Clinical trial NCT03303625
Conditions: Respiratory Syncytial Viruses Respiratory Tract Infections
Sponsor: Janssen Vaccines & Prevention B.V.
Start date: 2017-11-29; Completion date: 2020-04-21
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the safety and tolerability of an intramuscular regimen of two doses (1\*10\^11 viral particles \[vp\]) of an investigational respiratory syncytial virus (RSV) vaccine candidate (adenovirus serotype 26 respiratory syncytial virus pre-fusion conformation stabilized F protein \[pre-F\] \[Ad26.RSV.preF\]) in adults aged 18 to 50 years and RSV-seropositive toddlers aged 12 to 24 months.

Detailed description:
The study, designed to assess the safety and tolerability of two doses given one month apart of Ad26.RSV.preF, an investigational RSV vaccine candidate based on a Ad26 vector expressing the RSV F protein, will be conducted in a double blinded manner. The study will be divided in two sequential cohorts: cohort 0 (18-50 year-old adults) and cohort 1 (12-24 month-old RSV seropositive toddlers). The vaccine safety will be monitored by reporting solicited and unsolicited adverse events (AEs) and all serious adverse events (SAEs). The data will be reviewed by an independent data monitoring committee (IDMC) to assess safety data and to ensure the continuing safety of the participants enrolled in this study. The safety will be monitored throughout the study.

Arms: arm 1: Participants aged greater than or equal to (\>=) 18 to lesser than or equal to (\<=) 50 years will receive vector Ad26.RSV.preF at 1\*10\^11 viral particles (vp) via intramuscular (IM) route (Group 1) on Day 1 and 29. arm 2: Participants aged \>= 18 to \<= 50 years will receive placebo via IM route (Group 2) on Day 1 and 29. arm 3: RSV seropositive participants aged \>=12 to \<=24 months will receive Ad26.RSV.preF at 5\*10\^10 vp via IM route (Group 3) on Day 1 and 29. arm 4: RSV seropositive participants aged \>= 12 to \<= 24 months will receive placebo via IM route (Group 4) on Day 1 and 29.
Interventions: intervention 1: Ad26.RSV.preF (1*10^11 vp) intervention 2: Ad26.RSV.preF (5*10^10 vp) intervention 3: Placebo
Intervention descriptions: intervention 1: Participants will receive two doses of 0.5 milliliter (mL) (1\*10\^11 vp) via IM route on Day 1 and 29 of Ad26.RSV.preF. intervention 2: RSV seropositive participants will receive two doses of 0.25 mL (5\*10\^10 vp) via IM route on Day 1 and 29 of Ad26.RSV.preF. intervention 3: Participants will receive either 0.5 mL (cohort 0) or 0.25 mL (cohort 1) of placebo via IM route on Day 1 and 29.

Protocol documents:
Prot_000.pdf: 
1
Status: Approved, Date: 18 April 2019
Janssen Vaccines & Prevention B.V.
Clinical Protocol
A Randomized, Double-blind, Phase 1/2a Study to Evaluate the Safety, Tolerability and 
Immunogenicity of Ad26.RSV.preF in Adults 18 to 50 Years of Age and RSV-Seropositive 
Toddlers 12 to 24 Months of Age
Protocol VAC18194RSV2001; Phase 1/2a
Amendment 4
VAC18194 (Ad26.RSV.preF)
EudraCT NUMBER: 2017-001345-27 
Status:
Approved
Date:
18 April 2019
Prepared by:
Janssen Vaccines & Prevention B.V.
EDMS number:
EDMS-ERI-114933015, 14.0
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.
NCT03303625


VAC18194 (Ad26.RSV.preF)
Clinical Protocol Amendment 4 VAC18194RSV2001
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Approved, Date: 18 April 2019
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 12
TIME AND EVENTS SCHEDULE – COHORT 0: ADULTS....................................................................... 22
TIME AND EVENTS SCHEDULE – COHORT 1: SEROPOSITIVE TODDLERS...................................... 24
ABBREVIATIONS ...................................................................................................................................... 27
1.
INTRODUCTION................................................................................................................................ 29
1.1.
Background .................................................................................................................................... 29
1.2.
Overall Rationale for the Study...................................................................................................... 34
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 34
2.1.
Objectives and Endpoints .............................................................................................................. 34
2.1.1.
Objectives ................................................................................................................................... 34
2.1.2.
Endpoints.................................................................................................................................... 35
2.2.
Hypothesis ..................................................................................................................................... 37
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 37
3.1.
Overview of Study Design.............................................................................................................. 37
3.2.
RTI – Procedures Specific to Cohort 1 .......................................................................................... 45
3.3.
Study Design Rationale.................................................................................................................. 46
3.4.
Risk/Benefit Section....................................................................................................................... 47
3.4.1.
Known Benefits........................................................................................................................... 47
3.4.2.
Potential Benefits........................................................................................................................ 47
3.4.3.
Known Risks............................................................................................................................... 47
3.4.4.
Potential Risks............................................................................................................................ 47
3.4.5.
Overall Benefit/Risk Assessment ............................................................................................... 50
4.
SUBJECT POPULATION.................................................................................................................. 51
4.1.
Inclusion Criteria ............................................................................................................................ 51
4.1.1.
Adult Subjects............................................................................................................................. 51
4.1.2.
Pediatric Subjects....................................................................................................................... 53
4.2.
Exclusion Criteria ........................................................................................................................... 54
4.2.1.
Adult Subjects............................................................................................................................. 54
4.2.2.
Pediatric Subjects....................................................................................................................... 55
4.3.
Prohibitions and Restrictions ......................................................................................................... 57
5.
STUDY VACCINE ALLOCATION AND BLINDING.......................................................................... 58
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 59
7.
STUDY VACCINE COMPLIANCE .................................................................................................... 60
8.
PRE-STUDY AND CONCOMITANT THERAPY ............................................................................... 60
9.
STUDY EVALUATIONS .................................................................................................................... 61
9.1.
Study Procedures........................................................................................................................... 61


VAC18194 (Ad26.RSV.preF)
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Approved, Date: 18 April 2019
9.1.1.
Overview..................................................................................................................................... 61
9.1.2.
Visit Windows ............................................................................................................................. 62
9.1.3.
Screening and Study Visits – Cohort 0 (Adults) ......................................................................... 62
9.1.3.1.
Screening Phase: Days –28 to 1............................................................................................. 62
9.1.3.2.
Active Phase – Day 1 to Day 211............................................................................................ 63
9.1.3.2.1.
Vaccination (Days 1 and 29)................................................................................................ 63
9.1.3.2.2.
Post-first Vaccination Follow-Up .......................................................................................... 65
9.1.3.2.3.
Post-second Vaccination Follow-Up .................................................................................... 65
9.1.3.2.4.
Final Visit – 6 Months After the Second Vaccination ........................................................... 66
9.1.3.2.5.
Early Withdrawal – Early Exit Visit ....................................................................................... 66
9.1.3.3.
Safety Follow-up Phase: Cohort 0 – After Day 211 ................................................................ 66
9.1.4.
Screening and Study Visits – Cohort 1 (Seropositive Toddlers) ................................................ 66
9.1.4.1.
Screening Phase: Days –42 to 1............................................................................................. 66
9.1.4.2.
Active Phase – Day 1 to Day 211............................................................................................ 68
9.1.4.2.1.
Vaccination (Days 1 and 29)................................................................................................ 68
9.1.4.2.2.
Post-first Vaccination Follow-Up .......................................................................................... 69
9.1.4.2.3.
Post-second Vaccination Follow-Up .................................................................................... 69
9.1.4.2.4.
Early Withdrawal – Early Exit Visit ....................................................................................... 70
9.1.4.3.
Safety Follow-up Phase: Cohort 1 – After Day 211 ................................................................ 70
9.2.
Study Evaluations .......................................................................................................................... 71
9.2.1.
Immunogenicity........................................................................................................................... 71
9.2.2.
Other Evaluations – RSV Infection............................................................................................. 72
9.2.3.
Safety Evaluations...................................................................................................................... 73
9.2.3.1.
Respiratory Tract Infections..................................................................................................... 75
9.2.3.2.
Clinical Laboratory Tests – Cohort 0 Only............................................................................... 75
9.2.3.3.
Vital Signs................................................................................................................................ 77
9.2.3.4.
Physical Examination .............................................................................................................. 77
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY VACCINE/ WITHDRAWAL 
FROM THE STUDY ........................................................................................................................... 77
10.1.
Completion ..................................................................................................................................... 77
10.2.
Discontinuation of Study Vaccine/Withdrawal from the Study....................................................... 78
10.3.
Contraindications to Vaccination.................................................................................................... 79
11.
STATISTICAL METHODS................................................................................................................. 80
11.1.
Analysis Sets.................................................................................................................................. 80
11.2.
Sample Size Determination ........................................................................................................... 80
11.3.
Criteria for Exploratory Endpoints .................................................................................................. 81
11.3.1.
Definitions for Exploratory Endpoints ......................................................................................... 81
11.3.1.1.
Presence of Severe LRTI as Assessed by the CEC ............................................................... 81
11.3.1.2.
Determination of RSV Positivity............................................................................................... 81
11.4.
Subject Information ........................................................................................................................ 82
11.5.
Immunogenicity Analyses .............................................................................................................. 82
11.6.
RSV Infection ................................................................................................................................. 82
11.7.
Safety Analyses ............................................................................................................................. 82
11.8.
Planned Analyses .......................................................................................................................... 83
11.9.
Data Review Committees............................................................................................................... 84
11.9.1.
Independent Data Monitoring Committee (IDMC) ...................................................................... 84
11.9.2.
Clinical Endpoint Committee (CEC) ........................................................................................... 84
11.10.
Study Vaccination Pausing Rules .................................................................................................. 85
12.
ADVERSE EVENT REPORTING ...................................................................................................... 86
12.1.
Definitions ...................................................................................................................................... 87
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 87
12.1.2.
Attribution Definitions.................................................................................................................. 88
12.1.3.
Severity Criteria .......................................................................................................................... 89
12.2.
Special Reporting Situations.......................................................................................................... 90


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12.3.
Procedures..................................................................................................................................... 90
12.3.1.
All Adverse Events...................................................................................................................... 90
12.3.2.
Serious Adverse Events ............................................................................................................. 91
12.3.3.
Pregnancy (Cohort 0 Subjects) .................................................................................................. 92
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 92
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 92
13.1.
Procedures..................................................................................................................................... 93
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 93
14.
STUDY VACCINE INFORMATION ................................................................................................... 93
14.1.
Physical Description of Study Vaccine........................................................................................... 93
14.2.
Packaging and Labeling................................................................................................................. 94
14.3.
Storage and Handling .................................................................................................................... 94
14.4.
Vaccine Accountability ................................................................................................................... 94
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 95
16.
ETHICAL ASPECTS ......................................................................................................................... 95
16.1.
Study-Specific Design Considerations........................................................................................... 95
16.2.
Regulatory Ethics Compliance....................................................................................................... 96
16.2.1.
Investigator Responsibilities ....................................................................................................... 96
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 97
16.2.3.
Informed Consent ....................................................................................................................... 98
16.2.4.
Privacy of Personal Data ............................................................................................................ 99
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 99
16.2.6.
Country Selection ....................................................................................................................... 99
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 100
17.1.
Protocol Amendments.................................................................................................................. 100
17.2.
Regulatory Documentation .......................................................................................................... 100
17.2.1.
Regulatory Approval/Notification .............................................................................................. 100
17.2.2.
Required Pre-study Documentation ......................................................................................... 100
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 101
17.4.
Source Documentation................................................................................................................. 101
17.5.
Case Report Form Completion .................................................................................................... 102
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 103
17.7.
Record Retention ......................................................................................................................... 103
17.8.
Monitoring .................................................................................................................................... 103
17.9.
Study Completion/Termination..................................................................................................... 104
17.9.1.
Study Completion/End of Study................................................................................................ 104
17.9.2.
Study Termination..................................................................................................................... 104
17.10.
On-Site Audits .............................................................................................................................. 105
17.11.
Use of Information and Publication.............................................................................................. 105
REFERENCES.......................................................................................................................................... 107
INVESTIGATOR AGREEMENT ............................................................................................................... 120
LAST PAGE.............................................................................................................................................. 120


VAC18194 (Ad26.RSV.preF)
Clinical Protocol Amendment 4 VAC18194RSV2001
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Approved, Date: 18 April 2019
LIST OF ATTACHMENTS
Attachment 1: 
Toxicity Tables for Cohort 0...................................................................................... 110
Attachment 2: 
Toxicity Tables for Cohort 1...................................................................................... 116
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Study Design............................................................................................................................. 16
Table 2:
Summary of Immunogenicity Assays (Humoral) ...................................................................... 18
Table 3:
Summary of Immunogenicity Assays (Cellular)........................................................................ 19
Table 4:
Other Ongoing Clinical Studies with Ad26.RSV.preF............................................................... 32
Table 5:
Study Design............................................................................................................................. 40
Table 6:
Summary of Immunogenicity Assays (Humoral) ...................................................................... 71
Table 7:
Summary of Immunogenicity Assays (Cellular)........................................................................ 72
FIGURES
Figure 1:
Enrollment and First Dose Strategy.......................................................................................... 41
Figure 2:
Schematic Overview of the Study for Cohort 0......................................................................... 43
Figure 3:
Schematic Overview of the Study for Cohort 1......................................................................... 44


VAC18194 (Ad26.RSV.preF)
Clinical Protocol Amendment 4 VAC18194RSV2001
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Approved, Date: 18 April 2019
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
06 July 2017
Amendment 1
29 August 2017
Amendment 1 / Finland-1
29 September 2017
Amendment 1 / UK-1
03 October 2017
Amendment 2
08 January 2018
Amendment 3
14 November 2018
Amendment 4
18 April 2019
Amendments below are listed beginning with the most recent amendment.
Amendment 4 (Issued date: 18 April 2019)
The overall reason for the amendment: This protocol amendment is made to reduce the overall number of RSV-
seropositive toddlers in the study from 48 to 36. The rationale for this reduction is as follows:
As of 18 April 2019, 35 seropositive toddlers have been enrolled in the current study (VAC18194RSV2001). The 
IDMC have reviewed available safety and immunogenicity data from the planned interim analysis, unblinded at 
the group level, when at least 24 toddlers had reached Day 29 or discontinued earlier. As enrollment was staggered 
over time, the analysis contained solicited and unsolicited AE data post-Dose 1 from 32 toddlers, of whom 30 
toddlers already had post-Dose 2 data and 28 were in follow-up.
The IDMC concluded that the safety profile was acceptable and supported progression to the next study 
(VAC18194RSV2002) in RSV-seronegative toddlers aged 12 to 24 months in which subjects will receive half the 
dose of Ad26.RSV.preF used in the current study (ie, 2.5x1010 vp). In addition, blinded safety review by the 
sponsor of additional data since the IDMC review has not revealed any safety concerns. Study 
VAC18194RSV2002 has already been initiated; as of 18 April 2019, 6 seronegative toddlers have been enrolled 
and have received their first vaccination.
The reduction in the number of seropositive toddlers in the current study is supported by the expectation that there 
would be no difference in the local and systemic reactogenicity between seropositive and seronegative toddlers.
The collection of safety data at the planned dose in seronegative toddlers in study VAC18194RSV2002 will 
therefore add to the overall safety database in this age group as planned. Furthermore, as RSV-seropositive 
toddlers are at limited to no risk of severe RSV disease, there would be limited value in continuation of the study.
The table below gives an overview of the rationale for each change and all affected sections
Rationale: As indicated above, the number of RSV-seropositive toddlers in this study is reduced from 48 to 36.
Synopsis: Overview of Study Design; Sample Size Determination 
3.1 Overview of Study Design
11.2 Sample Size Determination
Amendment 3 (Issued date: 14 November 2018)
The overall reason for the amendment: To potentially aid recruitment in the current study, this protocol 
amendment is made to allow enrollment of RSV seropositive toddlers who have been screened for a different 
clinical study of the sponsor (ie, VAC18194RSV2002) if RSV seropositivity was determined using the RSV EIA or 
virus neutralization assay.
Other updates and clarifications are made as specified below.


VAC18194 (Ad26.RSV.preF)
Clinical Protocol Amendment 4 VAC18194RSV2001
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Approved, Date: 18 April 2019
The table below gives an overview of the rationale for each change and all affected sections
Rationale: Added clarification that RSV-seropositive subjects can be enrolled if their serostatus has been
confirmed by either RSV EIA or virus neutralization assay from a different study of the sponsor.
Synopsis: Other Evaluations – RSV Infection
Time and Events Schedule
4.1.2 Inclusion Criteria – Pediatric Subjects
9.1.4.1 Screening Phase: Days –42 to 1
9.2.2 Other Evaluations – RSV Infection
Rationale: Change of EIA cut-off criterion for seropositivity to titers >10 EIA units.
Synopsis: Other Evaluations – RSV Infection
9.2.2 Other Evaluations – RSV Infection
Rationale: Update of preclinical information.
1.1 Background
Rationale: Update of clinical information.
1.1 Background
Rationale: Clarification of wording of Exclusion Criterion 23 for pediatric subjects.
4.2.2 Exclusion Criteria – Pediatric Subjects
Rationale: Clarification of the exclusion criterion for known allergies at screening refers to vaccines or vaccine 
components, but not to egg allergies.
4.2.2 Exclusion Criteria – Pediatric Subjects
Rationale: Clarification that the exclusion criterion for urticaria, eczema and atopic dermatitis relates to a 
moderate to severe history of these illnesses.
4.2.2 Exclusion Criteria – Pediatric Subjects
Rationale: Clarification that telephone calls to subjects for RTI monitoring after the first dose will be made 
during both the active and safety follow-up phases.
Synopsis: Overview of Study Design
Time and Events Schedule
3.1 Overview of Study Design
9.1.4.3 Safety Follow-up Phase
Rationale: Clarification that during each 28-day post-vaccination period, all RTIs will be reported and that 
during the RSV season, but outside the 28-day post-vaccination period, only RTIs for which a combination of 
respiratory symptoms develop, will be reported.
Synopsis: RTI – Procedures Specific to Cohort 1; Other Evaluations – RSV Infection; Safety Evaluations
Time and Events Schedule
3.2 RTI – Procedures Specific to Cohort 1
3.4.5 Overall Benefit/Risk Assessment
9.2.2 Other Evaluations – RSV Infection
Rationale: Clarification that in the event of an ongoing AE or other situation precluding subject vaccination 
within 10 days, subjects may be vaccinated beyond the 10-day window at the discretion of the sponsor.


VAC18194 (Ad26.RSV.preF)
Clinical Protocol Amendment 4 VAC18194RSV2001
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Approved, Date: 18 April 2019
Time and Events Schedule
3.4.5 Overall Benefit/Risk Assessment
9.1.3.2.1 Vaccination (Days 1 and 29)
9.1.4.2.1 Vaccination (Days 1 and 29)
10.3 Contraindications to Vaccination
Rationale: Clarification that any subject who receives study vaccine beyond the Day 29 window specified in the 
Time and Events Schedule would not be included in the per-protocol immunogenicity analyses.
11.1 Analysis Sets
Rationale: For operational reasons, removal of the requirement for surveillance of primary care physicians, 
and/or hospitals’ urgent care facilities to monitor for subjects seeking medical attention for an RTI.
3.4.5 Overall Benefit/Risk Assessment
Rationale: Specification that the 1 year post-first vaccination safety follow-up telephone call should take place 
within a ±14 days visit window.
Time and Events Schedule
9.1.2 Visit Windows
Rationale: Other minor changes, clarifications and corrections made throughout the protocol.
Amendment 2 (Issued date: 08 January 2018)
The overall reason for the amendment:
This amendment is made to increase the number of seropositive toddlers by 12 to generate additional safety data, to 
specify post-vaccination monitoring time and to correct minor changes, clarifications and corrections made 
throughout the protocol.
The table below gives an overview of the rationale for each change and all affected sections
Rationale: To add 12 extra seropositive toddlers to Cohort 1.
Synopsis
3.1 Overview of Study Design
11.2 Sample Size Determination
Rationale: Removal of Attachment 3 containing information for sites in the United Kingdom (removal already 
effected via prior separate country-specific amendments: Clinical Trial Protocol Amendment 1 / Finland 1 – 29 
September 2017 and Clinical Trial Protocol Amendment 1 / UK 1 – 03 October 2017).
3.4.2 Potential Benefits
Attachment 3
Rationale: Specification of monitoring time to be a minimum of 30 or 60 minutes post-vaccination in accordance 
with local approvals (change already effected via prior separate country specific amendment: Clinical Trial 
Protocol Amendment 1 / Finland 1 – 29 September 2017).
Synopsis
Time and Events Schedule
3.1 Overview of Study Design
3.4.5 Overall Benefit/Risk Assessment
9.1.3.2.1 Vaccination (Days 1 and 29)
9.1.4.2.1 Vaccination (Days 1 and 29)
9.2.3 Safety Evaluations


VAC18194 (Ad26.RSV.preF)
Clinical Protocol Amendment 4 VAC18194RSV2001
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Approved, Date: 18 April 2019
Rationale: Clarification that a least 5 toddlers in the active group are to have received first dose in a clinic setting
and to have completed Visit 3 with no safety concerns before moving to vaccination of study subjects in a non-
clinic setting.
Synopsis
Time and Events Schedule
3.1 Overview of Study Design
9.1.4 Screening and Study Visits – Cohort 1 (Seropositive Toddlers)
Rationale: Deletion of the wording “In addition, for a selection of tables, tabulations per dose by vaccine will be 
provided.”, as the per dose analysis will no longer be carried out.
Synopsis
11.7 Safety Analysis
Rationale: Clarification that the unblinded pharmacist or other qualified individual will have no other study 
function from randomization onwards
Synopsis
3.1 Overview of Study Design
5 Study Vaccine Allocation and Blinding
6 Dosage and Administration
14.3 Storage and Handling
Rationale: To specify that the blood volume drawn for serology testing will not exceed 15mL and adjust total 
blood volume that will be collected.
Time and Events Schedule
9.1.1 Overview
Rationale: Other minor changes, clarifications and corrections made throughout the protocol.
Amendment 1 / UK-1 (Issued date: 03 October 2017)
The overall reason for the amendment:
This amendment is made to remove the offer of vaccination with a locally marketed vaccine with proven benefit for 
pediatric subjects for sites in the United Kingdom as this provision was not endorsed by the UK Central Ethics 
Committee.
The table below gives an overview of the rationale for each change and all affected sections
Rationale: As above.
3.4.2 Potential Benefits
Attachment 3
Amendment 1 / Finland-1 (Issued date: 29 September 2017)
The overall reason for the amendment:
This amendment is to clarify that, according to the requirements of the local ethics committee in Finland, the 
immediate post-vaccination observation period for toddlers in Cohort 1 should be a minimum of 60 minutes.
The table below gives an overview of the rationale for each change and all affected sections


