off date in case 
of interim
c)
One minute prior to date 
and time of the challenge
d)
23:59 at the date of last 
contact 
(for 
early 
discontinuation)
Follow-up 
Vaccination 
3
One minute after Post-
Dose period end
Minimum of: 
a)
23:59 at the date of last 
contact 
(for 
early 
discontinuation)
b)
23:59 
at 
the 
date 
of 
database cut-off date in case 
of interim
c)
One 
minute 
prior 
to 
Challenge
Challenge
4
Post-
Challenge  
2
Date and time of 
challenge (Study Day 0)
Minimum of: 
a)
Maximum (28 days after 
challenge at 23.59, 
scheduled visit 4 weeks 
after challenge at 23:59)
b)
23:59 
at 
the 
date 
of 
database cut-off date in case 
of interim
c)
23:59 at the date of last 
contact (for early 
discontinuation)
Follow-up 
Challenge
5
One minute after Post-
Challenge period end
Minimum of:
a)
23:59 
at 
the 
date 
of 
database cut-off date in case 
of interim
b)
23:59 at the date of last 
contact. (for completed or 
discontinued subjects)
a in case an earlier date is available (eg. for lab or vital signs), then use the very first date to include all data


VAC18193  (JNJ-64400141)
Statistical Analysis Plan VAC18193RSV2002
Approved, Date: 30 July 2018
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The Follow-up Vaccination phase will only be created in case a subject was challenged to the 
later than 32 days after vaccination. Moreover, if for one subject no challenge was performed, 
the Follow-up Vaccination phase should be created and to capture any observations after the 
Vaccination phase.
3.2.
Pooling Algorithm for Analysis Centers
No pooling algorithm will apply, only one site will be used.
3.3.
Analysis Sets
Vaccination assignment will follow the as-treated principle.
3.3.1.
Full Analysis Set (FA)
The Full Analysis (FA) Set includes all subjects who were randomized and received at least one 
dose of study vaccine, regardless of the occurrence of protocol deviations. All safety analyses 
will be based on the FA set. As a sensitivity analysis, key immunogenicity tables will also be 
based on the FA set.
3.3.2.
Intent -to-Treat-Challenge Set (ITTc)
The Intent-to-Treat-Challenge (ITTc) population is a subset of the FA set that includes all 
randomized, vaccinated and challenged subjects. All efficacy analyses will be performed on the 
ITTc population. Important subject information tables might be repeated based on the ITTc 
population as well.
3.3.3.
Immunogenicity Analysis Set
The Per-protocol Immunogenicity (PPI) Set will include all randomized and vaccinated 
subjects for whom immunogenicity data are available, excluding subjects with major protocol 
deviations expecting to impact the immunogenicity outcomes.
In addition, for subjects who experience a natural RSV infection (based on RT-PCR, or other 
sources), samples taken after the natural infection will not be included in the PPI set.
The analysis of immunogenicity will be based on the PPI set.
4.
DATA MONITORING COMMITTEE REVIEW
An internal data monitoring committee (DRC) will be commissioned for this study, comprised of 
sponsor personnel not directly involved in the conduct of the study, who have expertise in 
clinical study conduct and vaccines. There are no planned DRC reviews. The DRC will only 
convene to discuss any significant or unexpected safety issues. The investigator and SRP will 
inform the DRC of any AE of concern.  In such a case, the study team or DRC members will 
indicate which analyses are needed, with this SAP serving as a guidance. If deemed necessary 
for safety review, the DRC may request the randomization codes and review unblinded data, if 
applicable.


VAC18193  (JNJ-64400141)
Statistical Analysis Plan VAC18193RSV2002
Approved, Date: 30 July 2018
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5.
SUBJECT INFORMATION
Subject information will be shown for the Full Analysis set.
5.1.
Demographics and Baseline Characteristics
Demographic characteristics and screening/baseline characteristics will be tabulated and 
summarized with descriptive statistics per vaccine regimen and over all subjects.
The following demographic and baseline characteristics will be summarized.

Sex (Female/Male)

Age (years)

Race

Ethnicity

Height (cm)

Weight (kg)

BMI (kg/m2)
5.2.
Disposition Information
The number and percentage of subjects 

screened

in the FA set

in the PPI 

in the ITTc set 

randomized, vaccinated and challenged 

randomized, vaccinated and not challenged 

not randomized, not vaccinated 

not randomized, vaccinated 

randomized, not vaccinated 
Discontinued subjects (study, vaccination discontinuation and discontinuation from challenge) 
with the reason of discontinuation will be tabulated per vaccine group and overall.
Also, the number of subjects and percentage per phase will be tabulated.
5.3.
Protocol Deviations
Major protocol deviations will be summarized.


VAC18193  (JNJ-64400141)
Statistical Analysis Plan VAC18193RSV2002
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5.4.
Concomitant Medications
The analysis of concomitant therapies will be done using the WHO drug coded terms.
There will be special attention to analgesics/antipyretics such as acetaminophen, non-steroidal 
anti-inflammatory drugs (NSAIDs) and aspirin, administered during 8 days following each 
vaccination (00:00 of day of vaccination + 7 days). 
Based on their start and stop date, concomitant therapies will be reported in each applicable
phase.
If a concomitant therapy record misses components of its start and/or stop dates (day and/or
month and/or year):

In case of partial start or stop dates, the concomitant therapy records will be allocated to
periods using the available partial information, without imputations. If, for example, 
only month and year are available, these will be compared to the month and the year of 
the periods, and the concomitant therapy record will be allocated to the period(s) where 
these date parts match. This rule may lead to assignment to multiple periods.