VAC18194 (Ad26.RSV.preF)
Clinical Protocol Amendment 4 VAC18194RSV2001
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Approved, Date: 18 April 2019
Rationale: To clarify that the immediate post-vaccination observation period for toddlers in Cohort 1 should be a 
minimum of 60 minutes.
Synopsis
Time and Events Schedule
3.1 Overview of Study Design
3.4.5 Overall Risk/Benefit Assessment
9.1.4.2.1 Vaccination (Days 1 and 29)
9.2.3 Safety Evaluations
Rationale: Removal of Attachment 3 containing information for sites in the United Kingdom.
3.4.2 Potential Benefits
Attachment 3
Amendment 1 (Issued date: 29 August 2017)
The overall reason for the amendment:
This amendment is made to clarify that the responsibility to break the blind for emergency reasons rests solely with 
the investigator. Additionally, the following changes were made: the definition of probable RSV infection was 
removed; a reference to the Study Training Manual was deleted; the time periods for collections of concomitant and 
prestudy medications were clarified; stipulation that subjects should both measure and grade any induration/ 
swelling in the subject diary was added; addition of virus neutralization assay as an alternative assay for assessment 
of RSV seropositivity at screening; and other minor inconsistencies were corrected.
The table below gives an overview of the rationale for each change and all affected sections
Rationale: To clarify that the responsibility to break the blind for emergency reasons rests solely with the 
investigator.
5 Study Vaccination Allocation and Blinding
Rationale: The definition of probable RSV infection was dependent on the results of local laboratory testing, and as
only results from the central laboratory would be considered as definitive, the definition of probable RSV infection 
has been removed.
Synopsis
3.2 RTI – Procedures Specific to Cohort 1
Rationale: Removal of reference to the Study Training Manual as this document is no longer produced.
9.1.1 Study Evaluations - Overview
Rationale: Clarification that collection of concomitant medications will be from the time of each vaccination until 
28 days after each vaccination, and that collection of pre-study therapies will be during the period up to 30 days 
prior to vaccination.
Synopsis
Time and Events Schedule
3.1 Overview of Study Design
8 Pre-study and Concomitant Therapy
Rationale: Addition of virus neutralization assay as an alternative assay for assessment of RSV seropositivity at 
screening.
Synopsis
9.2.2 Other Evaluations – RSV Infection


VAC18194 (Ad26.RSV.preF)
Clinical Protocol Amendment 4 VAC18194RSV2001
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Approved, Date: 18 April 2019
Rationale: Clarification that the solicited local AE induration/swelling should be both measured and graded by 
subjects in their diaries.
Synopsis
9.2.3 Safety Evaluations


VAC18194 (Ad26.RSV.preF)
Clinical Protocol Amendment 4 VAC18194RSV2001
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Approved, Date: 18 April 2019
SYNOPSIS
A Randomized, Double-blind, Phase 1/2a Study to Evaluate the Safety, Tolerability and 
Immunogenicity of Ad26.RSV.preF in Adults 18 to 50 Years of Age and RSV-Seropositive Toddlers 
12 to 24 Months of Age
The adenovirus-vectored vaccine candidate assessed in this study is:
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 respiratory syncytial virus (RSV) A2 strain.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Objectives
Primary Objectives

To assess the safety and tolerability of an intramuscular regimen of two doses of 1x1011 viral 
particles (vp) of Ad26.RSV.preF in adults aged 18 to 50 years.

To assess the safety and tolerability of an intramuscular regimen of two doses of 5x1010 vp of 
Ad26.RSV.preF in RSV-seropositive toddlers aged 12 to 24 months.
Secondary Objective

To assess the humoral and cellular immune responses as measured by virus neutralization assay, 
F-protein binding antibodies (pre-F and post-F) and intracellular cytokine staining (ICS; to assess 
T-helper [Th]1/Th2 subtyping).
Exploratory Objectives

To further assess the humoral and cellular immune responses elicited by Ad26.RSV.preF. The assays 
to be used may include, but are not limited to, RSV strain cross-neutralization, anti-F protein 
antibody specificity and functionality characterization, adenovirus neutralization assays, molecular 
antibody characterization (avidity, Fc cell interaction, antibody isotyping), evaluation of the cellular 
immune response (interferon gamma [IFNγ] enzyme-linked immunospot [ELISpot] assay) and 
functional and memory immune response (by ICS), and cytokine profiles of RSV F-protein peptide-
stimulated peripheral blood mononuclear cell (PBMC) supernatant.

To assess RSV infection rates in Ad26.RSV.preF and placebo subjects.

To monitor for severe RSV-lower respiratory tract infection (LRTI) in Cohort 1 (RSV-seropositive 
toddlers aged 12 to 24 months).

To assess symptoms of respiratory illness via the respiratory tract infection (RTI) symptoms form.
Primary Endpoints – Safety and Tolerability

Solicited local and systemic adverse events (AEs) for 7 days after each vaccination.

Unsolicited AEs for 28 days after each vaccination (ie, from informed consent form [ICF] signature 
through the following 28 days post-first vaccination, and for subsequent vaccinations from time of 
vaccination through the following 28 days).


VAC18194 (Ad26.RSV.preF)
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Approved, Date: 18 April 2019

Serious adverse events (SAEs) from ICF signature to the end of the study.
Secondary Endpoints – Immune Responses
The analysis of the immunogenicity of vaccine regimens will include the characterization of humoral as 
well as cellular responses. The focus of the immunogenicity analysis is on virus neutralizing antibodies
(VNAs), F-protein antibodies (pre-F and/or post-F) and Th1/Th2 cytokine profile response.
Humoral Immune Response

RSV neutralization A strain
Analysis of RSV A neutralizing antibodies.

RSV F-protein enzyme-linked immunosorbent assay (ELISA; pre- and/or post-fusion F antibodies)
Analysis of antibodies binding to RSV F protein in post-fusion and pre-fusion form.
Cell-mediated Immune Response

Intracellular cytokine staining 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, tumor necrosis factor alpha (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).
Exploratory Endpoints – Immune Responses
Additional exploratory analyses may be performed to investigate vaccine-elicited immune responses 
further. These may include, but are not limited to, the following assays:
Humoral Immune Response

RSV cross-neutralization of B and/or other A strain(s)

F-protein antibody specificity characterization

Adenovirus neutralization assay

Functional and molecular antibody characterization
Cell-mediated Immune Response

IFNELISpot assay

Cytokine analysis
Exploratory Endpoints – RSV Infection

For Cohort 1 only, RSV infection confirmed by either reverse transcriptase polymerase chain 
reaction (RT-PCR), or by serology for, but not limited to, protein G and/or N if no RT-PCR is 
available. To detect asymptomatic RSV infections, a fold increase will be applied to call a subject 


VAC18194 (Ad26.RSV.preF)
Clinical Protocol Amendment 4 VAC18194RSV2001
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Approved, Date: 18 April 2019
seropositive to G and/or N ELISA (or F in case of placebo subjects). Fold increases for RSV 
infection will be determined based on the (suspected) infection and the convalescent blood samples. 

In Cohort 1 throughout the study:
o
Severe RSV-LRTI: for subjects in Cohort 1, severe RSV-LRTI will be defined as the presence 
of severe LRTI as assessed by the clinical endpoint committee (CEC), and a positive assessment 
for RSV.
o
RSV medically-attended respiratory tract infection (MA-RTI): all subjects with RSV-RTI that is 
medically attended, ie, when the subject’s parent/legal guardian seeks medical attention outside 
of normal study procedures, including health care professional’s visit to the home, clinic visit, 
emergency room attendance, and hospital admission. (Note: medical attention outside normal 
study procedures will as much as possible also be captured on the RSV Symptoms Form.)
Note: Data on these 2 exploratory endpoints will be collected to assess the feasibility of, and gain 
expertise in the collection of such events for future studies.
Hypothesis
No formal statistical hypothesis is planned. The study will evaluate whether Ad26.RSV.preF is safe, well-
tolerated and immunogenic in adults and RSV-seropositive toddlers.
OVERVIEW OF STUDY DESIGN
In this document, unless otherwise specified, any reference to activities to be performed by the subject 
refers to adult subjects or the parent/legal guardian for pediatric subjects.
This is a multi-center, randomized, double-blinda, Phase 1/2a study, to be conducted in 12 male and 
female adults aged ≥18 to ≤50 years and 36 male and female toddlers aged ≥12 to ≤24 months of age, 
seropositive for RSV within 42 days prior to dosing.
Subjects will be enrolled into sequential age cohorts:

18 to 50 year-old adults, into Cohort 0

12 to 24 month-old seropositive toddlers, into Cohort 1
In Cohort 0, subjects will be randomized 2:1 to receive either Ad26/Ad26 (1x1011 vp in 0.5 mL) or
placebo/placebo (saline), and in Cohort 1, subjects will be randomized 2:1 to receive either Ad26/Ad26 
(5x1010 vp in 0.25 mL) or placebo/placebo (Table 1).
The study will have three phases: a screening phase, an active phase and a safety follow-up phase
through 1 year after the first dose. The durations of the respective phases are as follows:
                                                
a The administrator of the vaccine may be unblinded but will not participate in any other study evaluation from 
randomization onwards. The site staff or qualified professional staff who will do the observation and the subjects 
will be blinded.


VAC18194 (Ad26.RSV.preF)
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Approved, Date: 18 April 2019
Phase
Cohort 0
Cohort 1
Screening:
up to 4 weeks
up to 6 weeks
Active:
30 weeks
dosing on Days 1 and 29
safety follow-up through 6 months post-final 
dose
immunogenicity at:

pre-Dose 1 (Day 1)

pre-Dose 2 (Day 29)

28 days post-Dose 2 (Day 57)

6 months post-Dose 2
(Day 211/Week 30)
30 weeks
dosing on Days 1 and 29
safety follow-up through 6 months post-final 
dose
immunogenicity at:

pre-Dose 1 (Day 1)

pre-Dose 2 (Day 29)

28 days post-Dose 2 (Day 57)

6 months post-Dose 2
(Day 211/Week 30)
Safety follow-up:
through 1 year after the first dose
through 1 year after the first dose
The end of the active phase will be when the last subject completes the visit at 6 months after the final 
dose. The end of the study will be the last subject’s last visit (by telephone) at the end of the safety 
follow-up phase.
An independent data monitoring committee (IDMC) will be established for this study to evaluate safety 
and tolerability data on a regular basis. An independent blinded CEC will be established for this study to 
assess any suspected case of severe LRTI in pediatric subjects.
First-dose Safety
For Cohort 0, 48-hour and 7-day safety will be monitored by the Principal Investigator(s) (PI[s]) and the 
Study Responsible Physician(s) (SRP[s])a; for Cohort 1, 48-hour safety will be monitored by the PI(s) and 
the SRP(s), and 7-day safety will be monitored by the IDMC. In the event of a significant safety finding, 
the IDMC will be consulted.
Note: At least 5 toddlers in the active group are to have received first dose in a clinic setting and to have 
completed Visit 3 with no safety concerns before moving to vaccination of study subjects in a non-clinic 
setting (safety information of the first 5 active toddlers will be monitored by the PI(s)/SRP(s) through 
Visit 3, and escalated to the IDMC in the event of a safety signal).
Enrollment will be staggered to allow safety assessments to be made 7 days after the first dose in all 
12 adults in Cohort 0 before enrolling and dosing seropositive toddlers in Cohort 1. Additionally, safety 
assessments will be made 7 days after the first dose in the first 12 seropositive toddlers (8 actives and 
4 placebos) in Cohort 1 before enrolling and dosing the remaining seropositive toddlers. These safety 
assessments are described more fully in Section 3.1. 
In addition, 48-hour safety will be checked after dosing sentinel subjects in both cohorts (2 subjects 
[1 active and 1 placebo] in each cohort).
Second-dose Safety
Post-second dose 48-hour and 7-day safety assessments will be monitored by the PI(s) and the SRP(s).
Administration of the second dose will also be staggered to allow safety assessments to be made 7 days 
after the second dose in all 12 adults in Cohort 0 before administering the second dose to seropositive 
toddlers in Cohort 1. Likewise, safety assessments will be made 7 days after the second dose in the first 
                                                
a The safety of Ad26.RSV.preF in elderly subjects at 5x1010 vp and 1x1011 vp will have been established in study 
VAC18193RSV1003 prior to initiation of the current study; the purpose of dosing Ad26.RSV.preF in Cohort 0 
in the current study is as a safety check for the new drug product formulation buffer, and consequently only PI 
and SRP review of Cohort 0 safety data is planned prior to dosing seropositive toddlers in Cohort 1. 


VAC18194 (Ad26.RSV.preF)
Clinical Protocol Amendment 4 VAC18194RSV2001
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Approved, Date: 18 April 2019
12 seropositive toddlers in Cohort 1 before administering the second dose to the remaining seropositive
toddlers in Cohort 1. These safety assessments are described more fully in Section 3.1. In addition, 
48-hour safety will be checked after dosing sentinel subjects in both cohorts.
The sponsor will monitor post-vaccination safety on an ongoing basis by reviewing blinded safety data.
Table 1:
Study Design
Cohort
Group
N
Day 1 
Day 29/Week 4 
ADULTS 18 to 50 years
0
Group 1
8
Ad26.RSV.preF (1x1011 vp)
Ad26.RSV.preF (1x1011 vp)
Group 2
4
Placebo
Placebo
TODDLERS 12 to 24 months: RSV seropositive
1
Group 3
24
Ad26.RSV.preF (5x1010 vp)
Ad26.RSV.preF (5x1010 vp)
Group 4
12
Placebo
Placebo
After each vaccination, all subjects will be closely observed for a minimum of 30 minutes post-
vaccination, or a minimum of 60 minutes post-vaccination according to local approvals, 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. Subjectsa 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 each study vaccine dosing day and 
on a daily basis for the following 7 days. Temperaturesb should be taken at approximately the same time 
each day, preferably in the eveningc and, for pediatric subjects, additionally whenever the child feels 
warm. Study-site personnel will collect and review subject diary information and confirm the entries at 
subsequent site visits.
Unsolicited AEs will be collected from the time of informed consent through 28 days after each dose. For 
both cohorts, all SAEs will be collected from ICF signature to the end of the study. All AEs, including 
any that are ongoing at 28 days after each dose, will be followed until clinical resolution or stabilization. 
Concomitant medications will be collected from the time of each vaccination through 28 days after each 
vaccination, and additionally outside of these periods when associated with any SAE.
Blood will be collected for immunogenicity assessments as follows:

Cohort 0: pre-vaccination for first and second doses, and at 28 days and 6 months after the second
dose

Cohort 1: pre-vaccination for first and second doses, and at 28 days and 6 months after the second 
dose
For Cohort 1, a blood sample will be taken for RSV serology at screeningd; the baseline sample for 
immunogenicity may either be drawn at the same screening visit or pre-dose on Day 1, at the discretion of 
the investigator.
                                                
a In Cohort 1, activities to be performed by the subject refers to the parent/legal guardian.
b Recommended orally for adult subjects; rectally or axillary for pediatric subjects (actual routes to be recorded in the eCRF).
c All Day 8 post-vaccination diary assessments, including temperature measurements, may be collected earlier to coincide with 
the corresponding clinic visit.
d 0.5 mL of blood for serostatus assessment can be collected by venous blood sample or fingerstick, at the discretion of the 
investigator. If 0.5 mL is collected at screening, baseline blood draw for immunogenicity should be on Day 1.


VAC18194 (Ad26.RSV.preF)
Clinical Protocol Amendment 4 VAC18194RSV2001
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Approved, Date: 18 April 2019
Safety Follow-up
Parents/legal guardians of subjects in Cohort 1 will be contacted by telephone (or clinic visit) through 1
year after the first dose (including during the active phase and safety follow-up phase: every 30 days ± 7 
days outside the RSV season, but every 14 days ± 3 days in season). During each 28-day post-vaccination 
period, calls will remind parents/legal guardians to contact the site in the event their child develops an 
RTI. During the RSV season, but outside the 28-day post-vaccination period, calls will remind 
parents/legal guardians to contact the site in the event their child develops a combination of symptoms of 
respiratory infection (persistent [>48 hours] clinical symptoms of rhinitis [sneezing or runny nose or 
congestion] and persistence [>24 hours] of one or more of the following: cough, abnormal breathing, 
fever, lethargy or decreased appetite). These calls will also check for any SAEs and associated 
concomitant medications since the previous visit or telephone contact.
RTI – PROCEDURES SPECIFIC TO COHORT 1
Monitoring of RTIs will take place during each 28-day post-vaccination period, and additionally during 
the RSV season after the first dose (even if it falls outside of the 28-day post-vaccination period). 
Monitoring for MA-RTIs and severe LRTIs will take place during the whole study period.
During each 28-day post-vaccination period, all RTIs will be reported, nasal turbinate samples will be 
collected as soon as possible after the onset of respiratory symptoms, and signs and symptoms will be 
recorded by the attending health care professional using the RTI Symptoms Form. 
If, during the RSV season, but outside the 28-day post-vaccination period, a subject shows persistent 
(>48 hours) clinical symptoms of rhinitis (sneezing or runny nose or congestion) and persistence 
(>24 hours) of one or more of the following 30,32,41,44: cough, abnormal breathing, fever, lethargy or 
decreased appetite, the study site should be notified. Nasal turbinate samples will be collected as soon as 
possible after the onset of these combined respiratory symptomsa. When nasal turbinate samples are 
collected, the attending health care professional will record signs and symptoms of the RTI using the RTI 
Symptoms Form.
Nasal turbinate samples will not be collected if less than 7 days after the previous sample collection.
Outside of the RSV season, nasal turbinate samples will only be collected from subjects with MA-RTIs or 
severe LRTIs.
Throughout the study, nasal turbinate samples will be collected from any subject with a MA-RTI or 
severe LRTI.
The criteria used to assess potential cases of RSV infection in subjects from Cohort 1 will be as follows:

Suspected RSV infection: subject has persistent (>48 hours) clinical symptoms of rhinitis (sneezing 
or runny nose or congestion) and persistence (>24 hours) of one or more of the following: cough, 
abnormal breathing, fever, lethargy or decreased appetite. Occurrence of this combination of 
symptoms in any subject would trigger collection of a nasal turbinate sample.

Confirmed RSV infection: subject with suspected RSV infection and positive for RSV on the basis 
of RT-PCR conducted centrally.
                                                
a These procedures should preferentially be performed at the study site. These procedures can be conducted at the subject’s home 
by site staff or qualified professional staff if the study site has an established standard operating procedure as such. In case of 
emergency, the procedures can be done in a hospital.


VAC18194 (Ad26.RSV.preF)
Clinical Protocol Amendment 4 VAC18194RSV2001
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Approved, Date: 18 April 2019
SUBJECT POPULATION
Cohort 0: Healthy (on the basis of physical examination, medical history and vital signs measurement 
performed at screening) male or female adults, aged ≥18 to ≤50 years old on the day of ICF signature.
Cohort 1: Healthy (on the basis of physical examination, medical history and vital signs measurement 
performed at screening) male or female toddlers, aged ≥12 months to ≤24 months on the day of ICF 
signature and seropositive for RSV within 42 days prior to dosing.
DOSAGE AND ADMINISTRATION
Ad26.RSV.preF (JNJ-64400141) will be supplied in single-use vials. Volumes of 0.5 mL (1x1011 vp) for 
adults and 0.25 mL (5x1010 vp) for toddlers will be used for intramuscular injection into the deltoid of the 
non-dominant arm for adults and into either anterolateral aspect of the thigh for toddlers.
Placebo will be supplied as sterile 0.9% saline for injection.
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.
The unblinded pharmacist, or other qualified individual, may also perform the administration, but will have 
no other study function from randomization onwardsa.
For adult subjects, injections should be administered in the deltoid. For pediatric subjects, injections should 
be administered in the anterolateral aspect of the thigh. Alternating injection sites will be used for the 
vaccinations on Day 1 and Day 29.
IMMUNOGENICITY EVALUATIONS
Humoral and cellular immunogenicity evaluations are summarized in Table 2 and Table 3, respectively. 
Sample collection and processing will be performed by the staff at the clinical sites according to current 
versions of approved standard operating procedures.
Table 2:
Summary of Immunogenicity Assays (Humoral)
Assay 
Purpose
Secondary endpoints
RSV neutralization A 
Analysis of neutralizing antibodies to the 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
Exploratory endpoints
RSV strain cross-neutralization 
Analysis of cross-neutralizing antibodies to B and/or a different A strain(s)
F-protein antibody specificity 
characterization 
Pre- and post-F specificity by binding or functional assays as ELISA, 
and/or competition ELISA. Adsorption of serum or plasma with pre-F and 
post-F protein before any antibody assay, epitope mapping, functional 
VNA
Adenovirus neutralization assay
Analysis of neutralizing antibodies to adenovirus
Functional and molecular 
antibody characterization
Analysis of antibody characteristics including ADCC, ADCP, avidity, Fc 
characteristics, Ig isotype, functional VNA and protective antibody 
assessments
ADCC = antibody-dependent cell-mediated cytotoxicity; ADCP = antibody-dependent cellular phagocytosis; ELISA = enzyme-
linked immunosorbent assay; F = fusion; Ig = immunoglobulin; RSV = respiratory syncytial virus; VNA = virus neutralizing 
antibody
                                                
a The unblinded pharmacist, or other qualified individual, may also perform the administration, but will have no 
other study function from randomization onwards.


VAC18194 (Ad26.RSV.preF)
Clinical Protocol Amendment 4 VAC18194RSV2001
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Approved, Date: 18 April 2019
Table 3:
Summary of Immunogenicity Assays (Cellular)
Assay 
Purpose
Secondary endpoints
Flow cytometry (ICS)*
Analysis of T-cell responses to RSV F-protein peptides for Th1/Th2 subtyping
Exploratory endpoints
IFNγ ELISpot
T-cell IFNγ responses to RSV F-protein peptides
ICS
Analysis of T-cell responses to RSV F-protein peptide-stimulated PBMCs
(including but not limited to, CD4/CD8, IL2, INFγ, TNFα, activation markers and 
memory)
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
* 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
In addition to RT-PCR performed on a nasal turbinate sample collected at the time of infection, any 
immunogenicity blood sample collected from any Cohort 1 subject who subsequently develops a 
suspected RTI may also be assayed by a serological assay (eg, ELISA specific to RSV protein G and/or 
N) to confirm RSV infection.
For adults, nasal turbinate samples, collected pre-dose on Days 1 and 29, 7 days post-Dose 1 (Day 8) and 
28 days post-Dose 2 (Day 57) will be used to assess any immunoglobulin (Ig) or cellular immune 
component.
OTHER EVALUATIONS – RSV INFECTION
RSV seropositivity of Cohort 1 subjects will be assessed by RSV enzyme immunoassay (EIA) or virus 
neutralization assay at screening. The cut-off for seropositivity by EIA is a titer >10 EIA units and the 
cut-off by virus neutralization assay is a titer >4. Note: RSV-seropositive toddlers may be recruited if 
RSV seropositivity was assessed via either of these assays in a different study of the sponsor.
Nasal turbinate samples, taken from any Cohort 1 subject with an RTI during each 28-day post-
vaccination period, and from any Cohort 1 subject with a specified combinationa of respiratory symptoms 
during the RSV season (but outside of the 28-day post-vaccination period), and from any Cohort 1 subject 
with a MA-RTI or severe LRTI during the whole study period, will be assessed for the presence of RSV 
infection by RT-PCR.
In addition, scheduled blood samples may be assessed for the presence of RSV antibodies by serology.
SAFETY EVALUATIONS
On a daily basis, for 7 days after each vaccination, each adult subject and each pediatric subject’s 
parent/legal guardian will be asked to record the following AEs via the diary card:

Solicited local AEs for all subjects: erythema (measured using the ruler supplied), 
swelling/induration (measured using the ruler supplied and graded using the functional scale), and 
pain/tenderness.
                                                
a Persistent (>48 hours) clinical symptoms of rhinitis (sneezing or runny nose or congestion) and persistence (>24 hours) of one 
or more of the following: cough, abnormal breathing, fever, lethargy or decreased appetite.


VAC18194 (Ad26.RSV.preF)
Clinical Protocol Amendment 4 VAC18194RSV2001
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Approved, Date: 18 April 2019

Solicited systemic AEs for adult subjects: fatigue, headache, myalgia, arthralgia, chills, nausea and 
fever (ie, body temperature ≥38 °C); for pediatric subjects: loss of appetite, vomiting, diarrhea, 
decreased activity/lethargy, irritability/crying and fever (ie, body temperature ≥38 °C).
Body temperaturea should be measured by the same method and at approximately the same time each day, 
preferably in the evening and, for pediatric subjects, additionally whenever the child feels warm using the 
thermometer supplied. All diary assessments, including body temperature 7 days after the first and second 
vaccinations may be collected earlier to coincide with the Day 8 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 through 28 days after the final vaccination. For both cohorts, 
all SAEs will be collected from ICF signature to the end of the study.
When nasal turbinate samples are collected from subjects with an RTI during each 28-day post-
vaccination period, and from subjects with a specified combination of respiratory symptoms during the 
RSV season, but outside the 28-day post-vaccination period, the attending health care professional will 
record signs and symptoms of the RTI using the RTI Symptoms Form. RTIs, preferably as a diagnosis, 
will also be reported on the AE page of the eCRF if they occur within 28 days following vaccination. Any 
RTI fulfilling the criteria of an SAE would be reported as such during the entire study. Any severe LRTI 
will be reported using the SAE reporting system and SAE form, regardless of whether the event fulfills 
the criteria of an SAE.
STATISTICAL METHODS
Sample Size Determination
The number of subjects chosen for this study will provide a preliminary safety and immunogenicity 
assessment. Placebo recipients are included for blinding and safety purposes and will provide additional 
control specimens for immunogenicity assays.
While mild to moderate vaccine reactions (local site and systemic responses) are expected, AEs that 
preclude further dose administration or more serious ones that would limit product development are not 
anticipated.
The following table shows the probabilities of observing at least one AE at given true AE rates:
True AE rate
Probability of observing at least one AE in N subjects
N=4
N=8
N=12
N=24
0.5%
2%
4%
6%
11%
1%
4%
8%
11%
21%
2.5%
10%
18%
26%
46%
5%
19%
34%
46%
71%
10%
34%
57%
72%
92%
25%
68%
90%
97%
100%
50%
94%
100%
100%
100%
                                                
a Recommended orally for adult subjects; rectally or axillary for pediatric subjects (actual routes to be recorded in the eCRF).


VAC18194 (Ad26.RSV.preF)
Clinical Protocol Amendment 4 VAC18194RSV2001
21
Approved, Date: 18 April 2019
Planned Analyses
The following analyses will be performed:

Cohort 0: primary analysis will be performed when all subjects have reached Day 57 (28 days 
post-Dose 2) or discontinued earlier. All available safety and immunogenicity data gathered so far 
will be included in the analysis; unblinded at the group level.

Cohort 1: interim analysis will be performed when at least 24 subjects have reached Day 29 
(28 days post-Dose 1) or discontinued earlier. All available safety and immunogenicity data gathered 
so far will be included in the analysis; unblinded at the group level.

Cohort 1: primary analysis will be performed when all subjects have reached Day 57 (28 days 
post-Dose 2) or discontinued earlier. All available safety and immunogenicity data gathered so far 
will be included in the analysis; unblinded at the group level.

Final analysis of both cohorts; at the end of the study, 1 year after the first dose; unblinded
Additional interim analyses (blinded or unblinded at the group level) 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 
or immunogenicity endpoint assessments, and will only be available to a selected group of sponsor 
personnel, excluding sponsor personnel involved in data collection or data management.
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 
ICS) will be calculated for continuous immunologic parameters at all timepoints. 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. All safety data will be analyzed descriptively by 
regimen.










VAC18194 (Ad26.RSV.preF)
Clinical Protocol Amendment 4 VAC18194RSV2001
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Approved, Date: 18 April 2019
l.
0.5 mL of blood for serostatus assessment can be collected at screening by venous blood sample or fingerstick, at the discretion of the investigator. If 0.5 mL is 
collected at screening, baseline blood draw for immunogenicity should be on Day 1.
m. Note: RSV-seropositive toddlers may be recruited if RSV seropositivity was assessed via RSV EIA or virus neutralization assay in a different study of the sponsor.
n.
Cohort 0: to include exclusion criteria 1, 4, 8, 9, 10, 11, 15, 16 and 17
o.
Cohort 1: to include exclusion criteria 21, 22, 25, 26, 28, and 32
p.
Blood for cellular immunity will also provide plasma for humoral assessments
q.
Investigator must check for acute illness or body temperature ≥38.0 °C at the time of vaccination. If before the first vaccination, the subject may be enrolled at a 
later date if within the screening window (otherwise, rescreening is required), or be withdrawn at the discretion of the investigator and after consultation with the 
sponsor. If before the second vaccination, the subject may be vaccinated up to, and no later than 10 days after the scheduled vaccination, or be withdrawn at the 
discretion of the investigator and after consultation with the sponsor. In the event of an ongoing AE or other situation precluding subject vaccination within 10 days, 
subjects may be vaccinated beyond the 10-day window at the discretion of the sponsor.
r.
Subjects will be closely observed for a minimum of 30 minutes post-vaccination, or a minimum of 60 minutes post-vaccination according to local approvals. Any 
unsolicited, solicited local and systemic AEs, and vital signs will be documented by study-site personnel following this observation period
s.
Concomitant medications will be collected from the time of each vaccination through 28 days after each vaccination, and additionally outside of these periods when 
associated with any SAE. Pre-study therapies administered up to 30 days before first dose of study vaccine will be recorded during screening
t.
Monitoring of RTIs will take place during each 28-day post-vaccination period, and additionally during the RSV season after the first dose (even if it falls outside of 
the 28-day post-vaccination period). During each 28-day post-vaccination period, nasal turbinate samples will be collected for all RTIs. If, during the RSV season,
but outside the 28-day post-vaccination period, a subject shows persistent (>48 hours) clinical symptoms of rhinitis (sneezing or runny nose or congestion) and 
persistence (>24 hours) of one or more of the following: cough, abnormal breathing, fever, lethargy or decreased appetite, the study site should be informed and 
nasal turbinate samples will be collected for these subjects. Note: Nasal turbinate samples will not be collected if less than 7 days after the previous sample 
collection
u.
When nasal turbinate samples are collected, the attending health care professional will record signs and symptoms of the RTI using the RTI Symptoms Form
v.
At Visit 2, rulers and thermometers will be distributed to subjects in Cohort 0, and to parent(s)/legal guardian(s) of subjects in Cohort 1
w.
At least 5 toddlers in the active group are to have received first dose in a clinic setting and to have completed Visit 3 with no safety concerns before moving to 
vaccination of study subjects in a non-clinic setting (safety information of the first 5 active toddlers will be monitored by the PI(s)/SRP(s) through Visit 3, and 
escalated to the IDMC in the event of a safety signal). 
x.
Blood draw for serology testing will not exceed 15mL
Note: Body temperatures for Cohort 0 recommended to be measured orally; body temperatures for Cohort 1 recommended to be measured either rectally or axillary
(actual routes to be recorded in the eCRF)
AE = adverse event; d = day; eCRF = electronic case report form; EIA = enzyme immunoassay; FU = follow-up; HIV = human immunodeficiency virus; ICF = 
informed consent form; LRTI = lower respiratory tract infection; mo = month; MA-RTI = medically-attended respiratory tract infection; RT-PCR = reverse transcriptase 
polymerase chain reaction; RSV = respiratory syncytial virus; RTI = respiratory tract infection; SAE = serious adverse event; vac = vaccination


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ABBREVIATIONS
Ad26
adenovirus serotype 26
Ad35
adenovirus serotype 35
AE
adverse event
BMI
body mass index
CEC
Clinical Endpoint Committee
CI
confidence interval
CS
circumsporozoite
DNA
deoxyribonucleic acid
eCRF
electronic case report form 
eDC
electronic data capture
EIA
enzyme immunoassay
ELISA
enzyme-linked immunosorbent assay
ELISpot
enzyme-linked immunospot
ERD
enhanced respiratory disease
FA
Full Analysis (set)
FDA
(US) Food and Drug Administration
FI
formalin-inactivated
FIH
first-in-human
GCP
Good Clinical Practice
β-hCG
β-human chorionic gonadotropin 
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Conference on Harmonisation
ICS
intracellular cytokine staining
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IFNγ
interferon gamma
Ig
immunoglobulin
IL
interleukin
IRB
Institutional Review Board
IWRS
interactive web response system
LRTI
lower respiratory tract infection
MA-RTI
medically-attended respiratory tract infection
PBMC
peripheral blood mononuclear cell
PI
principal investigator
PPI
Per-protocol Immunogenicity (set)
PQC
Product Quality Complaint
RSV
respiratory syncytial virus
RTI
respiratory tract infection
RT-PCR
reverse transcriptase polymerase chain reaction
SAE
serious adverse event
SRP
study responsible physician
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
Th 
T-helper (cell)
TNFα
tumor necrosis factor alpha
UK
United Kingdom
US
United States
VNA
virus neutralizing antibody


VAC18194 (Ad26.RSV.preF)
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Approved, Date: 18 April 2019
vp
viral particles
WHO
World Health Organization


VAC18194 (Ad26.RSV.preF)
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Approved, Date: 18 April 2019
1.
INTRODUCTION
A human adenovirus-vectored vaccine candidate which has shown promise in preclinical animal 
models of respiratory syncytial virus (RSV) 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.
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
Background
RSV is considered to be the most important cause of serious acute respiratory illness in infants 
and children under 5 years of age.18,39,44 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.32
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.36,38,40,42,43 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.16 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.35,39,44
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.6,18
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.21 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.31
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 


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Approved, Date: 18 April 2019
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.2,5,34 Furthermore, in mice, Ad26- and Ad35-vectored 
vaccines with 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.37
Thus, in contrast with the Th2-skewed profile of FI-RSV vaccine, which has been associated 
with ERD upon infection with RSV, the likely Th1 profile of an adenoviral-vectored RSV 
vaccine reduces the likelihood of disease enhancement in RSV-seronegative infants.
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. 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 


VAC18194 (Ad26.RSV.preF)
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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.15,17 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. The full 
length membrane-bound RSV F protein in a pre-F conformation encoded by this vector differs 
by only five amino acids from the wild-type F protein used in the FA2 construct.25 This change 
in the transgene confers more stability to the pre-fusion form of the protein.25 This change also 
induces higher immune responses against pre-fusion epitopes because the majority of 
neutralizing antibodies target the pre-fusion protein conformation.27,33 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.47
Ad26.RSV.preF Preclinical Data
In preclinical studies in mice and cotton rats, Ad26.RSV.preF is immunogenic, 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 following Ad26.RSV.preF immunization 
was T-helper 1 (Th1)-biased, based on the ratio of the Th1 cytokine IFNγ to Th2 cytokines, and 
on the ratio of RSV F-specific IgG2a/IgG1 antibodies. Also, in neonatal mice, Ad26.RSV.preF 
was immunogenic and induced both humoral and cellular responses, with similar Th1 bias. In 
rodent models, single immunization with Ad26.RSV.preF induced dose-dependent protection in 
the upper and lower respiratory tract from RSV challenge with the RSV A2 strain (in cotton rats 
and mice) and the RSV B strain (in cotton rats only). Histopathologic features of ERD were not 
observed in the lung after RSV challenge of mice and cotton rats vaccinated with 
Ad26.RSV.preF over a large dose range, including vaccine doses that were fully protective, as 
well as non-protective vaccine doses at which RSV replication in the lung was observed.47


VAC18194 (Ad26.RSV.preF)
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Approved, Date: 18 April 2019
Ad26.RSV.preF Clinical Data
Ad26.RSV.preF is currently under evaluation in three other ongoing clinical studies: Phase 1 
study (VAC18193RSV1003), and two Phase 2a studies (VAC18193RSV2002 and 
VAC18193RSV2003) (Table 4).
Table 4:
Other Ongoing Clinical Studies with Ad26.RSV.preF
Study Identifier
Clinical 
Phase
Vaccine
N Planned
Study Population
VAC18193RSV1003
1
Ad26.RSV.preF 
72
Adult subjects aged 60 years and older
VAC18193RSV2002
2a
Ad26.RSV.preF
44-70
Adult subjects aged 18 to 50 years
VAC18193RSV2003
2a
Ad26.RSV.preF
180
Adult subjects aged 60 years and older
In one of these studies, interim safety and immunogenicity data are available, as follows:
VAC18193RSV1003: This is an ongoing single-center, randomized, placebo-controlled, double-
blind, FIH, Phase 1 study to evaluate the safety, tolerability and immunogenicity of 2 
Ad26.RSV.preF vaccinations, administered 1 year apart, in 72 male and female subjects aged 60 
years and older in stable health. Subjects have been randomized in parallel to one of five study 
groups and have received 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 (at the study group level) analysis 28 days 
post-dose 1 from all 72 subjects who received Ad26.RSV.preF (5×1010 vp or 1×1011 vp) or 
placebo confirmed that the 1×1011 vp dose of Ad26.RSV.preF was more immunogenic compared 
with the 5×1010 vp dose. Data from this ongoing study, which is still blinded, show that the 
Ad26.RSV.preF vaccine is immunogenic and that there is a favorable Th1/Th2 profile. 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-
                                                
CCI


VAC18194 (Ad26.RSV.preF)
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Approved, Date: 18 April 2019
tolerated when tested in a nonclinical single-dose intramuscular safety study in rabbits,47 and will 
be assessed in Cohort 0 before commencement of dosing Cohort 1 in the current study.
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 levels for Ad26.RSV.preF used in this study are 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];10,34 and Ebola 
glycoprotein [in Ad26.ZEBOV against Ebola virus]29). 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,a 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 
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 5x1010 vp and 1x1011 vp in the current study.
To date, Ad26-vectored vaccines have only been tested in adults and the elderly (ie, subjects 
≥18 years); Ad35-vectored vaccines have been tested in 904 subjects, including 555 adults and 
349 infants. Data from Bacillus Calmette-Guérin (BCG)-primed infants immunized with Ad35 
encoding for TB antigens (AERAS-402) indicated that the highest immune responses were 
obtained following administration of 1x1011 vp. The safety of this Ad35-based TB vaccine was 
acceptable when tested in infants aged 14 weeks and older at doses from 1.5x108 vp to 
1x1011 vp.
Study Design
In the current study, homologous regimens will be evaluated in subjects in two sequential 
cohorts.

In 18 to 50 year-old adults (Cohort 0): 
1x1011 vp Ad26.RSV.preF (or placebo) on Days 1 and 29

In 12 to 24 month-old RSV-seropositive toddlers (Cohort 1): 
5x1010 vp Ad26.RSV.preF (or placebo) on Days 1 and 29
                                                
a 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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Approved, Date: 18 April 2019
A dose of 1x1011 vp will be used for adults in Cohort 0 based on an acceptable safety profile of 
Ad26.RSV.preF at 1x1011 vp from the unblinded (at the group level) interim analysis 28 days 
post-Dose 1 from all 72 elderly subjects in study VAC18193RSV1003, in addition to supporting 
safety data from dosing Ad26.ZEBOV at 1x1011 vp.
A dose of 5x1010 vp will be used for toddlers in Cohort 1 as this is the anticipated dose to be 
used in a future study in 12-24 month-old seronegative toddlers. Dosing ranging would occur in
a future study in 6 to 12 month-old seronegative subjects.
Enrollment and dosing will be staggered to allow safety assessments to be made in adults before 
enrolling and dosing seropositive toddlers, as described fully in Section 3.1 below.
An independent data monitoring committee (IDMC) will be established for this study to evaluate 
safety and tolerability data on a regular basis. Refer to Section 11.9.1, for details.
An independent blinded clinical endpoint committee (CEC) will be established for this study to 
assess any suspected case of severe lower LRTI in pediatric subjects. Refer to Section 11.9.2, for 
details.
1.2.
Overall Rationale for the Study
This study seeks to evaluate the safety and immunogenicity of Ad26.RSV.preF at a dose of 
5x1010 vp in RSV-seropositive toddlers aged 12 to 24 months (Cohort 1). As this is the first study 
using Ad26.RSV.preF in Formulation Buffer 2, the reactogenicity profile of Ad26.RSV.preF in 
this new formulation buffer will be first assessed in an adult run-in cohort (Cohort 0) before 
dosing the toddlers.
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
2.1.1.
Objectives
Primary Objectives
The primary objectives are:

To assess the safety and tolerability of an intramuscular regimen of two doses of 1x1011 vp 
of Ad26.RSV.preF in adults aged 18 to 50 years.

To assess the safety and tolerability of an intramuscular regimen of two doses of 5x1010 vp 
of Ad26.RSV.preF in RSV-seropositive toddlers aged 12 to 24 months.
Secondary Objective
The secondary objective is:


VAC18194 (Ad26.RSV.preF)
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Approved, Date: 18 April 2019

To assess the humoral and cellular immune responses as measured by virus neutralization 
assay, F-protein binding antibodies (pre-F and post-F) and intracellular cytokine staining 
(ICS; to assess Th1/Th2 subtyping).
Exploratory Objectives
The exploratory objectives are:

To further assess the humoral and cellular immune responses elicited by Ad26.RSV.preF. 
The assays to be used may include, but are not limited to, RSV strain cross-neutralization, 
anti-F protein 
antibody 
specificity 
and 
functionality 
characterization, 
adenovirus 
neutralization assays, molecular antibody characterization (avidity, Fc cell interaction, 
antibody isotyping), evaluation of the cellular immune response (IFNγ enzyme-linked 
immunospot [ELISpot] assay) and functional and memory immune response (by ICS), and 
cytokine profiles of RSV F-protein peptide-stimulated peripheral blood mononuclear cell 
(PBMC) supernatant.

To assess RSV infection rates in Ad26.RSV.preF and placebo subjects

To monitor for severe RSV-LRTI in Cohort 1 (RSV-seropositive toddlers aged 12 to 
24 months)

To assess symptoms of respiratory illness via the respiratory tract infection (RTI) symptoms 
form
2.1.2.
Endpoints
Primary Endpoints – Safety and Tolerability

Solicited local and systemic AEs for 7 days after each vaccination.

Unsolicited AEs for 28 days after each vaccination (ie, from informed consent form [ICF]
signature through the following 28 days post-first vaccination, and for subsequent 
vaccinations from time of vaccination through the following 28 days).

SAEs from ICF signature to the end of the study.
Secondary Endpoints – Immune Responses
The analysis of the immunogenicity of vaccine regimens will include the characterization of 
humoral as well as cellular responses. The focus of the immunogenicity analysis is on virus 
neutralizing antibodies (VNAs), F-protein antibodies (pre-F and/or post-F) and Th1/Th2 
cytokine profile response.
Humoral Immune Response

RSV neutralization A strain
Analysis of RSV A neutralizing antibodies.


VAC18194 (Ad26.RSV.preF)
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Approved, Date: 18 April 2019

RSV F-protein enzyme-linked immunosorbent assay (ELISA; pre- and/or post-fusion F 
antibodies)
Analysis of antibodies binding to RSV F protein in post-fusion and pre-fusion form.
Cell-mediated Immune Response

Intracellular cytokine staining 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)
Exploratory Endpoints – Immune Responses
Additional exploratory analyses may be performed to investigate vaccine-elicited immune 
responses further. These may include, but are not limited to, the following assays:
Humoral Immune Response

RSV cross-neutralization of B and/or other A strain(s)
The strain cross-neutralizing capacity of the vaccine-induced immune response will be 
assessed.

F-protein antibody specificity characterization
Pre- and post-F specificity by binding or functional assays as ELISA, and/or competition 
ELISA. Adsorption of serum or plasma with pre-F and post-F protein before any antibody 
assay, epitope mapping, functional VNAs.

Adenovirus neutralization assay
This assay assesses neutralizing antibody responses against the adenoviral vector.

Functional and molecular antibody characterization
Functional characterization of antibodies may be performed in assays including antibody-
dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis 
(ADCP).9 A molecular characterization of vaccine-elicited antibodies will include antibody 
avidity, Fc characterization and Ig isotype, functional VNA and protective antibody 
assessments.
Cell-mediated Immune Response

IFNγ ELISpot assay
An ELISpot assay is used to quantify the amount of PBMCs able to produce IFNγ upon 
RSV F-protein peptide antigen stimulation.


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Approved, Date: 18 April 2019

Cytokine analysis
Cytokine profiles of (in vitro) stimulated PBMC supernatant will be analyzed to assess the 
quantity and quality of the elicited immune responses, including Th1/Th2 balance. Analysis 
will include, but is not limited to, IFN, IL-2, IL-4, IL-5, IL-13, and TNF.
Exploratory Endpoints – RSV Infection

For Cohort 1 only, RSV infection confirmed by either reverse transcriptase polymerase 
chain reaction (RT-PCR), or by serology for, but not limited to, protein G and/or N if no 
RT-PCR is available. To detect asymptomatic RSV infections, a fold increase will be 
applied to call a subject seropositive to G and/or N ELISA (or F in case of placebo subjects). 
Fold increases for RSV infection will be determined based on the (suspected) infection and 
the convalescent blood samples.