In case of a completely missing start date, the concomitant therapy will be considered as 
having started before the trial.
In case of a completely missing end date, the concomitant therapy will be considered as ongoing 
at the end of the trial.
6.
EFFICACY 
6.1.
Primary Efficacy Endpoint
The primary endpoint is the area under the viral load-time curve (VL-AUC in log10 copies/ml) of
RSV-A Memphis 37b as determined by quantitative RT-PCR assay of nasal wash samples. Nasal 
wash samples are taken every 12 (±1) hours beginning two days (ie, in the morning) after 
inoculation of the challenge virus. VL-AUC is calculated based on the viral load values 
measured twice daily, starting with the baseline value, and ending with the last available value 
before discharge.
In the calculation of the AUC, not only the date, but also the timing (the real hours, minutes and 
seconds as captured in the database should be used, but the AUC result should be reported in 
hours), of the assessment, is taken into account:
  = ∑
[()]

[ −()]


                                             (1)
where 
 = ()  !"#$ 
% = ()  !"#$ ( −1)
' = (  !"#$ 


VAC18193  (JNJ-64400141)
Statistical Analysis Plan VAC18193RSV2002
Approved, Date: 30 July 2018
13
% = )*(  !"#$ )!* ℎ!$,! 
-./0 = #,%1 2* #3   ()  !"#$ 
-./(04) = #,%1 2* #3   ()  !"#$ ( −1)
6.1.1.
Primary Efficacy Analysis
For this primary efficacy endpoint, the exact Wilcoxon Rank Sum test will be performed and the 
one-sided p-value will be interpreted at the 5% and 20% significance level, specifically only 
analysing the statistical significance of a reduction in VL-AUC in the active versus placebo 
groups.
At the time of database lock of the primary analysis, the results of the quantitative RT-PCR assay 
will be reported as:

Either an actual viral load value in log10 copies/mL

Or ‘Not Quantifiable’ for values below lower limit of quantification (LLOQ).
At the time of database lock of the final analysis, additional detail will be added for the values 
below the lower limit of quantification and results will be reported at that time as:

Either an actual viral load value in log10 copies/mL

‘Detected’ for value between the lower limit of quantification (LLOQ) and the limit of 
detection (LOD) of the assay

‘Not Detected’ for values below the LOD of the assay
For the primary analysis, values below the LLOQ (indicated as ‘Not Quantifiable’ in the 
database) will be imputed with 0.
At the time of the final analysis, the same analysis will be repeated, so values below the LLOQ 
(indicated as ‘Detected’ or ‘Not Detected’) will be imputed   with0. 
As a sensitivity analysis at the time of final analysis, the analysis will be repeated but now 
imputing the ‘Detected’ with LLOQ/2 and the ‘Not Detected’ with 0.
These imputations will be used when calculating the AUC based on equation (1).  In addition, in 
case there are missing results in the first timepoint after challenge and/ or the last timepoint after 
challenge of the AUC, the missing value should be imputed with 0. No other missing values will 
be imputed.   


VAC18193  (JNJ-64400141)
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6.2.
Secondary and Exploratory Efficacy Endpoints
The secondary efficacy endpoints are the following:

Total clinical symptom score over time, with special interest to day 6 and 7. The total 
clinical symptom score is determined as the sum of the scores (grades) of the 13 self-
reportable symptoms on the Subject Symptoms Card (SSC). 
Note: ‘The symptom scores will be translated into numerical values as follows:
0 = ‘I have No symptom’
1 = ‘just noticeable’
2 =’ It’s clearly bothersome from time to time, but it doesn’t stop me from participating 
in activities’
3 =’It’s quite bothersome most or all the time and it stops me from participating in 
activities’
4 =’ Symptoms at rest’

The viral load of RSV-A Memphis 37b as determined by quantitative RT-PCR assay of 
nasal wash samples over time, with special interest on Day 6 and Day 7 post challenge.

The peak viral load is defined as the maximum viral load as determined by quantitative RT-
PCR assay of nasal wash samples, observed over the whole quarantine period.

The viral load of RSV-A Memphis 37b as determined by quantitative culture of RSV of 
nasal wash samples and the corresponding AUC, with special interest on Day 6 and Day 7 
post challenge. The AUC will be calculated based on equation (1). In case the first timepoint 
after challenge and/ or last timepoint after challenge is missing, it will be set to zero. No other 
missing time point will be imputed.
The viral load values from the quantitative culture of RSV (plaque assay) range from 1.70 to 
5.90 in log10 PFU/ml. The following imputation rules will be used:
o
<1.70 log10 PFU/ml not detected -> 0 
o
<1.70 log10 PFU/ml detected -> 1.70 
o
<2.70 log10 PFU/ml not detected -> 0
o
<2.70 log10 PFU/ml detected -> 2.70 
o
>5.90 log10 PFU/ml -> 6.00 
o
INVALID -> missing

Weight of mucus produced over time and the corresponding AUC. The AUC will be 
calculated based on equation (1). In case the first timepoint after challenge and/ or last time 
point after challenge is missing, it will be set to zero, no other missing time point will be 
imputed.

Number of tissues used per time point.


VAC18193  (JNJ-64400141)
Statistical Analysis Plan VAC18193RSV2002
Approved, Date: 30 July 2018
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
Proportion of subjects with symptomatic RSV infection. Symptomatic RSV infection is 
defined in two ways:
o
Conservative: the subject has two or more quantifiable RT-PCR measurements on 
different samples and the subject has one of the following:

symptoms from two different categories (Upper Respiratory, Lower 
Respiratory, Systemic) from the SSC, regardless of grade and assessment 
timepoint OR

any Grade 2 symptom from any category.
o
Liberal (RT-PCR): two or more quantifiable RT-PCR measurements plus any 
clinical symptom of any severity from the SSC.
The SSC categories are defined as follows:
o
Upper Respiratory symptoms: runny nose, stuffy nose, sneezing, sore throat, 
earache
o
Lower Respiratory symptoms: cough, shortness of breath, chest tightness, wheeze
o
Systemic symptoms: malaise, headache, muscle and/or joint ache, chilliness/ 
feverishness
Note: the quantifiable RT-PCR assessment and the symptoms should not necessarily occur at the 
same day.
The exploratory efficacy endpoints are the following:

Proportion of subjects with symptomatic RSV infection based on RT-PCR or serology.  
Symptomatic RSV infection is defined as:

Liberal (RT-PCR or Serology): the subject has two or more quantifiable RT-PCR 
measurements or serology confirmation of RSV (4-fold increase in G a or G b Elisa, 28 
days after challenge), and any clinical symptom of any severity.

AUC of the total clinical symptom score. The AUC for the total clinical symptom score will 
be calculated based on equation (1). In case the first and/or last time point is missing, it will be 
set to zero, no other missing time point will be imputed.

Clinical symptom scores per item over time

Respiratory parameters measured by spirometry:

Forced expiratory volume in 1 second (%) – FEV1

Forced vital capacity (%) – FVC

FEV1/FVC Ratio (%) – FEV1/FVC


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6.2.1.
Secondary and Exploratory Efficacy Endpoint Analysis
For viral loads of RSV-A Memphis 37b as determined by quantitative RT-PCR assay and by 
quantitative culture of RSV, number of observations, mean, standard error, median, first and 
third interquartile will be tabulated and means with standard errors will also be graphically 
presented per time point. 
For clinical symptoms scores, total clinical symptom scores, mucus weight and number of 
tissues, number of observations, mean, standard error, median, first and third interquartile will be 
tabulated and means with standard errors will also be graphically presented per time point. 
For peak viral load based on the quantitative RT-PCR assay, number of observations, mean, 
standard error, median, first and third interquartile will be tabulated for both groups and 
graphically presented with boxplots. Exact Wilcoxon Rank Sum tests will also be performed to 
compare the mean in the active versus placebo groups and the corresponding p-values will be 
presented. Note the study is only powered for the primary efficacy endpoint and not for any of 
the secondary one, interpreting these p-values should be done with caution.
For AUCs of viral loads, clinical symptoms and mucus weight, number of observations, mean, 
median, first and third interquartile (q1, q3) will be calculated for both groups and graphically 
presented with boxplots. Exact Wilcoxon Rank Sum tests will also be performed to compare 
AUCs in the active versus placebo groups and the corresponding p-values will be presented. 
Note the study is only powered for the primary efficacy endpoint and not for any of the 
secondary one, interpreting these p-values should be done with caution. 
Descriptive statistics (number of observations, mean, standard errors, median, q1, q3) of values 
and changes from baseline for FEV1, FVC, and FEV1/FVC will be summarized at each 
scheduled timepoint. Mean with standard errors of actual values and changes from baseline will 
also be graphically presented. Finally, spirometry values that are below the clinically important 
limits, provided in the table below, will be classified as ‘abnormally low’ and the percentage of 
subjects with ‘abnormally low’ values will be summarized.
Table 3:
Spirometry Clinical Important Limits
Parameter 
Clinically Important Limits
FEV1
80%
FVC
80%
FEV1/FVC
70%
The proportion of subjects with symptomatic RSV infection per group for each one of the three 
with symptomatic RSV infection definitions, Conservative, Liberal (RT-PCR), Liberal (RT-PCR 
or Serology), will be tabulated and presented graphically with bar charts. Moreover, the 
difference in proportions and corresponding confidence intervals (CIs) will be calculated, if 
available.  These will also be presented graphically with a forest plot.


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The relation between viral load and clinical symptoms will be graphically explored. Moreover, 
summary statistics of efficacy endpoints might be repeated, for the infected and for the not 
infected subjects based on the three symptomatic RSV infection definitions. 
Finally, subject specific profiles of viral loads total clinical symptom scores, mucus weight and 
tissue count will be created.
7.
SAFETY
Safety analyses will be performed on the FA. Continuous variables will be summarized using the 
following statistics, as appropriate: number of observations, median, quartiles (Q1 and Q3), 
minimum and maximum. Frequencies and percentages (one decimal place) will be generated for 
categorical variables. No formal comparisons between groups will be provided. 
One type of safety tables will be shown. The by regimen layout, safety data will be analyzed by 
vaccine regimens as designed per protocol; data will be presented by period. Denominator for the 
percentages is the number of subjects in the considered population and period for a certain 
regimen (incidence per 100 subjects/phase).
7.1.
Adverse Events (AE)
7.1.1.
Definitions
Solicited AEs, collected for 7 days after vaccination, shown in the tables are extracted from the 
diary pages of the CRF. For unsolicited AEs, only AEs with start date (grade and/or relation) 
within the 28-day period following vaccination or challenge will be presented in the safety tables 
except for SAE, which will be captured and tabulated in the outputs covering the whole study 
period. All other collected unsolicited adverse events will be presented through listings.
Solicited local AEs will be by definition considered as related to the study vaccine.
The severity of the AEs will be classified as grade 1 to 4. Solicited events that are graded less 
than grade 1, are not considered as AE. In case no grades are available, the grading of the 
solicited events will occur according to the grading list in Attachment 1.
7.1.2.
Analysis of Adverse Events
Number and percentage of subjects with at least one particular AE (unsolicited/solicited) will be 
tabulated. Unsolicited AEs will be summarized by System Organ Class and Preferred Term. 
Solicited AEs will be summarized by class (local, systemic) and preferred term.
For solicited AEs following tables will be provided: summary, by worst severity grade, grade 3, 
related (systemic only), time to onset (in days) and duration (in days) for most frequent events
and body temperature. Note: For solicited events, duration is defined as number of days from the 
start of the event until resolution of the event. The time to first onset is defined as (date of first 
onset – reference date + 1). The reference date is the start date of the regimen period.