In Cohort 1 throughout the study:
o
Severe RSV-LRTI
o
RSV medically-attended respiratory tract infection (MA-RTI)
Refer to Section 9.2 for evaluations related to endpoints.
2.2.
Hypothesis
No formal statistical hypothesis is planned. The study will evaluate whether Ad26.RSV.preF is 
safe, well-tolerated and immunogenic in adults and RSV-seropositive toddlers.
3.
STUDY DESIGN AND RATIONALE
In this document, unless otherwise specified, any reference to activities to be performed by the 
subject refers to adult subjects or the parent/legal guardian for pediatric subjects.
3.1.
Overview of Study Design
This is a multi-center, randomized, double-blinda, Phase 1/2a study, to be conducted in 12 male 
and female adults aged ≥18 to ≤50 years and 36 male and female toddlers aged ≥12 to 
≤24 months of age, seropositive for RSV within 42 days prior to dosing.
Subjects will be enrolled into sequential age cohorts:

18 to 50 year-old adults, into Cohort 0

12 to 24 month-old seropositive toddlers, into Cohort 1
                                                
a The administrator of the vaccine may be unblinded but will not participate in any other study evaluation from 
randomization onwards. The site staff or qualified professional staff who will do the observation and the subjects 
will be blinded.


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In Cohort 0, subjects will be randomized 2:1 to receive either Ad26/Ad26 (at 1x1011 vp) or
placebo/placebo, and in Cohort 1, subjects will be randomized 2:1 to receive either Ad26/Ad26 
(at 5x1010 vp) or placebo/placebo (Table 5).
The standard dose (5x1010 vp) is the dose the most commonly used in previous studies and other 
programs with good safety and immunogenicity profiles. The high dose (1x1011 vp) has been 
shown in study VAC18192RSV1003 to be well tolerated in elderly subjects and at least as 
immunogenic, and is therefore appropriate for adults in this study. The standard dose is thought 
to be the proper dose to start with for preliminary ERD assessment in toddlers as ERD could be 
linked to a suboptimal immune response. The high dose will be first tested in further studies in 
seropositive toddlers, before being used in seronegative infants. Dose ranging will be performed 
in 6-12M seronegative, closer to the target population.
The study will have three phases: a screening phase, an active phase and a safety follow-up 
phase through 1 year after the first dose. The durations of the respective phases are as follows:
Phase
Cohort 0
Cohort 1
Screening:
up to 4 weeks
up to 6 weeks
Active:
30 weeks
dosing on Days 1 and 29
safety follow-up through 6 months post-final 
dose
immunogenicity at:

pre-Dose 1 (Day 1)

pre-Dose 2 (Day 29)

28 days post-Dose 2 (Day 57)

6 months post-Dose 2
(Day 211/Week 30)
30 weeks
dosing on Days 1 and 29
safety follow-up through 6 months post-final 
dose
immunogenicity at:

pre-Dose 1 (Day 1)

pre-Dose 2 (Day 29)

28 days post-Dose 2 (Day 57)

6 months post-Dose 2
(Day 211/Week 30)
Safety follow-up:
through 1 year after the first dose
through 1 year after the first dose
The end of the active phase will be when the last subject completes the visit at 6 months after the 
final dose. The end of the study will be the last subject’s last visit (by telephone) at the end of the 
safety follow-up phase.
First-dose Safety
For Cohort 0, 48-hour and 7-day safety will be monitored by the Principal Investigator(s) (PI[s]) 
and the Study Responsible Physician(s) (SRP[s])a; for Cohort 1, 48-hour safety will be 
monitored by the PI(s) and the SRP(s), and 7-day safety will be monitored by the IDMC. In the 
event of a significant safety finding, the IDMC will be consulted.
Note: At least 5 toddlers in the active group are to have received first dose in a clinic setting and 
                                                
a The safety of Ad26.RSV.preF in elderly subjects at 5x1010 vp and 1x1011 vp will have been established in study 
VAC18193RSV1003 prior to initiation of the current study; the purpose of dosing Ad26.RSV.preF in Cohort 0 
in the current study is as a safety check for the new drug product formulation buffer, and consequently only PI 
and SRP review of Cohort 0 safety data is planned prior to dosing seropositive toddlers in Cohort 1. 


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to have completed Visit 3 with no safety concerns before moving to vaccination of study subjects 
in a non-clinic setting (safety information of the first 5 active toddlers will be monitored by the 
PI(s)/SRP(s) through Visit 3, and escalated to the IDMC in the event of a safety signal).
Enrollment will be staggered to allow safety assessments to be made 7 days after the first dose in 
all 12 adults in Cohort 0 before enrolling and dosing seropositive toddlers in Cohort 1. 
Additionally, safety assessments will be made 7 days after the first dose in the first 
12 seropositive toddlers (8 actives and 4 placebos) in Cohort 1 before enrolling and dosing the 
remaining seropositive toddlers, as indicated below (see also Figure 1). In addition, 48-hour 
safety will be checked after dosing sentinel subjects in both cohorts. The sentinel cohort 
approach with 2 subjects (1 active and 1 placebo) in each cohort 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.

Enroll and dose 2 sentinel subjects (adults) in Cohort 0: 1 of these 2 sentinel subjects will 
receive Ad26.RSV.preF.

After satisfactory completion of 48-hour safety review after the first dose for these 
2 Cohort 0 subjects, the remaining 10 subjects in Cohort 0 will be enrolled and receive the 
first dose. The PI(s)/SRP(s) will assess post-first dose reactogenicity by review of 7-day 
safety data for all 12 Cohort 0 subjects.

After satisfactory completion of this safety review, 2 sentinel subjects (seropositive toddlers) 
in Cohort 1 will be enrolled and receive the first dose: one of these 2 sentinel subjects will 
receive Ad26.RSV.preF.

After satisfactory completion of 48-hour safety review after the first dose for these 
2 Cohort 1 subjects, 10 more subjects in Cohort 1 will be enrolled and receive the first dose. 
The IDMC will assess post-first dose reactogenicity by review of 7-day safety data for the 
first 12 Cohort 1 subjects (8 actives and 4 placebos).

After satisfactory completion of this safety review, the remaining subjects in Cohort 1 will 
be enrolled and receive the first dose.
In all post-first dose 48-hour and 7-day safety reviews, safety data for review will include 
solicited and unsolicited AEs and SAEs. Additionally, for Cohort 0 safety laboratory data will be 
included in the 7-day safety review. In the absence of clinically relevant findings, enrollment and 
dosing for the next cohort of subjects will continue as described above.
Second-dose Safety
Post-second dose 48-hour and 7-day safety assessments will be monitored by the PI(s) and the 
SRP(s). Administration of the second dose will also be staggered to allow safety assessments to 
be made 7 days after the second dose in all 12 adults in Cohort 0 before administering the second 
dose to seropositive toddlers in Cohort 1. Likewise, safety assessments will be made 7 days after 
the second dose in the first 12 seropositive toddlers in Cohort 1 before administering the second 
dose to the remaining seropositive toddlers in Cohort 1. In addition, 48-hour safety will be 


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checked after dosing sentinel subjects in both cohorts. Safety data for review will include 
solicited and unsolicited AEs and SAEs. In the absence of clinically relevant findings, 
enrollment and dosing for the next cohort of subjects will continue as described above.
The sponsor will monitor post-vaccination safety on an ongoing basis by reviewing blinded 
safety data.
Table 5:
Study Design
Cohort
Group
N
Day 1 
Day 29/Week 4 
ADULTS 18 to 50 years
0
Group 1
8
Ad26.RSV.preF (1x1011 vp)
Ad26.RSV.preF (1x1011 vp)
Group 2
4
Placebo
Placebo
TODDLERS 12 to 24 months: RSV seropositive
1
Group 3
24
Ad26.RSV.preF (5x1010 vp)
Ad26.RSV.preF (5x1010 vp)
Group 4
12
Placebo
Placebo




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After each vaccination, all subjects will be closely observed for a minimum of 30 minutes post-
vaccination, or a minimum of 60 minutes post-vaccination according to local approvals, 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. Subjectsa 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 each study vaccine dosing day and on a daily basis for 
the following 7 days. Temperaturesb should be taken at approximately the same time each day, 
preferably in the eveningc and, for pediatric subjects, additionally whenever the child feels warm. 
Study-site personnel will collect and review subject diary information and confirm the entries at 
subsequent site visits.
Unsolicited AEs will be collected from the time of informed consent through 28 days after each 
dose. For both cohorts, all SAEs will be collected from ICF signature to the end of the study. All 
AEs, including any that are ongoing at 28 days after each dose, will be followed until clinical 
resolution or stabilization. Concomitant medications will be collected from the time of each 
vaccination through 28 days after each vaccination, and additionally outside of these periods 
when associated with any SAE.
Blood will be collected for immunogenicity assessments as follows:

Cohort 0: pre-vaccination for first and second doses, and at 28 days and 6 months after the 
second dose

Cohort 1: pre-vaccination for first and second doses, and at 28 days and 6 months after the 
second dose
For Cohort 1, a blood sample will be taken for RSV serology at screeningd; the baseline sample 
for immunogenicity may either be drawn at the same screening visit or pre-dose on Day 1, at the 
discretion of the investigator.
Unscheduled study visits may be performed based on investigator’s clinical judgment and may 
include further evaluations, as needed.
Diagrams of the entire study design by cohort are provided in Figure 2 (Cohort 0) and Figure 3
(Cohort 1).
                                                
a In Cohort 1, activities to be performed by the subject refers to the parent/legal guardian.
b Recommended orally for adult subjects; rectally or axillary for pediatric subjects (actual routes to be recorded in the eCRF).
c All Day 8 post-vaccination diary assessments, including temperature measurements, may be collected earlier to coincide with 
the corresponding clinic visit.
d 0.5 mL of blood for serostatus assessment can be collected by venous blood sample or fingerstick, at the discretion of the 
investigator. If 0.5 mL is collected at screening, baseline blood draw for immunogenicity should be on Day 1.






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appetite). These calls will also check for any SAEs and associated concomitant medications since 
the previous visit or telephone contact.
3.2.
RTI – Procedures Specific to Cohort 1
Monitoring of RTIs will take place during each 28-day post-vaccination period, and additionally 
during the RSV season after the first dose (even if it falls outside of the 28-day post-vaccination 
period). Monitoring for MA-RTIs and severe LRTIs will take place during the whole study 
period.
During each 28-day post-vaccination period, all RTIs will be reported, nasal turbinate samples 
will be collected as soon as possible after the onset of respiratory symptoms, and signs and 
symptoms will be recorded by the attending health care professional using the RTI Symptoms 
Form. 
If, during the RSV season, but outside the 28-day post-vaccination period, a subject shows 
persistent (>48 hours) clinical symptoms of rhinitis (sneezing or runny nose or congestion) and 
persistence (>24 hours) of one or more of the following30,32,41,44: cough, abnormal breathing, 
fever, lethargy or decreased appetite, the study site should be notified. Nasal turbinate samples 
will be collected as soon as possible after the onset of these combined respiratory symptomsa.
When nasal turbinate samples are collected, the attending health care professional will record 
signs and symptoms of the RTI using the RTI Symptoms Form.
Nasal turbinate samples will not be collected if less than 7 days after the previous sample 
collection.
Outside of the RSV season, nasal turbinate samples will only be collected from subjects with 
MA-RTIs or severe LRTIs (for definition of MA-RTI and severe LRTI, please refer to 
Section 11.3.1).
Throughout the study, nasal turbinate samples will be collected from any subject with a MA-RTI 
or severe LRTI.
The criteria used to assess potential cases of RSV infection in subjects from Cohort 1 will be as 
follows:

Suspected RSV infection: subject has persistent (>48 hours) clinical symptoms of rhinitis 
(sneezing or runny nose or congestion) and persistence (>24 hours) of one or more of the 
following: cough, abnormal breathing, fever, lethargy or decreased appetite.
Occurrence of this combination of symptoms in any subject would trigger collection of a 
nasal turbinate sample.
                                                
a These procedures should preferentially be performed at the study site. These procedures can be conducted at the subject’s home 
by site staff or qualified professional staff if the study site has an established standard operating procedure as such. In case of 
emergency, the procedures can be done in a hospital.


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
Confirmed RSV infection: subject with suspected RSV infection and positive for RSV on 
the basis of RT-PCR conducted centrally.
Data on the clinical course of infection including information regarding oxygenation status, 
supplemental oxygen requirements and specific drug treatments should be collected, as well as 
any other concurrent respiratory illness present at the time of the diagnosis of the event and up to 
symptom resolution.
To ensure the rapid follow-up of any severe LRTI or MA-RTI, study sites will need to make 
arrangements with primary care physicians, emergency departments and/or hospitals’ urgent care 
facilities to be notified when a subject is being seen. Further details will be provided in the Trial 
Center File. Any parent/legal guardian who seeks medical attention for their child due to an RTI 
should make the attending health care professional aware that their child is taking part in an RSV 
vaccine study. Each child’s parent/legal guardian will be given a wallet card with key study 
information and site contact details (see Section 12.3.1). These details should be shared with the 
attending health care professional.
Note: Any RTI falling within the 28-day post-vaccination period will be reported as an 
unsolicited AE, preferably as a diagnosis. Any RTI fulfilling the criteria of an SAE would be 
reported as such during the entire study. Any severe LRTI will be reported using the SAE 
reporting system and SAE form, regardless of whether the event fulfills the criteria of an SAE.
3.3.
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 
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. This 
study uses Formulation Buffer 1. All 72 subjects have been randomized and have received the 
first dose. Based on acceptable safety and immunogenicity data from the unblinded (at the group 
level) interim analysis 28 days post-Dose 1 from all 72 subjects in this study, the current study 
will be initiated firstly for adults 18 to 50 years of age. After 7-day safety has been verified by 
the PI/SRP in the first 12 adults, enrollment of seropositive toddlers 12-24 months of age will 
commence.


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3.4.
Risk/Benefit Section
3.4.1.
Known Benefits
The clinical benefits of vaccination with Ad26.RSV.preF have yet to be established.
3.4.2.
Potential Benefits
Ad26.RSV.preF is under development for prophylaxis of RSV, however vaccine efficacy has not 
yet been investigated. There is no direct medical benefit to the subject for participation in this 
clinical study. Although study subjects may benefit from clinical testing and physical 
examination, they may receive no direct benefit from participation. Others may benefit from 
knowledge gained in this study that may aid in the development of an RSV vaccine.
3.4.3.
Known Risks
Single doses of 5x1010 vp or 1x1011 vp of Ad26.RSV.preF are under investigation in the ongoing 
FIH Phase 1 study VAC18193RSV1003 in elderly subjects. Preliminary safety data from an 
unblindeda interim analysis 28 days post-Dose 1 from 41 subjects who received Ad26.RSV.preF 
or placebo did not reveal any safety concerns at either dose level.
3.4.4.
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 in 
adult subjects, and loss of appetite, vomiting, diarrhea, decreased activity/lethargy, 
irritability/crying in pediatric subjects. 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. 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. Sites should have medical treatment and 
medically qualified staff available in case of severe allergic reactions following vaccine 
administration.
                                                
a At the group level.


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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. 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
An Ad35-vectored vaccine (AERAS-402) has been tested in two completed clinical studies in 
infants: data from these studies indicate acceptable safety at doses from 1.5x108 vp to 1x1011 vp 
in infants aged 14 weeks and older.
Risks Related to RSV Vaccines
In the 1960s, a FI-RSV vaccine was associated with ERD in young children, characterized by an 
increased rate of RSV-mediated, severe LRTI in the vaccinated individuals compared with the 
control group.8,13,21,22 Children aged between 2 months and 7 years of age were vaccinated; the 
risk of ERD was highest among children under 6 months of age. In the study with the most 
severe outcomes, RSV infection was confirmed in 20/31 (65%) children who received the 
FI-RSV vaccine, with 16/20 children requiring hospitalization due to severe LRTI (52% of all 
FI-RSV vaccinees, representing 80% of those being RSV-infected). In contrast, while RSV 
infection was observed in 21/40 (53%) children who received a control vaccine, only one 
hospitalization due to severe LRTI (2.5% of all control vaccinees, representing 5% of those 
being RSV-infected) was required. Two of the FI-RSV vaccinated children died.22 ERD is 
characterized by increased pulmonary inflammatory response and mucin production leading to 
reduced oxygen exchange in the lungs.
Although the mechanisms for ERD are not fully understood, it is thought that FI-RSV: 1) may 
have failed to induce adequate neutralizing antibody titers; 2) may have led to an overproduction 
of binding antibodies promoting immune complex deposition and hypersensitivity reactions; 
3) may have failed to induce adequate numbers of memory CD8 T cells important for viral 
clearance; and 4) may have induced a Th2-skewed allergic type T cell response.31


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In general, adenoviral-vectored vaccines have been shown to promote a Th1-biased response.37
Single immunization with low doses of Ad26.RSV.preF protects cotton rats from challenge with 
the vaccine-homologous RSV-A2 and the heterologous B Wash strain, without induction of any 
histopathological signs of ERD. This Th1 profile of Ad26.RSV.preF reduces the likelihood of 
disease enhancement in RSV-seronegative infants.
Risks from Collection of Nasal Turbinate Samples
Collection of nasal turbinate samples may cause a nosebleed.
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 (Cohort 0 Only)
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 ICF until at least 3 months after the last vaccination (see Section 4.1). Use of 
hormonal contraception should start at least 28 days before the first administration of study 
vaccine. Women who are pregnant or breast-feeding, or are planning to become pregnant while 
enrolled in the study until 3 months after the final dose of study vaccine, will be excluded from 
the study. 
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. Note: Planning for 
routine childhood vaccinations will be available from the site to ensure that these can be taken at 
appropriate times during the study.
Unknown Risks
There may be other serious risks that are not known.


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3.4.5.
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:
Preliminary safety data from the ongoing clinical studies and safety data generated with the 
related vaccines containing different inserts revealed no significant safety issues. 
Only subjects who meet all inclusion criteria and none of the exclusion criteria (specified in 
Section 4) 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.
Safety will be closely monitored throughout the study:
After each vaccination, subjects will remain in the clinic and be closely observed by study 
staff for at least total 30 minutes post-vaccination, or a minimum of 60 minutes post-
vaccination according to local approvals, or longer if deemed necessary by the 
investigator, to monitor the development of any acute reactions. Any unsolicited, 
solicited local or systemic AEs will be documented during this period. Subjects will use a 
diary to document solicited local and systemic AEs in the evening after each vaccination 
and then daily for the next 7 days at approximately the same time each day.
Subjects will undergo safety follow-up by study staff 72 hours after each vaccination by 
telephone. 
Unsolicited AEs will be documented from immediately prior to until 28 days after each 
vaccination. All SAEs will be recorded from signing the ICF through 1 year after the first
vaccination.
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.
Several safety measures are included in this protocol to minimize the potential risk to subjects, 
including the following:
Enrollment will be staggered to allow safety assessments to be made 7 days after the first 
dose in all 12 adults before enrolling and dosing seropositive toddlers. Additionally, safety 
assessments will be made 7 days after the first dose in the first 12 seropositive toddlers 
(8 actives and 4 placebos) before enrolling and dosing the remaining seropositive toddlers. 
For Cohort 0, 7-day safety will be monitored by the PI and SRP; for Cohort 1, 7-day safety 
will be monitored by the IDMC. In addition, 48-hour safety will be checked by the PI and 
SRP after dosing sentinel subjects in both cohorts. These safety assessments at 48 hours 
and 7 days post-first dose are described more fully in Section 3.1.
For all subjects, there are pre-specified rules that would result in pausing of further 
vaccinations if predefined conditions occur, preventing exposure of new subjects to study 
vaccine until the PI/SRP and/or IDMC reviews all safety data (see Section 11.10).


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Subjects will discontinue study vaccine for the reasons included in Section 10.2.
If acute illness (excluding minor illnesses such as diarrhea) or fever (body temperature 
≥38.0°C) occur at the scheduled time for the first vaccination, the subject may be enrolled 
at a later datea, or be withdrawn at the discretion of the investigator and after consultation 
with the sponsor.
If acute illness (excluding minor illnesses such as diarrhea) or fever (body temperature 
≥38.0°C) occur at the scheduled time for the second vaccination, the subject may be 
vaccinated up to 10 days beyond the scheduled vaccination, or be withdrawn from further 
vaccination at the discretion of the investigator and after consultation with the sponsor. In 
the event of an ongoing AE or other situation precluding subject vaccination within 10 
days, subjects may be vaccinated beyond the 10-day window at the discretion of the 
sponsor.
Contraindications to vaccination are included in Section 10.3.
Careful monitoring will be in place to check for incidence of any severe RSV-LRTI in 
Cohort 1. During each 28-day post-vaccination period all suspected cases of RSV infection 
will be identified for follow-up, and nasal turbinate samples will be analyzed. During the 
RSV season, but outside the 28-day post-vaccination period, suspected cases of RSV 
infection will be identified for follow-up from a defined set of clinical symptoms; nasal 
turbinate samples will be analyzed for identification and confirmation of RSV infection. 
Individual cases of severe LRTI may be reviewed by the IDMC.
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 within 28 days before administration of the first 
dose of study vaccine for Cohort 0, and within 42 days before administration of the first dose of 
study vaccine for Cohort 1. Each potential subject must satisfy all of the following criteria to be 
enrolled in the study.
4.1.
Inclusion Criteria
4.1.1.
Adult Subjects
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, and is willing and able to comply with all study procedures and adhere to 
the prohibitions and restrictions specified in this protocol.
                                                
a If within the screening window. Otherwise, rescreening is required.