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For unsolicited AEs following tables will be provided: summary table (including SAE, fatal 
outcome, AESI and discontinuation), all events, most frequent, grade 3, permanent stop of 
vaccine, related, SAE.
Listings and/or subject narratives will be provided as appropriate, for those subjects who die, 
discontinue study vaccinations due to an AE, or experience a severe or serious AE.
7.1.3.
Phase allocation of Adverse Events
Solicited events are always allocated to the Post Dose period.
Solicited AEs from the diary will be added to the ADAM for unsolicited AEs according to the 
same principles. This means the same event occurring on different days will be allocated to one 
row with the start date of the AE being the first date of the event and the end date for the event is 
the last subsequent day of the event. A change in grade will trigger a new row to be added. The 
same occurs in case of non-subsequent events (for example grade 1 nausea on day 1, 2 and 3 and 
also on day 6 and 7, which will be allocated to two rows; the duration of the event is 7 days). For 
further details related to transforming the on-site assessments and diaries of solicited AEs into 
analysis format please refer to Attachment 2.
Step 1: Allocation of events to the periods:
Adverse events in the SDTM database are allocated to periods based on their start date/time. If 
the start date/time of an event falls between (or on) the start and stop date/time of a period, the 
AE is attributed to that period (treatment-emergent principle).
- In case of partial start or stop dates (i.e. time and/or day and/or month and/or year missing), the 
events are allocated to the periods using the available partial information on start and end date; 
no imputation will be done. If, for instance, the AE start date only month and year are available, 
these data are compared to the month and year information of the periods. This rule may lead to 
multiplication of the event as a consequence of its assignment to multiple periods.
- In case of a completely missing start date, the event is allocated to the first active treatment 
phase (post dose period), except if the end date of the AE falls before the start of the first active 
treatment phase (post dose period).
- In case of a completely missing end date, the date is imputed by the cut-off date of the analysis 
for subjects still ongoing in the study, and by the end date of the last period for subjects who 
discontinued or completed the trial.
Step 2: Combination of events:
Overlapping/consecutive events are defined as events of the same subject with the same 
preferred term which have at least 1 day overlap or for which the start date of an event is 1 day 
after the end date of the preceding event. Overlapping/consecutive events may be combined into 
one AE or not, according to the following rules:


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1) If overlapping/consecutive events start in one of the following periods - Screening or follow 
up (i.e. non-active periods) - followed by an AE in - post-dose or challenge period (active period) 
- they are allocated to their respective periods and are considered as separate events.
2) In case overlapping/consecutive events start within a single period, they are considered as one 
and the same AE. The individual events which contribute to this AE are retained as individual 
records in the ADaM database but are assigned the same onset, period, and total duration. All 
related attributes to the AE/phase/period should also be consistent with the new event.
3) In case overlapping/consecutive events start in both an active period followed by a non active 
period, they are allocated to the active period only and are considered as one and the same AE. 
The individual events which contribute to this AE are retained as individual records in the 
ADaM database but are assigned the same onset, treatment period, and total duration. All related 
attributes to the AE/phase/period should also be consistent with the new event.
4) In case an active period is followed by another active period, and the overlapping/consecutive 
events start in both periods, they are allocated to their respective period and are considered as 
separate AEs. The same rule applies for 2 non-active periods. 
Remarks:
1. Events can only be combined into one and the same AE if their start and stop dates are known.
2. In case the completely missing end date is imputed (for period allocation), this date is also 
considered as a complete date.
3. Time is not considered when determining overlap of events.
7.1.4.
Missing Data
Missing data will not be imputed. Subjects who do not report an event will be considered as 
subjects without an event. The analysis of the solicited AEs will include only documented safety 
data.
7.1.5.
Solicited Local (Injection Site) Reactions 
The analysis of local solicited adverse events, for all subjects after vaccination will include:

Erythema

Induration/swelling

Pain/tenderness
7.1.6.
Solicited Systemic Adverse Events 
The analysis of systemic solicited adverse events for adult subjects after vaccination will include:

Fatigue

Headache


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
Myalgia

Arthralgia

Chills

Nausea

Fever (ie, body temperature ≥ 38 °C)
7.2.
Clinical Laboratory Tests
For laboratory safety parameters, only abnormalities emerging will be tabulated by worst 
abnormality grade using the FDA table in Attachment 1. Blood and urine for laboratory safety 
assessments will be collected within 56 days of vaccination, pre-vaccination, at 7 days post 
vaccination, prior to challenge on Day –1 or Day –2, post challenge at day 12 and Day 28. 
Moreover, blood for assessment of cardiac enzymes will also collected on Days 3, 7, and 11.
An abnormality (toxicity grade or abnormality based on normal ranges) will be considered as 
emerging in a particular period if it is worse than the baseline value. If the baseline is missing, 
the abnormality is always considered emerging. A shift from ‘abnormally low’ at baseline to 
‘abnormally high’ post baseline (or vice versa) is also emerging. In case a laboratory test result is 
censored (no numeric value is available, but only a verbatim term) then a numeric value will be 
imputed by a value exceeding the cut-off value with one unit. (<x: subtract 1 unit from x, >x: add 
1 unit to x; <3.45 is imputed with 3.44).
In case no toxicity grades are defined for a test, the abnormalities (above/below normal range) 
will be used. In determining toxicity grades, the following rules are applied:

worst grades/abnormalities are determined over the whole observational period for each trial 
period separately, including all post-baseline measurements of that period.