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2
Subject is a man or woman, ≥18 to ≤50 years old on the day of ICF signature.
3
Subject must be in good health, without significant medical illness, on the basis of physical 
examination, medical history, and vital signs measurement.
4
Subject must be healthy on the basis of clinical laboratory tests performed at screening. 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.
5
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
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*.
                                                
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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*Sexual abstinence is considered an effective method only if defined as refraining 
from heterosexual intercourse from signing the informed consent until 3 months after 
the last dose of study vaccine. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the subject.
ii. agrees to remain on an effective method of contraception from signing the 
informed consent until 3 months after the last dose of study vaccine. Use of 
hormonal contraception should start at least 28 days before the first 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.
6
All women of childbearing potential must:
a.
Have a negative highly sensitive serum β-human chorionic gonadotropin (β-hCG) 
pregnancy test at screening
b. Have a negative urine β-hCG pregnancy test immediately prior to each study vaccine 
administration
7
From the time of first vaccination through 3 months after the final vaccination, subject agrees 
not to donate blood.
4.1.2.
Pediatric Subjects
8
Each child’s parent/legal guardian must sign an ICF indicating that he/she understands the 
purpose of and procedures required for the study, are willing for his/her child to participate 
in the study and attend all scheduled visits, and are willing and able to comply with all 
study procedures, including maintaining contact with the site for 1 year following the first 
dose, and adhere to the prohibitions and restrictions specified in this protocol.
Note: For each subject, at least one parent, or legal guardian, according to local 
regulations, must give written consent.
9
Criterion amended per Amendment 3:
9.1 Subject is male or female, whose age on the day of ICF signature is ≥12* months to 
≤24 months and who is seropositive for RSV.
Note: RSV-seropositive toddlers may be recruited if RSV seropositivity was assessed 
via RSV EIA or virus neutralization assay in a different study of the sponsor. In the 
event that a subject is not able to be randomized during the 42-day screening period, 
eg, due to illness or other circumstances, a subject may be rescreened and 
reconsented. However, a new serostatus blood sample would not be needed if the 
previous sample was deemed seropositive.
*Window of up to minus 2 weeks


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10
Subject is the product of a normal term pregnancy ≥37 weeks, with a minimum birth 
weight of 2.5 kg.
11
Subject must be in good health without any significant medical illness on the basis of 
physical examination, medical history, and vital signs performed at screening.
12
Subject has received all routine immunizations appropriate for his or her age according to 
local guidelines.
13
Each child’s parent(s)/legal guardian(s) must have access to a consistent means of contact 
either by telephone contact or email/computer.
4.2.
Exclusion Criteria
4.2.1.
Adult Subjects
1.
Subject has acute illness (this does not include minor illnesses such as diarrhea) or 
temperature ≥38.0 ºC/100.4 °F within 24 hours prior to the first dose of study vaccine.
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.
3.
Subject has history of malignancy within 5 years before screening (exceptions are 
squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or 
malignancy, which is considered cured with minimal risk of recurrence).
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 the last dose 
of study vaccine. 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.
Subject has HIV type 1 or type 2 infection.
7.
Subject has had major psychiatric illness and/or drug or alcohol abuse which in the 
investigator’s opinion would compromise the subject’s safety and/or compliance with the 
study procedures.
8.
Subject has current or past abuse of recreational or narcotic drugs or alcohol, which in the 
investigator’s opinion would compromise the subject’s safety and/or compliance with the 
study procedures.
9.
Subject is in receipt of, or planning to receive, licensed live attenuated vaccine within 
28 days of each study vaccination (ie, before and after); other licensed vaccines (ie, not 


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live: eg, influenza, tetanus, hepatitis A, hepatitis B or rabies) should be given at least 
14 days before or 14 days after each study vaccination.
10.
Subject has received an investigational drug or used an invasive investigational medical 
device within 30 days or received an investigational vaccine within 6 months before the 
planned administration of the first dose of study vaccine or is currently enrolled or plans to 
participate in another investigational study during the course of this study. Note: 
Participation in an observational clinical study (ie, with no intervention) is allowed upon 
approval of the sponsor.
11.
Subject has received treatment with Ig in the 2 months, or blood products in the 4 months 
before the planned administration of the first dose of study vaccine or has any plans to 
receive such treatment during the study.
12.
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).
13.
Subject has a history of chronic urticaria (recurrent hives), eczema and/or atopic dermatitis.
14.
Subject has a history of acute polyneuropathy (eg, Guillain-Barré syndrome).
15.
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 first administration of study vaccine (Note: ocular, 
topical or inhaled steroids are allowed)

Administration of antineoplastic and immunomodulating agents or radiotherapy during 
the study and within 6 months before first administration of study vaccine
16.
Subject has a contraindication to intramuscular injections and blood draws, eg, bleeding 
disorders.
17.
Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant 
while enrolled in this study or within 3 months after the last dose of study vaccine.
18.
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.
19.
Subject cannot communicate reliably with the investigator.
20.
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 and observation.
4.2.2.
Pediatric Subjects
21.
Subject has moderate or severe illness (this does not include minor illnesses such as 
diarrhea) or temperature ≥38.0 ºC/100.4 °F within 24 hours prior to the first dose of study 
vaccine; enrollment at a later date is permitted.


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22.
Subject’s weight is below 10th percentile according to World Health Organization (WHO) 
pediatric growth and weight charts.7
23.
Criterion amended per Amendment 3:
23.1 Subject has any clinically significant acute or chronic medical condition that, in the 
opinion of the investigator, would preclude participation: eg, history of seizure 
disorders, bleeding/clotting disorder, autoimmune disease, active malignancy, 
systemic infections, congenital heart disease, history of any pulmonary condition 
requiring medication, atopy, reactive airway disease, medically-confirmed wheezing, 
bronchoconstriction 
or 
treatment 
with 
a 
β2 
agonist, 
cystic 
fibrosis, 
bronchopulmonary dysplasia, chronic pulmonary disease, medically-confirmed 
apnea, hospitalization for respiratory illness, or mechanical ventilation for respiratory 
illness.
24.
Subject has major congenital anomalies or known cytogenetic disorders (eg, Down’s 
syndrome).
25.
Subject has had major surgery within the 4 weeks prior to randomization or has planned 
major surgery through the course of the study.
26.
Subject is in receipt of, or planning to receive, live attenuated vaccine (eg, measles, mumps 
and rubella [MMR] or varicella, but excluding rotavirus vaccine) within 28 days of each 
study vaccination (ie, before and after); other vaccines (eg, influenza, pertussis, polio or 
rotavirus) should be given at least 14 days before or 14 days after each study vaccination. 
Note: Planning for routine childhood vaccinations will be available from the site to ensure 
that these can be taken at appropriate times during the study.
27.
Subject has known or suspected immunodeficiency, such as known HIV infection.
28.
Subject has received an investigational drug or used an invasive investigational medical 
device within 30 days or received an investigational vaccine within 6 months before the 
planned administration of the first dose of study vaccine or is currently enrolled or plans to 
participate in another investigational study during the course of this study. Note:
Participation in an observational clinical study (ie, with no intervention) is allowed upon 
approval of the sponsor.
29.
Criterion amended per Amendment 3:
29.1 Subject has a known allergy to vaccines or vaccine components (including any of the 
constituents of the study vaccine), or history of anaphylaxis or other serious adverse 
reactions to vaccines or vaccine components (including any of the constituents of the 
study vaccine). Note: subjects with egg allergies can be enrolled.
30.
Criterion amended per Amendment 3:
30.1 Subject has a history of the following moderate to severe chronic conditions: 
urticaria (recurrent hives), eczema and/or atopic dermatitis.
31.
Subject has a history of acute polyneuropathy (eg, Guillain-Barré syndrome).


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32.
Subject has chronic or recurrent use of immunomodulators/suppressors, eg, cancer 
chemotherapeutic agents, oral or parenteral corticosteroids for at least 5 days within 
42 days prior to randomization, or planned during the course of the study.
33.
Subject has a history of receipt of blood products or Ig within 3 months of randomization. 
Subject has been in receipt of palivizumab/Synagis® or received any other vaccine or 
monoclonal/polyclonal antibody in a previous RSV study at any time prior to 
randomization.
34.
Subject has a contraindication to intramuscular injections and blood draws, eg, bleeding 
disorders.
35.
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.
36.
Subject’s parent(s)/legal guardian(s) cannot communicate reliably with the investigator.
37.
Subject is a family member of either the investigator, study-site employee, or employee of 
the sponsor.
Note: Investigators should ensure that all study enrollment criteria have been met at screening. If 
a subject’s clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study vaccine is given 
such that 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.
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.
Refer to Section 8, for details regarding prohibited and restricted therapy during the study.
2.
Agree to follow all requirements that must be met during the study as noted in the inclusion 
and exclusion criteria (Section 4.1.1 and Section 4.2.1, respectively, for adult subjects, and 
Section 4.1.2 and Section 4.2.2, respectively, for pediatric subjects).
3.
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 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.
4.
Cohort 1 only: Subjects should receive all routine immunizations according to applicable 
national guidelines. A subject will not postpone, forego or delay the receipt of any 
recommended vaccine according to local schedules (eg, in Europe, the applicable national 


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immunization schedules,11 and the equivalent in other countries) due to participation in the 
current study. All subjects should receive routine immunizations according to schedule.
5.
STUDY VACCINE ALLOCATION AND BLINDING
Study Vaccine Allocation
Central randomization will be implemented in this study. Within each cohort, subjects will be 
randomly assigned to one of the two groups based on a computer-generated randomization 
schedule prepared before the study by or under the supervision of the sponsor. The 
randomization will be balanced by using randomly permuted blocks. Initially 2 sentinel subjects 
(one Ad26.RSV.preF and one placebo) will be enrolled to monitor for any unexpected severe 
adverse reaction to the vaccine. Therefore, the randomization of the first block will be phased to 
accommodate this. The remainder of the blocks will be filled to have an overall 2:1 
randomization ratio. No stratification will be applied. The interactive web response system 
(IWRS) will assign a unique code, which will dictate the group assignment for the subject. The 
requestor must use his or her own user identification and personal identification number when 
contacting the IWRS, and will then give the relevant subject details to uniquely identify the 
subject.
If randomized subjects are withdrawn from vaccination before the first dose is administered, 
additional subjects may be recruited to replace these subjects at the discretion of the sponsor. 
Any 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 +1000 (for example subject 0001 would be replaced by subject 
1001). These additional subjects should also be randomized through IWRS.
Any randomized subject who is withdrawn from the study for reasons other than due to an AE 
after the first dose but before the second dose might be replaced at the discretion of the sponsor. 
Any 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 +2000.
Blinding
The investigator will not be provided with randomization codes until the final analysis is 
performed. The codes will be maintained within the IWRS, which has the functionality to allow 
the investigator to break the blind for an individual subject.
Unblinding (ie, at the subject level) will only occur at the time of database lock of the final 
analysis. While the responsibility to break the study vaccine allocation code in emergency 
situations resides solely with the investigator, it is recommended that the investigator contact the 
sponsor or its designee 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 
such cases, the investigator may in an emergency determine the identity of the study vaccine by 
contacting the IWRS. In the event the blind is broken, the sponsor must be informed as soon as 


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possible. The date, time and reason for the unblinding must be documented by the IWRS, in the 
appropriate section of the electronic case report form (eCRF), and in the source document. The 
documentation received from the IWRS indicating the code break must be retained with the 
subject’s source documents in a secure manner.
The subjects, study-site personnel, and investigator, and sponsor personnel will be blinded to 
study vaccine allocation throughout the study, except for the pharmacist or qualified staff 
member with primary responsibility for study vaccine preparation and dispensing. The pharmacy 
and preparation of study vaccines will be monitored by an independent study vaccine monitor 
(see Section 17.8).
Note: the unblinded pharmacist, or other qualified individual, may also perform the vaccine 
administration, but will have no other study function from randomization onwards.
The primary analysis, and any other interim analysis performed before the final analysis, will be 
performed on data unblinded at the group levela; there will be no unblinding at the subject level. 
These data will only be available to a selected group of sponsor personnel, excluding sponsor 
personnel involved in data collection or data management.
In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed.
If the randomization code is broken by the investigator or the study-site personnel, the subject 
must discontinue further study vaccine administration and must be followed as appropriate (see 
Section 10.2 for details). If the randomization code is broken by the sponsor for safety reporting 
purposes, the subject should not discontinue further study vaccine administration and may 
remain in the study (if the randomization code is still blinded to the study-site personnel and the 
subject).
6.
DOSAGE AND ADMINISTRATION
Ad26.RSV.preF (JNJ-64400141) will be supplied in single-use vials. Volumes of 0.5 mL 
(1x1011 vp) for adults and 0.25 mL (5x1010 vp) for toddlers will be used for intramuscular 
injection.
Placebo will be supplied as sterile 0.9% saline for injection.
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. 
                                                
a To preserve the blind at the subject level, dummy subject identification numbers will be used to link the data to the 
randomization codes. The results of this analysis will only be distributed to sponsor personnel not directly involved in data
collection and data management.


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Note: the unblinded pharmacist, or other qualified individual, may also perform the 
administration, but will have no other study function from randomization onwards. 
Further details on study vaccine preparation will be provided in the Investigational Product 
Preparation Instructions.
For adult subjects, injections should be administered in the deltoid. For pediatric subjects, 
injections should be administered in the anterolateral aspect of the thigh. Alternating injection 
sites will be used for the vaccinations on Day 1 and Day 29.
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 each study vaccine administration will be recorded in the eCRF.
8.
PRE-STUDY AND CONCOMITANT THERAPY
Pre-study therapies administered up to 30 days before the first dose of study vaccine must be 
recorded in the eCRF during screening.
Concomitant therapies will be collected and recorded in the eCRF from time of each vaccine 
administration through 28 days after each vaccination, 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. (Note: The use of EMLA® Cream [2.5% lidocaine and 2.5% prilocaine] as a 
topical anesthetic will not be prohibited during the study.)
For adult subjects: chronic (longer than 10 days) or recurrent use of systemic corticosteroids 
is prohibited during the study and within 6 months before first administration of study vaccine 
(Note: ocular, topical or inhaled steroids are allowed). Antineoplastic and immunomodulating 
agents or radiotherapy are prohibited in the 6 months prior to screening and during the study.
For pediatric subjects: chronic or recurrent use of immunomodulators/suppressors, eg, cancer 
chemotherapeutic agents, oral or parenteral corticosteroids for at least 5 days within 42 days 
prior to randomization, or planned during the course of the study.
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 (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 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.
For pediatric subjects: planning for routine childhood vaccinations will be available from the 
site to ensure that these can be taken at appropriate times during the study.
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 regimens will include physical assessment by 
study-site personnel, 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 Cohort 0 subject, and each Cohort 1 subject’s parents/legal guardian or caregiver will be 
provided with a thermometer, ruler, and subject diary to measure and record body temperature 
and solicited local (at injection site) and systemic events.
The diary includes instructions 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 diary will be reviewed by the study personnel at visits 
indicated on the Time and Events Schedule.
For Cohort 0, at each visit/telephone call, each adult subject should be informed that, in the event 
of developing a combination of symptoms of respiratory infection (persistent [>48 hours] clinical 
symptoms of rhinitis [sneezing or runny nose or congestion] and persistence [>24 hours] of one 
or more of the following: cough, abnormal breathing, fever, lethargy or decreased appetite), they 
should contact the site as soon as possible.
For Cohort 1 only, at each visit/telephone call, each subject’s parents/legal guardian or caregiver 
should be informed that, in the event that their child develops a combination of symptoms of 
respiratory infection (persistent [>48 hours] clinical symptoms of rhinitis [sneezing or runny 
nose or congestion] and persistence [>24 hours] of one or more of the following: cough, 
abnormal breathing, fever, lethargy or decreased appetite), they should contact the site as soon as 
possible.


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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 in Cohort 0 over approximately 
34 weeks from screening will be approximately 295 mL.
The total blood volume to be collected from each subject in Cohort 1 over approximately 
36 weeks from screening will be approximately 14.5 mL.
9.1.2.
Visit Windows
For the following visits, windows will be allowed as indicated:

Second vaccination: ± 3 days (both cohorts)

3 days post-vaccination safety only visit: ± 1 day

7 days post-vaccination safety only visit: ± 2 days

28 days post-final vaccination safety and immunogenicity visit: ± 3 days

6 months post-final vaccination safety and immunogenicity visit: ± 14 days

1 year post-first vaccination safety follow-up telephone call: ± 14 days
9.1.3.
Screening and Study Visits – Cohort 0 (Adults)
9.1.3.1.
Screening Phase: Days –28 to 1
Only healthy subjects without acute illness or fever and complying with the inclusion and 
exclusion criteria specified in Section 4.1.1 and Section 4.2.1, respectively, will be included into 
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. All the 
procedures described in the Time and Events Schedule will only take place after written 
informed consent has been obtained.
The following evaluations will be performed to determine eligibility requirements as specified in 
the inclusion and exclusion criteria:

Physical examination including vital signs measurement (systolic and diastolic blood 
pressure, respiratory rate, heart rate and body temperature) and height and weight

Demographic information

Medical history

Review of pre-study medications

Review of inclusion/exclusion criteria

Serology testing (HIV type 1 or type 2, hepatitis B, hepatitis C)


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
Blood sampling for hematology and biochemistry laboratory testing

Women of childbearing potential: serum β-hCG pregnancy testing
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 
first vaccination (Visit 2) within 28 days. If necessary, the screening visit may be split into 
several visits.
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 Grades 1 or 2 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 9.2.3.2.
After laboratory data, medical history and physical examination 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 the signing of the ICF until 
28 days after the first vaccination and from the second vaccination through the following 
28 days, together with information about any concomitant medications. SAEs will be collected 
from ICF signature through 1 year after the first dose.
9.1.3.2.
Active Phase – Day 1 to Day 211
9.1.3.2.1.
Vaccination (Days 1 and 29)
Visit 2: Day 1/Day of Randomization/Vaccination 1
After re-check of inclusion and exclusion criteriaa, 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 
Day 1 visit re-scheduled, 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 as 
well as pre-dose samples for safety laboratory testing (hematology and biochemistry) and a nasal 
turbinate sample for immunogenicity assessment will be collected. All women must have a 
negative urine pregnancy test pre-dose. Before the first vaccination, the investigator must check 
for any symptoms of an acute illness or body temperature ≥38.0 °C. In such a situation, the 
                                                
a To include exclusion criteria 1, 4, 8, 9, 10, 11, 15, 16 and 17.


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subject may be enrolled at a later datea, or be withdrawn at the discretion of the investigator and 
after consultation with the sponsor.
Administration of first dose of study vaccine.
Subjects will be closely observed for a minimum of 30 minutes post-vaccination, or a minimum 
of 60 minutes post-vaccination according to local approvals, 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.
Visit 5: Day 29/Vaccination 2
Verification of selected eligibility criteria,b,c abbreviated physical examination (at the discretion 
of the investigator) and measurement of vital signs will be performed for all subjects 
pre-vaccination. Pre-dose samples for immunogenicity assessments as well as a nasal turbinate 
sample for immunogenicity assessment will be collected. All women must have a negative urine 
pregnancy test pre-dose. Before the second vaccination, the investigator must check for any 
symptoms of an acute illness or body temperature ≥38.0 °C. In such a situation, the subject may 
be vaccinated up to, and no later than 10 days after the scheduled vaccination, or be withdrawn at 
the discretion of the investigator and after consultation with the sponsor. In the event of an 
ongoing AE or other situation precluding subject vaccination within 10 days, subjects may be 
vaccinated beyond the 10-day window at the discretion of the sponsor.
Administration of second dose of study vaccine.
Subjects will be closely observed for a minimum of 30 minutes post-vaccination, or a minimum 
of 60 minutes post-vaccination according to local approvals, 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.
                                                
a If within the screening window. Otherwise, rescreening is required.
b To include fever and any acute illness that precludes vaccination; also receipt of any routine immunizations.
c To include exclusion criteria 1, 4, 8, 9, 10, 11, 15, 16 and 17.


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9.1.3.2.2.
Post-first Vaccination Follow-Up
Sentinel Subjects: 48 Hours Post-first Vaccination
At 48 hours after the first vaccination, a telephone call will be made to sentinel subjects only to 
collect safety information (solicited and unsolicited AEs, SAEs and concomitant medications).
Visits 3 and 4 (3 and 7 Days Post-first Vaccination)
Visit 3 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).
Visit 4 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 safety laboratory testing (hematology and biochemistry) 
and a nasal turbinate sample for immunogenicity assessment will be collected. The subject diary 
will be reviewed and collected. If Visit 4 occurs before the end of Day 8 (ie, before the end of the 
post-vaccination diary period), review of the diary will still take place, but the diary will be 
returned by the subject at Visit 5.
Note: If any of the 12 Cohort 0 subjects come in earlier than Day 8 for Visit 4 (allowed window 
is ±2 days), a subsequent phone call will be made at the end of the diary period to collect diary 
card information recorded between the actual visit and the end of the diary period on Day 8.
9.1.3.2.3.
Post-second Vaccination Follow-Up
Sentinel Subjects: 48 Hours Post-second Vaccination
At 48 hours after the second vaccination, a telephone call will be made to sentinel subjects only 
to collect safety information (solicited and unsolicited AEs, SAEs and concomitant medications).
Post-second Vaccination: Visits 6 and 7 (7 Days and 28 Days Post-second Vaccination)
Visit 6 at 7 days after the second 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. The subject diary will be reviewed and collected. If Visit 6 occurs 
before the end of the diary period after the second vaccination, review of the diary will still take 
place, but the diary will be returned by the subject at Visit 7.
Visit 7 at 28 days after the second vaccination will include an abbreviated physical examination 
(at the discretion of the investigator), vital signs measurement (at the discretion of the 
investigator), recording of any unsolicited AEs/SAEs and concomitant medications. Blood 
samples for immunogenicity assessments,
as well as a nasal turbinate sample for 
immunogenicity assessment will be collected.


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9.1.3.2.4.
Final Visit – 6 Months After the Second Vaccination
Visit 8 at 6 months after the second vaccination will include an abbreviated physical examination 
(at the discretion of the investigator), vital signs measurement (at the discretion of the 
investigator), recording of any SAEs and associated concomitant medications. Blood samples 
will be collected for immunogenicity assessments.
9.1.3.2.5.
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 final visit (Section 9.1.3.2.4) will be 
performed. Samples for safety laboratory testing (hematology and biochemistry) will only be 
collected if the early exit is within 7 days of the first vaccination. Samples for immunogenicity 
assessments will only be collected if the early exit is at least 14 days after the previous blood 
draw for immunogenicity. A nasal turbinate sample for immunogenicity assessment will be 
collected if the early exit is within 14 days of the previous vaccination.
If the early exit visit occurs within 7 days of the last vaccination, solicited AEs will be recorded; 
if the early exit visit occurs within 28 days of the last vaccination, unsolicited AEs will be 
recorded.
9.1.3.3.
Safety Follow-up Phase: Cohort 0 – After Day 211
During the safety follow-up phase, any SAEs and associated concomitant medications will be 
reported through 1 year after the first dose.
Adults will be contacted by telephone call at the end of the safety follow-up phase.
The follow-up phase will include all subjects who received at least one dose of study vaccine.
9.1.4.
Screening and Study Visits – Cohort 1 (Seropositive Toddlers)
Note: It is possible for any visit for a pediatric subject to be conducted in the subject’s home if 
the study site has an established standard operating procedure as such. However, at least 5 
toddlers in the active group are to have received first dose in a clinic setting and to have 
completed Visit 3 with no safety concerns before moving to vaccination of study subjects in a 
non-clinic setting (safety information of the first 5 active toddlers will be monitored by the 
PI(s)/SRP(s) through Visit 3, and escalated to the IDMC in the event of a safety signal).
9.1.4.1.
Screening Phase: Days –42 to 1
Only healthy subjects without acute illness or fever and complying with the inclusion and 
exclusion criteria specified in Section 4.1.2 and Section 4.2.2, respectively, will be included into 
the study. The investigator will provide detailed information on the study to the subject’s
parent/legal guardian and will obtain his/her written informed consent prior to each subject’s 
participation in the study. All the procedures described in the Time and Events Schedule will 
only take place after written informed consent has been obtained.