The abnormalities ‘abnormally low’ and ‘abnormally high’ are considered equally important, 
i.e. if a subject has as well an abnormally low as an abnormally high value post-baseline, 
both abnormalities are shown in the tables. (This means that the sum of the percentages can 
by more than 100%)

Note: as the grading scale for some parameters in the grading table has some gaps (zones 
where no toxicity grade definition exists), laboratory results falling in these zones will be 
allocated to the adjacent worst-case grade.

If a laboratory value falls within the grading as specified in the grading table but also within 
the local lab normal limits, the value is considered as normal. 

HGB: for hemoglobin grades are based on both actual values and changes. Those grading 
will be listed separately.  In addition, for the grading on the changes of HGB, the 
corresponding actual value should be at least grade 1.


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
Only the lab values are used in determining the toxicity grades. For some lab parameters, 
extra clinical assessments are available to attribute grade 4 toxicity (eg. requiring 
hospitalization or dialysis), but these are not taken into account in the lab analysis
For the grades, no distinction will be made between test results of samples obtained under fasting 
and under non-fasting conditions: in case limits under fasting and non-fasting conditions differ, 
the limits of the conditions (fasting/non-fasting) of scheduled visits as planned in the CTP will 
always be used, also for samples obtained under a different condition (e.g. samples of 
withdrawal visits).
7.3.
Vital Signs and Physical Examination Findings
Similar to laboratory tests, only vital signs abnormalities emerging after vaccination and after 
challenge will be tabulated by worst abnormality grade. 
Heart rate (beats per minutes, bpm), respiratory rate (breaths per minute), systolic blood pressure 
(mmHg) and diastolic blood pressure (mmHg) will be collected. The respective vital signs 
abnormalities are defined in Table 4. Moreover, only the vital signs values will be used, no 
clinical interpretations, therefore, grade 3 and 4 is shown combined as grade 4 always requires 
clinical interpretation.
Table 4:
Vital Signs Toxicity 
Vital Signs 
Grade 1
Grade 2
Grade 3/4
Tachycardia – beats (HR) per minute
101 – 115
116 – 130
>130
Bradycardia – beats (HR) per minute
50 – 54
45 – 49
< 45
Hypertension (systolic) - mm Hg
141 – 150
151 – 155
>155
Hypertension (diastolic) - mm Hg
91 – 95
96 – 100
>100
Hypotension (systolic) - mm Hg
85 – 89
80 – 84
< 80
Respiratory Rate - breaths per minute
17-20
21-25
>25
Temperature from diary and on-site assessments from day of vaccination will be allocated to 
predefined temperature intervals (from 37.5° C until 40°C, in steps of half degree increments; eg 
<37.5, 37.5-<38, 38-<38.5, … >40). A table will be created, showing the maximum temperature 
for both diary and onsite assessments combined.
A listing of temperatures from Day -2 or -1 will also be provided.
Temperature collected during the post challenge period will be summarized descriptively over 
each timepoint.
Finally, a listing of subjects with fever according to the FDA grading table, across the entire 
study period, will be provided.
Any abnormal physical examination result will be documented as AEs, by the investigator.  


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7.4.
Electrocardiograms
ECGs will be carried on Days -2 or -1, 3, 7 and 11 for safety assessment.
The following measurements will be analysed:

HR (bpm)

PR (ms)

QRS (ms)

Uncorrected QT (ms)
QT values will be corrected for RR, even if provided in the DB. The following QT correction 
methods will be used (rounded to the integer value):
5'6( () = 5'( () 78 1000
::( () : Bazett′s square −root corrected QT
5'K( () = 5'( () 78 1000
::( ()
L
: Fridericia′s cube −root corrected QT
If RR is missing, but HR is available from the same ECG reading, the following replacement will 
be made in the above formulas.
1000
::( () = P:(Q" )
60
If HR is missing, it will be calculated using RR (if available) and rounded to the integer value 
(see formula above). HR from the vital signs section (i.e. pulse) will not be used in this ECG 
analysis section.
Any rounding will be performed after computation of the applicable parameters, and before any 
further handling.
Abnormalities for the Actual Values
The actual values for HR, PR, QRS and QTc will be categorized into abnormalities using the
boundaries defined in the following table (Limits in this table overrule those presented in the
protocol.):


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Abnormality Codes
HR
PR
QRS
QTcorrected
“abnormally low”
NAP
NAP
“abnormally high”
≥ 210 bpm
≥ 120 ms
“abnormally low Grade 1”
[50-54]
“abnormally low Grade 2”
[45-49]
“abnormally low Grade 3”
<45 bpm
“abnormally high Grade 1”
[101,115]
“abnormally high Grade 2”
[116,130]
“abnormally high Grade 3”
>130
“]450 ms, 480 ms]”
450 ms < QTc ≤ 480 
ms
“]480 ms, 500 ms]”
480 ms < QTc ≤ 500 
ms
“More than 500 ms”
QTc > 500 ms

No abnormalities will be defined for actual uncorrected QT values.

Uncorrected QT ≥ 500 ms will be flagged and only shown in listings.
Abnormalities on the Changes from Reference (QTc Parameters)
Abnormalities on the change from reference will only be defined for corrected QT, as follows:
1.
< 30 ms
2.
[30; 60] ms
3.
> 60 ms
Only increases by ≥30 ms will be considered as abnormalities.
Note: The QTc definitions for abnormalities follow the ICH E14 guidance.
Parameters to Analyze

actual values: HR, PR, QRS, QT and QTc

abnormality classifications for the actual values: HR, PR, QRS, QTc

abnormality classification for the increases from reference: QTc

worst emergent abnormalities: HR, PR, QRS, QTc, QTc change
Percentages will be calculated relative to the total number of subjects with data.
Note: RR values will only be listed, as well as any original QTc parameter, if provided in the
DB. Recalculated HR values will be flagged.