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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, body 
temperature) and height and weight

Demographic information

Medical history

Review of pre-study medications

Review of inclusion/exclusion criteria

Blood sample for immunogenicity testing*

Blood sample for RSV antibody testing**
*Collection of blood samples for immunogenicity assessments can be either at screening, or pre-
dose on Day 1 at the discretion of the investigator. 
**0.5 mL of blood for serostatus assessment can be collected at screening by venous blood 
sample or fingerstick, at the discretion of the investigator. If 0.5 mL is collected at screening, the 
baseline blood draw for immunogenicity should be on Day 1.
RSV seropositivity of Cohort 1 subjects will be assessed by RSV EIA or virus neutralization 
assay at screening. Note: RSV-seropositive toddlers may be recruited if RSV seropositivity was 
assessed via either of these assays in a different study of the sponsor. In the event that a subject is 
not able to be randomized during the 42-day screening period, eg, due to illness or other 
circumstances, a subject may be rescreened and reconsented. However, a new serostatus blood 
sample would not be needed if the previous sample was deemed seropositive.
General eligibility for this clinical study will be dependent on results of the medical assessment. 
Study subjects who qualify for inclusion based on the medical history and physical examination 
will be scheduled for enrollment and first vaccination (Visit 2) within 42 days. If necessary, the 
screening visit may be split into several visits.
After medical history and physical examination 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 the signing of the ICF until 
28 days after the first vaccination and from the second vaccination through the following 
28 days, together with information about any concomitant medications. SAEs (and any 
associated concomitant medications) will be collected from ICF signature through 1 year after 
the first dose.


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9.1.4.2.
Active Phase – Day 1 to Day 211
9.1.4.2.1.
Vaccination (Days 1 and 29)
Visit 2: Day 1/Day of Randomization/Vaccination 1
After re-check of inclusion and exclusion criteria,a abbreviated physical examination (at the 
discretion of the investigator) and measurement of vital signs, body height and weight, eligible 
subjects will be randomized as described in Section 5. If medical status and/or physical 
examination suggests significant changes have occurred since screening, either the Day 1 visit 
can be re-scheduled, or the subject excluded from the study if he/she fails to meet the inclusion 
and exclusion criteria. Before the first vaccination, the investigator must check for any symptoms 
of an acute illness or body temperature ≥38.0 °C. In such a situation, the subject may be enrolled 
at a later dateb, or be withdrawn at the discretion of the investigator and after consultation with 
the sponsor.
Collection of blood samples for immunogenicity assessments can be either at screening, or pre-
dose on Day 1 at the discretion of the investigator. If 0.5 mL of blood for RSV serology only is 
collected at screening, blood draw for immunogenicity should be on Day 1.
Administration of first dose of study vaccine.
Subjects will be closely observed for a minimum of 30 minutes post-vaccination, or a minimum 
of 60 minutes post-vaccination according to local approvals, 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.
A subject diary, thermometer, and ruler will be provided to measure and record body temperature 
and solicited local and systemic AEs for 7 days post-vaccination.
Visit 5: Day 29/Vaccination 2
After verification of selected eligibility criteria,c abbreviated physical examination (at the 
discretion of the investigator) and measurement of vital signs, body height and weight will be 
performed for all subjects pre-vaccination. Pre-dose samples for immunogenicity assessments
will be collected. Before the second vaccination, the investigator must check for any symptoms 
of an acute illness. In such a situation, the subject may be vaccinated up to, and no later than 10 
days after the scheduled vaccination, or be withdrawn at the discretion of the investigator and 
after consultation with the sponsor. In the event of an ongoing AE or other situation precluding 
                                                
a Exclusion criterion 21, 22, 25, 26, 28, and 32.
b If within the screening window. Otherwise, rescreening is required.
c Exclusion criterion 21, 22, 25, 26, 28 and 32.


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subject vaccination within 10 days, subjects may be vaccinated beyond the 10-day window at the 
discretion of the sponsor.
Administration of second dose of study vaccine.
Subjects will be closely observed for a minimum of 30 minutes post-vaccination, or a minimum 
of 60 minutes post-vaccination according to local approvals, 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.
A subject diary, thermometer, and ruler will be provided to measure and record body temperature 
and solicited local and systemic AEs for 7 days post-vaccination. 
9.1.4.2.2.
Post-first 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 parent/legal guardian 
or caregiver of sentinel subjects only to collect safety information (solicited and unsolicited AEs, 
SAEs and concomitant medications).
Visits 3 and 4 (3 and 7 Days Post-first Vaccination)
Visit 3 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).
Visit 4 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, 
concomitant medications and RTIs. The subject diary will be reviewed and collected. If Visit 4 
occurs before the end of Day 8 (ie, before the end of the post-vaccination diary period), review 
of the diary will still take place, but the diary will be returned by the subject’s parent/guardian or 
caregiver at Visit 5.
Note: If any of the first 12 Cohort 1 subjects come in earlier than Day 8 for Visit 4 (allowed 
window is ±2 days), a subsequent phone call will be made at the end of the diary period to 
collect diary card information recorded between the actual visit and the end of the diary period 
on Day 8.
9.1.4.2.3.
Post-second Vaccination Follow-Up
Sentinel Subjects: 48 Hours Post-second Vaccination
At 48 hours after the second vaccination, a telephone call will be made to the parent/legal 
guardian or caregiver of sentinel subjects only to collect safety information (solicited and 
unsolicited AEs, SAEs and concomitant medications).


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Post-second Vaccination: Visits 6, 7, 8 and 9 (3, 7 and 28 Days and 6 Months Post-second 
Vaccination)
Visit 6 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).
Visit 7 at 7 days after the second vaccination will include an abbreviated physical examination 
(at the discretion of the investigator), vital signs measurement, and recording of any AEs/SAEs, 
concomitant medications and RTIs. The subject diary will be reviewed and collected. If Visit 7 
occurs before the end of the diary period after the second vaccination, review of the diary will 
still take place, but the diary will be returned by the subject’s parent/guardian or caregiver at 
Visit 8.
Visit 8 at 28 days after the second vaccination will include an abbreviated physical examination 
(at the discretion of the investigator), vital signs measurement (at the discretion of the 
investigator), measurement of body height and weight, recording of any unsolicited AEs/SAEs, 
concomitant medications, and RTIs. Blood samples will be collected for immunogenicity 
assessments.
Visit 9 at 6 months after the second vaccination will include an abbreviated physical examination 
(at the discretion of the investigator), vital signs measurement (at the discretion of the 
investigator), measurement of body height and weight, recording of any SAEs and associated
concomitant medications, and RTIs. Blood samples will be collected for immunogenicity 
assessments. Visit 9 (Day 211) will be the final visit of the active phase for Cohort 1 subjects.
Note: If Visit 9 occurs during the RSV season, an additional visit will be made by telephone at 
the end of the RSV season to collect safety information.
9.1.4.2.4.
Early Withdrawal – Early Exit Visit
For those subjects who are unable to continue participation in the study up to Day 211, but for 
whom consent is not withdrawn, an early exit visit will be conducted as soon as possible. In the 
event of early withdrawal from the study, all procedures required at Visit 9 (Section 9.1.4.2.3) 
will be performed. Samples for immunogenicity assessments will be collected at the early exit 
visit as follows: if the early exit visit is before Day 29, 4 mL for cellular assessments and 1 mL 
for humoral assessments will be collected; if the early exit visit is after Day 29, only 2 mL for 
humoral assessments will be collected.
If the early exit visit occurs within 7 days of the last vaccination, solicited AEs will be recorded; 
if the early exit visit occurs within 28 days of the last vaccination, unsolicited AEs will be 
recorded.
9.1.4.3.
Safety Follow-up Phase: Cohort 1 – After Day 211
Each subject’s parent/legal guardian or caregiver will be contacted by telephone call (or clinic 
visit) through 1 year after the first dose, including during the active phase and safety follow-up 
phase (every 30 days ± 7 days outside the RSV season, but every 14 days ± 3 days in season).


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During each 28-day post-vaccination period, calls will remind parents/legal guardians to contact 
the site in the event their child develops an RTI. During the RSV season, but outside the 28-day 
post-vaccination period, calls will remind parents/legal guardians to contact the site in the event 
their child develops a combination of symptoms of respiratory infection (persistent [>48 hours] 
clinical symptoms of rhinitis [sneezing or runny nose or congestion] and persistence [>24 hours] 
of one or more of the following: cough, abnormal breathing, fever, lethargy or decreased 
appetite). These calls will also check for SAEs and associated concomitant medications, any 
MA-RTIs or severe LRTIs, and any subsequent medical care that may have been sought, since 
the previous visit or telephone contact (includes contacts with subjects who received at least one 
dose of study vaccine but withdrew from further dosing).
The follow-up phase will include all subjects who received at least one dose of study vaccine.
9.2.
Study Evaluations
9.2.1.
Immunogenicity
Venous blood samples will be collected for the determination of humoral and cellular responses, 
respectively, according to the Time and Events Schedules. Sample collection and processing will 
be performed by the staff at the clinical sites according to current versions of approved standard 
operating procedures.
Humoral and cellular immunogenicity evaluations are summarized in Table 6 and Table 7, 
respectively.
Table 6:
Summary of Immunogenicity Assays (Humoral)
Assay 
Purpose
Secondary endpoints
RSV neutralization A 
Analysis of neutralizing antibodies to the 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
Exploratory endpoints
RSV strain cross-neutralization 
Analysis of cross-neutralizing antibodies to B and/or a different A strain(s)
F-protein antibody specificity 
characterization 
Pre- and post-F specificity by binding or functional assays as ELISA, 
and/or competition ELISA. Adsorption of serum or plasma with pre-F and 
post-F protein before any antibody assay, epitope mapping, functional 
VNA
Adenovirus neutralization assay
Analysis of neutralizing antibodies to adenovirus
Functional and molecular 
antibody characterization
Analysis of antibody characteristics including ADCC, ADCP, avidity, Fc 
characteristics, Ig isotype, functional VNA and protective antibody 
assessments
ADCC = antibody-dependent cell-mediated cytotoxicity; ADCP = antibody-dependent cellular phagocytosis; ELISA = enzyme-
linked immunosorbent assay; F = fusion; Ig = immunoglobulin; RSV = respiratory syncytial virus; VNA = virus neutralizing 
antibody


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Table 7:
Summary of Immunogenicity Assays (Cellular)
Assay 
Purpose
Secondary endpoints
Flow cytometry (ICS)*
Analysis of T-cell responses to RSV F-protein peptides for Th1/Th2 subtyping
Exploratory endpoints
IFNγ ELISpot
T-cell IFNγ responses to RSV F-protein peptides
ICS
Analysis of T-cell responses to RSV F-protein peptide-stimulated PBMCs
(including but not limited to, CD4/CD8, IL2, INFγ, TNFα, activation markers and 
memory)
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
* 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
In addition to RT-PCR performed on a nasal turbinate sample collected at the time of infection, 
any immunogenicity blood sample collected from any Cohort 1 subject who subsequently 
develops a suspected RTI may also be assayed by a serological assay (eg, ELISA specific to 
RSV protein G and/or N) to confirm RSV infection.
For adults, nasal turbinate samples, collected pre-dose on Days 1 and 29, 7 days post-Dose 1 
(Day 8) and 28 days post-Dose 2 (Day 57) will be used to assess any Ig or cellular immune 
component.
Instructions for the collection, handling, storage, and shipment of blood and nasal turbinate
samples for immunogenicity assay are found in the Laboratory Manual that will be provided. 
Collection, handling, storage, and shipment of blood and nasal turbinate 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.
Other Evaluations – RSV Infection
RSV seropositivity of Cohort 1 subjects will be assessed by RSV EIA or virus neutralization 
assay at screening. The cut-off for seropositivity by EIA is a titer >10 EIA units and the cut-off 
by virus neutralization assay is a titer >4. Note: RSV-seropositive toddlers may be recruited if 
RSV seropositivity was assessed via either of these assays in a different study of the sponsor.
Nasal turbinate samples, taken from any Cohort 1 subject with an RTI during each 28-day post-
vaccination period, and from any Cohort 1 subject with a combination of respiratory symptomsa
during the RSV season (but outside of the 28-day post-vaccination period), and from any 
Cohort 1 subject with a MA-RTI or severe LRTI during the whole study period, will be assessed 
for the presence of RSV infection by RT-PCR. The actual dates and times of sample collection 
must be recorded in the eCRF or laboratory requisition form.
                                                
a Persistent (>48 hours) clinical symptoms of rhinitis (sneezing or runny nose or congestion) and persistence (>24 hours) of one 
or more of the following: cough, abnormal breathing, fever, lethargy or decreased appetite.


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In addition, scheduled blood samples may be assessed for the presence of RSV antibodies by 
serology.
9.2.3.
Safety Evaluations
Any reference to activities to be performed by the subject refers to adult subjects or the parent/legal 
guardian for pediatric subjects.
Any clinically relevant changes occurring from ICF signature until 28 days after the first 
vaccination, and from the time of subsequent vaccinations through the following 28 days, 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.
The study will include the following evaluations of safety and tolerability according to the 
timepoints provided in the Time and Events Schedule.
Adverse Events
AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject’s legally acceptable representative). AEs will be followed by the investigator as specified 
in Section 12, Adverse Event Reporting.
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 each 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, or a minimum 60-minute post-vaccination assessment of solicited events at the 
site (according to local approvals). Diary information will be transcribed by the study personnel 
in the appropriate eCRF pages.
Injection Site (Local) Adverse Events
Each subject 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.


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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 parent/care giver or health care provider).14
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.23,24
Systemic Adverse Events
Subjects will be instructed on how to record daily temperaturea using a thermometer provided 
for home use. Subjects should record the temperature in the diary in the evening of the day of 
vaccination, and then daily for the next 7 days approximately at the same time each dayb. If 
more than one measurement is made on any given day, the highest temperature of that day 
will be used in the eCRF.
Fever is defined as endogenous elevation of body temperature ≥38° C, as recorded in at least 
one measurement.28
                                                
a Recommended orally for adult subjects; rectally or axillary for pediatric subjects (actual routes to be recorded in the eCRF).
b All Day 8 post-vaccination diary assessments, including temperature measurements, may be collected earlier to coincide with 
the corresponding clinic visit.


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Subjects will also be instructed on how to note daily in the diary for 7 days post-vaccination 
symptoms of the following events: for adult subjects – fatigue, headache, myalgia, arthralgia, 
chills, nausea and fever (ie, body temperature ≥38 °C); for pediatric subjects – loss of 
appetite, vomiting, diarrhea, decreased activity/lethargy, irritability/crying 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, Severity Criteria.
If a solicited local or systemic AE is not resolved by 7 days post-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.
9.2.3.1.
Respiratory Tract Infections
RTIs will be reported as follows:

During the 28-day period after each vaccination, all RTIs will be reported.

During the RSV season, but outside the 28-day period after each vaccination, RTIs will be 
reported for which a combination of respiratory symptomsa develop.

Outside the RSV season, only MA-RTIs and severe LRTIs will be reported (ie, for the 
whole study period).
RTIs, preferably as a diagnosis, will also be reported on the AE page of the eCRF if they occur 
within 28 days following vaccination. Any RTI fulfilling the criteria of an SAE would be 
reported as such during the entire study. Any severe LRTI will be reported using the SAE 
reporting system and SAE form, regardless of whether the event fulfills the criteria of an SAE.
9.2.3.2.
Clinical Laboratory Tests – Cohort 0 Only
Blood samples for serum chemistry and hematology will be collected at screening, 
pre-vaccination on Day 1 and on Day 8. The following tests will be performed by a local
laboratory (*parameters only measured at screening):

Hematology Panel
hemoglobin
white blood cell (WBC) count with differential
platelet count
prothrombin time*
activated partial thromboplastin time*
fibrinogen*
                                                
a Persistent (>48 hours) clinical symptoms of rhinitis (sneezing or runny nose or congestion) and persistence (>24 hours) of one 
or more of the following: cough, abnormal breathing, fever, lethargy or decreased appetite.


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
Biochemistry Panel
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.
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).
      sodium
      potassium
      creatinine
      blood urea nitrogen 
      aspartate aminotransferase (AST)
      alanine aminotransferase (ALT)


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Screening Procedures
For entry into the study, each subject must be healthy on the basis of clinical laboratory tests 
performed at screening. 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 (HIV type 1 or type 2, hepatitis B, hepatitis C 
serology) will be performed locally at screening for Cohort 0 only.
9.2.3.3.
Vital Signs
Blood pressure (Cohort 0 only) 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):

Heart rate (beats per minutes, bpm), respiratory rate (breaths per minute), systolic blood 
pressure (mmHg) and diastolic blood pressure (mmHg)

Body temperature (oral route recommended for Cohort 0, rectal or axillary route 
recommended for Cohort 1)
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.
9.2.3.4.
Physical Examination
Full physical examination, including length/height and body weight, will be carried out at 
screening. 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.
Note: For Cohort 0, physical examination will only be required at the screening visit.
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.
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY VACCINE/ 
WITHDRAWAL FROM THE STUDY
10.1.
Completion
A subject will be considered to have completed study vaccination if he or she has received all 
study vaccinations. A subject will be considered to have completed the study if he or she has 
completed assessments through to the end of the study (see Section 17.9.1).


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10.2.
Discontinuation of Study Vaccine/Withdrawal from the Study
Discontinuation of Study Vaccine
A subject will not be automatically withdrawn from the study if they have to discontinue from 
study vaccination before the end of the study vaccine regimen.
Subjects will be discontinued from study vaccine administration for the reasons listed below. 
These subjects must not receive any additional dose of study vaccine but should continue other 
study procedures, eg, safety follow-up:

Anaphylactic reaction following vaccination, not attributable to causes other than 
vaccination

Pregnancy (Cohort 0 only)

Any related SAE

Any related AE, worsening of health status or intercurrent illness that, in the opinion of the 
investigator, requires study vaccine discontinuation
Withdrawal from the Study
Each subject has the right to withdraw (Cohort 1: “subject’s parent/legal guardian has the right to 
withdraw their child”) from the study at any time for any reason without affecting the right to 
treatment by the investigator. Although the subject (Cohort 1: “subject’s parent/legal guardian”)
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

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 discontinuation/
withdrawal. The measures taken to follow up must be documented.


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When a subject is withdrawn 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. However, 
any randomized subject withdrawn from the study for reasons other than due to an AE after the 
first dose but before the second dose might be replaced at the discretion of the sponsor.
If a subject withdraws early from the study, assessments for early withdrawal should be obtained 
(see Section 9.1.3.2.5 and Section 9.1.4.2.4).
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.
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:

Severe acute illness at the time of vaccination. This does not include minor illnesses such as 
diarrhea.

Fever (body temperature ≥38.0 °C) at the time of vaccination.
If any of these events occur at the scheduled time for the first vaccination, enrollment at a later 
date is permitteda at the discretion of the investigator and after consultation with the sponsor. If 
any of these events occur at the scheduled time for the second vaccination, the subject may be 
vaccinated up to 10 days beyond the scheduled vaccination, or be withdrawn from further 
vaccination at the discretion of the investigator and after consultation with the sponsor. In the 
event of an ongoing AE or other situation precluding subject vaccination within 10 days, subjects 
may be vaccinated beyond the 10-day window at the discretion of the sponsor.
Note: Medically indicated vaccines should be given at least 14 days before or 14 days after study 
vaccine administration (see Section 4.3).
                                                
a If within the screening window. Otherwise, rescreening is required.


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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 Statistical Analysis Plan (SAP).
Planned analyses are described in Section 11.8.
11.1.
Analysis Sets
The Full Analysis Set (FA) includes all subjects who were randomized and received at least one 
dose of study vaccine, regardless of the occurrence of protocol deviations. Vaccination 
assignment will follow the as-treated principle. 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.
The Per-protocol Immunogenicity Set (PPI) 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, the following samples will not be included in the PPI set:

If subjects miss one or more doses, but continue the planned visit schedule, samples taken 
after the planned but missed dose(s) will not be taken into account;

For subjects who experience a natural RSV infection (based on RT-PCR, or other sources), 
samples taken after the natural infection are not be taken into account.

Any subject who receives study vaccine beyond the Day 29 window specified in the Time 
and Events Schedule would not be included in the per-protocol immunogenicity analyses.
The analysis of immunogenicity will be based on the PPI set.
11.2.
Sample Size Determination
The number of subjects chosen for this study will provide a preliminary safety and 
immunogenicity assessment. Placebo recipients are included for blinding and safety purposes 
and will provide additional control specimens for immunogenicity assays.
While mild to moderate vaccine reactions (local site and systemic responses) are expected, AEs 
that preclude further dose administration or more serious ones that would limit product 
development are not anticipated.
The following table shows the probabilities of observing at least one AE at given true AE rates:


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True AE rate
Probability of observing at least one AE in N subjects
N=4
N=8
N=12
N=24
0.5%
2%
4%
6%
11%
1%
4%
8%
11%
21%
2.5%
10%
18%
26%
46%
5%
19%
34%
46%
71%
10%
34%
57%
72%
92%
25%
68%
90%
97%
100%
50%
94%
100%
100%
100%
11.3.
Criteria for Exploratory Endpoints
11.3.1.
Definitions for Exploratory Endpoints
The exploratory endpoints shown below will be collected to assess the feasibility of, and gain 
expertise in the collection of such events for future studies.

RSV MA-RTI:
All subjects with RSV-RTI that is medically attended, ie when the
subject’s parent/legal guardian seeks medical attention outside of normal
study procedures, including health care professional’s visit to the home,
clinic visit, emergency room attendance, and hospital admission. (Note: 
medical attention outside normal study procedures will as much as 
possible also be captured on the RSV Symptoms Form.)

Severe LRTI:
For subjects in Cohort 1, severe RSV-LRTI will be defined as the
presence of severe LRTI as assessed by the CEC, and a positive
assessment for RSV.
11.3.1.1.
Presence of Severe LRTI as Assessed by the CEC
For subjects with an SAE related to respiratory disease, the CEC will determine the presence or 
absence of severe LRTIs by reviewing all available clinical information related to respiratory 
disease, with a special focus on the following characteristics (“WHO” criteria30):

Respiratory infection defined as cough or difficulty breathing
AND

LRTI defined as fast breathing or oxygen saturation (SpO2) <95%
AND

≥1 of the severe disease feature:
o
oximetry <93%
o
lower chest wall indrawing
11.3.1.2.
Determination of RSV Positivity

A subject is considered RSV positive if he/she has a positive RT-PCR for RSV on nasal 
turbinate samples (central laboratory).