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In Case of Missing Date or Time Parts
ECG records with missing assessment date- or time-parts (any: day, month or year) will not be 
used for descriptive statistics, unless the scheduled target day or time is known and a unique
study day allocation is possible taking this additional information into account. These 
assessments will be allocated to the right study day using the available date (time) information, 
and the information on their assessment schedule. In case it is not possible to assign a study day 
to those measurements they will only appear in a listing, including a flag.
Emergent Definition for Abnormalities
Abnormalities defined on actual values: the abnormality worsened as compared to the 
abnormality at reference; this also includes the shift from ‘abnormally high’ to ‘abnormally low’
and vice-versa. Post-reference abnormalities are always treatment-emergent with regard to 
missing abnormalities at reference. The abnormalities ‘abnormally high’ and ‘abnormally low’
are considered equally important.
Abnormalities on changes from reference are always defined as emergent (QTc).
8.
IMMUNOGENICITY
The analysis of immunogenicity will use the PPI set.
8.1.
Exploratory Parameters
The following humoral and cellular immune responses may be measured as part of the evaluation 
of exploratory objectives, if available: 
Immunogenicity against the insert:
Humoral immune response

RSV neutralization RSV-A Memphis 37b 

Intranasal pre-F antibody, from nasal wash samples.

RSV F protein enzyme-linked immunosorbent assay (ELISA; pre- and/or post-fusion F 
antibodies). 

RSV G/N ELISA

RSV neutralization A strain (titers of neutralizing antibodies). 

RSV neutralization B and/ or a different A strain (titers of neutralizing antibodies), 

Functional and molecular antibody characterization.
Cell-mediated immune response

ELISpot IFNγ assay (units: SFU/106 PBMC). An ELISpot assay is used to quantify the 
amount of peripheral blood mononuclear cells (PBMCs) able to produce IFNγ upon RSV 
F-protein peptide stimulation.


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
Intracellular cytokine staining (ICS, unit: % of subset) or cytokine analysis. Analysis of CD4 
and CD8 T-cell subsets and their cytokine expression patterns will be determined by flow 
cytometry after RSV F-protein peptide stimulation (including, but not limited to CD4/CD8, 
interleukin-2 [IL-2], IFNγ, TNFα and Th1/Th2 subtyping).
*Cytokine analysis for Th1/Th2 profiling will be done in cases where no ICS data can be 
generated due to insufficient number of PBMCs for ICS assay (see exploratory endpoints 
below for description)

Cytokine analysis, Cytokine profiles of (in vitro) stimulated PBMC supernatant will be 
analysed to assess the quantity and quality of the elicited immune responses, including 
Th1/Th2 balance. Analysis will include, but is not limited to, IFNγ, IL-2, IL-4, IL-5, IL-13, 
and TNFα, if available.
Immunogenicity against the vector:

Adenovirus neutralization assay
This assay assesses neutralizing antibody responses against the Ad26 vectors.
8.2.
Handling of Missing and/or Unquantifiable Immune Response Data 
Missing immune response data will not be imputed.  
Depending on the assay, a lower limit of quantification (LLOQ) will be available or a provisional 
cutoff will be set at the analysis level.  Values below the LLOQ or cut-off will be treated as 
follows:

Values will be imputed based on the type of analysis. For the calculation of the geometric 
mean titer, values below LLOQ will be imputed to LLOQ/2. While for the calculation of the 
geometric mean of the increase from baseline, values below LLOQ will be imputed to 
LLOQ. The LLOQ values per assay are available in the database.

For ICS assays: no valid LLOQ is available.  A provisional cut-off is put at 0.02%.  (only for 
total cytokine response).  For the individual cytokine combinations of IFNg, TNFa and IL2, 
negative values will be imputed with 0.  For descriptive statistics or graphs on actual values,
values below the cut-off will be imputed to a value of cut-off/2. For Th1 and Th2, a 
provisional cut-off of 0.001% is used.  These values might change in the future, depending 
on progressing insight.  For descriptive statistics or graphs on actual values, values below the 
cut-off will be imputed to a value of cut-off/2.

For all assays: values above the upper limit of quantification (ULOQ) will be imputed with 
2xULOQ.


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8.3.
Immune Response Analysis
No formal hypothesis on immunogenicity will be tested.
8.3.1.
Immunogenicity against the insert:
8.3.1.1.
Humoral assays
For VNA and ELISA assays, if available, following results will be calculated: N, geometric 
mean§ and corresponding 95% CI of the actual values and fold increases from baseline will be 
tabulated and graphically presented. §calculate the mean and corresponding 95%CI of the log2 transformed 
values, back-transform this mean [i.e. 2^mean] and CI [i.e. 2^CI].
Tables showing fold increases will also present the percentage of subjects with an x-fold increase 
(for several values of x).
Actual values and fold changes from baseline are tabulated and shown as dot plots with dots for 
subject values, and the corresponding geometric mean and 95% CI per time point for each assay. 
In addition, GMT plots over time, combining the regimens in one graph (without individual 
subject dots) will also be created. 
Ratios of actual values and of fold changes from baseline between humoral assays may also be 
presented.
Subject profiles of the actual values over time will be graphically presented.
Reverse distribution curves of the actual values are provided for selected time points.
In the graphs, original values will be displayed on the log2 scale.
Scatterplot with humoral assays may be provided for the most important time points. In these 
scatter-plots the actual values will be shown, even if they are below the LLOQ, but the LLOQ 
cut-off will be visualized in the graph per assay if some values are below LLOQ. 
8.3.1.2.
Cellular assays
For ICS and PBMC secreted cytokines, if available, analyses may include: 
Total Cytokine response: the % of subsets expressing at least IFNg, TNFa or IL2 will be 
calculated for CD4 and CD8, separately. 
For total cytokine responses, tables with number of observations, median, first and third 
interquartile per timepoint will be provided.
Subject profiles of the actual values over time will be graphically presented.
Actual values are shown as box plots with dots for subject values, and the corresponding median 
and the first and third quartile (Q1, Q3) per time point.


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In addition, box plots over time, combining the regimens in one graph (without individual 
subject dots) will also be created.
For all cytokine combinations (IFNg and/or TNFa and/or IL2) pie charts reflecting the 
distribution of each of the cytokine combinations (the proportion of a specific cytokine 
combination of the CD4 or CD8 T-cells secreting at least one cytokine) and bar charts reflecting 
the median magnitude of each combination will be graphically presented. Tables with the 
corresponding descriptive statistics will be provided.
Th1 and Th2:  Th1 is defined as all CD4+ IFNγ+ and Th2 as all CD4+ IL4+ cells.  Subject 
profiles and graphs of the actual values over time (box-plot type) will be created.  In addition, at 
time points of interest, scatterplots of Th1 vs Th2 might be created.
For the graphs, original values will be displayed on the log10 scale.
The technical details for the calculation of the ICS values to be used in the graphs will be
outlined in the DPS.
For ELISpot, if available following results will be calculated: N, median, quartiles and range of 
the actual values will be tabulated and graphically presented per timepoint. 
Subject profiles of the actual values over time will be graphically presented.
Actual values are shown as box plots with dots for subject values, and the corresponding median 
and interquartile range per time point for each assay. In addition, box plots over time, combining 
the regimens in one graph (without individual subject dots) will also be created. For the graphs, 
original values will be displayed on the log10 scale. Scatterplot with humoral and cellular assays 
may be provided for the most important time points.
8.3.2.
Immunogenicity against the vector
For VNA against the vector, if available following statistics will be calculated: N, geometric 
mean§(see above for the calculation) and corresponding 95% CI of the actual values.
Subject profiles of the assays against the insert will be repeated, highlighting subjects with pre-
existing immunity at baseline against the vectors.
Scatterplots of the Adeno assay versus the assays against the inserts may be provided for the 
most important time points. In these scatter-plots the actual values will be shown, even if they 
are below the LLOQ. 
9.
EFFICACY VERSUS IMMUNOGENICITY
The relationship between immunogenicity parameters and VL-AUC, AUC of clinical symptoms 
and of mucus weight will be graphically explored, with scatterplots for the most important time 
points. Moreover, descriptive statistics of humoral and cellular assays might be presented by 
symptomatic RSV infection definition. 


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ATTACHMENTS
Attachment 1: Guidance for Industry: Toxicity Grading Scale for Healthy Adult 
and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials
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. 
If a laboratory value falls within the grading as specified below but also within the local 
laboratory normal limits, the value is considered as normal.
Blood, Serum, or 
Plasma 
Mild
(Grade 1)
Moderate   
(Grade 2)
Severe
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)
Sodium – Hyponatremia 
mmol/L
132 – 134
130 – 131
125-129
< 125
Sodium – Hypernatremia 
mmol/L
144-145
146 – 147
148-150
>150
Potassium –
Hyperkalemia mmol/L
5.1 – 5.2
5.3 – 5.4
5.5-5.6
>5.6
Potassium –
Hypokalemia mmol/L
3.5-3.6
3.3-3.40
3.1-3.2
<3.1
Glucose – Hypoglycemia 
mmol/L
3.83-3.61
<3.61-3.05
<3.05-2.5
<2.5
Glucose – Hyperglycemia 
Fasting – mmol/L
5.55-6.11
>6.11-6.94
>6.94
Insulin 
requirements or 
hyperosmolar 
coma
Glucose – Hyperglycemia 
Random – mmol/L
6.11-6.94
>6.94-11.10
>11.10
Blood Urea Nitrogen 
mmol/L
8.2-9.3
>9.3 – 11.1
> 11.1
Requires dialysis
Creatinine – umol/L
133 – 150
>150 – 177
>177-221
>221 or requires 
dialysis
Calcium – hypocalcemia 
mmol/L
2.10-2.00
<2.00-1.87
<1.87-1.75
<1.75
Calcium – hypercalcemia 
mmol/L
2.62-2.74
>2.74-2.87
>2.87-3
3
Magnesium –
hypomagnesemia 
mmol/L
0.62-0.53
<0.53-0.45
<0.45-0.37
<0.37
Phosphorous –
hypophosphatemia 
mmol/L
0.81-0.74
<0.74-0.65
<0.65-0.52
0.52
CPK – mg/dL
1.25-1.5xULN
1.6-3.0xUNL
3.1-10xULN
>10 x ULN
Albumin –
Hypoalbuminemia g/L
31-28
<28-25
<25
--
Total Protein –
Hypoproteinemia g/L
60-55
<55-50
<50
--
Alkaline phosphate – U/L
1.1 – 2xULN
2.1-3xULN
3.1-10xULN
> 10 x ULN
AST U/L
1.1-2.5xULN
2.6-5xULN
5.1-10xULN
>10 x ULN