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
If a RT-PCR test result for RSV is missing (ie, not available or not conclusive), the CEC 
will assess RSV positivity using all available clinical and laboratory information.
11.4.
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. BMI will 
only be calculated for Cohort 0 (adults). For the toddlers, the weight and length percentiles 
according to the WHO pediatric growth and weight charts will be tabulated.7
11.5.
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 ICS) will be calculated for continuous immunologic parameters at all 
timepoints. 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.
RSV Infection
Incidence of any RSV infection, as described in Section 3.2, in Ad26.RSV.preF and placebo 
subjects will be summarized by descriptive statistics.
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 after 
vaccination up to 28 days post-vaccination, 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.
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.


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Summaries and/or listings may be provided separately for AEs with onset outside the above 
defined timeframe (ie, beyond 28 days post-vaccination) and that were reported pre-dose at the 
moment of subsequent vaccinations for studies using multiple doses.
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.
Clinical Laboratory Tests (Cohort 0 Only)
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.
Vital Signs
A tabulation of the distribution of temperatures per half degree intervals will be provided. For 
heart rate and respiratory rate, the percentage of subjects with values beyond clinically relevant 
limits will be summarized.
Physical Examination
Physical examination abnormalities will be listed.
11.8.
Planned Analyses
The following analyses will be performed:

Cohort 0: primary analysis will be performed when all subjects have reached Day 57 
(28 days post-Dose 2) or discontinued earlier. All available safety and immunogenicity data 
gathered so far will be included in the analysis; unblinded at the group level.

Cohort 1: interim analysis will be performed when at least 24 subjects have reached Day 29 
(28 days post-Dose 1) or discontinued earlier. All available safety and immunogenicity data 
gathered so far will be included in the analysis; unblinded at the group level.

Cohort 1: primary analysis will be performed when all subjects have reached Day 57 
(28 days post-Dose 2) or discontinued earlier. All available safety and immunogenicity data 
gathered so far will be included in the analysis; unblinded at the group level.

Final analysis of both cohorts; at the end of the study, 1 year after the first dose; unblinded
Additional interim analyses (blinded or unblinded at the group level) 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 


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early termination or later safety or immunogenicity endpoint assessments, and will only be 
available to a selected group of sponsor personnel, excluding sponsor personnel involved in data 
collection or data management.
11.9.
Data Review Committees
11.9.1.
Independent Data Monitoring Committee (IDMC)
An IDMC will be established to review safety data, and as needed on an ad hoc basis to ensure 
the continuing safety of the subjects enrolled in this study. The IDMC will convene to discuss 
any situation that meets a study vaccination pausing rule (see Section 11.10).
The IDMC will also monitor severe LRTI. The presence of severe LRTI will be determined by 
the CEC, a separate committee (see Section 11.9.2). The outcome of the adjudication of the CEC 
as well as the determination of RSV positivity will be provided to the IDMC.
The IDMC will monitor severe LRTI as detailed in the IDMC charter.
The IDMC will consist of members independent of the sponsor, including at least one medical 
expert in the relevant therapeutic area and at least one statistician. The IDMC responsibilities, 
authorities, and procedures will be documented in its charter. An external statistician 
independent of the sponsor and not involved in the interim, primary, and final analyses of the 
study will prepare the data and perform all analyses for review by the IDMC.
In any case(s) under review, the IDMC will review blinded data first, but is entitled to and has 
the right to require submission of unblinded data if deemed necessary.
Individual treatment information and other information essential to maintaining the blinded and 
controlled study design including the detailed results of the IDMC analyses will not be revealed 
to anyone outside of the IDMC.
Details on the intervals of the safety evaluations and on how the integrity of the study will be 
maintained when the blind is broken with an IDMC analysis will be provided in the IDMC 
charter.
Safety data from the interim and primary analyses will be shared with the IDMC.
If any question arises related to safety, the IDMC will be convened.
11.9.2.
Clinical Endpoint Committee (CEC)
The CEC is an independent panel consisting of external medical experts with relevant experience 
in RSV in children. At all times during the study, the CEC will stay blinded, and hence CEC 
members will not be part of the IDMC. Full details of CEC responsibilities, authorities, and 
procedures will be documented in its charter.


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The presence of severe LRTI will be determined by the CEC. By review of all available clinical 
and laboratory information, including clinical information from SAE forms related to respiratory 
disease, the CEC will decide whether a given situation concerns a severe LRTI. The outcome of 
the adjudication of the CEC, as well as the determination of RSV positivity, will be provided to 
the IDMC.
For subjects with an SAE related to respiratory disease, the CEC will determine the presence or 
absence of severe LRTIs by reviewing all available clinical information related to respiratory 
disease, with a special focus on the following characteristics (“WHO” criteria30):

Respiratory infection defined as cough or difficulty breathing
AND

LRTI defined as fast breathing or oxygen saturation (SpO2) <95%
AND

≥1 of the severe disease feature:
o
oximetry <93%
o
lower chest wall indrawing
11.10. Study Vaccination Pausing Rules
The PIs 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 IDMC review is carried out and subsequent communication between the sponsor and the 
investigators takes place.
The occurrence of any of the following events will lead to suspension of further study 
vaccination, and trigger a meeting of the IDMC to discuss study suspension, adaptation or 
discontinuation of further vaccination:
1. One or more subjects in the same cohort 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 in the same cohort experience anaphylaxis clearly not attributable to 
other causes than vaccination with study vaccine; OR
3. Two or more subjects in the same cohort 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 in the same cohort 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 in Cohort 0 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


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6. Death of any subject, regardless of causality.
Note: The count of subjects for each pausing rule will be across all study sites. After the first 
IDMC meeting triggered by the occurrence of a given pausing rule, the IDMC will convene 
thereafter for each additional subject meeting that pausing rule.
To enable prompt response to a situation that would trigger pausing rules 3 or 4, the investigator 
should update the eCRF with information on any Grade 3 or 4 AE on the same day that the AE is 
reported.
If any of the above specific pausing rules are met, the IDMC 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.
Vaccinations for an individual subject may be suspended for safety concerns other than those 
described above, at the discretion of the investigator if he/she feels the subject’s safety may be 
threatened. 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 IDMC will need to be convened.
Central randomization will be implemented in this study. Central randomization ensures that 
study recruitment and dosing can be effectively halted simultaneously across all sites in the event 
of a situation meeting any of the pausing rules. Sponsor activities and responsibilities related to 
temporary study suspension and restart are described in the Sponsor’s applicable standard 
operating procedures (SOPs).19,20
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 standard operating procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.


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Method of Detecting AEs and SAEs
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 (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, 
Overview).
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: The sponsor collects unsolicited AEs starting with the signing of the ICF for 28 days after 
the first vaccination, and from the time of subsequent vaccinations through the following 
28 days, and solicited AEs from the time of each vaccination for 7 days post-vaccination (refer to 
Section 12.3.1, All Adverse Events, for time of last AE recording). For both cohorts, all SAEs 
will be collected from ICF signature to the end of the study. RTIs, preferably as a diagnosis, will 
be reported on the AE page of the eCRF if they occur within 28 days following vaccination; any 
RTI fulfilling the criteria of an SAE would be reported as such during the entire study period.
Any severe LRTI will be reported using the SAE reporting system and SAE form, regardless of 
whether the event fulfills the criteria of an SAE.


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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:

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 or to alternative causes (eg, natural history 
of the underlying diseases, concomitant therapy). This applies to all AEs, whether serious or 
non-serious.


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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 and the AE 
(without determining the extent of probability); there is a reasonable possibility that the study 
vaccine contributed to the AE.
Unrelated: there is no suspicion that there is a relationship between the study vaccine and the 
AE; there are other more likely causes and administration of the study vaccine 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 reported as AEs will be coded for severity using the toxicity grading 
table in Attachment 1 (for Cohort 0), and in Attachment 2 (for Cohort 1). Note: For Cohort 0, 
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): Awareness of symptoms that are easily tolerated, causing minimal discomfort 
and not interfering with everyday activities.
Moderate (Grade 2): Sufficient discomfort is present to cause interference with normal activity.
Severe (Grade 3): Extreme distress, causing significant impairment of functioning or 
incapacitation. Prevents normal everyday activities.
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 investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
For Cohort 0, 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 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 respective
toxicity grading table.


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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 SAE page of the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
Unsolicited AEs and special reporting situations will be reported from the time a signed and 
dated ICF is obtained until 28 days (including relevant visit window, if applicable) after first 
dose of study vaccine, and thereafter, for 28 days (including relevant visit window, if applicable) 
after each subsequent dose of study vaccine. Unsolicited AEs with the onset date outside the time 
frame defined above (>28 days after previous study vaccination) that are ongoing on the day of 
the subsequent vaccination should be recorded on the eCRF AE page.
Solicited AEs will be recorded by each subject in the subject diary for 7 days after each 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 data (and clinical 
laboratory data for Cohort 0), 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, 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”). Investigators must record in the eCRF their opinion concerning the relationship of 
the AE to study vaccine. All measures required for AE management must be recorded in the 
source document and reported according to sponsor instructions.
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.
Subjects 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 SAE 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 AE (eg, social reasons such as 
pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the 
eCRF). Note: Hospitalizations that were planned before the signing of the ICF, and where 
the underlying condition for which the hospitalization was planned has not worsened, will 
not be considered SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE.
The cause of death of a 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 (Cohort 0 Subjects)
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 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, Serious Adverse 
Events). 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 colorless frozen liquid to be thawed prior to use. 
Ad26.RSV.preF will be filled in stoppered and sealed 2 mL single-use glass vials. Injection 
volumes of 0.5 mL (1x1011 vp) for adults and 0.25 mL (5x1010 vp) for toddlers will be used. 
Refer to the Investigator’s Brochure for details of the components of Ad26.RSV.preF and a list 
of excipients.
Placebo
Placebo will be supplied as sterile 0.9% saline for injection in 2 mL ampoules.


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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 
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.
For adult subjects, injections should be administered in the deltoid. For pediatric subjects, 
injections should be administered in the anterolateral aspect of the thigh. Alternating injection 
sites will be used for the vaccinations on Day 1 and Day 29. The study vaccine will be prepared by 
the unblinded site pharmacist, or other qualified individual and administered by a study vaccine 
administrator.
Note: the unblinded pharmacist, or other qualified individual, may also perform the 
administration, but will have no other study function from randomization onwards.
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 


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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 ampoules, 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. Returned study vaccine must not be 
dispensed again, even to the same subject. 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 sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator’s Brochure for Prophylactic RSV Vaccine

Investigational Product Preparation Instructions/Investigational Product Procedures Manual

Laboratory Manual (including procedures for collection of nasal turbinate samples)

Trial Center File

IWRS Manual

Electronic Data Capture (eDC) Manual/eCRF completion guidelines and randomization 
instructions

Sample ICF

Subject diaries

Rulers

Thermometers

RTI Symptoms Forms

Contact information page(s)
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Cohort 0 only: 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 


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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.
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.44,45
Cohort 1 only: The parents/legal guardian of potential subjects will be fully informed of the risks 
and requirements of the study and, during the study, will be given any new information that may 
affect their decision for their child to continue participation. They will be told that their consent for 
their child 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 
parents/legal guardian who are fully able to understand the risks, benefits, and potential AEs of the 
study, and provide their consent voluntarily will be able to enroll their child in the study.
When referring to the signing of the ICF, the terms legal guardian and legally acceptable 
representative refer to the legally appointed guardian of the child with authority to authorize 
participation in research. For each subject, his or her parent(s) (preferably both parents, if 
available) or legally acceptable representative(s), as required by local regulations, must give 
written consent (permission) according to local requirements after the nature of the study has been 
fully explained and before the performance of any study-related assessments. For the purposes of 
this study, all references to subjects who have provided consent refers to the subjects and his or her 
parent(s) or the subject’s legal guardian(s) or legally acceptable representative(s) who have 
provided consent according to this process.
The total blood volume drawn from each pediatric subject will not exceed the most stringent 
(European Medicines Agency) guidelines for pediatric subjects in clinical trials: blood loss 
should not exceed 3% of total blood volume over four weeks, and it should not exceed 1% of 
total blood volume at any single time.12
See Section 3.4 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.


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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 
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


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
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
In this section, any reference to activities to be performed by the subject refers to adult subjects or the 
parent/legal guardian for pediatric subjects.
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The ICF(s) must be signed before performance of any study-
related activity. The ICF(s) that is/are used must be approved by both the sponsor and by the 
reviewing IEC/IRB and be in a language that the subject can read and understand. The informed 
consent should be in accordance with principles that originated in the Declaration of Helsinki, 
current ICH and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential 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.


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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 (or parent/legal guardian for pediatric subjects)
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 (or parent/legal guardian for pediatric subjects) 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.
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, including samples from subjects who were 
screened but not randomized, 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).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product.


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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 PI.

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 


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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 PI, 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
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 


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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 visits at 7 days after each 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 a hospital or 
clinic record to document medical care (eg, electronic source documents) as well as the clinical 
study-specific data fields as determined by the protocol. This data is electronically extracted for 
use by the sponsor. If eSource is utilized, references made to the eCRF in the protocol include 
the eSource system but information collected through eSource may not be limited to that found 
in the eCRF.
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.
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).


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
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 
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 


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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 active phase will be when the last subject completes the visit 6 months after the 
final dose (Visit 8 Cohort 0; Visit 9 for Cohort 1). The end of the study will be the last subject’s 
last visit (by telephone) at the end of the safety follow-up phase (1 year after the first dose). 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. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study vaccine development


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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 
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.
Arrangements on publication policy will be addressed in the Clinical Trial Agreement.


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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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Janssen Research and Development. Temporary Suspension, Premature Study Termination, and Study Closure. 
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21.
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Magro M, Mas V, Chappell K, et al. Neutralizing antibodies against the preactive form of respiratory syncytial 
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Marcy SM, Kohl KS, Dagan R, et al. Fever as an adverse event following immunization: case definition and 
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Milligan ID, Gibani MM, Sewell R, et al. Safety and immunogenicity of novel adenovirus type 26- and 
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Modjarrad K, Giersing B, Kaslow DC, et al. WHO consultation on Respiratory Syncytial Virus Vaccine 
Development Report from a World Health Organization Meeting held on 23-24 March 2015. Vaccine. 
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Moghaddam A, Olszewska W, Wang B, et al. A potential molecular mechanism for hypersensitivity caused by 
formalin-inactivated vaccines. Nat Med. 2006:12;905-907.
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Nair H, Nokes DJ, Gessner BD, et al. Global burden of acute lower respiratory infections due to respiratory 
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Ngwuta JO, Chen M, Modjarrad K, et al. Prefusion F-specific antibodies determine the magnitude of RSV 
neutralizing activity in human sera. Sci Transl Med. 2015:7;309ra162.
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Ouedraogo A, Tiono AB, Kargougou D, et al. A phase 1b randomized, controlled, double-blinded dosage-
escalation trial to evaluate the safety, reactogenicity and immunogenicity of an adenovirus type 35 based 
circumsporozoite malaria vaccine in Burkinabe healthy adults 18 to 45 years of age. PLoS One. 
2013:8;e78679.
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Paramore LC, Ciuryla V, Ciesla G, Liu L. Economic impact of respiratory syncytial virus-related illness in the 
US: an analysis of national databases. Pharmacoeconomics. 2004:22;275-284.
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Peebles RS, Jr. Viral infections, atopy, and asthma: is there a causal relationship? J Allergy Clin Immunol. 
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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 
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sequelae: systematic review and meta-analysis. Pediatr Infect Dis J. 2013:32;820-826.
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Shay DK, Holman RC, Newman RD, et al. Bronchiolitis-associated hospitalizations among US children, 1980-
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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.


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41.
Simoes EA, Carbonell-Estrany X, Guilbert T, et al. Clinical Endpoints for Respiratory Syncytial Virus 
Prophylaxis Trials in Infants and Children in High-income and Middle-income Countries. Pediatr Infect Dis J. 
2015:34;1086-1092.
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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.
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Simoes EA, Groothuis JR, Carbonell-Estrany X, et al. Palivizumab prophylaxis, respiratory syncytial virus, 
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Stockman LJ, Curns AT, Anderson LJ, Fischer-Langley G. Respiratory syncytial virus-associated 
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47.
Data on file.


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Attachment 1: Toxicity Tables for Cohort 0
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
visit or
hospitalization
Tenderness
Mild discomfort 
to
Touch
Discomfort with
Movement
Significant
discomfort at rest
Emergency room 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)
38.0 – 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
Emergency room visit or 
hospitalization for arrhythmia
Bradycardia - beats per 
minute***
50 – 54
45 – 49
< 45
Emergency room visit or 
hospitalization for arrhythmia
Hypertension (systolic) 
- mm Hg
141 – 150
151 – 155
>155
Emergency room visit or 
hospitalization for malignant 
hypertension
Hypertension 
(diastolic) - mm Hg
91 – 95
96 – 100
>100
Emergency room visit or 
hospitalization for malignant 
hypertension
Hypotension (systolic) 
- mm Hg
85 – 89
80 – 84
< 80
Emergency room 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
Emergency room 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
Emergency room 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
Emergency room visit or 
hospitalization
Fatigue
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
Emergency room visit or 
hospitalization
Myalgia
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
Emergency room visit or 
hospitalization
Systemic Illness
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life-threatening 
(Grade 4)
Illness or clinical AE
(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
Emergency room 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 central 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 central 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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Clinical Protocol Amendment 4 VAC18194RSV2001
115
Approved, Date: 18 April 2019
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 central 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.










VAC18194 (Ad26.RSV.preF)
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Approved, Date: 18 April 2019
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully 
informed regarding the study vaccine, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature:
Date:
(Day Month Year)
Sponsor’s Responsible Medical Officer:
Name (typed or printed):
Institution:
Janssen Research and Development
Signature:
electronic signature appended at the end of the protocol
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the 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
PPD


 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
18Apr2019, 10:33:33 AM, UTC
Document Approval
PPD

SAP_001.pdf: 
1
Approved, Date: 25 April 2018
Janssen Vaccines & Prevention B.V.
Statistical Analysis Plan
A Randomized, Double-blind, Phase 1/2a Study to Evaluate the Safety, Tolerability and 
Immunogenicity of Ad26.RSV.preF in Adults 18 to 50 Years of Age and RSV-Seropositive 
Toddlers 12 to 24 Months of Age
Protocol VAC18194RSV2001; Phase 1/2a
VAC18194  (Ad26.RSV.preF)
Status:
Approved
Date:
25 April 2018
Prepared by:
Janssen Vaccines & Prevention B.V.
Document No.: EDMS-ERI-151449597
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.
NCT03303625


VAC18194  (Ad26.RSV.preF)
Statistical Analysis Plan VAC18194RSV2001
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Approved, Date: 25 April 2018
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 ................................................................................................................................ 6
1.2.
Trial Design ...................................................................................................................................... 6
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 7
1.4.
Sample Size Justification ................................................................................................................. 7
1.5.
Randomization and Blinding ............................................................................................................ 7
1.6.
Changes to planned analyses.......................................................................................................... 8
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 8
2.1.
Study phases ................................................................................................................................... 8
2.1.1.
Phase definitions .......................................................................................................................... 9
2.2.
Pooling Algorithm for Analysis Centers.......................................................................................... 10
2.3.
Analysis Sets.................................................................................................................................. 10
2.3.1.
Full Analysis Set (FA) ................................................................................................................. 10
2.3.2.
Immunogenicity Analysis Set...................................................................................................... 10
2.3.2.1.
Per Protocol Immunogenicity Population (PPI) ....................................................................... 10
3.
DATA MONITORING COMMITTEE REVIEW................................................................................... 10
4.
SUBJECT INFORMATION................................................................................................................ 11
4.1.
Demographics and Baseline Characteristics ................................................................................. 11
4.2.
Disposition Information................................................................................................................... 11
4.3.
Treatment Compliance................................................................................................................... 11
4.4.
Protocol Deviations ........................................................................................................................ 11
4.5.
Concomitant Medications............................................................................................................... 11
5.
SAFETY............................................................................................................................................. 12
5.1.
Adverse Events (AE)...................................................................................................................... 12
5.1.1.
Definitions.................................................................................................................................... 12
5.1.2.
Analysis of Adverse Events ........................................................................................................ 13
5.1.3.
Phase allocation of Unsolicited Adverse Events ........................................................................ 13
5.1.4.
Missing Data ............................................................................................................................... 15
5.1.5.
Solicited Local (Injection Site) Reactions ................................................................................... 15
5.1.6.
Solicited Systemic Adverse Events ............................................................................................ 15
5.2.
Clinical Laboratory Tests................................................................................................................ 15
5.3.
Vital Signs and Physical Examination Findings ............................................................................. 16
6.
IMMUNOGENICITY ANALYSIS........................................................................................................ 17
6.1.
Parameters..................................................................................................................................... 17
6.2.
Handling of Missing and/or Unquantifiable Immune Response Data ............................................ 18
6.3.
Immune Response Analysis .......................................................................................................... 19
6.3.1.
Immunogenicity against the insert:............................................................................................. 19
6.3.1.1.
Humoral assays....................................................................................................................... 19
6.3.1.2.
Cellular assays ........................................................................................................................ 20
6.3.2.
Immunogenicity against the vector ............................................................................................. 21
7.
RSV INFECTIONS............................................................................................................................. 21


VAC18194  (Ad26.RSV.preF)
Statistical Analysis Plan VAC18194RSV2001
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Approved, Date: 25 April 2018
ATTACHMENTS......................................................................................................................................... 22
Attachment 1:
Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials....................... 22
Attachment 2:
Toxicity tables for cohort 1.......................................................................................... 27
Attachment 3:
Transforming the on-site assessments and diaries of solicited AEs into 
analysis format ........................................................................................................... 30
LIST OF IN-TEXT TABLES
Table 1:
Study Design............................................................................................................................... 7
Table 2:
Phase Definitions........................................................................................................................ 9
Table 3:
Vital Signs Toxicity table for Cohort 0....................................................................................... 17


VAC18194  (Ad26.RSV.preF)
Statistical Analysis Plan VAC18194RSV2001
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Approved, Date: 25 April 2018
ABBREVIATIONS
AE
adverse event
CEC
Clinical Endpoint Committee
CI
confidence interval
CRF
case report form
CSR
Clinical Study Report
DMC
Data Monitoring Committee
DPS
Data Presentation Specifications
IDMC
Independent Data Monitoring Committee
eCRF
ELISA
ELISpot
GMC
FA
electronic case report form
Enzyme-linked immunosorbent assay
enzyme-linked immunospot 
Geometric mean antibody concentration
Full Analysis Set
FDA
Food and Drug Administration
ICH
International Conference on Harmonization
ITT
ICS
IU/ml
Intent-to-Treat
Intracellular Cytokine Staining
International units per milliliter
IVRS
LLOQ
interactive voice response system
lower limit of quantification
LOCF
last observation carried forward
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
SD
TLF
standard deviation
Tables, Listings and Figures 
DEFINITION OF TERMS
Active vaccine
Ad26.RSV.preF
Study vaccine
Ad26.RSV.preF or Placebo


VAC18194  (Ad26.RSV.preF)
Statistical Analysis Plan VAC18194RSV2001
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Approved, Date: 25 April 2018
1.
INTRODUCTION
This is the Statistical Analysis Plan (SAP) applicable for the VAC18194RSV2001 trial. This 
SAP is applicable for the following analysis: 

Cohort 0: primary analysis will be performed when all subjects have reached Day 57
(28 days post-Dose 2) or discontinued earlier. All available safety and immunogenicity 
data gathered so far will be included in the analysis; unblinded at the group level.