VAC18193  (JNJ-64400141)
Statistical Analysis Plan VAC18193RSV2002
Approved, Date: 30 July 2018
29
Blood, Serum, or 
Plasma 
Mild
(Grade 1)
Moderate   
(Grade 2)
Severe
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)
ALT U/L
1.1-2.5xULN
2.6-5xULN
5.1-10xULN
>10 x ULN
Bilirubin – when LFT is 
normal
1.1-1.5xULN.
1.6-2.0xULN
2.0-3.0 x ULN
>3.0 x ULN
Bilirubin – accompanied 
by graded LFT (ALT or 
AST)
1.1-1.25xULN
1.26-1.5xULN
1.51-1.75 x ULN
> 1.75 x ULN
Amylase- U/L
1.1-1.5xULN.
1.6-2.0xULN
2.1 – 5.0 x ULN
> 5.0 x ULN
Lipase- U/L
1.1-1.5xULN.
1.6-2.0xULN
2.1 – 5.0 x ULN
> 5.0 x ULN
Cholesterol – mmol/L
64.89-67.80
>67.80-72.64
>72.64
--
Hemoglobin (Female) -
g/L
110 – 120
95 – 109
80 – 94
< 80
Hemoglobin (Female) 
change from baseline 
value- g/L
Any decrease –
15
16-20
21 – 50
> 50
Hemoglobin (Male) - g/L
125 -135
105 – 124
85 – 104
< 85
Hemoglobin (Male) 
change from baseline 
value - g/L
Any decrease –
15
16-20
21 – 50
> 50
WBC Increase – 10E9/L
10.8-15.0
>15.0-20.0
>20.0-25
>25
WBC Decrease - 10E9/L
3.5-2.5
<2.5-1.5
1-<1.5
<1
Lymphocytes Decrease -
10E9/L
1.00-0.75
<0.75-0.50
<0.50-0.25
<0.25
Neutrophils Decrease -
10E9/L
2.0-1.5
<1.5-1.0
<1.0-0.5
<0.5
Eosinophils - 10E9/L
0.65-1.50
>1.50-5.00
>5.00
Hypereosinophilic
Platelets Decreased -
10E9/L
140-125
<125-100
<100-25
<25
PT – seconds 
(prothrombin time)
1.0-1.10xULN
1.11-1.20xULN
1.21-1.25xULN
>1.25xULN
PTT – seconds (partial 
thromboplastin time)
1.0-1.2xULN
1.21-1.4xULN
>1.41-1.5xULN
> 1.5 x ULN
Fibrinogen increase –
umol/L
11.76-14.70
>14.70-17.65
>17.65
--
Fibrinogen decrease -
umol/L
5.88-4.41
<4.41-3.68
<3.68-2.94
<2.94 or 
associated with 
gross bleeding or 
disseminated 
intravascular 
coagulation (DIC)
”ULN” is the upper limit of the normal range.


VAC18193  (JNJ-64400141)
Statistical Analysis Plan VAC18193RSV2002
Approved, Date: 30 July 2018
30
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


VAC18193  (JNJ-64400141)
Statistical Analysis Plan VAC18193RSV2002
Approved, Date: 30 July 2018
31
Attachment 2: Transforming the on-site assessments and diaries of solicited AEs 
into analysis format
When creating the analysis dataset for solicited AEs, solicited AEs (recorded by day on the SR 
and FA domains) need to be converted into the same format as unsolicited AEs (recorded by 
event). For this purpose, the start date of the AE will be considered as the date of first occurrence 
of the solicited AE. If on subsequent day(s), the same grade is reported, the last reported date is 
used as the end date of the AE. A new record is created in case the grade of the event changes. If 
there is a time gap of at least one day between two (or more) occurrences of the same solicited 
AE, then the second (and/or next) occurrence will be considered as a new AE. In case no data is 
reported for a day, this is analyzed as no event reported. If the on-site assessment differs in grade 
or relatedness with the Day 1 diary data, the on-site assessment should be recorded as a separate 
record in the database. 
The example below shows how the solicited AE should be converted into a format of unsolicited 
AEs:
Data from the Subject Diary 
Subject: 0001
Solicited systemic AE: Headache
On site 
assessment
DIARY DATA
Solicited 
AE
Day 1 
01Jan16
Day 1
01Jan16
Day 2
02Jan16
Day 3
03Jan16
Day 4
04Jan16
Day 5
05Jan16
Day 6
06Jan16
Day 7
07Jan16
Day 8
08Jan16
Grade
2
1
1
0
3
3
1
0
0
Relatedness Doubtful
Probable
The data should be converted and stored in the AE dataset as follows:
Subject No.
AE
Start Date 
(Char)
Stop Date
(Char)
Severity
Relatedness
AEID
0001
Headache
01Jan16
01Jan16
2
Doubtful
1
0001
Headache
01Jan16
02Jan16
1
Probable
1
0001
Headache
04Jan16
05Jan16
3
Probable
1
0001
Headache
06Jan16
06Jan16
1
Probable
1
If a solicited AE ends after day 8:
-
The last day that AE was reported and the maximum severity (or/and diameter for local AEs) 
after Day 8 are captured in the CRF. For this a separate record needs to be created, in case 
this severity deviates from the previous record.


VAC18193  (JNJ-64400141)
Statistical Analysis Plan VAC18193RSV2002
Approved, Date: 30 July 2018
32
For the calculation of duration, the first and last day is used, irrespective of whether 
interruptions occurred in between by missing reporting days or Grade 0 events. In the above 
example, the 4 records contribute to the same AE, therefore AEID (AE identification) is set to 
the same value and the duration of the AE is set to 6 for all records.
Notes:

For solicited AEs time should not be taken into account to allocate an event to a phase, 
the event is per definition of solicited AEs collected post-dose and should therefore not 
be allocated to inactive phases.

To complete the start and end-date based on diary data, the date will be calculated based 
on the day the AE is reported relative to vaccination and not on the reported date. For 
example, if the vaccination is on 1st JAN2016, and the AE starts on DAY 3, the start date 
will be set to the 3rd of January 2016 independent of the reported actual date.