Cohort 1: interim analysis will be performed when 12 subjects have reached Day 8 or 
discontinued earlier. All available safety of the 12 subjects and all available 
immunogenicity data gathered up to that point will be included in the analysis; unblinded 
at the group level.  For the safety analysis snapshot data will be used: there will be no 
formal cleaning for this analysis. Data will be cleaned in an ongoing basis.

Cohort 1: interim analysis will be performed when at least 12 subjects have reached 
Day 29 or discontinued earlier. All available safety and all immunogenicity data gathered 
up to that point will be included in the analysis; unblinded at the group level.

Cohort 1:
Depending on the outcome of the first 2 interim analysis of Cohort 1 an 
additional interim analysis may be performed when at least 24 subjects have reached 
Day 29 (28 days post-Dose 1) or discontinued earlier. All available safety and 
immunogenicity data gathered so far will be included in the analysis; unblinded at the 
group level.

Cohort 1: primary analysis will be performed when all subjects have reached Day 57
(28 days post-Dose 2) or discontinued earlier. All available safety and immunogenicity 
data gathered so far will be included in the analysis; unblinded at the group level.

Final analysis of both cohorts; at the end of the study, 1 year after the first dose; 
unblinded.

Additional interim analyses (blinded or unblinded at the group level) 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 safety and immunogenicity 
analysis. Tables, listings and figures (TLF) which need to be generated for each analysis will be 
described in separate data presentation specifications (DPS) document.


VAC18194  (Ad26.RSV.preF)
Statistical Analysis Plan VAC18194RSV2001
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Approved, Date: 25 April 2018
1.1.
Trial Objectives
Primary Objective

To assess the safety and tolerability of an intramuscular regimen of two doses of 1x1011 viral 
particles (vp) of Ad26.RSV.preF in adults aged 18 to 50 years.

To assess the safety and tolerability of an intramuscular regimen of two doses of 5x1010 vp 
of Ad26.RSV.preF in RSV-seropositive toddlers aged 12 to 24 months.
Secondary Objectives

To assess the humoral and cellular immune responses as measured by virus neutralization 
assay, F-protein binding antibodies (pre-F and post-F) and intracellular cytokine staining 
(ICS; to assess Th1/Th2 subtyping).
Exploratory Objectives

To further assess the humoral and cellular immune responses elicited by Ad26.RSV.preF. 
The assays to be used may include, but are not limited to, RSV strain cross-neutralization, 
anti-F protein 
antibody 
specificity 
and 
functionality 
characterization, 
adenovirus 
neutralization assays, molecular antibody characterization (avidity, Fc cell interaction, 
antibody isotyping), evaluation of the cellular immune response (interferon gamma [IFNγ] 
enzyme-linked immunospot [ELISpot] assay) and functional and memory immune response 
(by ICS), and cytokine profiles of RSV F-protein peptide-stimulated peripheral blood 
mononuclear cell (PBMC) supernatant.

To assess RSV infection rates in Ad26.RSV.preF and placebo subjects.

To monitor for severe RSV-lower respiratory tract infection (LRTI) in Cohort 1
(RSV-seropositive toddlers aged 12 to 24 months).

To assess symptoms of respiratory illness via the respiratory tract infection (RTI) symptoms 
1.2.
Trial Design
This is a multi-center, randomized, double-blind, Phase 1/2a study, to be conducted in 12 male 
and female adults aged ≥18 to ≤50 years and 36 male and female RSV-seropositive toddlers aged 
≥12 to ≤24 months of age.
Subjects will be enrolled into sequential age cohorts:

18 to 50-year-old adults, into Cohort 0

12 to 24-month-old seropositive toddlers, into Cohort 1
In Cohort 0, subjects will be randomized 2:1 to receive either Ad26/Ad26 (1x1011 vp in 0.5 mL) 
or placebo/placebo (saline), and in Cohort 1, subjects will be randomized 2:1 to receive either 
Ad26/Ad26 (5x1010 vp in 0.25 mL) or placebo/placebo. A schematic overview of the study 
design and groups is depicted in Table 1 .


VAC18194  (Ad26.RSV.preF)
Statistical Analysis Plan VAC18194RSV2001
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Approved, Date: 25 April 2018
Table 1:
Study Design
Cohort
Group
N
Day 1
Day 29/Week 4
ADULTS 18 to 50 years
0
Group 1
8
Ad26.RSV.preF (1x1011 vp)
Ad26.RSV.preF (1x1011 vp)
Group 2
4
Placebo
Placebo
TODDLERS 12 to 24 months: RSV seropositive 
1
Group 3
32
Ad26.RSV.preF (5x1010 vp)
Ad26.RSV.preF (5x1010 vp)
Group 4
16
Placebo
Placebo
The study will have three phases: a screening phase, an active phase and a safety follow-up 
phase through 1 year after the first dose.
The end of the active phase will be when the last subject completes the visit at 6 months after the 
final
dose. The end of the study will be the last subject’s last visit (by telephone) at the end of the 
safety follow-up phase. For further information related to the design of the study refer to CTP, 
Section 3.1. 
1.3.
Statistical Hypotheses for Trial Objectives
The objective of the study is to evaluate whether Ad26.RSV.preF is safe, well-tolerated and 
immunogenic in adults and RSV-seropositive toddlers. No formal statistical hypothesis is 
planned. Safety parameters will be summarized descriptively. Geometric mean titers with 95% 
confidence intervals (CI) for humoral assays and medians with interquartile for cellular assays 
will be calculated.
1.4.
Sample Size Justification
The number of subjects chosen for this study will provide a preliminary safety and 
immunogenicity assessment. Placebo recipients are included for blinding and safety purposes 
and will provide additional control specimens for immunogenicity assays.
1.5.
Randomization and Blinding
Central randomization will be implemented in this study. Within each cohort, subjects will be 
randomly assigned to one of the two groups based on a computer-generated randomization 
schedule prepared before the study by or under the supervision of the sponsor. The 
randomization will be balanced by using randomly permuted blocks. No stratification will be 
applied. The interactive web response system (IWRS) will assign a unique code, which will 
dictate the group assignment for the subject. The requestor must use his or her own user 
identification and personal identification number when contacting the IWRS, and will then give 
the relevant subject details to uniquely identify the subject.
The subjects, study-site personnel, and investigator will be blinded to study vaccine allocation 
throughout the study, except for the pharmacist or qualified staff member with primary 
responsibility for study vaccine preparation and dispensing. Unblinding will occur at the time of 


VAC18194  (Ad26.RSV.preF)
Statistical Analysis Plan VAC18194RSV2001
8
Approved, Date: 25 April 2018
the first interim analysis. The results will only be available to a selected group of sponsor 
personnel, excluding personnel involved in data collection and data management. For further 
information please refer to CTP Section 5.
1.6.
Changes to planned analyses
Two addition interim analyses for Cohort 1 have been added, for the purpose of informing future 
vaccine-related decisions in a timely manner. The first interim analysis will be performed when 
12 subjects have reached Day 8, and the second one when at least 12 subjects have reached Day 
29. Given that the first interim analysis coincides with the planned IDMC analysis, the IDMC 
members will receive immediately unblinded at the group level safety results instead of blinded, 
as specified in the CTP. That way the IDMC and the study team will possess the same 
information regarding safety. Moreover, the conduct of the planned interim analysis, when at 
least 24 subjects of Cohort 1 have reached Day 29 (28 days post-Dose 1) or discontinued earlier, 
will be dependent on the outcome of the previous interim analyses and is at the discretion of the 
sponsor.  
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Study phases
A baseline (or reference) value will be defined as the value of the last available assessment prior 
to the first vaccination on Day 1.
The safety analysis will present all results by period. Immunogenicity results will be presented 
per scheduled time point as appropriate. Listings will be shown per phase and time point.
Study day or relative day is defined as follows:
Study Day = visit date - date of Day 1 + 1; if visit date > date of Day 1 (date of first 
vaccination).
Study Day = visit date - date of Day 1; if visit date < date of Day 1 (date of first 
vaccination).




VAC18194  (Ad26.RSV.preF)
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Approved, Date: 25 April 2018
2.2.
Pooling Algorithm for Analysis Centers
Data will be pooled across the different centers.
2.3.
Analysis Sets
2.3.1.
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. Vaccination 
assignment will follow the as-treated principle. 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.
2.3.2.
Immunogenicity Analysis Set
2.3.2.1.
Per Protocol Immunogenicity Population (PPI)
The Per-protocol Immunogenicity Set (PPI) will include all randomized and vaccinated 
subjects for whom immunogenicity data are available, excluding subject samples with major 
protocol deviations expecting to impact the immunogenicity outcomes.
In addition, the following samples will not be included in the PPI set:

If subjects miss one or more doses, but continue the planned visit schedule, samples taken 
after the planned but missed dose(s) will not be taken into account;

For subjects who experience a natural RSV infection (based on RT-PCR, or other sources), 
samples taken after the natural infection are not be taken into account.
The analysis of immunogenicity will be based on the PPI set.
3.
DATA MONITORING COMMITTEE REVIEW
An independent data monitoring committee (IDMC) will be established to monitor severe LRTI. 
The presence of severe LRTI will be determined by the Clinical Endpoint Committee (CEC), a 
separate committee (see CTP Section 11.9.2). The outcome of the adjudication of the CEC as 
well as the determination of RSV positivity will be provided to the IDMC.
The IDMC will review 7-day post-dose 1 safety data of the first 12 Cohort 1 subjects and will 
convene as needed on an ad hoc basis to ensure the continuing safety of the subjects enrolled in 
this study. The IDMC will also convene to discuss any situation that meets a study vaccination 
pausing rule. The IDMC will monitor severe RSV-LRTI as detailed in the IDMC charter. A 
separate SAP for the IDMC analysis will be provided.


VAC18194  (Ad26.RSV.preF)
Statistical Analysis Plan VAC18194RSV2001
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Approved, Date: 25 April 2018
4.
SUBJECT INFORMATION
Subject information will be shown for the full analysis set.
4.1.
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), only for Cohort 0

Weight (kg), only for Cohort 0

BMI (kg/m2), only for Cohort 0

Growth Percentile, weight by age*, only for Cohort 1

Growth Percentile, height/length by age *, only for Cohort 1
4.2.
Disposition Information
The number and percentage of subjects screened, subjects in the FA set, subjects in the PPI set, 
subjects vaccinated and not randomized, subjects randomized and not vaccinated and 
discontinued subjects (study discontinuation and vaccination discontinuation) 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.
4.3.
Treatment Compliance
The number of missed vaccinations will be tabulated.
4.4.
Protocol Deviations
Major protocol deviations will be summarized.
4.5.
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.


VAC18194  (Ad26.RSV.preF)
Statistical Analysis Plan VAC18194RSV2001
12
Approved, Date: 25 April 2018
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.
5.
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. 
Two types of safety tables will be shown. In the by regimen layout, safety data will be analyzed
by vaccine regimens as designed per protocol; data will be presented by period as well as over 
the entire regimen. Denominator for the percentages is the number of subjects in the considered 
population and period for a certain regimen (incidence per 100 subjects/period). In the second, 
by vaccine, safety data will be presented by the different vaccines used in the study but by 
considering every vaccination administered as a separate safety episode. Denominator for the 
percentages is the number of vaccinations administered of a certain vaccine (rate per 
100 vaccinations of a particular vaccine).
5.1.
Adverse Events (AE)
5.1.1.
Definitions
Solicited AEs shown in the tables are extracted from the diary pages of the CRF. For unsolicited 
AEs, only the AEs starting (grade and/or relation) within the 28-day period following each 
vaccination 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.


VAC18194  (Ad26.RSV.preF)
Statistical Analysis Plan VAC18194RSV2001
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Approved, Date: 25 April 2018
5.1.2.
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: Duration for solicited AEs 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 period.
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.
5.1.3.
Phase allocation of Unsolicited Adverse Events
Solicited events are always allocated to the respective Post Dose period.
Solicited AEs from the diary will be added to the ADAM database 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.


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- In case of a completely missing start date, the event is allocated to the first active treatment 
phase (post dose 1 period), except if the end date of the AE falls before the start of the first active 
treatment phase (post dose 1 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:
1) If overlapping/consecutive events start in one of the following periods - Screening or post
dose extension (i.e. non-active periods) followed by an AE in post-dose 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.


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5.1.4.
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.
5.1.5.
Solicited Local (Injection Site) Reactions
The analysis of local solicited adverse events, for all subjects will include:

Erythema

Induration/swelling

Pain/tenderness
5.1.6.
Solicited Systemic Adverse Events 
The analysis of systemic solicited adverse events for adult subjects will include:

Fatigue

Headache

Myalgia

Arthralgia

Chills

Nausea

Fever (ie, body temperature ≥ 38 °C)
The analysis of systemic solicited adverse events for pediatric subjects will include:

Loss of appetite

Vomiting 

Diarrhea

Decreased activity/lethargy

irritability/crying

Fever (ie, body temperature ≥ 38 °C)
5.2.
Clinical Laboratory Tests
For laboratory safety parameters, only abnormalities emerging after vaccination will be tabulated 
by worst abnormality grade using the FDA table in Attachment 1.
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).


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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 lab 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. 
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).
5.3.
Vital Signs and Physical Examination Findings
Similarly, only vital signs abnormalities emerging after vaccination will be tabulated by worst 
abnormality grade. 
For cohort 0, 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 3. 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.


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Statistical Analysis Plan VAC18194RSV2001
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Approved, Date: 25 April 2018
Table 3:
Vital Signs Toxicity table for Cohort 0
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
For Cohort 1, heart rate (beats per minutes, bpm) and respiratory rate (breaths per minute) will 
be collected. Since no vital sign toxicity table is available for toddlers any abnormality will be 
recorded as an AE, by the investigator. Only respiratory rates will be summarized with 
descriptive statistics.
For both cohorts, temperature (diary, on site assessments) 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). Tables will show the maximum temperature for both diary and 
onsite assessments separately. A listing of subjects with fever according to the FDA grading 
table will also be provided.
Respiratory rates will also be summarized descriptively for both Cohorts.
Any abnormal physical examination result will be documented as AEs, by the investigator.  
6.
IMMUNOGENICITY ANALYSIS
The analysis of immunogenicity will use the PPI set. The most important tables might be 
repeated on the FA set as a sensitivity analysis. 
6.1.
Parameters
The following humoral and cellular immune responses will be measured in the different vaccine 
regimen tested. However not all assays will be available for all immunogenicity analyses covered 
by this SAP. Further information on which assays will be analyzed in each one of the analysis, 
will be included in the corresponding DPS documents.


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Statistical Analysis Plan VAC18194RSV2001
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Immunogenicity against the insert:
Humoral immune response

RSV neutralization A strain (titers of neutralizing antibodies). 

RSV F protein enzyme-linked immunosorbent assay (ELISA; pre- and/or post-fusion F 
antibodies). 

RSV neutralization B and/ or a different A strain (titers of neutralizing antibodies), if 
available. 

Functional and molecular antibody characterization, if available.
Cell-mediated immune response

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)

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, if available.

PBMC secreted cytokines and ELISpot IFNγ are exploratory endpoints and will only be 
analyzed, if available.

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. This is an 
exploratory endpoint and will only be analyzed if available.
6.2.
Handling of Missing and/or Unquantifiable Immune Response Data 
Missing immune response data will not be imputed. 


VAC18194  (Ad26.RSV.preF)
Statistical Analysis Plan VAC18194RSV2001
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Approved, Date: 25 April 2018
Values below the lower limit of quantification (LLOQ) or the provisional cut-off will be treated 
differently according to the assay: 

Humoral Assays: 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 LLOQ/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 LLOQ will be imputed to a value of LLOQ/2.

For all assays: values above ULOQ will be imputed with 2xULOQ.
6.3.
Immune Response Analysis
No formal hypothesis on immunogenicity will be tested.
6.3.1.
Immunogenicity against the insert:
6.3.1.1.
Humoral assays
For VNA and ELISA assays 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.
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.
A scatterplot with the VNA versus ELISA will 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. 


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6.3.1.2.
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. 
Tables with the corresponding descriptive statistics 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 for each assay.
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. 
Tables with the corresponding descriptive statistics 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 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.


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Statistical Analysis Plan VAC18194RSV2001
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Approved, Date: 25 April 2018
6.3.2.
Immunogenicity against the vector
For VNA, if available following statistics will be calculated: N, geometric mean§(see above for the 
calculation) and corresponding 95% CI of the actual values.
Scatterplots with the assays against the vector versus the assays against the inserts might be 
created for the most important time points. In these scatter-plots the actual values will be shown, 
even if they are below the LLOQ.
7.
RSV INFECTIONS
In case of a severe LRTI being present in Cohort 1, then all potential cases of RSV infection will 
be summarized in the following two categories and based on their severity (severe/ non-severe).

Suspected RSV infection: subject has persistent (>48 hours) clinical symptoms of rhinitis 
(sneezing or runny nose or congestion) and persistence (>24 hours) of one or more of the 
following: cough, abnormal breathing, fever, lethargy or decreased appetite. Occurrence of 
this combination of symptoms in any subject would trigger collection of a nasal turbinate 
sample.

Confirmed RSV infection: subject with suspected RSV infection and positive for RSV on 
the basis of RT-PCR conducted centrally.


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Statistical Analysis Plan VAC18194RSV2001
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Approved, Date: 25 April 2018
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.
Serum *
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life 
Threatening
(Grade 4)**
Sodium – Hyponatremia mEq/L 132 – 134
130 – 131
125 – 129
< 125
Sodium – Hypernatremia mEq/L 144 – 145
146 – 147
148 – 150
> 150
Potassium – Hyperkalemia 
mEq/L
5.1 – 5.2
5.3 – 5.4
5.5 – 5.6
> 5.6
Potassium – Hypokalemia 
mEq/L
3.5 – 3.6
3.3 – 3.4
3.1 – 3.2
< 3.1
Glucose – Hypoglycemia mg/dL 65 – 69
55 – 64
45 – 54
< 45
Glucose – Hyperglycemia
Fasting – mg/dL
Random – mg/dL
100 – 110
110 – 125
111 – 125
126 – 200
>125
>200
Insulin 
requirements or 
hyperosmolar 
coma
Blood Urea Nitrogen
BUN mg/dL
23-26
27 – 31
> 31
Requires dialysis
Creatinine – mg/dL
1.5 – 1.7
1.8 – 2.0
2.1 – 2.5
> 2.5 or requires 
dialysis
Calcium – hypocalcemia mg/dL 8.0 – 8.4
7.5 – 7.9
7.0 – 7.4
< 7.0
Calcium – hypercalcemia mg/dL 10.5 – 11.0
11.1 – 11.5
11.6 – 12.0
> 12.0
Magnesium – hypomagnesemia 
mg/dL
1.3 – 1.5
1.1 – 1.2
0.9 – 1.0
< 0.9
Phosphorous –
hypophosphatemia mg/dL
2.3 – 2.5
2.0 – 2.2
1.6 – 1.9
< 1.6
CPK – mg/dL
1.25 – 1.5 x 
ULN***
1.6 – 3.0 x 
ULN
3.1 –10 x 
ULN
> 10 x ULN
Albumin – Hypoalbuminemia 
g/dL
2.8 – 3.1
2.5 – 2.7
< 2.5
--
Total Protein – Hypoproteinemia 
g/dL
5.5 – 6.0
5.0 – 5.4
< 5.0
--


VAC18194  (Ad26.RSV.preF)
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Approved, Date: 25 April 2018
Serum *
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life 
Threatening
(Grade 4)**
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 
institutional normal parameters. Institutional normal reference ranges should be provided to 
demonstrate that they are appropriate.
** The clinical signs or symptoms associated with laboratory abnormalities might result in 
characterization of the laboratory abnormalities as Potentially Life Threatening (Grade 4). For 
example. a low sodium value that falls within a grade 3 parameter (125-129 mE/L) should be 
recorded as a grade 4 hyponatremia event if the subject had a new seizure associated with the low 
sodium value.
***”ULN” is the upper limit of the normal range.


VAC18194  (Ad26.RSV.preF)
Statistical Analysis Plan VAC18194RSV2001
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Approved, Date: 25 April 2018
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**
ï€ 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)
International Normalized Ratio 
(INR)***
1.1 to < 1.5 x 
ULN
1.5 to < 2.0 x 
ULN
2.0 to < 3.0 x 
ULN
≥ 3.0 x ULN
* The laboratory values provided in the tables serve as guidelines and are dependent upon 
institutional normal parameters. Institutional normal reference ranges should be provided to 
demonstrate that they are appropriate.
** "ULN" is the upper limit of the normal range.
***: For INR, the values in the table are based on the Division of AIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events, 2014 (version 2.0)


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Approved, Date: 25 April 2018
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 
forhyperglycemia
Blood (microscopic) - red blood 
cells per high power field 
(rbc/hpf)
1 - 10
11 - 50
> 50 and/or 
gross blood
Hospitalization or 
packed red blood 
cells (PRBC) 
transfusion
* The laboratory values provided in the tables serve as guidelines and are dependent upon 
institutional normal parameters. Institutional normal reference ranges should be provided to 
demonstrate that they are appropriate.


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Vital Signs *
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Fever (°C) **
(°F) *
38.0 – 38.4
100.4 – 101.1
38.5 – 38.9
101.2 – 102.0
39.0 – 40
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 judgement when 
characterizing bradycardia among some healthy subject populations, for example, conditioned 
athletes.








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Attachment 3: 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.
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 


VAC18194  (Ad26.RSV.preF)
Statistical Analysis Plan VAC18194RSV2001
31
Approved, Date: 25 April 2018
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.